Bio

Bio


Dr. Muffly specializes in blood and marrow transplant and cellular therapies. Her interests include clinical research with a focus on improving outcomes in acute leukemia and blood and marrow transplantation.

Clinical Focus


  • acute leukemia
  • blood and marrow transplant
  • Hematology

Academic Appointments


Administrative Appointments


  • Senior Fellow, Lymphoma Program, University of Chicago (2011 - 2013)
  • Senior Fellow, Leukemia & Transplantation Program - University of Chicago (2011 - 2013)
  • Senior Fellow, Adolescent & Young Adult Clinic, University of Chicago (2012 - 2013)
  • Bone Marrow Transplant Fellow, Colorado Blood Cancer Institute, Denver CO (2013 - 2014)
  • Clinical Assistant Professor of Medicine, Stanford University (2014 - 2018)
  • Assistant Professor of Medicine, Stanford University (2018 - Present)

Honors & Awards


  • Herbert Armory Hare Honor Medical Society, Jefferson Medical College (2007)
  • Excellence in Teaching Award, Dartmouth Hitchcock Medical Center (2010)
  • Illinois Medical Oncology Society Fellow Research Award Recipient, . (2012)
  • NIH T32CA9566 Training Grant Recipient, . (2012)
  • Richard and Debra Gonzalez Fellowship Grant Recipient, University of Chicago (2012)
  • American Society of Blood & Marrow Transplantation Travel Grant Recipient, . (2013)
  • Conquer Cancer Foundation of ASCO Jane C Wright, MD Young Investigator Award, . (2013)

Boards, Advisory Committees, Professional Organizations


  • Member, American Society of Clinical Oncology (2014 - Present)
  • Member, American Society of Hematology (2014 - Present)

Professional Education


  • Board Certification: American Board of Internal Medicine, Hematology (2020)
  • Board Certification: American Board of Internal Medicine, Medical Oncology (2020)
  • Fellowship: University of Chicago Dept of Urology (2013) IL
  • Medical Education: Jefferson Medical College (2007) PA
  • Internship: Dartmouth Hitchock Medical Center NH
  • Residency: Dartmouth Hitchcock Medical Center NH

Research & Scholarship

Current Research and Scholarly Interests


Dr. Muffly's interests include health services research and clinical trials with a focus on acute leukemia and blood and marrow transplantation.

Clinical Trials


  • Autologous CD22 CAR T Cells in Adults w/ Recurrent or Refractory B Cell Malignancies Recruiting

    The primary purpose of this study is to test whether CD22-CAR T cells can be successfully made from immune cells collected from adults with relapsed/refractory B-cell malignancies (leukemia and lymphoma).

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  • Axicabtagene Ciloleucel Expanded Access Study Recruiting

    A multicenter, open-label expanded access protocol for the treatment of subjects with relapsed/refractory large B-cell lymphoma.

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  • CD8+ Memory T-Cells as Consolidative Therapy After Donor Non-myeloablative Hematopoietic Cell Transplant in Treating Patients With Leukemia or Lymphoma Recruiting

    This phase II trial studies how well cluster of differentiation 8 (CD8)+ memory T-cells work as a consolidative therapy following a donor non-myeloablative hematopoietic cell transplant in treating patients with leukemia or lymphoma. Giving total lymphoid irradiation and anti-thymocyte globulin before a donor hematopoietic cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening. Once the donated stem cells begin working, the patient's immune system may see the remaining cancer cells as not belonging in the patient's body and destroy them. Giving an infusion of the donor's white blood cells, such as CD8+ memory T-cells, may boost this effect and may be an effective treatment to kill any cancer cells that may be left in the body (consolidative therapy).

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  • Ibrutinib in Treating Patients With Refractory or Relapsed Lymphoma After Donor Stem Cell Transplant Recruiting

    This phase II trial studies how well ibrutinib works in treating patients after a donor stem cell transplant for lymphoma that is not responding to treatment or has come back. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

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  • JSP191 Antibody Targeting Conditioning in MDS/AML Patients Undergoing Hematopoietic Cell Transplantation Recruiting

    This is a Phase 1 study to evaluate the safety and tolerability of an antibody conditioning regimen known as JSP191, in combination with low dose radiation and fludarabine, in patients with Myelodysplastic Syndrome or Acute Myeloid Leukemia undergoing blood stem cell transplantation

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  • MAGE A10ᶜ⁷⁹⁶T for Advanced NSCLC Recruiting

    This first time in human study is intended for men and women at least 18 years of age who have advanced lung cancer which has grown or returned after being treated. In particular, it is a study for subjects who have a blood test positive for HLA-A*02:01 and/or HLA-A*02:06 and a tumor test positive for MAGE A10 protein expression (protein or gene). This trial is a dose escalation trial that will evaluate 3 doses of transduced cells administered after a lymphodepleting chemotherapy regimen using a 3+3 dose escalation design .The study will take the subject's T cells, which are a natural type of immune cell in the blood, and send them to a laboratory to be modified. The changed T cells used in this study will be the subject's own T cells that have been genetically changed with the aim of attacking and destroying cancer cells. When the MAGE A10ᶜ⁷⁹⁶T cells are available, subjects will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine, followed by the T cell infusion. The purpose of this study is to test the safety of genetically changed T cells and find out what effects, if any, they have in subjects with lung cancer. The study will evaluate three different cell dose levels in order to find out the target cell dose. Once the target cell dose is determined, additional subjects will be enrolled to further test the safety and effects at this cell dose. Subjects will be seen frequently by the Study Physician right after receiving their T cells back and up to first 6 months. After that, subjects will be seen every three months. Subjects will be seen every 6 months by their Study Physician for the first 5 years after the T cell infusion. If the T cells are found in the blood at five years, then the subjects will continue to be seen once a year until the T cells are no longer found in the blood for a maximum of 15 years. If the T cells are no longer found in the blood at 5 years, then the subject will be contacted by the Study Physician for the next 10 years. Subjects who have a confirmed response or clinical benefit ≥4 weeks after the first T-cell infusion and whose tumor continues to express the appropriate antigen target may be eligible for a second infusion. All subjects, completing or withdrawing from the Interventional Phase of the study, will enter a 15-year long-term follow-up phase for observation of delayed adverse events. All subjects will continue to be followed for overall survival during the long-term follow-up phase.

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  • Obinutuzumab in cGVHD After Allogeneic Peripheral Blood Stem Cell Transplantation Recruiting

    This research study is studying a drug called obinutuzumab as a means of preventing chronic Graft vs. Host Disease (cGVHD).

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  • Phase I Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory B Cell Malignancies Recruiting

    This phase I trial studies the best dose and side effects of CD19/CD22 chimeric antigen receptor (CAR) T cells when given together with chemotherapy, and to see how well they work in treating children or young adults with CD19 positive B acute lymphoblastic leukemia that has come back or does not respond to treatment. A CAR is a genetically-engineered receptor made so that immune cells (T cells) can attack cancer cells by recognizing and responding to the CD19/CD22 proteins. These proteins are commonly found on B acute lymphoblastic leukemia. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving CD19/CD22-CAR T cells and chemotherapy may work better in treating children or young adults with B acute lymphoblastic leukemia.

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  • Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors Recruiting

    This randomized phase III trial studies how well standard-dose combination chemotherapy works compared to high-dose combination chemotherapy and stem cell transplant in treating patients with germ cell tumors that have returned after a period of improvement or did not respond to treatment. Drugs used in chemotherapy, such as paclitaxel, ifosfamide, cisplatin, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as filgrastim or pegfilgrastim, and certain chemotherapy drugs, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. It is not yet known whether high-dose combination chemotherapy and stem cell transplant are more effective than standard-dose combination chemotherapy in treating patients with refractory or relapsed germ cell tumors.

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  • Stanford Letter or Traditional Advance Directive in Advance Care Planning in Patients Undergoing Bone Marrow Transplant Recruiting

    The purpose of the proposed research study is to evaluate whether bone marrow transplant patients prefer the Stanford letter advance care planning tool to the standard Advance directive. Completion of advance care planning prior to BMT is very important, but not often done. The investigators believe that the Stanford Letter will be preferred by patients and will allow them to feel more comfortable and share more of their wishes with family members and the medical team.

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  • Total Body Irradiation +/- Total Lymphoid Irradiation & Anti-Thymocyte Globulin in Non-myeloablative Hematopoietic Cell Transplantation Recruiting

    The purpose of this study is to evaluate whether addition of a low dose of total body irradiation (TBI) to a standard preparation for transplant [total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG)] conditioning will help to augment donor chimerism without reducing tolerability of this regimen or increasing the risk of graft-vs-host disease (GVHD)

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  • A Study of Ruxolitinib in Combination With Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease (REACH-1) Not Recruiting

    The purpose of this study is to assess the efficacy of ruxolitinib in combination with corticosteroids in subjects with Grades II to IV steroid-refractory acute graft-versus-host disease (GVHD).

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • A Trial of the FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor Gilteritinib Administered as Maintenance Therapy Following Allogeneic Transplant for Patients With FLT3/Internal Tandem Duplication (ITD) Acute Myeloid Leukemia (AML) Not Recruiting

    The purpose of this study is to compare relapse-free survival between participants with FLT3/ITD AML in first morphologic complete remission (CR1) who undergo hematopoietic stem cell transplant (HCT) and are randomized to receive gilteritinib or placebo beginning after the time of engraftment for a two year period.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Calcineurin Inhibitor-Free Interventions for Prevention of Graft-versus-Host Disease (BMT CTN 1301) Not Recruiting

    The study is designed as a three arm randomized Phase III, multicenter trial comparing two calcineurin inhibitor (CNI)-free strategies for Graft-versus-Host Disease (GVHD) prophylaxis to standard tacrolimus and methotrexate (Tac/Mtx) in patients with hematologic malignancies undergoing myeloablative conditioning hematopoietic stem cell transplantation.

    Stanford is currently not accepting patients for this trial.

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  • Donor Regulatory T Cells in Treating Patients With Visceral Acute Graft-versus-Host Disease After Stem Cell Transplant Not Recruiting

    This phase I trial studies the side effects and best dose of donor regulatory T cells in treating patients with graft-versus-host disease affecting the liver or gastrointestinal organs (visceral) within 100 days (acute) after undergoing a stem cell transplant. Graft-versus-host disease occurs when donor immune cells infused in a stem cell transplant attack the gut, skin, liver, or other organ systems of the patient. Regulatory T cells are a type of immune cell that may be able to reduce the attack of the donor's immune cells on the patient's normal cells and help treat graft-vs-host disease.

    Stanford is currently not accepting patients for this trial. For more information, please contact Joanne Otani, 650-721-2372.

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  • Efficacy of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma Not Recruiting

    The purpose of this study is to evaluate whether axicabtagene ciloleucel therapy improves the clinical outcome compared with standard of care second-line therapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Expanded Access Protocol for Tabelecleucel for Patients With Epstein-Barr Virus-Associated Viremia or Malignancies Not Recruiting

    The primary objective of this protocol is to provide expanded access to tabelecleucel to participants with Epstein-Barr virus-associated diseases and malignancies for whom there are no other appropriate therapeutic options, and who are not eligible to enroll in clinical studies designed to support the development and registration of tabelecleucel.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Ibrutinib in Combination With Corticosteroids vs Placebo in Combination With Corticosteroids in Subjects With New Onset cGVHD Not Recruiting

    To evaluate the safety and efficacy of ibrutinib in combination with prednisone in subjects with newly diagnosed moderate to severe cGVHD.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Post T-plant Infusion of Allogeneic Cytokine Induced Killer (CIK) Cells as Consolidative Therapy in Myelodysplastic Syndromes/Myeloproliferative Disorders Not Recruiting

    Allogeneic stem cell transplantation (transplant of blood cells from another individual) is a treatment option for patients with myelodysplasia or myeloproliferative Disorders. During the course of this study, it will be evaluated whether a particular type of blood cell, called a cytokine-induced killer (CIK) cell, may add benefit to allogeneic stem cell transplantation. CIK cells are present in small quantities in the bloodstream but their numbers can be expanded after a brief period of nurturing in a laboratory.

    Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.

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  • Safety and Efficacy of KTE-C19 in Combination With Atezolizumab in Adults With Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Not Recruiting

    The primary objective of phase 1 is to evaluate the safety of KTE-C19 and atezolizumab combination regimens. The primary objective of phase 2 is to evaluate the efficacy of KTE-C19 and atezolizumab, as measured by complete response rate in participants with refractory diffuse large B-cell lymphoma (DLBCL).

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Study of Quality of Life in Older vs. Younger Adult Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndromes Not Recruiting

    This is a multi-center, Phase II, cross-sectional study comparing quality of life (QOL) as assessed by patient-reported outcomes (PROs) in older (≥65 years) adults vs younger (55-64 years) undergoing allogeneic hematopoietic cell transplantation (HCT) for myelodysplastic syndromes (MDS).

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Chin, MS, 650-721-4183.

