CD22-Directed CAR T-Cell Therapy Induces Complete Remissions in CD19-Directed CAR-Refractory Large B-Cell Lymphoma.
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/µL), 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
A phase 2 study of brentuximab vedotin in patients with CD30-positive advanced systemic mastocytosis.
2019; 3 (15): 2264?71
There is an unmet need for effective therapies for advanced systemic mastocytosis (advSM). CD30 is expressed on the surface of neoplastic mast cells (MC) in more than 50% of patients with advSM. Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate with preclinical evidence supporting both an antineoplastic effect and an attenuation of immunoglobulin E-associated mediator release. These observations are the basis for this phase 2 trial of BV monotherapy (1.8 mg/kg IV every 3 weeks up to 8 cycles) in patients with CD30-positive advSM. The primary objective was to determine the efficacy of BV according to International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRT-ECNM) response criteria. Secondary objectives included evaluation of safety, changes in bone marrow (BM) MC burden, serum tryptase level, flow cytometric quantification of MC surface expression of CD30, and self-reported symptom burden. The trial enrolled 10 patients with a diagnosis of CD30+ advSM (aggressive SM, SM with an associated hematologic neoplasm [SM-AHN], or mast cell leukemia [MCL]) with 1 or more signs of SM-related organ damage. According to IWG-MRT-ECNM criteria, none of the patients demonstrated better than stable disease with BV. In addition, there were no significant reductions in BM MC burden, serum tryptase levels, or MC surface expression of CD30. Self-reported symptom scores showed no durable improvement with BV treatment. We conclude that BV is not active as a single agent in CD30+ advSM. This trial was registered at www.clinicaltrials.gov as #NCT01807598.
View details for DOI 10.1182/bloodadvances.2019000152
View details for PubMedID 31350306
- An Unusual Cause of Epistaxis: Paranasal Sinus Myeloid Sarcoma CASE REPORTS IN HEMATOLOGY 2019
An Unusual Cause of Epistaxis: Paranasal Sinus Myeloid Sarcoma.
Case reports in hematology
2019; 2019: 1312630
We report a case of a 65-year-old female who presented with right-sided headaches, blurring of vision in the right eye, cold-induced epistaxis, and facial numbness in the trigeminal nerve distribution. Laboratory studies revealed a significant number of myeloblasts on peripheral smear with granulated cytoplasm, irregular nuclei, and prominent vacuoles. Magnetic resonance imaging (MRI) of the brain demonstrated a T1-enhancing 1.5?cm right-sided dural-based lesion involving the medial sphenoid wing, cavernous sinus, infratemporal fossa, and sphenoid sinus region. An endoscopic biopsy of the lesion within the sphenoid sinus confirmed the diagnosis of myeloid sarcoma, with myeloblasts comprising 30% of cellularity by flow cytometry. A subsequent bone marrow biopsy revealed a hypercellular marrow with 23% blasts by flow cytometry that demonstrated a similar immunophenotypic pattern to those seen in the sinus mass. Fluorescence in situ hybridization (FISH) testing revealed the balanced translocation t(8;21)(q22;q22.1), consistent with a diagnosis of acute myeloid leukemia with RUNX1-RUNX1T1-balanced translocation by WHO 2016 criteria. Myeloid sarcoma represents a rare extramedullary presentation of acute myeloid leukemia (AML), either alone or in conjunction with blood or bone marrow involvement. This case emphasizes the need for a broad differential diagnosis and an aggressive work-up for any unusual paranasal sinus mass.
View details for PubMedID 30891319
View details for PubMedCentralID PMC6390259
Clinical Validation of KIT Inhibition in Advanced Systemic Mastocytosis.
