No abstract

An observational study was conducted at 18 transplant centers in the United States and Canada to characterize the platelet recovery of patients receiving myeloablative therapy and stem cell transplantation and to determine the clinical variables influencing recovery, determine platelet utilization and cost, and incidence of hemorrhagic events. The study included 789 evaluable patients transplanted in 1995. Clinical, laboratory, and outcome data were obtained from the medical records. Variables associated with accelerated recovery in multivariate models included (1) higher CD34 count; (2) higher platelet count at the start of myeloablative therapy; (3) graft from an HLA-identical sibling donor; and (4) prior stem cell transplant. Variables associated with delayed recovery were (1) prior radiation therapy; (2) posttransplant fever; (3) hepatic veno-occlusive disease; and (4) use of posttransplant growth factors. Disease type also influenced recovery. Recipients of peripheral blood stem cells (PBSC) had faster recovery and fewer platelet transfusion days than recipients of bone marrow (BM). The estimated average 60-day platelet transfusion cost per patient was $4,000 for autologous PBSC and $11,000 for allogeneic BM transplants. It was found that 11% of all patients had a significant hemorrhagic event during the first 60 days posttransplant, contributing to death in 2% of patients. In conclusion, clinical variables influencing platelet recovery should be considered in the design and interpretation of clinical strategies to accelerate recovery. Enhancing platelet recovery is not likely to have a significant impact on 60-day mortality but could significantly decrease health care costs and potentially improve patient quality of life.

In this multicenter, randomized, double-blind, placebo-controlled trial of autologous bone marrow cell therapy for CLI, the therapy was well tolerated without significant adverse events. The BMAC group demonstrated trends toward improvement in amputation, pain, quality of life, Rutherford classification, and ABI when compared with controls. This pilot allowed us to identify several areas for improvement for future trials and CLI studies. These recommendations include elimination of treadmill testing, stratification by Rutherford class, and more liberal inclusion of patients with renal insufficiency. Our strongest recommendation is that CLI studies that include Rutherford 4 patients should incorporate a composite endpoint reflecting pain and quality of life.

An observational study was conducted at 18 transplant centers in the United States and Canada to characterize the platelet recovery of patients receiving myeloablative therapy and stem cell transplantation and to determine the clinical variables influencing recovery, determine platelet utilization and cost, and incidence of hemorrhagic events. The study included 789 evaluable patients transplanted in 1995. Clinical, laboratory, and outcome data were obtained from the medical records. Variables associated with accelerated recovery in multivariate models included (1) higher CD34 count; (2) higher platelet count at the start of myeloablative therapy; (3) graft from an HLA-identical sibling donor; and (4) prior stem cell transplant. Variables associated with delayed recovery were (1) prior radiation therapy; (2) posttransplant fever; (3) hepatic veno-occlusive disease; and (4) use of posttransplant growth factors. Disease type also influenced recovery. Recipients of peripheral blood stem cells (PBSC) had faster recovery and fewer platelet transfusion days than recipients of bone marrow (BM). The estimated average 60-day platelet transfusion cost per patient was $4,000 for autologous PBSC and $11,000 for allogeneic BM transplants. It was found that 11% of all patients had a significant hemorrhagic event during the first 60 days posttransplant, contributing to death in 2% of patients. In conclusion, clinical variables influencing platelet recovery should be considered in the design and interpretation of clinical strategies to accelerate recovery. Enhancing platelet recovery is not likely to have a significant impact on 60-day mortality but could significantly decrease health care costs and potentially improve patient quality of life.

Monoclonal antibodies were raised against hemocytes of the colonial ascidian Botryllus schlosseri as possible tools to study hemocyte differentiation. In this species, blood cells are involved in various biological functions, such as immunosurveillance, encapsulation of foreign bodies, metal accumulation, and allorecognition. The latter process drives the fusion or rejection of contacting colonies, according to whether they do or do not share at least one allele at the fusibility/histocompatibility (Fu/HC) locus. Hemocytes take part in the rejection reaction, which suggests that they express molecules, coded by the Fu/HC locus, on their surface. A homozygous colony at the Fu/HC locus was used to produce the antibodies, which were screened by immunocytochemistry on hemocyte monolayers, immunohistochemistry on colony paraffin sections, and immunoblotting on colony homogenates. Here, we report on one of the obtained antibodies (1D8), which recognized a surface epitope on hemocytes of the donor colony and other colonies, apparently in a manner specific to the Fu/HC genotype. It also labeled a single 80‐kDa band in colony homogenates. In addition, it specifically recognized tunic cells, germ cells, and their accessory cells. These results strengthen the assumption of a close relationship among these types of cells and blood cells, and suggest a close relationship among the above cells, probably deriving from undifferentiated blood cells. J. Exp. Zool. (Mol. Dev. Evol.) 316:284–295, 2011. © 2011 Wiley‐Liss, Inc.