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Publications

All Publications


  • Decreased Early Mortality in Young Adult Patients With Acute Lymphoblastic Leukemia Treated at Specialized Cancer Centers in California JOURNAL OF ONCOLOGY PRACTICE Alvarez, E. M., Malogolowkin, M., Li, Q., Brunson, A., Pollock, B. H., Muffly, L., Wun, T., Keegan, T. M. 2019; 15 (4): 200-+
  • Does Treatment Setting Matter? Evaluating Resource Utilization for Adolescents Treated in Pediatric vs Adult Cancer Institutions JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Parsons, H. M., Muffly, L., Alvarez, E. M., Keegan, T. M. 2019; 111 (3): 224–25
  • Hematopoietic Cell Transplantation in Young Adult Acute Lymphoblastic Leukemia: A United States Population-Level Analysis. Journal of adolescent and young adult oncology Muffly, L., Li, Q., Alvarez, E., Kahn, J., Winestone, L., Cress, R., Penn, D. C., Keegan, T. H. 2019

    Abstract

    In this population-based evaluation of adolescents and young adults (AYA) acute lymphoblastic leukemia (ALL), we describe patterns of care (POC) and outcomes regarding hematopoietic cell transplantation (HCT) in first complete remission (CR1). Data were abstracted from the 2013 United States Surveillance, Epidemiology, and End Results POC study; newly diagnosed AYA ALL were included. Multivariable logistic regression evaluated associations with HCT in CR1; Cox proportional hazards regression evaluated survival associations. Of 399 AYAs with ALL included, 102 (28.5%) underwent HCT in CR1. High-risk cytogenetics (odds ratio [OR]=4.86, 95% confidence interval [CI]=3.02-7.83) and hyper-cyclophosphamide, vincristine, adriamycin, and dexamethasone (CVAD) induction (OR=1.84, 95% CI=1.07-3.16) were associated with HCT in CR1. Two-year cumulative incidence of relapse, relapse-free survival (RFS), and overall survival (OS) of the entire cohort were 28.3% (95% CI=23.4-33.4), 69.3% (95% CI=63.6-74.3%), and 84.1% (95% CI=79.7-87.5), respectively. Two-year RFS was significantly higher in patients receiving CR1 HCT relative to chemotherapy (83.6%, 95% CI=72.6-90.5% vs. 64.3%, 95% CI=57.5-70.3), but no difference was seen in 2-year OS (88.9%, 95% CI=80.8-93.7 vs. 82.5%, 95% CI=77.2-86.7). Treatment at a nonteaching hospital was independently associated with inferior OS (hazard ratio=2.15, 95% CI=1.23-3.76). Although the ALL landscape is changing, these data provide a snapshot of the use and outcomes of HCT for AYA ALL across the United States.

    View details for PubMedID 30657424

  • Patterns of care and outcomes in adolescent and young adult acute lymphoblastic leukemia: a population-based study BLOOD ADVANCES Muffly, L., Alvarez, E., Lichtensztajn, D., Abrahao, R., Gomez, S., Keegan, T. 2018; 2 (8): 895–903

    Abstract

    Adolescents and young adults (AYAs, 15-39 years) with acute lymphoblastic leukemia (ALL) represent a heterogeneous population who receive care in pediatric or adult cancer settings. Using the California Cancer Registry, we describe AYA ALL patterns of care and outcomes over the past decade. Sociodemographics, treatment location, and front-line therapies administered to AYAs diagnosed with ALL between 2004 and 2014 were obtained. Cox regression models evaluated associations between ALL setting and regimen and overall survival (OS) and leukemia-specific survival (LSS) for the entire cohort, younger AYA (<25 years), and AYAs treated in the adult cancer setting only. Of 1473 cases, 67.7% were treated in an adult setting; of these, 24.8% received a pediatric ALL regimen and 40.7% were treated at a National Cancer Institute (NCI)-designated center. In multivariable analyses, front-line treatment in a pediatric (vs adult) setting (OS HR = 0.53, 95% confidence interval [CI], 0.37-0.76; LSS HR = 0.51, 95% CI, 0.35-0.74) and at an NCI/Children's Oncology Group (COG) center (OS HR = 0.80, 95% CI, 0.66-0.96; LSS HR = 0.80, 95% CI, 0.65-0.97) were associated with significantly superior survival. Results were similar when analyses were limited to younger AYAs. Outcomes for AYAs treated in an adult setting did not differ following front-line pediatric or adult ALL regimens. Our population-level findings demonstrate that two-thirds of AYAs with newly diagnosed ALL are treated in an adult cancer setting, with the majority receiving care in community settings. Given the potential survival benefits, front-line treatment of AYA ALL at pediatric and/or NCI/COG-designated cancer centers should be considered.

    View details for PubMedID 29669756

    View details for PubMedCentralID PMC5916002

  • Adoption of Pediatric-Inspired Acute Lymphoblastic Leukemia Regimens by Adult Oncologists Treating Adolescents and Young Adults: A Population-Based Study CANCER Muffly, L., Lichtensztajn, D., Shiraz, P., Abrahao, R., McNeer, J., Stock, W., Keegan, T., Gomez, S. L. 2017; 123 (1): 122-130

    Abstract

    Studies have demonstrated superior outcomes for adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) who are treated using pediatric versus adult therapeutic regimens. To the best of our knowledge, whether adult oncologists in the United States have adopted this approach to ALL in AYA patients is currently unknown. The objective of the current study was to provide a population-based description of ALL treatment patterns in AYA individuals over the past decade.Data regarding AYA patients aged 15 to 39 years and diagnosed with ALL between 2004 and 2014 while living in the Greater Bay Area were obtained from the Greater Bay Area Cancer Registry (GBACR). Treating facilities were designated as pediatric or adult centers; induction treatment regimens were abstracted from registry text data fields.Of 304 patients diagnosed in the GBACR catchment region, complete treatment data were available for 229 (75%). The location of care was identified for 296 patients (97%) treated at 31 unique centers. Approximately 70% of AYA patients received induction therapy at an adult treatment center. All AYA patients who were treated at pediatric centers received pediatric ALL regimens. Among AYA patients treated by adult oncologists with complete treatment data, none received a pediatric regimen before 2008. Between 2008 and 2012, while the US Adult Intergroup C10403 pediatric-inspired ALL protocol was open to accrual, 31% of AYA patients treated by adult oncologists received pediatric regimens. This rate fell to 21% from 2013 through 2014. Adult facilities treating ≥ 2 AYA patients with ALL per year captured in the GBACR were more likely to administer pediatric regimens than lower volume centers (P = .03).As of 2014, only a minority of AYA patients with ALL received pediatric ALL regimens at adult cancer centers. Cancer 2017;122-130. © 2016 American Cancer Society.

    View details for DOI 10.1002/cncr.30322

    View details for Web of Science ID 000394719100016

    View details for PubMedCentralID PMC5161602

  • Outcomes with Autologous or Allogeneic Stem Cell Transplantation in Patients with Plasma Cell Leukemia in the Era of Novel Agents. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Lemieux, C., Johnston, L. J., Lowsky, R., Muffly, L. S., Craig, J. K., Shiraz, P., Rezvani, A., Frank, M. J., Weng, W., Meyer, E., Shizuru, J., Arai, S., Negrin, R., Miklos, D. B., Sidana, S. 2020

    Abstract

    Plasma cell leukemia (PCL) is a rare and very aggressive plasma cell disorder. The optimal treatment approach, including whether to pursue an autologous (autoSCT) or allogeneic (alloSCT) transplant is not clear as there is lack of clinical trial based evidence. This single center retrospective study describes the outcomes of 16 patients with PCL (N=14 primary PCL) who underwent either autoSCT (N=9) or alloSCT (N=7) for PCL in the era of novel agents, between 2007 and 2019. Median age of the cohort was 58 years. High-risk cytogenetics were seen in 50% of patients. All patients received a proteasome inhibitor (PI) and/or immunomodulatory drug (IMiD) based regimen before transplant. At transplant, 10 (62%) patients obtained at least a very good partial response. Response after autoSCT (3 month) was at least VGPR in 6 (67%, CR=5) patients. All patients undergoing alloSCT achieved CR at 3 months. Maintenance was used in 5 patients (56%) after autoSCT. Median PFS from transplant in the autoSCT vs. alloSCT group was 6 vs. 18 months, p=0.09, while median OS from transplant was 19 vs. 40 months (p=0.41), respectively. The median OS from diagnosis was 27 vs. 49 months, p=0.50, respectively. Of all the deaths, 10 (91%) patients died of relapsed disease. In conclusion, alloSCT was not observed to offer any significant survival advantage over autoSCT in PCL, which is comparable to other recent reports and relapse remains the primary cause of death.

    View details for DOI 10.1016/j.bbmt.2020.08.035

    View details for PubMedID 32961371

  • How I Approach the Patient Who Has MRD or Relapse After Transplant CLINICAL LYMPHOMA MYELOMA & LEUKEMIA Muffly, L. 2020; 20: S32–S33
  • Late Effects in Survivors of Adolescent and Young Adult Acute Lymphoblastic Leukemia. JNCI cancer spectrum Muffly, L., Maguire, F. B., Li, Q., Kennedy, V., Keegan, T. H. 2020; 4 (4): pkaa025

    Abstract

    Background: Knowledge regarding late effects (medical conditions and subsequent neoplasms) in survivors of adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL) is lacking.Methods: Using the population-based California Cancer Registry linked with California hospitalization data, we evaluated late effects in 1069 AYAs (aged 15-39years) diagnosed with ALL in California between 1995 and 2012 and surviving a minimum of 3 years from diagnosis.Results: The estimated 10-year cumulative incidence of subsequent endocrine disease (28.7%, 95% confidence interval [CI] = 25.8% to 31.6%) and cardiac disease (17.0%, 95% CI = 14.6% to 19.5%) were strikingly high; avascular necrosis (9.6%, 95% CI = 7.8% to 11.6%), liver disease (6.5%, 95% CI = 5.0% to 8.3%), respiratory disease (6.2%, 95% CI = 4.8% to 8.0%), seizure and/or stroke (4.3%, 95% CI = 3.1% to 5.8%), renal disease (3.1%, 95% CI = 2.1% to 4.4%), and second neoplasms (1.4%, 95% CI = 0.7% to 2.4%) were estimated to occur at 10years with the reported frequencies. Multivariable analyses including the entire patient cohort demonstrated that public or no insurance (vs private and/or military insurance) and receipt of hematopoietic cell transplantation were independently associated with the occurrence of all late effects considered. In multivariable analyses limited to the 766 AYAs who were not transplanted, we continued to find a statistically significant association between public and no insurance and the occurrence of all late effects. Frontline regimen type (pediatric vs adult) was not statistically significantly associated with any of the late effect categories.Conclusions: This large population-based analysis is among the first to describe late effects in survivors of AYA ALL. The strong association between insurance type and late effects suggests that AYAs with public or no insurance may have reduced access to survivorship care following completion of ALL therapy.

    View details for DOI 10.1093/jncics/pkaa025

    View details for PubMedID 32704618

  • Hematopoietic Cell Transplantation for Philadelphia Chromosome Negative Adult Acute Lymphoblastic Leukemia in the Modern Era of Immune Therapy. Current hematologic malignancy reports Yurkiewicz, I., Craig, J., Muffly, L. 2020

    Abstract

    PURPOSE OF REVIEW: This review will discuss the data and controversies related to HCT in the front-line and relapsed/refractory setting in the context of newly available targeted immunotherapies.RECENT FINDINGS: Recent studies in adult Ph-negative ALL support the use of measurable residual disease (MRD) response to front-line therapy to guide consolidation. As such, most MRD-negative patients do not require front-line HCT. Blinatumomab benefits patients with B-ALL with MRD+ complete response (CR) and can be used as a bridge to HCT; whether HCT is still required in this setting is an area of ongoing inquiry. Blinatumomab and inotuzumab result in high rates of MRD negative CR in adults with relapsed/refractory ALL and allow more patients with relapsed disease to receive HCT. Chimeric antigen receptor T cell (CAR-T) therapies may serve as a bridge to HCT or as a stand-alone therapy for relapsed/refractory patients; data suggests there may be greater benefit to consolidating CAR-T with HCT in HCT-naive adults. The decision to incorporate consolidative allogeneic HCT into front-line therapy should be primarily guided by MRD status and the ALL regimen utilized. Targeted immunotherapies result in high MRD-negative CR rates, allowing more adults with relapsed/refractory ALL to be successfully bridged to HCT; early incorporation of these therapies may also prove valuable in reducing the need for HCT in the front-line setting by increasing MRD negative CR rates.

    View details for DOI 10.1007/s11899-020-00579-0

    View details for PubMedID 32358681

  • Access to specialized care and outcomes in adults with acute leukemias BLOOD ADVANCES Muffly, L., Bhatt, V. R. 2020; 4 (7): 1538
  • Access to specialized care and outcomes in adults with acute leukemias. Blood advances Muffly, L., Bhatt, V. R. 2020; 4 (7): 1538

    View details for DOI 10.1182/bloodadvances.2019000660

    View details for PubMedID 32289165

  • Late effects after ablative allogeneic stem cell transplantation for adolescent and young adult acute myeloid leukemia. Blood advances Lee, C. J., Kim, S., Tecca, H. R., Bo-Subait, S., Phelan, R., Brazauskas, R., Buchbinder, D., Hamilton, B. K., Battiwalla, M., Majhail, N. S., Lazarus, H. M., Shaw, P. J., Marks, D. I., Litzow, M. R., Chhabra, S., Inamoto, Y., DeFilipp, Z., Hildebrandt, G. C., Olsson, R. F., Kasow, K. A., Liesveld, J. L., Rotz, S. J., Badawy, S. M., Bhatt, N. S., Yared, J. A., Page, K. M., Arellano, M. L., Kent, M., Farhadfar, N., Seo, S., Hematti, P., Freytes, C. O., Rovo, A., Ganguly, S., Nathan, S., Burns, L., Shaw, B. E., Muffly, L. S. 2020; 4 (6): 983–92

    Abstract

    There is marked paucity of data regarding late effects in adolescents and young adults (AYAs) who undergo myeloablative conditioning (MAC) allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). We evaluated late effects and survival in 826 1-year disease-free survivors of MAC HCT for AYA AML, with an additional focus on comparing late effects based upon MAC type (total body irradiation [TBI] vs high-dose chemotherapy only). The estimated 10-year cumulative incidence of subsequent neoplasms was 4% (95% confidence interval [CI], 2%-6%); 10-year cumulative incidence of nonmalignant late effects included gonadal dysfunction (10%; 95% CI, 8%-13%), cataracts (10%; 95% CI, 7%-13%), avascular necrosis (8%; 95% CI, 5%-10%), diabetes mellitus (5%; 95% CI, 3%-7%), and hypothyroidism (3%; 95% CI, 2%-5%). Receipt of TBI was independently associated with a higher risk of cataracts only (hazard ratio [HR], 4.98; P < .0001) whereas chronic graft-versus-host disease (cGVHD) was associated with an increased risk of cataracts (HR, 3.22; P = .0006), avascular necrosis (HR, 2.49; P = .006), and diabetes mellitus (HR, 3.36; P = .03). Estimated 10-year overall survival and leukemia-free survival were 73% and 70%, respectively, and did not differ on the basis of conditioning type. In conclusion, late effects among survivors of MAC HCT for AYA AML are frequent and are more closely linked to cGVHD than type of conditioning.