Current hematologic malignancy reports
PURPOSE OF REVIEW: We discuss recent developments in the treatment of advanced systemic mastocytosis (advSM) with inhibitors of the KIT receptor tyrosine kinase.RECENT FINDINGS: advSM is a heterogeneous group of neoplasms of poor prognosis characterized by the accumulation of neoplastic mast cells. The canonical KIT D816V mutation is present in approximately 90% of SM patients, and its detection is critical for both diagnosis and therapeutic decision-making. The multikinase/KIT inhibitor midostaurin was recently approved for advSM. This agent can reverse SM-related organ damage and disease symptoms, and decrease the bone marrow mast cell burden and splenomegaly. However, complete remissions are rare and durability of responses is variable. Potent and selective KIT D816V inhibitors including avapritinib (BLU-285) and DCC-2618 have entered clinical trials, and rational combination strategies are under development. The clinical efficacy of KIT inhibitors validate KIT as a key oncogenic driver in mast cell neoplasms. An improved understanding of the genetic heterogeneity beyond KIT will help inform the dynamics of response and relapse.
View details for PubMedID 30155614
- The Hemorrhage that Wasn't: Polycythemia Presenting as a Pseudointracranial Hemorrhage in Pedestrian vs Automobile Trauma Alert JOURNAL OF EMERGENCY MEDICINE CASE REPORTS 2018; 9 (2): 26?29
- Voriconazole-induced periostitis after allogeneic stem cell transplantation AMERICAN JOURNAL OF HEMATOLOGY 2015; 90 (6): 574-575
Oscillatory haematopoiesis in adults with sickle cell disease treated with hydroxycarbamide
BRITISH JOURNAL OF HAEMATOLOGY
2015; 168 (5): 737-746
Hydroxycarbamide therapy has been associated with significant oscillations in peripheral blood counts from myeloid, lymphoid and erythroid lineages in patients with polycythaemia vera and chronic myeloid leukaemia. We retrospectively evaluated serial blood counts over an 8-year period from 44 adult patients with sickle cell disease receiving hydroxycarbamide. Platelet counts, leucocyte counts, haemoglobin values and reticulocyte counts, apportioned by hydroxycarbamide status, were analysed using a Lomb-Scargle periodogram algorithm. Significant periodicities were present in one or more counts in 38 patients receiving hydroxycarbamide for a mean duration of 4·81 years. Platelet and leucocyte counts oscillated in 56·8% and 52·3% of patients, respectively. These oscillations generally became detectable within days of initiating therapy. During hydroxycarbamide therapy, the predominant periods of oscillation were 27 ± 1 d for platelet counts and 15 ± 1 d for leucocyte counts. Despite an absolute decrease in leucocyte and platelet counts during hydroxycarbamide treatment, the amplitudes between nadirs and zeniths remained similar regardless of exposure. Our observations appear consistent with previously proposed models of cyclic haematopoiesis, and document that hydroxycarbamide-induced oscillations in blood counts are innocuous phenomena not limited to myeloproliferative disorders as described previously. We speculate the known cell cycle inhibitory properties of hydroxycarbamide may accentuate otherwise latent constitutive oscillatory haematopoiesis.
View details for DOI 10.1111/bjh.13203
View details for Web of Science ID 000349611300015
View details for PubMedID 25377027
Inhibiting adipose tissue lipogenesis reprograms thermogenesis and PPAR? activation to decrease diet-induced obesity.
2012; 16 (2): 189-201
De novo lipogenesis in adipocytes, especially with high fat feeding, is poorly understood. We demonstrate that an adipocyte lipogenic pathway encompassing fatty acid synthase (FAS) and PexRAP (peroxisomal reductase activating PPAR?) modulates endogenous PPAR? activation and adiposity. Mice lacking FAS in adult adipose tissue manifested increased energy expenditure, increased brown fat-like adipocytes in subcutaneous adipose tissue, and resistance to diet-induced obesity. FAS knockdown in embryonic fibroblasts decreased PPAR? transcriptional activity and adipogenesis. FAS-dependent alkyl ether phosphatidylcholine species were associated with PPAR? and treatment of 3T3-L1 cells with one such ether lipid increased PPAR? transcriptional activity. PexRAP, a protein required for alkyl ether lipid synthesis, was associated with peroxisomes and induced during adipogenesis. PexRAP knockdown in cells decreased PPAR? transcriptional activity and adipogenesis. PexRAP knockdown in mice decreased expression of PPAR?-dependent genes and reduced diet-induced adiposity. These findings suggest that inhibiting PexRAP or related lipogenic enzymes could treat obesity and diabetes.
View details for PubMedID 22863804