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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-+
View details for DOI 10.1200/JOP.18.00264

View details for Web of Science ID 000467137600015
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
View details for DOI 10.1093/jnci/djy123

View details for Web of Science ID 000467901100003
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
Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma BLOOD ADVANCES Baird, J. H., Epstein, D. J., Tamaresis, J. S., Ehlinger, Z., Spiegel, J. Y., Craig, J., Claire, G. K., Frank, M. J., Muffly, L., Shiraz, P., Meyer, E., Arai, S., Brown, J., Johnston, L., Lowsky, R., Negrin, R. S., Rezvani, A. R., Weng, W., Latchford, T., Sahaf, B., Mackall, C. L., Miklos, D. B., Sidana, S. 2021; 5 (1): 143?55
View details for DOI 10.1182/bloodadvances.2020002732

View details for Web of Science ID 000607932700016
Routine use of gemtuzumab ozogamicin in 7?+?3-based inductions for all 'non-adverse' risk AML. Leukemia & lymphoma Ladha, A., Hui, G., Cheung, E., Berube, C., Coutre, S. E., Gotlib, J., Liedtke, M., Zhang, T. Y., Muffly, L., Mannis, G. N. 2021: 1?6
View details for DOI 10.1080/10428194.2021.1876869

View details for PubMedID 33491527
Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma. Blood advances Baird, J. H., Epstein, D. J., Tamaresis, J. S., Ehlinger, Z., Spiegel, J. Y., Craig, J., Claire, G. K., Frank, M. J., Muffly, L., Shiraz, P., Meyer, E., Arai, S., Brown, J. W., Johnston, L., Lowsky, R., Negrin, R. S., Rezvani, A. R., Weng, W. K., Latchford, T., Sahaf, B., Mackall, C. L., Miklos, D. B., Sidana, S. 2021; 5 (1): 143?55
Abstract

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has significantly improved outcomes in the treatment of refractory or relapsed large B-cell lymphoma (LBCL). We evaluated the long-term course of hematologic recovery, immune reconstitution, and infectious complications in 41 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) at a single center. Grade 3+ cytopenias occurred in 97.6% of patients within the first 28 days postinfusion, with most resolved by 6 months. Overall, 63.4% of patients received a red blood cell transfusion, 34.1% of patients received a platelet transfusion, 36.6% of patients received IV immunoglobulin, and 51.2% of patients received growth factor (granulocyte colony-stimulating factor) injections beyond the first 28 days postinfusion. Only 40% of patients had recovered detectable CD19+ B cells by 1 year, and 50% of patients had a CD4+ T-cell count <200 cells per ?L by 18 months postinfusion. Patients with durable responses to axi-cel had significantly longer durations of B-cell aplasia, and this duration correlated strongly with the recovery of CD4+ T-cell counts. There were significantly more infections within the first 28 days compared with any other period of follow-up, with the majority being mild-moderate in severity. Receipt of corticosteroids was the only factor that predicted risk of infection in a multivariate analysis (hazard ratio, 3.69; 95% confidence interval, 1.18-16.5). Opportunistic infections due to Pneumocystis jirovecii and varicella-zoster virus occurred up to 18 months postinfusion in patients who prematurely discontinued prophylaxis. These results support the use of comprehensive supportive care, including long-term monitoring and antimicrobial prophylaxis, beyond 12 months after axi-cel treatment.

View details for DOI 10.1182/bloodadvances.2020002732

View details for PubMedID 33570626
Allogeneic hematopoietic cell transplantation (alloHCT) for patients over 65 years old is not associated with worse symptoms/function than younger patients - a Center for International Blood and Marrow Transplant Research (CIBMTR) study Shaw, B., Brazauskas, R., Burns, L. J., Mattila, D., Musseter, A., Chen, M., Vasu, S., Pidala, J., Muffly, L., Uberti, J., Tamari, R., Tamari, R., Leckrone, E., Myers, J., Mau, L., Rizzo, J., Saber, W., Horowitz, M. M., Lee, S. J., Flynn, K. E. SPRINGER. 2020: S29
View details for Web of Science ID 000584632700070
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
View details for Web of Science ID 000564055100015
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
Philadelphia chromosome positive acute lymphoblastic leukemia in adults: Therapeutic options and dilemmas in 2020. Seminars in hematology Muffly, L., Kebriaei, P. 2020; 57 (3): 137?41
Abstract

The incorporation of tyrosine kinase inhibitors (TKI) into front-line therapy for adults with Philadelphia chromosome positive acute lymphoblastic leukemia has dramatically altered response rates and significantly improved outcomes, such that this entity may no longer be considered a high risk acute lymphoblastic leukemia subgroup. In this review article, we summarize approaches to front-line therapy in the TKI era, including intensive chemotherapy-based regimens and deintensified therapy. We also review optimal disease monitoring strategies, discuss the role of consolidative hematopoietic cell transplantation, and touch on options for relapsed disease. The incorporation of novel targeted agents in conjunction with TKIs into front-line therapy will likely alter the future therapeutic approaches to this disease.