    View details for DOI 10.1182/bloodadvances.2019001126

    View details for PubMedID 32168378

  • The Current Genomic and Molecular Landscape of Philadelphia-like Acute Lymphoblastic Leukemia. International journal of molecular sciences Shiraz, P., Payne, K. J., Muffly, L. 2020; 21 (6)

    Abstract

    Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk B-cell Acute Lymphoblastic Leukemia (B-ALL) characterized by a gene expression profile similar to Ph-positive B-ALL but lacking the BCR-ABL1 translocation. The molecular pathogenesis of Ph-like B-ALL is heterogenous and involves aberrant genomics, receptor overexpression, kinase fusions, and mutations leading to kinase signaling activation, leukemogenic cellular proliferation, and differentiation blockade. Testing for the Ph-like signature, once only a research technique, is now available to the clinical oncologist. The plethora of data pointing to poor outcomes for this ALL subset has triggered investigations into the role of targeted therapies, predominantly involving tyrosine kinase inhibitors that are showing promising results.

    View details for DOI 10.3390/ijms21062193

    View details for PubMedID 32235787

  • Prospective Randomized Study of Advance Directives in Allogeneic Hematopoietic Cell Transplant Recipients Muffly, L., Ramirez, Y., Burnash, S., Bisetti, E., Rezvani, A., Sundaram, V. ELSEVIER SCIENCE INC. 2020: S199
  • Feasibility of Centralized Electronic Patient-Reported Outcome (ePRO) Collection By an Outcome Registry, a CIBMTR Study of Patients on the Centers for Medicaid & Medicare Coverage with Evidence Development (CMS CED) Myelodysplasia Protocol Shaw, B. E., Burns, L. J., Mattila, D., Mussetter, A., Chen, M., Vasu, S., Pidala, J. A., Muffly, L., Uberti, J., Tamari, R., Leckrone, E., Myers, J., Brazauskas, R., Mau, L., Rizzo, J., Saber, W., Horowitz, M. M., Lee, S. J., Flynn, K. ELSEVIER SCIENCE INC. 2020: S66
  • Transplant Physicians' Attitudes on Candidacy for Allogeneic Hematopoietic Cell Transplantation (HCT) in Older Patients: The Need for a Standardized Geriatric Assessment (GA) Tool Mishra, A., Preussler, J. M., Al-Mansour, Z., Bachanova, V., Bhatt, V., Bredeson, C., Chhabra, S., D'Souza, A., Dahi, P. B., DeFilipp, Z., Gowda, L., Hacker, E., Hashmi, S. K., Howard, D. S., Jakubowski, A. A., Jayani, R., Johnston, L., Koll, T., Lin, R. J., McCurdy, S. R., Michaelis, L. C., Muffly, L., Nathwani, N., Olin, R. L., Popat, U. R., Rodriguez, C., Rosko, A., Runaas, L., Sabloff, M., Shore, T. B., Shune, L., Sorror, M. L., Sung, A. D., Ustun, C., Wood, W., Burns, L. J., Artz, A. S. ELSEVIER SCIENCE INC. 2020: S45–S46
  • Allogeneic Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia: Significant Increase in Survival in the Post-Targeted Immunotherapy Era Muffly, L., Arai, S., Johnston, L., Lowsky, R., Meyer, E. H., Miklos, D. B., Negrin, R. S., Rezvani, A., Shiraz, P., Shizuru, J. A., Sidana, S., Weng, W., Cunanan, K. ELSEVIER SCIENCE INC. 2020: S106
  • Hepatic veno-occlusive disease in allogeneic stem cell transplant recipients with prior exposure to gemtuzumab ozogamicin or inotuzumab ozogamicin. Leukemia & lymphoma Ladha, A., Mannis, G., Muffly, L. 2020: 1–7

    Abstract

    Hepatic veno-occlusive disease (VOD/sinusoidal obstructive syndrome) represents a constellation of clinical findings including right upper quadrant pain, jaundice, hepatomegaly, and ascites. In the post-hematopoietic stem cell transplant (SCT) setting, the reported incidence has been 10-15%, with severe VOD historically resulting in high mortality rates. Novel agents including calicheamicin conjugated with CD33 (gemtuzumab ozogamicin; GO) and CD22 (inotuzumab ozogamicin; InO) are increasingly used for the treatment of acute myeloid leukemia and acute lymphoblastic leukemia, respectively. Both GO and InO are highly active, but also have unique hepatotoxicity profiles, including a higher risk of VOD in recipients of SCT. Introduction of GO and InO into pre-SCT leukemia management adds additional complexity to SCT patient selection and toxicity monitoring. In this article, we describe and review the risks and management associated with VOD in SCT recipients exposed to GO and InO.

    View details for DOI 10.1080/10428194.2020.1827247

    View details for PubMedID 32988266

  • Calcineurin-inhibitor induced pain syndrome after stem cell transplant. Leukemia & lymphoma Varma, A., Loya, J., Junaid Hussain, M., Don Yun, H., Gobbi, E. K., Reimer, A., Nathan, S., Ustun, C., Muffly, L. 2020: 1–4

    View details for DOI 10.1080/10428194.2020.1765235

    View details for PubMedID 32431182

  • Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia in Adolescents and Young Adults. JCO oncology practice Wang, A. Y., Muffly, L. S., Stock, W. 2020: JOP1900197

    Abstract

    Adolescents and young adults (AYAs) with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) represent a unique patient population with a disproportionate survival disadvantage compared with younger children. Substantial progress has been made as we began to understand and address the multifaceted drivers behind this outcome disparity. New insights into the biology of B-cell ALL have uncovered distinct genetic characteristics more commonly found in AYAs that affect prognosis. Dramatic improvements in survival have been achieved with the use of pediatric-inspired protocols in the front-line setting, as well as antibody-based and chimeric antigen receptor T-cell therapies in the relapsed and refractory setting. Guided by the incorporation of minimal residual disease testing to inform clinical decision making, these represent major paradigm shifts in management. Efforts to design clinical trials geared toward AYAs and to enroll AYAs in available clinical trials will ensure ongoing progress. Holistic care of AYAs with ALL further involves recognition of psychosocial issues arising as a consequence of their diagnosis and the delivery of age-appropriate supportive care.

    View details for DOI 10.1200/JOP.19.00197

    View details for PubMedID 32048928

  • How I Approach the Patient Who Has MRD or Relapse After Transplant. Clinical lymphoma, myeloma & leukemia Muffly, L. 2020; 20 Suppl 1: S32–S33

    View details for DOI 10.1016/S2152-2650(20)30453-5

    View details for PubMedID 32862860

  • Nonmyeloablative allogeneic transplantation achieves clinical and molecular remission in cutaneous T-cell lymphoma. Blood advances Weng, W. K., Arai, S., Rezvani, A., Johnston, L., Lowsky, R., Miklos, D., Shizuru, J., Muffly, L., Meyer, E., Negrin, R. S., Wang, E., Almazan, T., Million, L., Khodadoust, M., Li, S., Hoppe, R. T., Kim, Y. H. 2020; 4 (18): 4474–82

    Abstract

    The majority of patients with refractory, advanced-stage mycosis fungoides (MF) or Sézary syndrome (SS) have a life expectancy of <5 years. Here, we report a phase 2 study of a novel nonmyeloablative allogeneic transplantation strategy tailored for this patient population. This study has completed the enrollment, and 35 patients (13 MF, 22 SS) have undergone transplant as planned. The majority (80%) of the patients had stage IV disease and received multiple previous systemic therapies. All patients had active disease at the time of conditioning using total skin electron beam therapy, total lymphoid irradiation, and antithymocyte globulin, and received allograft infusion as outpatients. Cyclosporine or tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis. Patients tolerated the transplant well, with 1- and 2-year nonrelapse mortality of 3% and 14%, respectively. The day +180 cumulative incidence of grade 2 to 4 acute GVHD was 16%, and the 2-year incidence of moderate/severe chronic GVHD was 32%. With a median posttransplant follow-up of 5.4 years, the 2-, 3-, and 5-year overall survival rates were 68%, 62%, and 56%. Using high-throughput sequencing of the T-cell receptor for minimal residual disease monitoring, we observed that 43% achieved molecular remission, which was associated with a lower incidence of disease progression or relapse (9% vs 87%; P = .02). Our study also showed that patients who were aged ≥65 years at the time of allotransplant had similar clinical outcomes compared with younger patients. Thus, we have developed an alternative and potentially curative nonmyeloablative allogeneic transplant regimen for patients with advanced stage MF/SS. This trial was registered at www.clinicaltrials.gov as #NCT00896493.

    View details for DOI 10.1182/bloodadvances.2020001627

    View details for PubMedID 32941647

  • Outcomes with autologous stem cell transplant vs. non-transplant therapy in patients 70 years and older with multiple myeloma. Bone marrow transplantation Lemieux, C., Muffly, L. S., Rezvani, A., Lowsky, R., Iberri, D. J., Craig, J. K., Frank, M. J., Johnston, L. J., Liedtke, M., Negrin, R., Weng, W. K., Meyer, E., Shizuru, J., Shiraz, P., Arai, S., Miklos, D. B., Sidana, S. 2020

    Abstract

    We evaluated 79 patients with multiple myeloma (MM) ≥70 years referred to our blood and marrow transplant clinic, within 1 year of diagnosis from 2010 to 2019, for consideration of autologous stem cell transplant (ASCT). Thirty-eight (48%) of 79 patients underwent ASCT. ASCT was not pursued in 41 (52%) patients due to: patient or physician preference in 80% (n = 33) or ineligibility in 20% (n = 8). Baseline characteristics of patients in the two groups were similar. Median PFS from treatment start amongst patients undergoing ASCT (n = 38) vs. not (n = 41) was 41 months vs. 33 months, p = 0.03. There was no difference in OS, with estimated 5-year OS of 73% vs. 83%, respectively (p = 0.86). Day +100 transplant-related mortality (TRM) was 0%. ASCT was an independent favorable prognostic factor for PFS in multivariate analysis, after accounting for HCT-CI score, performance status, hematologic response, and maintenance. Finally, patients ≥70 years undergoing ASCT had similar PFS compared to a contemporaneous institutional cohort of patients <70 years (n = 631) (median PFS from transplant: 36 vs. 47 months, p = 0.25). In this retrospective analysis, ASCT was associated with low TRM and better PFS in fit older adults with MM compared to non-transplant therapy, with comparable benefits as seen in younger patients.

    View details for DOI 10.1038/s41409-020-01026-7

    View details for PubMedID 32782351

  • Treatment Complications and Survival Among Children and Young Adults With Acute Lymphoblastic Leukemia. JCO oncology practice Alvarez, E. M., Malogolowkin, M., Hoch, J. S., Li, Q., Brunson, A., Pollock, B. H., Muffly, L., Wun, T., Keegan, T. H. 2020: JOP1900572

    Abstract

    We previously demonstrated lower early mortality for young adults (YAs) with acute lymphoblastic leukemia (ALL) who received induction treatment at specialized cancer centers (SCCs) versus community hospitals. The aim of this study is to determine the impact of inpatient location of treatment throughout therapy on long-term survival, complications, and cost-associations that have not yet been evaluated at the population level.Using the California Cancer Registry linked to a hospitalization database, we identified patients, 0-39 years of age, diagnosed with first primary ALL who received inpatient treatment between 1991 and 2014. Patients were classified as receiving all or part or none of their inpatient treatment at an SCC within 3 years of diagnosis. Inverse probability-weighted, multivariable Cox regression models estimated the associations between location of treatment and sociodemographic and clinical factors with survival. We compared 3-year inpatient costs overall and per day by age group and location of care.Eighty-four percent (0-18 years; n = 4,549) of children and 36% of YAs (19-39 years; n = 683) received all treatment at SCCs. Receiving all treatment at an SCC was associated with superior leukemia-specific (hazard ratio [HR], 0.76; 95% CI, 0.67 to 0.88) and overall survival (HR, 0.87; 95% CI, 0.77 to 0.97) in children and in YAs (HR, 0.71; 95% CI, 0.61 to 0.83; HR, 0.70; 95% CI, 0.62 to 0.80) even after controlling for complications. The cost of inpatient care during the full course of therapy was higher in patients receiving all of their care at SCCs.Our results demonstrate that inpatient treatment at an SCC throughout therapy is associated with superior survival; therefore, strong consideration should be given to referring these patients to SCCs.

    View details for DOI 10.1200/JOP.19.00572

    View details for PubMedID 32525752

  • Pediatric-inspired protocols in adult acute lymphoblastic leukemia: are the results bearing fruit? Muffly, L., Curran, E. AMER SOC HEMATOLOGY. 2019: 17–23
  • Central Nervous System Relapse in Adolescents and Young Adults with Acute Lymphoblastic Lymphoma Treated with Total Body Irradiation and Hematopoietic Stem Cell Transplantation Kozak, M., Yoo, C., Muffly, L., Hiniker, S. M. ELSEVIER SCIENCE INC. 2019: E472
  • Comparison of high doses of total body irradiation in myeloablative conditioning prior to hematopoietic cell transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Sabloff, M., Chhabra, S., Wang, T., Fretham, C., Kekre, N., Abraham, A., Adekola, K., Auletta, J. J., Barker, C., Beitinjaneh, A. M., Bredeson, C., Cahn, J., Diaz, M. A., Freytes, C., Gale, R. P., Ganguly, S., Gergis, U., Guinan, E., Hamilton, B., Hashmi, S., Hematti, P., Hildebrandt, G., Holmberg, L., Hong, S., Lazarus, H. M., Martino, R., Muffly, L., Nishihori, T., Perales, M., Yared, J., Mineishi, S., Stadtmauer, E. A., Pasquini, M. C., Loren, A. W. 2019

    Abstract

    Malignancy relapse is the most common cause of treatment failure among recipients of hematopoietic cell transplantation (HCT). Conditioning dose intensity can reduce disease relapse, but it is offset by toxicities. Improvements in radiotherapy techniques and supportive care may translate to better outcomes with higher irradiation doses in the modern era. This study compares outcomes of recipients of increasing doses of high dose total body irradiation (TBI) divided into intermediate high dose (IH 13-13.75 Gy) and high dose (HD 14 Gy) to standard dose (SD 12Gy) with cyclophosphamide (Cy). A total of 2,721 patients ages of 18 to 60 with hematologic malignancies receiving HCT from 2001 to 2013 were included. Cumulative incidence of non-relapse mortality (NRM) at 5 years was 28% (95% Cumulative Incidence [CI] 25-30%), 32% (95%CI 29-36%) and 34% (95%CI 28-39%) for SD, IH and HD, respectively (p=0.02). Patients receiving IH-TBI had a 25% higher risk of NRM compared to SD-TBI (12 Gy) (p=0.007). Corresponding cumulative incidence of relapse was 36% (95%CI 34-38%), 32% (95%CI 29-36%) and 26% (95%CI 21-31%) (p=0.001). Hazard ratio for mortality compared to SD were 1.06 (95% 0.94-1.19, p=0.36) for IH and 0.89 (95% CI 0.76-1.05, p=0.17) for HD. The study demonstrates that despite improvements in supportive care, myeloablative conditioning using higher doses of TBI (with Cy) leads to worse non-relapse mortality and offers no survival benefit over SD, despite reducing disease relapse.