Introduction: Although outcomes for patients with multiple myeloma (MM) have improved with recent advances in treatment, relapse is still frequent. Early relapse is associated with poorer outcomes (Majithia et al., Leukemia 2016;30:2208-13) and is thought to reflect more aggressive disease, particularly within 12 months of autologous stem cell transplantation (ASCT). In the randomized phase 3 CANDOR study, progression-free survival (PFS) was significantly improved in patients with relapsed or refractory MM (RRMM) receiving carfilzomib, dexamethasone, and daratumumab (KdD) compared with carfilzomib and dexamethasone (Kd) (ClinicalTrials.gov, NCT03158688; Usmani et al., Blood 2019;134:LBA-6). In this post hoc analysis of the CANDOR study, we studied the safety and efficacy of KdD vs Kd in patients with early or late relapse following the most recent therapy. Methods: In the CANDOR study, patients with RRMM who received 1-3 prior lines of therapy were randomized 2:1 to receive KdD or Kd. The primary endpoint was PFS; secondary endpoints included overall response rate (ORR), rate of complete response or better (≥CR), and safety. In this analysis, subgroups were defined by relapse timing following the most recent therapy. Relapse <12 months from initiation of the most recent line of therapy was defined as early, and relapse ≥12 months from initiation of the most recent line of therapy was defined as late (except for the subgroup of patients who received only one prior line of therapy, where a cutoff of 18 months was used to define early and late relapse). For the subgroup of patients with prior ASCT, relapse <12 months following prior transplant was classified as early, and relapse ≥12 months following prior transplant was classified as late. Median PFS was estimated using the Kaplan-Meier method, while hazard ratios (HRs) and 95% CIs were estimated from a nonstratified Cox regression model. Response rates were defined per the International Myeloma Working Group Uniform Response Criteria. Results: In total, 452 patients (156 of whom received prior ASCT) were included in this post hoc analysis; 210 patients received 1 prior line of therapy, and 242 patients received ≥2 prior lines of therapy. PFS HRs (KdD vs Kd) were consistent across subgroups regardless of early or late relapse, including in patients with prior ASCT (Figure). In patients who received 1 prior line of therapy, the ORR was 86.4% vs 57.6% for early relapsers in the KdD vs Kd arms and 93.9% vs 88.9% for late relapsers, respectively. The rate of ≥CR was 28.8% vs 3.0% for early relapsers and 39.0% vs 16.7% for late relapsers. In patients who received ≥2 prior lines of therapy, the ORR was 75.3% vs 65.1% for early relapsers in the KdD vs Kd arms and 82.9% vs 86.1% for late relapsers. The rate of ≥CR was 19.8% vs 4.7% for early relapsers and 28.0% vs 16.7% for late relapsers. The rates of grade ≥3 treatment-emergent adverse events (TEAEs) observed in the early and late relapse subgroups were similar to that in the overall CANDOR population. Conclusion: In this post hoc analysis from the phase 3 CANDOR study, efficacy results were generally consistent across early and late relapse subgroups. In particular, rates of ≥CR were higher with KdD vs Kd among patients with early relapse. The rates of grade ≥3 TEAEs were consistent with the safety profile of overall KdD and Kd cohorts. These results support the use of KdD in patients with RRMM, regardless of early or late relapse, prior ASCT, or whether patients relapsed after one prior line of therapy or 2 or more prior lines of therapy. Disclosures Weisel: Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Geils:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Karlin:Celgene: Other: Personal fees; Sanofi: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees. Mollee:Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees. Sunami:Celgene: Honoraria, Research Funding; Novartis: Research Funding; GSK: Research Funding; Janssen: Research Funding; AbbVie: Research Funding; Sanofi: Research Funding; MSD: Research Funding; Alexion Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ono: Honoraria, Research Funding. Goldrick:Amgen: Current Employment, Current equity holder in publicly-traded company. Fang:Amgen: Current Employment, Current equity holder in publicly-traded company. Fowler:Amgen: Current Employment, Current equity holder in publicly-traded company. Mateos:EDOMundipharma: Consultancy; Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Consultancy; GSK: Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Carfilzomib is a proteasome inhibitor and daratumumab is an anti-CD38 monoclonal antibody, which can both be used to treat RRMM.

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Pyrimethamine, a substituted pyrimidine with potent folate antagonistic properties, was given orally to treat two episodes of meningeal leukemia in a longterm survivor with acute myeloblastic leukemia. Remissions of seven and at least 6 mo duration were obtained on the two occasions. Spinal fluid concentrations of pyrimethamine were 10-25% of the simultaneous plasma concentrations. Considerations regarding lipid solubility, body distribution, and easily reversible toxicity of pyrimethamine suggest that further therapeutic trials are warranted, especially in childhood lymphoblastic leukemia.