View details for DOI 10.1053/j.seminhematol.2020.09.002

View details for PubMedID 33256903
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
View details for Web of Science ID 000526961000042
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
Assessment of Measurable Residual Disease (MRD) in Adult Patients With Acute Lymphocytic Leukemia: Best Use and a Case Report CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY Muffly, L. 2020; 18 (3)
View details for Web of Science ID 000619716900004
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
View details for Web of Science ID 000516887900144
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
View details for Web of Science ID 000516887900088
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
View details for Web of Science ID 000516887900291
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
View details for Web of Science ID 000516887900060
Clinical Actionability of Measurable Residual Disease (MRD) Assessment in the Management of Patients With Hematologic Malignancies: A Case-Based Monograph CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY Wolf, J., Fonseca, R., Muffly, L. 2020; 18 (3)
View details for Web of Science ID 000619716900001
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 S�zary 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
CD22-Directed CAR T-Cell Therapy Induces Complete Remissions in CD19-Directed CAR-Refractory Large B-Cell Lymphoma. Blood Baird, J. H., Frank, M. J., Craig, J., Patel, S., Spiegel, J. Y., Sahaf, B., Oak, J. S., Younes, S., Ozawa, M., Yang, E., Natkunam, Y., Tamaresis, J. S., Ehlinger, Z., Reynolds, W. D., Arai, S., Johnston, L., Lowsky, R., Meyer, E., Negrin, R. S., Rezvani, A. R., Shiraz, P., Sidana, S., Weng, W. K., Davis, K. L., Ramakrishna, S., Schultz, L., Mullins, C. D., Jacob, A. P., Kirsch, I. R., Feldman, S. A., Mackall, C. L., Miklos, D. B., Muffly, L. 2020
Abstract

The prognosis for patients with large B-cell lymphoma (LBCL) progressing after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first three consecutive patients with autologous CAR19-refractory LBCL treated with a single infusion of autologous 1�106 CAR+ T-cells/kg targeting CD22 (CAR22) as part of a phase I dose escalation study. CAR22 therapy was relatively well tolerated, without any observed non-hematologic adverse events higher than grade 2. Following infusion, all three patients achieved complete remission, with all responses ongoing at the time of last follow up (mean 7.8 months, range 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range 85.4-350 cells/�L), and persisted beyond three months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA (ctDNA) beyond six months post-infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients who have failed prior CAR T-cell therapies. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT04088890).

View details for DOI 10.1182/blood.2020009432

View details for PubMedID 33512414
Pediatric-inspired protocols in adult acute lymphoblastic leukemia: are the results bearing fruit? Muffly, L., Curran, E. AMER SOC HEMATOLOGY. 2019: 17?23
View details for Web of Science ID 000538564000003
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
View details for DOI 10.1016/j.ijrobp.2019.06.1447

View details for Web of Science ID 000485671501366
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
View details for DOI 10.1016/j.bbmt.2019.04.001

View details for Web of Science ID 000483008500026
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
View details for DOI 10.1089/jayao.2018.0140

View details for Web of Science ID 000473442700004
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
View details for DOI 10.1002/ajmg.a.61115

View details for Web of Science ID 000468322800023
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
View details for DOI 10.1200/JCO.2019.37.15_suppl.e18138

View details for Web of Science ID 000487345802114
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
View details for Web of Science ID 000487345806323
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)
View details for DOI 10.1172/jci.insight.127244

View details for Web of Science ID 000468146300016
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
View details for Web of Science ID 000475965900243
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
View details for DOI 10.1016/j.jpainsymman.2018.12.297

View details for Web of Science ID 000456406900300
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
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
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
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., Ringd�n, O., van der Poel, M., Murthy, H. S., Liu, H., Mori, S., De Oliveira, S., Bola�os-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
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
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
View details for DOI 10.1182/blood-2018-99-113597

View details for Web of Science ID 000454842804265
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
View details for DOI 10.1182/blood-2018-99-113031

View details for Web of Science ID 000454837600306
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
View details for DOI 10.1182/blood-2018-99-111553

View details for Web of Science ID 000454837602217
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
View details for DOI 10.1182/blood-2018-99-117445

View details for Web of Science ID 000454837602274
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
View details for DOI 10.1182/blood-2018-99-110142

View details for Web of Science ID 000454837601199
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
View details for DOI 10.1182/blood-2018-99-113261

View details for Web of Science ID 000454837601285
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
View details for DOI 10.1182/blood-2018-99-113633

View details for Web of Science ID 000454842805058
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
View details for DOI 10.1182/blood-2018-99-119382

View details for Web of Science ID 000454842805146
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
View details for DOI 10.1182/blood-2018-99-111205

View details for Web of Science ID 000454842803001
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
View details for Web of Science ID 000444343400290
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
View details for Web of Science ID 000444343400024
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
View details for Web of Science ID 000425476000186
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
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
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
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., Fern�ndez-Vi�a, 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., Abrah�o, 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

Lori Muffly

Assistant Professor of Medicine (Blood and Marrow Transplantation and Cellular Therapy) at the Stanford University Medical Center

Medicine - Blood & Marrow Transplantation

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