    View details for DOI 10.1016/j.bbmt.2019.08.012

    View details for PubMedID 31473319

  • Healthcare Utilization is High in Adult Patients Relapsing after Allogeneic Hematopoietic Cell Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Langston, J. A., Sundaram, V., Periyakoil, V. S., Muffly, L. 2019; 25 (8): 1659–65
  • Hematopoietic Cell Transplantation in Young Adult Acute Lymphoblastic Leukemia: A United States Population-Level Analysis JOURNAL OF ADOLESCENT AND YOUNG ADULT ONCOLOGY Muffly, L., Li, Q., Alvarez, E., Kahn, J., Winestone, L., Cress, R., Penn, D. C., Keegan, T. M. 2019; 8 (3): 254–61
  • Acute leukemia in a patient with 15q overgrowth syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Bodle, E. E., Gupta, R., Cherry, A. M., Muffly, L., Manning, M. A. 2019; 179 (6): 1025–29
  • Cost-effectiveness of chimeric antigen receptor T-cell therapy in multiply relapsed or refractory adult large B-cell lymphoma. Lin, J., Muffly, L. S., Spinner, M., Barnes, J. I., Owens, D. K., Goldhaber-Fiebert, J. D. AMER SOC CLINICAL ONCOLOGY. 2019
  • Delays in diagnosis in young patients with leukemia and lymphoma. Winestone, L., McPheeters, J., Puccetti, D., Wilkes, J., Muffly, L. S., Kahn, J., Henk, H. J., Ginsberg, J. P., Keegan, T., Pollock, B. H., Alvarez, E. AMER SOC CLINICAL ONCOLOGY. 2019
  • Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients JCI INSIGHT Meyer, E. H., Laport, G., Xie, B. J., MacDonald, K., Heydari, K., Sahaf, B., Tang, S., Baker, J., Armstrong, R., Tate, K., Tadisco, C., Arai, S., Johnston, L., Lowsky, R., Muffly, L., Rezvani, A. R., Shizuru, J., Weng, W., Sheehan, K., Miklos, D., Negrin, R. S. 2019; 4 (10)
  • EEG Findings in Chimeric Antigen Receptor T-Cell (CAR-T) Related Encephalopathy Syndrome Satyanarayan, S., Markert, M., Hovsepian, D., Post, D., Muffly, L., Miklos, D., Thomas, R., Scott, B. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Health Care Utilization is High in Adult Patients Relapsing After Allogeneic Hematopoietic Cell Transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Langston, J. A., Sundaram, V., Periyakoil, V. S., Muffly, L. 2019

    Abstract

    Disease relapse is the leading cause of death for patients with acute leukemia (AL) and myelodyspastic syndrome (MDS) who undergo allogeneic hematopoietic cell transplantation (HCT). Relapse post-HCT is associated with poor prognosis; however, the inpatient health care utilization of this population is unknown. Here we describe survival, intensity of health care utilization, and characteristics associated with high resource utilization at the end-of-life (EOL). Adult patients with AL/MDS who underwent HCT at a large regional referral center with subsequent relapse between 2005 and 2015 were included in this retrospective study. We compared the distribution of demographic and clinical characteristics of patients as well as health care utilization over two years post-relapse and at EOL by post-relapse disease-directed therapeutic interventions. We created a composite score for EOL healthcare utilization intensity summing the presence of any of the following criteria: death in the hospital, the use of chemotherapy, emergency department, hospitalization, intensive care unit, intubation, cardiopulmonary resuscitation, or hemodialysis in the last month of life. Higher scores indicate more intense health care use at EOL. Multivariable linear regression analysis was used to determine variables (demographic characteristics, post-relapse treatment group, advance directives documentation, palliative care referral, time to relapse) associated with EOL healthcare utilization intensity. 154 patients were included; median age at relapse was 56 years (IQR 39-63), 55% were male, 79% had AL, median time from HCT to relapse was 6 months (IQR 3-10 months). Following relapse, 28% received supportive care only, 50% received chemotherapy only, and 22% received chemotherapy plus cell therapy (either donor lymphocyte infusion (DLI), second HCT, or DLI plus second HCT). With the exception of time until relapse, baseline characteristics (gender, age, race, graft versus host disease, year of treatment) did not significantly differ by post-relapse treatment group. One hundred and thirty-six patients (88%) died within two years of relapse; survival differed significantly by post-relapse treatment group, with those receiving disease directed treatment showing lower risk of death. Health care utilization in AL/MDS patients following post-HCT relapse was high overall with 44% visiting the ED at least once (22% >= 2 times), 93% hospitalized (55% >= 2 times; 16% >= 5 times), and 38% using the ICU (median length of stay 5 days; IQR 3-10 days). Utilization was high even among those receiving only supportive care. For those patients who died, the mean (SD) intensity score for EOL healthcare use was 1.8 (1.8). Most (70%) had a marker of high-intensity healthcare utilization at the EOL or died in hospital. In multivariable analysis, post-relapse chemotherapy plus cell therapy (estimate (95% CI): 1.30 (0.35-2.26) compared to no treatment was associated with more intense EOL health care use; no other variables were associated with intensity of EOL health care use. Health care utilization following post-HCT relapse is associated with receipt of disease-directed therapy, but remains high across all groups despite known poor prognosis. Interventions are needed to minimize nonbeneficial treatments and promote goal-concordant EOL care in this seriously ill patient population.

    View details for PubMedID 30959162

  • Acute leukemia in a patient with 15q overgrowth syndrome. American journal of medical genetics. Part A Bodle, E. E., Gupta, R., Cherry, A. M., Muffly, L., Manning, M. A. 2019

    Abstract

    Overgrowth syndromes are rare genetic conditions which present as global or segmental hyperplasia and are sometimes associated with increased risk of malignancy. Trisomy of the terminal portion of 15q which includes the IGFR1 gene, produces a rare overgrowth phenotype that has been termed 15q overgrowth syndrome (15q OGS). Upregulation of IGF1R has long been implicated in oncogenesis of multiple cancer types, including acute leukemias, and has been shown to render cells more susceptible to other transforming events. To date, too few cases of 15q OGS have been reported to identify any cancer predisposition. We present a case of a 34-year-old female with intellectual disability, macrocephaly, and subtle dysmorphic features who was diagnosed with mixed phenotype acute leukemia (lymphoid and myeloid). Prior to initiation of therapy she was referred to medical genetics for further evaluation and was identified as having a chromosomal translocation resulting in a partial trisomy of chromosome 15q, consistent with 15q OGS. A review of the literature for cases of malignancy in individuals with increased copy number of 15q revealed only one other reported patient. Given the small number of reported individuals, we cannot rule out an increased risk of cancer associated with this chromosomal overgrowth syndrome. Although concerns have been raised regarding treatment feasibility in the setting of chromosomal disorders, the reported patient underwent successful treatment with allogeneic hematopoietic stem-cell transplant.

    View details for PubMedID 30861314

  • Decreased Early Mortality in Young Adult Patients With Acute Lymphoblastic Leukemia Treated at Specialized Cancer Centers in California. Journal of oncology practice Alvarez, E. M., Malogolowkin, M., Li, Q., Brunson, A., Pollock, B. H., Muffly, L., Wun, T., Keegan, T. H. 2019: JOP1800264

    Abstract

    PURPOSE:: Studies suggest that patients with acute lymphoblastic leukemia (ALL) have superior survival when treated at specialized cancer centers (SCCs). However, the association of early mortality (< 60 days) with location of initial care, sociodemographic factors, and complications has not been evaluated in pediatric and young adult (YA) patients with ALL.METHODS:: Using the California Cancer Registry linked to hospitalization data, we identified pediatric and YA patients with ALL who received inpatient leukemia treatment between 1991 and 2014. Patients were classified as receiving all or part/none of their care at an SCC (Children's Oncology Group- or National Cancer Institute-designated cancer center). Propensity scores were created for treatment at an SCC in each age group. Multivariable, inverse probability-weighted Cox proportional hazards regression models identified factors associated with early mortality. Results are presented as hazard ratios (HRs) and 95% CIs.RESULTS:: Among 6,531 newly diagnosed pediatric (≤ 18 years) and YA (19 to 39 years of age) patients with ALL, 1.6% of children and 5.4% of YAs died within 60 days of diagnosis. Most children received all of their care at an SCC (n = 4,752; 85.7%) compared with 35.5% of YAs (n = 1,779). Early mortality rates were lower in pediatric patients and those receiving all care at an SCC (pediatric: all, 1.5%, v part/none, 2.4%; P = .049; YAs: all, 3.2%, v part/none, 6.6%; P = .001). However, in adjusted models, receiving all care at an SCC was associated with significantly lower early mortality in YAs (HR, 0.51; 95% CI, 0.32 to 0.81), but not in pediatric patients (HR, 0.77; 95% CI, 0.47 to 1.25).CONCLUSION:: YAs with ALL experience significant reductions in early mortality after treatment at SCCs.

    View details for PubMedID 30849003

  • Does Treatment Setting Matter? Evaluating Resource Utilization for Adolescents Treated in Pediatric vs Adult Cancer Institutions. Journal of the National Cancer Institute Parsons, H. M., Muffly, L., Alvarez, E. M., Keegan, T. H. 2019; 111 (3): 224–25

    View details for PubMedID 30053066

  • Health Care Utilization and Intensity at End of Life is High Amongst Adults Who Relapse Following Allogeneic Hematopoietic Cell Transplantation Langston, J., Sundaram, V., Periyakoil, V., Muffly, L. ELSEVIER SCIENCE INC. 2019: 506
  • Assessment of Older Adult Candidates for Allogeneic Hematopoietic Cell Transplantation: Updates and Remaining Questions. Expert review of hematology Kennedy, V. E., Muffly, L. S. 2019

    Abstract

    INTRODUCTION: Allogeneic hematopoietic cell transplantation (allo-HCT) has seen marked growth among older adults, where chronological age is no longer a barrier to transplant. As allo-HCT expands to older and potentially less fit individuals, prognosticating transplant outcomes in this population remains an ongoing need. Areas Covered: This review summarizes pre-transplant assessment tools in optimizing patient selection and predicting transplant outcomes in older adults, including comorbidity indices, psychosocial assessment, geriatric assessment, serum biomarkers, and disease risk. This review also discusses the impact of donor age and clonal hematopoiesis of indeterminate significance on transplant outcomes. Expert Opinion: Determining which patients should be referred for transplant remains challenging, especially in older adults. Chronological age is an insufficient prognostic metric, and refining, validating, and developing novel pre-transplant risk assessment tools for geriatric patients offers great potential benefit to the field.

    View details for PubMedID 30632411

  • Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Multiply Relapsed or Refractory Adult Large B-Cell Lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Lin, J. K., Muffly, L. S., Spinner, M. A., Barnes, J. I., Owens, D. K., Goldhaber-Fiebert, J. D. 2019: JCO1802079

    Abstract

    Two anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapies are approved for diffuse large B-cell lymphoma, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel; each costs $373,000. We evaluated their cost effectiveness.We used a decision analytic Markov model informed by recent multicenter, single-arm trials to evaluate axi-cel and tisagenlecleucel in multiply relapsed/refractory, adult, diffuse large B-cell lymphoma from a US health payer perspective over a lifetime horizon. Under a range of plausible long-term effectiveness assumptions, each therapy was compared with salvage chemoimmunotherapy regimens and stem-cell transplantation. Main outcomes were undiscounted life years, discounted lifetime costs, discounted quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (3% annual discount rate). Sensitivity analyses explored uncertainty.In an optimistic scenario, assuming a 40% 5-year progression-free survival (PFS), axi-cel increased life expectancy by 8.2 years at $129,000/QALY gained (95% uncertainty interval, $90,000 to $219,000). At a 30% 5-year PFS, improvements in life expectancy were more modest (6.4 years) and expensive ($159,000/QALY gained [95% uncertainty interval, $105,000 to $284,000]). In an optimistic scenario, assuming a 35% 5-year PFS, tisagenlecleucel increased life expectancy by 4.6 years at $168,000/QALY gained (95% uncertainty interval, $105,000 to $414,000/QALY). At a 25% 5-year PFS, improvements in life expectancy were smaller (3.4 years) and more expensive ($223,000/QALY gained [95% uncertainty interval, $123,000 to $1,170,000/QALY]). Administering CAR-T to all indicated patients would increase US health care costs by approximately $10 billion over 5 years. Price reductions to $250,000 and $200,000, respectively, or payment only for initial complete response (at current prices) would allow axi-cel and tisagenlecleucel to cost less than $150,000/QALY, even at 25% PFS.At 2018 prices, it is possible that both CAR-T therapies meet a less than $150,000/QALY threshold. This depends on long-term outcomes compared with chemoimmunotherapy and stem-cell transplantation, which are uncertain. Widespread adoption would substantially increase non-Hodgkin lymphoma health care costs. Price reductions or payment for initial response would improve cost effectiveness, even with modest long-term outcomes.

    View details for DOI 10.1200/JCO.18.02079

    View details for PubMedID 31157579

  • Pediatric-inspired protocols in adult acute lymphoblastic leukemia: are the results bearing fruit? Hematology. American Society of Hematology. Education Program Muffly, L., Curran, E. 2019; 2019 (1): 17–23

    Abstract

    Observational findings demonstrating improved survival for younger adults following pediatric, as opposed to adult, acute lymphoblastic leukemia (ALL) regimens have been translated into international, prospective multicenter clinical trials testing the pediatric regimen in young adult ALL. The results of these studies confirm the feasibility of delivering the pediatric regimen in the adult oncology setting and establish the superiority of this approach relative to historical adult cooperative group regimen results. Specific toxicities, including thrombosis, hepatotoxicity, and osteonecrosis, are more prevalent in adults receiving the pediatric regimen relative to young children. Persistent minimal residual disease (MRD) is a strong prognostic indicator in adults receiving the pediatric regimen; sensitive, high-quality MRD evaluation should be performed in all patients receiving these therapies. Incorporation of targeted agents, particularly in the frontline and MRD+ setting, will usher in the next era of the pediatric regimen in adult ALL.

    View details for DOI 10.1182/hematology.2019000009

    View details for PubMedID 31808881

  • Central Nervous System Relapse After Stem Cell Transplantation in Adolescents and Young Adults with Acute Lymphoblastic Leukemia: A Single-Institution Experience. Journal of adolescent and young adult oncology Kozak, M. M., Yoo, C. H., Gutkin, P. M., von Eyben, R., Agarwal, R., Donaldson, S. S., Muffly, L., Hiniker, S. M. 2019

    Abstract

    Purpose: To evaluate outcomes and central nervous system (CNS) relapse in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL), who underwent total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (allo-SCT). Methods: A total of 136 AYA patients with ALL who received TBI before allo-SCT between 1998 and 2018 were reviewed. Twenty patients received cranial radiation in their initial treatment before conditioning for transplant and were excluded. Competing risk analysis was used to estimate the cumulative incidence of relapse. Kaplan-Meier and log-rank tests were used to calculate overall survival (OS) and to identify factors predictive of relapse. OS and time to relapse were calculated from date of allo-SCT. Results: One hundred sixteen patients were included in the analysis. Median age was 27 years and median follow-up time was 42 months. Twenty-six patients suffered a disease relapse and 49 died, 26 of posttransplantation complications. The median time to relapse was 7 months and the 5-year OS was 60%. Seven patients had a CNS relapse: 4 of 20 patients (25%) with pre-SCT CNS disease had a post-allo-SCT CNS relapse compared to 3 of 97 (3.1%) without pre-SCT CNS disease. Median time to CNS relapse was 7 months. Patients with post-SCT CNS relapse had median OS of 19 months. Conclusions: AYA patients with CNS disease who undergo an allo-SCT have a high rate of CNS relapse. The addition of additional CNS-directed therapy to transplant protocols warrants further investigation.

    View details for DOI 10.1089/jayao.2019.0121

    View details for PubMedID 31747341

  • Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients. JCI insight Meyer, E. H., Laport, G., Xie, B. J., MacDonald, K., Heydari, K., Sahaf, B., Tang, S. W., Baker, J., Armstrong, R., Tate, K., Tadisco, C., Arai, S., Johnston, L., Lowsky, R., Muffly, L., Rezvani, A. R., Shizuru, J., Weng, W. K., Sheehan, K., Miklos, D., Negrin, R. S. 2019; 4 (10)

    Abstract

    BACKGROUNDIn preclinical murine and early clinical studies of hematopoietic cell transplantation, engineering of donor grafts with defined ratios of CD4+CD25+FoxP3+ Tregs to conventional T cells (Tcons) results in the prevention of graft-versus-host disease and improved immune reconstitution. The use of highly purified primary graft Tregs for direct cell infusion has potential advantages over impure immunomagnetic selection or culture expansion, but has not been tested clinically. We performed a phase I study of the timed addition of CD34-selected hematopoietic stem cells and Tregs, followed by Tcons for the treatment of patients with high-risk hematological malignancies.METHODSWe present interim evaluation of a single-center open phase I/II study of administration of human leukocyte-matched Tregs and CD34-selected hematopoietic cells, followed by infusion of an equal ratio of Tcons in adult patients undergoing myeloablative hematopoietic stem cell transplantation (HCT) for high-risk or active hematological malignancies. Tregs were purified by immunomagnetic selection and high-speed cell sorting.RESULTSHere we report results for the first 12 patients who received Tregs of between 91% and 96% purity. Greater than grade II GVHD was noted in 2 patients in the first cohort of 5 patients, who received cryopreserved Tregs, but neither acute nor chronic GVHD was noted in the second cohort of 7 patients, who received fresh Tregs and single-agent GVHD prophylaxis. Patients in the second cohort appeared to have normal immune reconstitution compared with patients who underwent transplantation and did not develop GVHD.CONCLUSIONOur study shows that the use of highly purified fresh Tregs is clinically feasible and supports continued investigation of the strategy.TRIAL REGISTRATIONClinicalTrials.gov NCT01660607.FUNDINGNIH NHBLI R01 HL114591 and K08HL119590.

    View details for PubMedID 31092732

  • Transplant for Acute Myeloid Leukemia in Patients Seventy Years and Older: Optimism and Opportunity. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Muffly, L. 2019

    View details for DOI 10.1016/j.bbmt.2019.07.024

    View details for PubMedID 31344450

  • Impact of cytogenetic abnormalities on outcomes of adult Philadelphia-negative acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation: a study by the Acute Leukemia Working Committee of the Center for International Blood and Marrow Transplant Research. Haematologica Lazaryan, A., Dolan, M., Zhang, M. J., Wang, H. L., Kharfan-Dabaja, M. A., Marks, D. I., Bejanyan, N., Copelan, E., Maijhail, N., Waller, E. K., Chao, N., Prestidge, T., Nishihori, T., Kebriaei, P., Inamoto, Y., Hamilton, B., Hashmi, S. K., Kamble, R. T., Bacher, U., Hildebrandt, G. C., Stiff, P. J., McGuirk, J., Aldoss, I., Beitinjaneh, A. M., Muffly, L., Vij, R., Olsson, R. F., Byrne, M., Schultz, K. R., Aljurf, M., Seftel, M., Savoie, M. L., Savani, B. N., Verdonck, L. F., Cairo, M. S., Hossain, N., Bhatt, V. R., Frangoul, H. A., Abdel-Azim, H., Al Malki, M., Munker, R., Rizzieri, D., Khera, N., Nakamura, R., Ringdén, O., van der Poel, M., Murthy, H. S., Liu, H., Mori, S., De Oliveira, S., Bolaños-Meade, J., Elsawy, M., Barba, P., Nathan, S., George, B., Pawarode, A., Grunwald, M., Agrawal, V., Wang, Y., Assal, A., Castillo Caro, P., Kuwatsuka, Y., Seo, S., Ustun, C., Politikos, I., Lazarus, H. M., Saber, W., Sandmaier, B. M., de Lima, M., Litzow, M., Bachanova, V., Weisdorf, D. 2019

    Abstract

    Cytogenetic risk stratification at diagnosis has long been one of the most useful tools to assess prognosis in acute lymphoblastic leukemia. To examine the prognostic impact of cytogenetic abnormalities on outcomes after allogeneic hematopoietic cell transplantation, we studied 1731 adults with Philadelphia-negative acute lymphoblastic leukemia in complete remission who underwent myeloablative or reduced intensity/non-myeloablative conditioning transplant from unrelated or matched sibling donors reported to Center for International Blood and Marrow Transplant Research. A total of 632 patients had abnormal conventional metaphase cytogenetics. Patients with abnormal cytogenetics had 40% leukemia-free survival and 42% overall survival at 5-years post-transplant, which was similar to those with normal karyotype. Of the previously established cytogenetic risk classifications, modified Medical Research Council-Eastern Cooperative Oncology Group score was the only independent prognosticator of leukemia-free survival (p=0.03). In the multivariable analysis, monosomy 7 predicted post-transplant relapse (hazard ratio=2.11; 95% confidence interval, 1.04-4.27) and treatment failure (hazard ratio=1.97; 1.20-3.24). Complex karyotype was prognostic for relapse (hazard ratio=1.69; 1.06-2.69), whereas t(8;14) predicted treatment failure (hazard ratio=2.85; 1.35-6.02) and overall mortality (hazard ratio=3.03; 1.44-6.41). This large study suggested a novel transplant-specific cytogenetic scheme with adverse (monosomy 7, complex karyotype, del(7q), t(8;14), t(11;19), del(11q), tetraploidy/near triploidy), intermediate (normal karyotype and all other abnormalities), and favorable (high hyperdiploidy) risks to prognosticate leukemia-free survival (p=0.02). Although some previously established high-risk Philadelphia-negative cytogenetic abnormalities of acute lymphoblastic leukemia can be overcome by transplant, monosomy 7, complex karyotype, and t(8;14) continue to pose significant risks and yield inferior outcomes.

    View details for DOI 10.3324/haematol.2019.220756

    View details for PubMedID 31558669

  • Nonmyeloablative TLI-ATG conditioning for allogeneic transplantation: mature follow-up from a large single-center cohort. Blood advances Spinner, M. A., Kennedy, V. E., Tamaresis, J. S., Lavori, P. W., Arai, S., Johnston, L. J., Meyer, E. H., Miklos, D. B., Muffly, L. S., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Weng, W. K., Hoppe, R. T., Strober, S., Lowsky, R. 2019; 3 (16): 2454–64

    Abstract

    Nonmyeloablative total lymphoid irradiation and antithymocyte globulin (TLI-ATG) conditioning is protective against graft-versus-host disease (GVHD), while retaining graft-versus-tumor activity across various hematologic malignancies. We report our comprehensive experience using TLI-ATG conditioning in 612 patients with hematologic malignancies who underwent allogeneic transplantation at Stanford University from 2001 to 2016. All patients received granulocyte colony-stimulating factor-mobilized peripheral blood grafts and cyclosporine and mycophenolate mofetil for GVHD prophylaxis. The median age was 60 years (range, 21-78), with a median follow-up of 6.0 years (range, 1.0-16.4). Common diagnoses included acute myeloid leukemia (AML; n = 193), myelodysplastic syndrome (MDS; n = 94), chronic lymphocytic leukemia (CLL; n = 80), non-Hodgkin lymphoma (NHL; n = 175), and Hodgkin lymphoma (HL; n = 35). Thirty-four percent of patients had a comorbidity index ≥3, 30% had a high to very high disease risk index, and 56% received unrelated donor grafts, including 15% with HLA-mismatched donors. Ninety-eight percent underwent transplant in the outpatient setting, and 57% were never hospitalized from days 0 through 100. The 1-year rates of nonrelapse mortality (NRM), grade II-IV acute GVHD, and extensive chronic GVHD were 9%, 14%, and 22%, respectively. The 4-year estimates for overall and progression-free survival were 42% and 32% for AML, 30% and 21% for MDS, 67% and 43% for CLL, 68% and 45% for NHL, and 78% and 49% for HL. Mixed chimerism correlated with the risk of relapse. TLI-ATG conditioning was well tolerated, with low rates of GVHD and NRM. Durable remissions were observed across hematologic malignancies, with particularly favorable outcomes for heavily pretreated lymphomas. Several efforts are underway to augment donor chimerism and reduce relapse rates while maintaining the favorable safety and tolerability profile of this regimen.

    View details for DOI 10.1182/bloodadvances.2019000297

    View details for PubMedID 31427277

  • Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Multiply Relapsed or Refractory Adult Large B-Cell Lymphoma Journal of Clinical Oncology Lin, J. K., Muffly, L. S., Spinner, M. A., Barnes, J. I., Owens, D. K., Goldhaber-Fiebert, J. D. 2019

    View details for DOI 10.1200/JCO.18.02079

  • Elevated Axicabtagene Ciloleucel (CAR-19) Expansion By Immunophenotyping Is Associated with Toxicity in Diffuse Large B-Cell Lymphoma Spiegel, J. Y., Sahaf, B., Hossain, N., Frank, M. J., Claire, G., Abramian, M., Latchford, T., Villa, B., Cancilla, J., Oak, J., Natkunam, Y., Long, S. R., Arai, S., Johnston, L. J., Lowsky, R., Meyer, E. H., Muffly, L. S., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Weng, W., Kong, K. A., Mackall, C. L., Miklos, D. B. AMER SOC HEMATOLOGY. 2018
  • Impact of Myeloablative Total Body Irradiation Versus Chemotherapy on Late Effects and Survival Among Adolescent and Young Adult Survivors of Hematopoietic Cell Transplantation for Acute Leukemia: A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis Lee, C. J., Kim, S., Tecca, H. R., Brazauskas, R., Battiwalla, M., Buchbinder, D. K., Flowers, M. D., Phelan, R., Shaw, B. E., Muffly, L. S. AMER SOC HEMATOLOGY. 2018
  • Medical Conditions Among Survivors of Adolescent and Young Adult Non-Hodgkin Lymphoma (NHL), Acute Lymphoblastic Leukemia (ALL) and Acute Myeloid Leukemia (AML) Keegan, T. M., Muffly, L. S., Li, Q., Alvarez, E., Brunson, A. M., Malogolowkin, M., Wun, T. AMER SOC HEMATOLOGY. 2018
  • Health Care Utilization Is High Amongst Adults Who Relapse Following Allogeneic Hematopoietic Cell Transplantation Langston, J., Sundaram, V., Periyakoil, V., Muffly, L. S. AMER SOC HEMATOLOGY. 2018
  • Disparities in Cancer-Related Mortality and Long-Term Survival in Adolescent and Young Adults with Hodgkin Lymphoma: A Population-Level Analysis across the United States Kahn, J. M., Keegan, T. M., Alvarez, E., Muffly, L. S., Parsons, H., Winestone, L. E., Bleyer, A. AMER SOC HEMATOLOGY. 2018
  • Hematopoietic Cell Transplantation in First Remission Amongst Adolescent and Young Adult Acute Lymphoblastic Leukemia: A Population-Level Analysis across the United States Muffly, L. S., Li, Q., Alvarez, E., Kahn, J. M., Winestone, L. E., Cress, R., Penn, D., Keegan, T. M. AMER SOC HEMATOLOGY. 2018
  • Nonmyeloablative Allogeneic Transplantation Using TLI-ATG Conditioning for Lymphoid and Myeloid Malignancies: Mature Follow-up from a Large, Single Institution Cohort Spinner, M. A., Kennedy, V. E., Tamaresis, J. S., Lavori, P. W., Elder, L. V., Arai, S., Johnston, L. J., Meyer, E. H., Miklos, D. B., Muffly, L. S., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Weng, W., Hoppe, R. T., Strober, S., Lowsky, R. AMER SOC HEMATOLOGY. 2018
  • 1 Study of CD19/CD22 Bispecific Chimeric Antigen Receptor (CAR) Therapy in Children and Young Adults with B Cell Acute Lymphoblastic Leukemia (ALL) Schultz, L. M., Davis, K. L., Baggott, C., Chaudry, C., Marcy, A., Mavroukakis, S., Sahaf, B., Kong, K. A., Muffly, L. S., Kim, S., Meyer, E. H., Fry, T. J., Qin, H., Miklos, D. B., Mackall, C. L. AMER SOC HEMATOLOGY. 2018
  • Phase I Experience with a Bi-Specific CAR Targeting CD19 and CD22 in Adults with B-Cell Malignancies Hossain, N., Sahaf, B., Abramian, M., Spiegel, J. Y., Kong, K., Kim, S., Mavroukakis, S., Oak, J., Natkunam, Y., Meyer, E. H., Frank, M. J., Feldman, S. A., Long, S. R., Qin, H., Fry, T. J., Muffly, L. S., Mackall, C. L., Miklos, D. B. AMER SOC HEMATOLOGY. 2018
  • Care at specialized cancer centers among young adults with acute lymphoblastic leukemia in California. Leukemia & lymphoma Alvarez, E., Muffly, L., Li, Q., Brunson, A., Wun, T., Chamberlain, L., Keegan, T. 2018; 59 (10): 2482–84

    View details for PubMedID 29424251

  • Treatment of young adults with Philadelphia-negative acute lymphoblastic leukemia and lymphoblastic lymphoma: Hyper-CVAD vs. pediatric-inspired regimens AMERICAN JOURNAL OF HEMATOLOGY Siegel, S. E., Advani, A., Seibel, N., Muffly, L., Stock, W., Luger, S., Shah, B., DeAngelo, D. J., Freyer, D. R., Douer, D., Johnson, R. H., Hayes-Lattin, B., Lewis, M., Jaboin, J. J., Coccia, P. F., Bleyer, A. 2018; 93 (10): 1254–66

    Abstract

    For young adults with acute lymphoblastic leukemia, pediatric-based regimens are likely to provide the following when compared to hyper-CVAD regimens: better disease control, less hospitalization time, diminished acute toxicities, decreased financial cost, more quality-adjusted life years, and fewer adverse late effects, such as infertility, myelodysplasia, and second malignant neoplasms. There are also reasons to expect less cardiac and cognitive dysfunction after pediatric regimens. The improved quality and quantity of life associated with pediatric regimens renders them preferable to hyper-CVAD regimens for the treatment of Philadelphia-negative B-precursor or T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma in young adults.

    View details for PubMedID 30058716

  • A Three-Step Letter Advance Directive Procedure to Facilitate Patient-Proxy Alignment in Advance Care Planning JOURNAL OF PALLIATIVE MEDICINE Alagappan, M., Richardson, M. T., Schoen, M. K., Muffly, L., Tierney, K., Jenkins, P., Neri, E., Kraemer, H. C., Periyakoil, V. S. 2018

    Abstract

    Little is known about the extent of alignment between hematopoietic stem cell transplant (HSCT) patients and their healthcare proxies with respect to advance care planning (ACP).To determine if a structured three-step process using the letter advance directive (LAD) could (1) allow for the differences in opinion between patient-proxy dyads to surface and (2) help bridge preexisting discordance about specific treatment choices.Blinded to each other, the HSCT patient (LAD-1) and proxy (LAD-2) each completed the LAD (step 1). They unmasked, compared LAD-1 and LAD-2, and discussed their choices (step 2). They completed a final letter directive (LAD-3) by consensus (step 3). Settings/Participants: Convenience sample of eighty dyads (patient and proxy) at a regional HSCT referral center.The mean patient-proxy concordance was 72.9% for the 12 questions in the LAD. Wanting to be pain free at the end of life was the statement with the most amount of agreement (88.75% in LAD-1, 91.25% in LAD-2, and 90% in LAD-3). Patient-proxy dyads had notable discordance related to specific treatments. The highest discordance was related to ventilator support (46.3% of patients refused it, while 58.8% of proxies refused on behalf of the patient). Overall, proxies were more likely than patients to opt in for dialyses and hospice care but more likely to opt out for cardiac resuscitation and sedation to palliate refractory symptoms. On open discussion, patient-proxy discordance mostly resolved in favor of the patient.The ACP process should allow for patient-proxy differences to surface, facilitate a discussion about the granular details with the goal of reaching consensus. Our three-step approach using the LAD is an effective way to identify areas of patient-proxy concordance and discordance about specific treatment preferences. A structured patient-proxy discussion using the LAD helped reconcile discordance and most often in favor of a patient's original wishes.

    View details for PubMedID 30247088

  • End-of-Life Care Intensity in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation: A Population-Level Analysis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Johnston, E. E., Muffly, L., Alvarez, E., Saynina, O., Sanders, L. M., Bhatia, S., Chamberlain, L. J. 2018: JCO2018780957

    Abstract

    Purpose Intensity of end-of-life care receives much attention in oncology because of concerns that high-intensity care is inconsistent with patient goals, leads to worse caregiver outcomes, and is expensive. Little is known about such care in those undergoing allogeneic hematopoietic cell transplantation (HCT), a population at high risk for morbidity and mortality. Patients and Methods We conducted a population-based analysis of patients who died between 2000 and 2013, within 1 year of undergoing an inpatient allogeneic HCT using California administrative data. Previously validated markers of intensity were examined and included: hospital death, intensive care unit (ICU) admission, and procedures such as intubation and cardiopulmonary resuscitation at end of life. Multivariable logistic regression models determined clinical and sociodemographic factors associated with: hospital death, a medically intense intervention (ICU admission, cardiopulmonary resuscitation, hemodialysis, intubation), and ≥ two intensity markers. Results Of the 2,135 patients in the study population, 377 were pediatric patients (age ≤ 21 years), 461 were young adults (age 22 to 39 years), and 1,297 were adults (age ≥ 40 years). The most common intensity markers were: hospital death (83%), ICU admission (49%), and intubation (45%). Medical intensity varied according to age, underlying diagnosis, and presence of comorbidities at time of HCT. Patients with higher-intensity end-of-life care included patients age 15 to 21 years and 30 to 59 years, patients with acute lymphoblastic leukemia, and those with comorbidities at time of HCT. Conclusion Patients dying within 1 year of inpatient allogeneic HCT are receiving medically intense end-of-life care with variations related to age, underlying diagnosis, and presence of comorbidities at time of HCT. Future studies need to determine if these patterns are consistent with patient and family goals.

    View details for PubMedID 30183467

  • Detection of Measurable Residual Disease by Next-Generation Sequencing in Paired Blood and Bone Marrow Samples from Patients with Lymphoid Malignancies Miklos, D., Muffly, L., Lee, L., Crossley, B. CIG MEDIA GROUP, LP. 2018: S295–S296
  • Minimal Residual Disease Monitoring of Acute Lymphoblastic Leukemia by High-Throughput Sequencing of the Peripheral Blood: Case Examples and Literature Review Muffly, L. CIG MEDIA GROUP, LP. 2018: S53–S55
  • Circulating tumor DNA assessment in patients with diffuse large B-cell lymphoma following CAR T-cell therapy. Leukemia & lymphoma Hossain, N. M., Dahiya, S., Le, R., Abramian, A. M., Kong, K. A., Muffly, L. S., Miklos, D. B. 2018: 1–4

    View details for PubMedID 29966461

  • Pediatric-Inspired Treatment Regimens for Adolescents and Young Adults With Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia A Review JAMA ONCOLOGY Siegel, S. E., Stock, W., Johnson, R. H., Advani, A., Muffly, L., Douer, D., Reed, D., Lewis, M., Freyer, D. R., Shah, B., Luger, S., Hayes-Lattin, B., Jaboin, J. J., Coccia, P. F., DeAngelo, D. J., Seibel, N., Bleyer, A. 2018; 4 (5): 725–34

    Abstract

    The incidence of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adolescent and young adult (AYA) patients (age range, 15-39 years) in the United States is increasing at a greater rate than in younger or older persons. Their optimal treatment has been increasingly debated as pediatric regimens have become more widely used in the age group. This review compares the basic features of pediatric and adult chemotherapy regimens for ALL and LBL, recognizes and describes the challenges of the pediatric regimen, and suggests strategies to facilitate its adoption for AYAs with ALL and LBL.All but 2 of 25 published comparisons of outcomes with pediatric and adult regimens for ALL and LBL in AYAs and 1 meta-analysis favor the pediatric regimen. After more than a half-century of clinical trials of the pediatric regimens, including at least 160 phase 3 trials in the United States, the pediatric regimens have become far more complex than most adult regimens. Asparaginase, a critical component of the pediatric regimens, is more difficult to administer to AYAs (and older patients) but nonetheless has a favorable benefit to toxicity ratio for AYAs. A dramatic reduction in outcome of ALL and LBL during the AYA years (the "survival cliff") is coincident with similar reductions in proportions of AYAs referred to academic centers and enrolled on clinical trials (the "accrual cliff" and "referral cliff").The accumulating data increasingly support treating AYAs with ALL and LBL with a pediatric-inspired regimen or an approved institutional or national clinical trial tailored for this patient group. A need to develop clinical trials specifically for AYAs and to encourage their participation is paramount, with a goal to improve both the quantity and quality of survival.

    View details for PubMedID 29450465

  • Decreased Early Mortality Associated With the Treatment of Acute Myeloid Leukemia at National Cancer Institute-Designated Cancer Centers in California CANCER Ho, G., Wun, T., Muffly, L., Li, Q., Brunson, A., Rosenberg, A. S., Jonas, B. A., Keegan, T. M. 2018; 124 (9): 1938–45

    Abstract

    To the authors' knowledge, few population-based studies to date have evaluated the association between location of care, complications with induction therapy, and early mortality in patients with acute myeloid leukemia (AML).Using linked data from the California Cancer Registry and Patient Discharge Dataset (1999-2014), the authors identified adult (aged ≥18 years) patients with AML who received inpatient treatment within 30 days of diagnosis. A propensity score was created for treatment at a National Cancer Institute-designated cancer center (NCI-CC). Inverse probability-weighted, multivariable logistic regression models were used to determine associations between location of care, complications, and early mortality (death ≤60 days from diagnosis).Of the 7007 patients with AML, 1762 (25%) were treated at an NCI-CC. Patients with AML who were treated at NCI-CCs were more likely to be aged ≤65 years, live in higher socioeconomic status neighborhoods, have fewer comorbidities, and have public health insurance. Patients treated at NCI-CCs had higher rates of renal failure (23% vs 20%; P = .010) and lower rates of respiratory failure (11% vs 14%; P = .003) and cardiac arrest (1% vs 2%; P = .014). After adjustment for baseline characteristics, treatment at an NCI-CC was associated with lower early mortality (odds ratio, 0.46; 95% confidence interval, 0.38-0.57). The impact of complications on early mortality did not differ by location of care except for higher early mortality noted among patients with respiratory failure treated at non-NCI-CCs.The initial treatment of adult patients with AML at NCI-CCs is associated with a 53% reduction in the odds of early mortality compared with treatment at non-NCI-CCs. Lower early mortality may result from differences in hospital or provider experience and supportive care. Cancer 2018;124:1938-45. © 2018 American Cancer Society.

    View details for PubMedID 29451695

  • Another reason to encourage psychosocial risk assessment in hematopoietic cell transplantation. Bone marrow transplantation Muffly, L., Artz, A. 2018

    View details for PubMedID 29588499

  • Infusion of donor-derived CD8(+) memory T cells for relapse following allogeneic hematopoietic cell transplantation BLOOD ADVANCES Muffly, L., Sheehan, K., Armstrong, R., Jensen, K., Tate, K., Rezvani, A. R., Miklos, D., Arai, S., Shizuru, J., Johnston, L., Meyer, E., Weng, W., Laport, G. G., Negrin, R. S., Strober, S., Lowsky, R. 2018; 2 (6): 681–90

    Abstract

    Murine models showed that CD8+CD44hi memory T (TM) cells could eradicate malignant cells without inducing graft-versus-host disease (GVHD). We evaluated the feasibility and safety of infusing freshly isolated and purified donor-derived phenotypic CD8+ TM cells into adults with disease relapse after allogeneic hematopoietic cell transplantation (HCT). Phenotypic CD8 TM cells were isolated after unmobilized donor apheresis using a tandem immunomagnetic selection strategy of CD45RA depletion followed by CD8+ enrichment. Fifteen patients received CD8+ TM cells at escalating doses (1 × 106, 5 × 106, or 10 × 106 cells per kg). Thirteen received cytoreduction before CD8+ TM cell infusion, and 9 had active disease at the time of infusion. Mean yield and purity of the CD8+ TM infusion were 38.1% and 92.8%, respectively; >90% had CD8+ T effector memory phenotype, cytokine expression, and secretion profile. No adverse infusional events or dose-limiting toxicities occurred; GVHD developed in 1 patient (grade 2 liver). Ten patients (67%) maintained or achieved response (7 complete response, 1 partial response, 2 stable disease) for at least 3 months after infusion; 4 of the responders had active disease at the time of infusion. With a median follow-up from infusion of 328 days (range, 118-1328 days), median event-free survival and overall survival were 4.9 months (95% confidence interval [CI], 1-19.3 months) and 19.6 months (95% CI, 5.6 months to not reached), respectively. Collection and enrichment of phenotypic CD8+ TM cells is feasible, well tolerated, and associated with a low incidence of GVHD when administered as a manipulated infusion of donor lymphocytes in patients who have relapsed after HCT. This trial was registered at www.clinicaltrials.gov as #NCT01523223.

    View details for PubMedID 29572391

  • Phase I/II Trial for Patients with Advanced Hematologic Malignancies Undergoing Myeloablative Allogeneic HCT with a T Cell Depleted Graft with Infusion of Conventional T Cells and Regulatory T Cells Meyer, E., Laport, G. G., Tantsura, I., Tang, S., Sahaf, B., Rangarajan, K., Armstrong, R., Tate, K., Tudisco, C., Sheehan, K., Arai, S., Johnston, L., Muffly, L., Lowsky, R., Rezvani, A., Weng, W., Miklos, D., Negrin, R. S. ELSEVIER SCIENCE INC. 2018: S145
  • Management of Acute Lymphoblastic Leukemia in Young Adults CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY Muffly, L., Reizine, N., Stock, W. 2018; 16 (2): 138–46

    Abstract

    Substantial interest in acute lymphoblastic leukemia (ALL) in young adults (YAs) and investigations focused on this patient population have resulted in therapeutic advancements that are changing the management paradigm and improving outcomes. The pediatric ALL approach is feasible and effective when administered by medical oncologists. Advanced diagnostics and minimal residual disease measurements aid in prognostication and have resulted in shifting recommendations regarding allogeneic hematopoietic cell transplant in first remission. Blinatumomab, inotuzumab, and chimeric antigen receptor T-cell therapies are transforming the treatment of relapsed/refractory ALL. This comprehensive review of the current management of ALL in YAs summarizes recent scientific developments and clinical trial findings related to ALL biology, frontline management approaches, novel therapies, and supportive care specific to this patient population. Finally, a practical guide to modern YA management for practicing clinicians is provided.

    View details for PubMedID 29741514

  • Advance Directive Utilization is Associated with Less Aggressive End-of-Life Care in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Cappell, K., Sundaram, V., Park, A., Shiraz, P., Gupta, R., Jenkins, P., Periyakoil, V. S., Muffly, L. 2018

    Abstract

    Background Allogeneic hematopoietic cell transplantation (HCT) is associated with significant morbidity and mortality, making advance care planning (ACP) and management especially important in this patient population. A paucity of data exists on the utilization of ACP amongst allogeneic HCT recipients, and the relationship between ACP and intensity of health care utilization in these patients. Methods We performed a retrospective review of patients receiving allogeneic HCT at our institution from 2008 to 2015 who had subsequently died following HCT. Documentation and timing of advance directive (AD) completion were abstracted from the electronic medical record. Outcomes of interest included (a) utilization of intensive care unit level of care (ICU) at (i) any time point following HCT, (ii) within 30 days of death, (iii) within 14 days of death, (b) use of mechanical ventilation at any time point following HCT, and (c) location of death. Univariate logistic regression was performed to explore associations between AD completion and each outcome. Results Of the 1031 patients who received allogeneic HCT during the study period, there were 422 (41%) decedents who are included in the analysis. Forty-four percent had AD documentation prior to death. A majority of patients (69%) indicated that if terminally ill, they did not wish to be subjected to life-prolonging treatment attempts. Race/ethnicity was significantly associated with AD documentation, with Non-Hispanic White patients documenting ADs more frequently (51%) compared to Hispanic (22%) or Asian patients (35%); p= 0.0007. Patients with AD were less likely to utilize the ICU during the transplant course (41% for patients with AD versus 52% of patients without AD; p= 0.03) and also were less likely to receive mechanical ventilation at any point following transplantation (21% versus 37%; p<0.001). AD documentation was also associated with decreased ICU utilization at the end-of-life; relative to patients without AD, patients with AD were more likely to die at home or in hospital as opposed to in the ICU (OR 0.44, 95% CI 0.27-0.72).ACP remains underutilized in allogeneic HCT. Adoption of a systematic practice to standardize AD documentation as part of allogeneic HCT planning has the potential to significantly reduce ICU utilization and mechanical ventilation while improving quality of care at end-of-life in HCT recipients.

    View details for PubMedID 29371107

  • Inotuzumab ozogamicin: a CD22 mAb-drug conjugate for adult relapsed or refractory B-cell precursor acute lymphoblastic leukemia DRUG DESIGN DEVELOPMENT AND THERAPY Yurkiewicz, I. R., Muffly, L., Liedtke, M. 2018; 12: 2293–2300

    Abstract

    Despite improved rates of remission and cure in newly diagnosed adult acute lymphoblastic leukemia (ALL), the prognosis for patients with relapsed or refractory disease remains poor and the 5-year overall survival rate after relapse is under 10%. A recent paradigm shift has focused on the promise of targeted immunotherapy rather than standard chemotherapy, as ALL blast cells express a variety of antigens, and monoclonal antibodies may be developed to identify and destroy the leukemic cells. Inotuzumab ozogamicin is a CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin. CD22 expression is detected on leukemic blasts in over 90% of patients with ALL. Based on promising results from preclinical studies, inotuzumab ozogamicin was tested in Phase 1/2 and Phase 3 clinical trials and it demonstrated improved complete remission rates, progression-free survival and overall survival in relapsed or refractory adult ALL compared to standard therapy. Ongoing studies are evaluating the value of inotuzumab ozogamicin when given in combination with chemotherapy as part of upfront treatment. This review discusses the drug's biochemical properties and mechanism of action, preclinical research outcomes, clinical trial results, adverse events and toxicities, drug approval and ongoing investigations.

    View details for PubMedID 30087554

  • Allogeneic transplantation using TLI-ATG conditioning for Hodgkin lymphoma after failure of autologous transplantation. Blood advances Spinner, M. A., Advani, R. H., Hoppe, R. T., Lowsky, R., Muffly, L. S. 2018; 2 (13): 1547–50

    View details for PubMedID 29970391

  • Validation of the Hematopoietic Cell Transplantation-Specific Comorbidity Index in Nonmyeloablative Allogeneic Stem Cell Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Veeraputhiran, M., Yang, L., Sundaram, V., Arai, S., Lowsky, R., Miklos, D., Meyer, E., Muffly, L., Negrin, R., Rezvani, A., Shizuru, J., Weng, W., Johnston, L. 2017; 23 (10): 1744–48

    Abstract

    The Hematopoietic Cell Transplantation (HCT)-Specific Comorbidity Index (HCT-CI) has been extensively studied in myeloablative and reduced-intensity conditioning regimens, with less data available regarding the validity of HCT-CI in nonmyeloablative (NMA) allogeneic transplantation. We conducted a retrospective analysis to evaluate the association between HCT-CI and nonrelapse mortality (NRM) and all-cause mortality (ACM) in patients receiving the total lymphoid irradiation and antithymocyte globulin (TLI/ATG) NMA transplantation preparative regimen. We abstracted demographic and clinical data from consecutive patients, who received allogeneic HCT with the TLI/ATG regimen between January 2008 and September 2014, from the Stanford blood and marrow transplantation database. We conducted univariable and multivariable Cox proportional hazards regression models to evaluate the association between HCT-CI and NRM and ACM. In all, 287 patients were included for analysis. The median age of the patients was 61 (range, 22 to 77) years. The median overall survival was 844 (range, 374 to 1484) days. Most patients had Karnofsky performance score of 90 or above (85%). Fifty-two (18%) patients relapsed within 3 months and 108 (38%) patients relapsed within 1 year, with a median time to relapse of 163 (range, 83 to 366) days. Among the comorbidities in the HCT-CI identified at the time of HCT, reduced pulmonary function was the most common (n = 89), followed by prior history of malignancy (n = 39), psychiatric condition (n = 38), and diabetes (n = 31). Patients with higher HCT-CI scores had higher mortality risks for ACM (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.22 to 3.14 for HCT-CI score 1 or 2 and HR, 1.85; 95% CI, 1.11 to 3.08 for HCT-CI score ≥ 3, compared with 0, respectively). Among individual HCT-CI variables, diabetes (HR, 2.31; 95% CI, 1.79 to 2.89; P = .003) and prior solid tumors (HR, 1.75; 95% CI, 1.02 to 3.00; P = .043) were associated with a higher risk of ACM. Higher HCT-CI scores were significantly associated with higher risk of death. HCT-CI is a valid tool for predicting ACM in NMA TLI/ATG allogeneic HCT.

    View details for PubMedID 28668491

  • Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States BLOOD Muffly, L., Pasquini, M. C., Martens, M., Brazauskas, R., Zhu, X., Adekola, K., Aljurf, M., Ballen, K. K., Bajel, A., Baron, F., Battiwalla, M., Beitinjaneh, A., Cahn, J., Carabasi, M., Chen, Y., Chhabra, S., Ciurea, S., Copelan, E., D'Souza, A., Edwards, J., Foran, J., Freytes, C. O., Fung, H. C., Gale, R., Giralt, S., Hashmi, S. K., Hildebrandt, G. C., Ho, V., Jakubowski, A., Lazarus, H., Luskin, M. R., Martino, R., Maziarz, R., McCarthy, P., Nishihori, T., Olin, R., Olsson, R. F., Pawarode, A., Peres, E., Rezvani, A. R., Rizzieri, D., Savani, B. N., Schouten, H. C., Sabloff, M., Seftel, M., Seo, S., Sorror, M. L., Szer, J., Wirk, B. M., Wood, W. A., Artz, A. 2017; 130 (9): 1156–64

    Abstract

    In this study, we evaluated trends and outcomes of allogeneic hematopoietic cell transplantation (HCT) in adults ≥70 years with hematologic malignancies across the United States. Adults ≥70 years with a hematologic malignancy undergoing first allogeneic HCT in the United States between 2000 and 2013 and reported to the Center for International Blood and Marrow Transplant Research were eligible. Transplant utilization and transplant outcomes, including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied. One thousand one hundred and six patients ≥70 years underwent HCT across 103 transplant centers. The number and proportion of allografts performed in this population rose markedly over the past decade, accounting for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid leukemia and myelodysplastic syndromes represented the most common disease indications. Two-year OS and PFS significantly improved over time (OS: 26% [95% confidence interval (CI), 21% to 33%] in 2000-2007 to 39% [95% CI, 35% to 42%] in 2008-2013, P < .001; PFS: 22% [16% to 28%] in 2000-2007 to 32% [95% CI, 29% to 36%] in 2008-2013, P = .003). Two-year TRM ranged from 33% to 35% and was unchanged over time (P = .54). Multivariable analysis of OS in the modern era of 2008-2013 revealed higher comorbidity by HCT comorbidity index ≥3 (hazard ratio [HR], 1.27; P = .006), umbilical cord blood graft (HR, 1.97; P = .0002), and myeloablative conditioning (HR, 1.61; P = .0002) as adverse factors. Over the past decade, utilization and survival after allogeneic transplant have increased in patients ≥70 years. Select adults ≥70 years with hematologic malignancies should be considered for transplant.

    View details for PubMedID 28674027

  • Coordination of Care in Survivorship After Treatment of Hematological Malignancies-The Journey is Not Over Yet. Current hematologic malignancy reports Lee, C. J., Muffly, L. S. 2017

    Abstract

    The number of adult survivors of hematologic malignancies is steadily growing. This population is at moderate to high risk for cancer survivorship issues including physical and psychosocial sequelae of intensive cancer therapies. Although cancer survivorship is a growing field in pediatric and solid tumor oncology, survivorship care and research has often been overlooked in the hematologic malignancies. In this review, we focus specifically on survivorship issues related to adult patients with hematologic malignancies and provide commentary on the role of cancer survivorship, proposed survivorship care models, and the economic and health policy obstacles associated with moving the cancer survivorship field forward in this very important patient population.

    View details for DOI 10.1007/s11899-017-0390-1

    View details for PubMedID 28534144

  • Pharmacologic maintenance strategies following allogeneic hematopoietic cell transplantation for acute myeloid leukemia. Leukemia & lymphoma Lee, C. J., Shiraz, P., Muffly, L. 2017; 58 (3): 516-527

    Abstract

    The use of pharmacologic agents to maintain remission following allogeneic hematopoietic cell transplantation (HCT) is a topic of increasing interest and exploration for patients with high-risk acute myeloid leukemia (AML). This review details published and ongoing studies focused on post-transplant pharmacologic maintenance for AML. While early phase studies have demonstrated the safety and tolerability of various maintenance approaches following HCT, the results of several ongoing randomized prospective studies will be required to determine the clinical efficacy needed to expand this approach from experimental to standard of care.

    View details for DOI 10.1080/10428194.2016.1205744

    View details for PubMedID 27685315

  • My Patient, the Superhero. Journal of clinical oncology Muffly, L. 2017: JCO2016696005-?

    View details for DOI 10.1200/JCO.2016.69.6005

    View details for PubMedID 28165900

  • Pharmacologic maintenance strategies following allogeneic hematopoietic cell transplantation for acute myeloid leukemia. Leuk Lymphoma CJ, L., P, S., L, M. 2017; 58 (3): 516-527
  • HLA-mismatched unrelated donor transplantation using TLI-ATG conditioning has a low risk of GVHD and potent antitumor activity. Blood advances Spinner, M. A., Fernández-Viña, M., Creary, L. E., Quinn, O., Elder, L., Arai, S., Johnston, L. J., Meyer, E. H., Miklos, D. B., Muffly, L. S., Negrin, R. S., Shizuru, J. A., Weng, W. K., Laport, G. G., Strober, S., Lowsky, R., Rezvani, A. R. 2017; 1 (17): 1347–57

    Abstract

    Many patients lack a fully HLA-matched donor for hematopoietic cell transplantation (HCT), and HLA mismatch is typically associated with inferior outcomes. Total lymphoid irradiation and antithymocyte globulin (TLI-ATG) is a nonmyeloablative conditioning regimen that is protective against graft-versus-host disease (GVHD), and we hypothesized that the protective effect would extend beyond HLA-matched donors. We report outcomes for all consecutively transplanted patients at Stanford University from December 2001 through May 2015 who received TLI-ATG conditioning and HCTs from 8 to 9 out of 10 HLA-mismatched unrelated donors (MMUDs, N = 72) compared with 10 out of 10 HLA-matched unrelated donors (MUDs, N = 193). The median age of the patients was 60 years with a median follow-up of 2 years, and there was a similar distribution of lymphoid and myeloid malignancies in both cohorts. There were no significant differences between MMUD and MUD cohorts in overall survival (46% vs 46% at 5 years, P = .86), disease-free survival (38% vs 28% at 5 years, P = .25), nonrelapse mortality (17% vs 12% at 2 years, P = .34), acute GVHD grades III-IV (6% vs 3% at day +100, P = .61), or chronic GVHD (39% vs 35% at 5 years, P = .49). There was a trend toward less relapse in the MMUD cohort (45% vs 60% at 5 years, hazard ratio: 0.71, P = .094), which was significant for patients with lymphoid malignancies (29% vs 57% at 5 years, hazard ratio: 0.55, P = .044). Achieving full donor chimerism was strongly associated with lower relapse rates. TLI-ATG conditioning may overcome the traditionally poorer outcome associated with HLA-mismatched donors and may be particularly well suited for patients with lymphoid malignancies who lack HLA-matched donors.

    View details for PubMedID 29296777

  • Adoption of pediatric-inspired acute lymphoblastic leukemia regimens by adult oncologists treating adolescents and young adults: A population-based study. Cancer Muffly, L., Lichtensztajn, D., Shiraz, P., Abrahão, R., McNeer, J., Stock, W., Keegan, T., Gomez, S. L. 2016

    Abstract

    Studies have demonstrated superior outcomes for adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) who are treated using pediatric versus adult therapeutic regimens. To the best of our knowledge, whether adult oncologists in the United States have adopted this approach to ALL in AYA patients is currently unknown. The objective of the current study was to provide a population-based description of ALL treatment patterns in AYA individuals over the past decade.Data regarding AYA patients aged 15 to 39 years and diagnosed with ALL between 2004 and 2014 while living in the Greater Bay Area were obtained from the Greater Bay Area Cancer Registry (GBACR). Treating facilities were designated as pediatric or adult centers; induction treatment regimens were abstracted from registry text data fields.Of 304 patients diagnosed in the GBACR catchment region, complete treatment data were available for 229 (75%). The location of care was identified for 296 patients (97%) treated at 31 unique centers. Approximately 70% of AYA patients received induction therapy at an adult treatment center. All AYA patients who were treated at pediatric centers received pediatric ALL regimens. Among AYA patients treated by adult oncologists with complete treatment data, none received a pediatric regimen before 2008. Between 2008 and 2012, while the US Adult Intergroup C10403 pediatric-inspired ALL protocol was open to accrual, 31% of AYA patients treated by adult oncologists received pediatric regimens. This rate fell to 21% from 2013 through 2014. Adult facilities treating ≥ 2 AYA patients with ALL per year captured in the GBACR were more likely to administer pediatric regimens than lower volume centers (P = .03).As of 2014, only a minority of AYA patients with ALL received pediatric ALL regimens at adult cancer centers. Cancer 2017;122-130. © 2016 American Cancer Society.

    View details for DOI 10.1002/cncr.30322

    View details for PubMedID 27622953

    View details for PubMedCentralID PMC5161602

  • Psychological morbidities in adolescent and young adult blood cancer patients during curative-intent therapy and early survivorship. Cancer Muffly, L. S., Hlubocky, F. J., Khan, N., Wroblewski, K., Breitenbach, K., Gomez, J., McNeer, J. L., Stock, W., Daugherty, C. K. 2016; 122 (6): 954-961

    Abstract

    Adolescents and young adults (AYAs) with cancer face unique psychosocial challenges. This pilot study was aimed at describing the prevalence of psychological morbidities among AYAs with hematologic malignancies during curative-intent therapy and early survivorship and at examining provider perceptions of psychological morbidities in their AYA patients.Patients aged 15 to 39 years with acute leukemia, non-Hodgkin lymphoma, or Hodgkin lymphoma who were undergoing curative-intent therapy (on-treatment group) or were in remission within 2 years of therapy completion (early survivors) underwent a semistructured interview that incorporated measures of anxiety, depression, and posttraumatic stress (PTS). A subset of providers (n = 15) concomitantly completed a survey for each of the first 30 patients enrolled that evaluated their perception of each subject's anxiety, depression, and PTS.Sixty-one of 77 eligible AYAs participated. The median age at diagnosis was 26 years (range, 15-39 years), 64% were male, and 59% were non-Hispanic white. On-treatment demographics differed significantly from early-survivor demographics only in the median time from diagnosis to interview. Among the 61 evaluable AYAs, 23% met the criteria for anxiety, 28% met the criteria for depression, and 13% met the criteria for PTS; 46% demonstrated PTS symptomatology. Thirty-nine percent were impaired in 1 or more psychological domains. Psychological impairments were as frequent among early survivors as AYAs on treatment. Provider perceptions did not significantly correlate with patient survey results.AYAs with hematologic malignancies experience substantial psychological morbidities while they are undergoing therapy and during early survivorship, with more than one-third of the patients included in this study meeting the criteria for anxiety, depression, or traumatic stress. This psychological burden may not be accurately identified by their oncology providers. Cancer 2015. © 2015 American Cancer Society.

    View details for DOI 10.1002/cncr.29868

    View details for PubMedID 26749023

  • The overlooked COST of multiple myeloma. The Lancet. Haematology de Souza, J. A., Muffly, L. 2015; 2 (10): e394-5

    View details for DOI 10.1016/S2352-3026(15)00192-1

    View details for PubMedID 26686034

  • Secondary solid cancer screening following hematopoietic cell transplantation. Bone marrow transplantation INAMOTO, Y., Shah, N. N., Savani, B. N., Shaw, B. E., Abraham, A. A., Ahmed, I. A., Akpek, G., Atsuta, Y., Baker, K. S., Basak, G. W., Bitan, M., DeFilipp, Z., GREGORY, T. K., Greinix, H. T., Hamadani, M., Hamilton, B. K., Hayashi, R. J., Jacobsohn, D. A., Kamble, R. T., Kasow, K. A., Khera, N., Lazarus, H. M., Malone, A. K., Lupo-Stanghellini, M. T., Margossian, S. P., Muffly, L. S., Norkin, M., Ramanathan, M., Salooja, N., Schoemans, H., Wingard, J. R., Wirk, B., Wood, W. A., Yong, A., Duncan, C. N., Flowers, M. E., Majhail, N. S. 2015; 50 (8): 1013-1023

    Abstract

    Hematopoietic stem cell transplant (HCT) recipients have a substantial risk of developing secondary solid cancers, particularly beyond 5 years after HCT and without reaching a plateau overtime. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to facilitate implementation of cancer screening appropriate to HCT recipients. The working group reviewed guidelines and methods for cancer screening applicable to the general population and reviewed the incidence and risk factors for secondary cancers after HCT. A consensus approach was used to establish recommendations for individual secondary cancers. The most common sites include oral cavity, skin, breast and thyroid. Risks of cancers are increased after HCT compared with the general population in skin, thyroid, oral cavity, esophagus, liver, nervous system, bone and connective tissues. Myeloablative TBI, young age at HCT, chronic GVHD and prolonged immunosuppressive treatment beyond 24 months were well-documented risk factors for many types of secondary cancers. All HCT recipients should be advised of the risks of secondary cancers annually and encouraged to undergo recommended screening based on their predisposition. Here we propose guidelines to help clinicians in providing screening and preventive care for secondary cancers among HCT recipients.

    View details for DOI 10.1038/bmt.2015.63

    View details for PubMedID 25822223

    View details for PubMedCentralID PMC4989866

  • Patient Selection for Allogeneic Hematopoietic Cell Transplantation (HCT): the Evolution of HCT Risk Assessment. Current hematologic malignancy reports Muffly, L. 2015; 10 (1): 28-34

    Abstract

    The use of allogeneic hematopoietic cell transplantation is expanding, with disproportionate growth witnessed in older adults with hematologic malignancies. As the chronological age barrier to transplant fades, refining the pre-hematopoietic cell transplantation (HCT) risk assessment to better capture host health status and disease characteristics is essential. This review summarizes recent efforts to move the field forward towards achieving this goal. Many of these risk assessment tools are currently included in prospective clinical trials; routine clinical use requires greater understanding of how to best incorporate this new information into HCT decision making.

    View details for DOI 10.1007/s11899-014-0241-2

    View details for PubMedID 25500987

  • Geriatric assessment to predict survival in older allogeneic hematopoietic cell transplantation recipients HAEMATOLOGICA Muffly, L. S., Kocherginsky, M., Stock, W., Chu, Q., Bishop, M. R., Godley, L. A., Kline, J., Liu, H., Odenike, O. M., Larson, R. A., Van Besien, K., Artz, A. S. 2014; 99 (8): 1373-1379

    Abstract

    Allogeneic hematopoietic cell transplantation is increasingly utilized in older adults. This study prospectively evaluated the prognostic utility of geriatric assessment domains prior to allogeneic transplantation in recipients aged 50 years and over. Geriatric assessment was performed prior to transplant, and included validated measures across domains of function and disability, comorbidity, frailty, mental health, nutritional status, and systemic inflammation. A total of 203 patients completed geriatric assessment and underwent transplant. Median age was 58 years (range 50-73). After adjusting for established prognostic factors, limitations in instrumental activities of daily living (HR 2.38, 95%CI: 1.59-3.56; P<0.001), slow walk speed (HR 1.80, 95%CI: 1.14-2.83; P=0.01), high comorbidity by hematopoietic cell transplantation-specific comorbidity index (HR 1.56, 95%CI: 1.07-2.28; P=0.02), low mental health by short-form-36 mental component summary (HR 1.67, 95%CI: 1.13-2.48; P=0.01), and elevated serum C-reactive protein (HR 2.51, 95%CI: 1.54-4.09; P<0.001) were significantly associated with inferior overall survival. These associations were more pronounced in the cohort 60 years and over. Geriatric assessment measures confer independent prognostic utility in older allogeneic transplant recipients. Implementation of geriatric assessment prior to allogeneic transplantation may aid appropriate selection of older adults.

    View details for DOI 10.3324/haematol.2014.103655

    View details for Web of Science ID 000342834300022

    View details for PubMedID 24816237

  • Pilot Study of Comprehensive Geriatric Assessment (CGA) in Allogeneic Transplant: CGA Captures a High Prevalence of Vulnerabilities in Older Transplant Recipients BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Muffly, L. S., Boulukos, M., Swanson, K., Kocherginsky, M., del Cerro, P., Schroeder, L., Pape, L., Extermann, M., Van Besien, K., Artz, A. S. 2013; 19 (3): 429-434

    Abstract

    Comprehensive geriatric assessment (CGA) is frequently used in oncology to measure the health status of older adults with cancer, but it has not been studied in allogeneic hematopoietic cell transplantation (HCT). We conducted a prospective pilot study of CGA in allogeneic HCT recipients aged ≥50 years to examine the prevalence of vulnerabilities in this population. Patients aged ≥50 years eligible for HCT were enrolled. CGA consisted mainly of self-reported, performance-based, and chart-extracted measures evaluating domains of comorbidity, physical and mental function, frailty, disability, and nutrition. Of 238 eligible patients, 166 completed CGA and underwent HCT. Only 1% had a Zubrod Performance Status score >1; 44% had high comorbidity defined by the Hematopoietic Cell Transplantation Comorbidity Index, and 66% had high comorbidity defined by the Cumulative Illness Rating Scale-Geriatrics. The presence of additional vulnerability was frequent. Disability was present in 40% by Instrumental Activities of Daily Living. Self-reported physical and mental function were significantly lower than population age group norms, 58% were pre-frail, and 25% were frail. Among those with Zubrod Performance Status score of 0, 28% demonstrated disability, 58% were pre-frail, 15% were frail, 35% reported low physical function, and 55% reported low mental function. CGA uncovers a substantial prevalence of undocumented impairments in functional status, frailty, disability, and mental health in older allogeneic HCT recipients.

    View details for DOI 10.1016/j.bbmt.2012.11.006

    View details for Web of Science ID 000315425700015

    View details for PubMedID 23160006

  • Microwave imaging for neoadjuvant chemotherapy monitoring: initial clinical experience BREAST CANCER RESEARCH Meaney, P. M., Kaufman, P. A., Muffly, L. S., Click, M., Poplack, S. P., Wells, W. A., Schwartz, G. N., di Florio-Alexander, R. M., Tosteson, T. D., Li, Z., Geimer, S. D., Fanning, M. W., Zhou, T., Epstein, N. R., Paulsen, K. D. 2013; 15 (2)

    Abstract

    Microwave tomography recovers images of tissue dielectric properties, which appear to be specific for breast cancer, with low-cost technology that does not present an exposure risk, suggesting the modality may be a good candidate for monitoring neoadjuvant chemotherapy.Eight patients undergoing neoadjuvant chemotherapy for locally advanced breast cancer were imaged longitudinally five to eight times during the course of treatment. At the start of therapy, regions of interest (ROIs) were identified from contrast-enhanced magnetic resonance imaging studies. During subsequent microwave examinations, subjects were positioned with their breasts pendant in a coupling fluid and surrounded by an immersed antenna array. Microwave property values were extracted from the ROIs through an automated procedure and statistical analyses were performed to assess short term (30 days) and longer term (four to six months) dielectric property changes.Two patient cases (one complete and one partial response) are presented in detail and demonstrate changes in microwave properties commensurate with the degree of treatment response observed pathologically. Normalized mean conductivity in ROIs from patients with complete pathological responses was significantly different from that of partial responders (P value = 0.004). In addition, the normalized conductivity measure also correlated well with complete pathological response at 30 days (P value = 0.002).These preliminary findings suggest that both early and late conductivity property changes correlate well with overall treatment response to neoadjuvant therapy in locally advanced breast cancer. This result is consistent with earlier clinical outcomes that lesion conductivity is specific to differentiating breast cancer from benign lesions and normal tissue.

    View details for DOI 10.1186/bcr3418

    View details for Web of Science ID 000330612000018

    View details for PubMedID 23621959

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