Efficacy and Outcome of Allogeneic Transplantation in IgD and Nonsecretory Myeloma. A Report on Behalf of the Myeloma Subcommittee of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation

AbstractWe have recently reported on the outcome of autologous transplantation in the rare myelomas (IgD, IgE, IgM, and nonsecretory [NS]) but there is no real information on the outcome of these conditions after allogeneic transplantation. We used the European Group for Blood and Marrow Transplantation myeloma database to compare the outcomes after allogeneic transplantation of 1354 common myelomas (IgG, IgA, and light chain myeloma) with the outcome in 26 IgD myelomas and 52 NS myelomas. There was little difference between common and the IgD and NS myeloma patients with respect to prognostic factors although the IgD group had a higher beta 2 microglobulin at diagnosis, shorter time to transplantation, and more T cell depletion. IgD and NS patients had a significantly greater achievement of complete remission at conditioning but this did not translate into equivalent progression-free survival and overall survival for the IgD patients although the NS outcome was very similar to that of common myeloma. The PFS and OS of IgD, common, and NS myelomas appear similar after allogeneic transplantation, despite a tendency for higher early relapse rate in IgD myeloma. Allogeneic transplantation may, therefore, be an option to investigate in prospective observational studies

Autologous Hematopoietic Stem Cell Transplantation vs Intravenous Pulse Cyclophosphamide in Diffuse Cutaneous Systemic Sclerosis: A Randomized Clinical Trial

Importance: High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. Objective: To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. Design, Setting, and Participants: The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation–registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. Interventions: HSCT vs intravenous pulse cyclophosphamide. Main Outcomes and Measures: The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. Results: A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. Conclusions and Relevance: Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit. Trial Registration: isrctn.org Identifier: ISRCTN5437125

Splenic irradiation before hematopoietic stem cell transplantation for chronic myeloid leukemia : long-term follow-up of a prospective randomized study

In the context of discussions on the reproducibility of clinical studies, we reanalyzed a prospective randomized study on the role of splenic irradiation as adjunct to the conditioning for hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML). Between 1986 and 1989, a total of 229 patients with CML were randomized; of these, 225 (98 %; 112 with, 113 without splenic irradiation) could be identified in the database and their survival updated. Results confirmed the early findings with no significant differences in all measured endpoints (overall survival at 25 years: 42.7 %, 32.0-52.4 % vs 52.9 %, 43.2-62.6 %; p = 0.355, log rank test). Additional splenic irradiation failed to reduce relapse incidence. It did not increase non-relapse mortality nor the risk of late secondary malignancies. Comforting are the long-term results from this predefined consecutive cohort of patients: more than 60 % were alive at plus 25 years when they were transplanted with a low European Society for Blood and Marrow Transplantation (EBMT) risk sore. This needs to be considered today when treatment options are discussed for patients who failed initial tyrosine kinase inhibitor therapy and have an available low risk HLA-identical donor.Peer reviewe

A frameshift polymorphism in P2X5 elicits an allogeneic cytotoxic T lymphocyte response associated with remission of chronic myeloid leukemia

Minor histocompatibility antigens (mHAgs) constitute the targets of the graft-versus-leukemia response after HLA-identical allogeneic stem cell transplantation. Here, we have used genetic linkage analysis to identify a novel mHAg, designated lymphoid-restricted histocompatibility antigen–1 (LRH-1), which is encoded by the P2X5 gene and elicited an allogeneic CTL response in a patient with chronic myeloid leukemia after donor lymphocyte infusion. We demonstrate that immunogenicity for LRH-1 is due to differential protein expression in recipient and donor cells as a consequence of a homozygous frameshift polymorphism in the donor. Tetramer analysis showed that emergence of LRH-1–specific CD8(+) cytotoxic T cells in peripheral blood and bone marrow correlated with complete remission of chronic myeloid leukemia. Furthermore, the restricted expression of LRH-1 in hematopoietic cells including leukemic CD34(+) progenitor cells provides evidence of a role for LRH-1–specific CD8(+) cytotoxic T cells in selective graft-versus-leukemia reactivity in the absence of severe graft-versus-host disease. These findings illustrate that the P2X5-encoded mHAg LRH-1 could be an attractive target for specific immunotherapy to treat hematological malignancies recurring after allogeneic stem cell transplantation

Allogeneic stem-cell transplantation in patients with Waldenstrom macroglobulinemia: report from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation.

Contains fulltext : 88046schattenberg.pdf (publisher's version ) (Closed access)PURPOSE: Allogeneic stem-cell transplantation (alloSCT) is a curative therapeutic option for patients with low-grade lymphoid malignancies. Information regarding alloSCT in Waldenstrom macroglobulinemia (WM) is limited. This study presents the long-term outcome of a large series of patients with WM treated with alloSCT. PATIENTS AND METHODS: A total of 86 patients received allograft by using either myeloablative (MAC; n = 37) or reduced-intensity conditioning (RIC; n = 49) regimens and were retrospectively studied. The median age was 49 years (range, 23 to 64 years); 47 patients had received three or more previous lines of therapy, and eight patients had experienced failure on a prior autologous stem-cell transplantation. A total of 59 patients (68.6%) had chemotherapy-sensitive disease at the time of alloSCT. Median follow-up of the surviving patients was 50 months (7 to 142 months). RESULTS: Nonrelapse mortality (NRM) at 3 years was 33% for MAC and 23% for RIC. The overall response rate was 75.6%. The relapse rates (RRs) at 3 years were 11% for MAC and 25% for RIC. Fourteen patients received donor lymphocyte infusions (DLIs) for disease relapse. PFS and OS at 5 years were 56% and 62% for MAC and 49% and 64% for RIC, respectively. The occurrence of chronic graft-versus-host disease (cGVHD) was associated with a higher NRM and a lower RR, leading to an improvement in PFS. CONCLUSION: alloSCT can induce durable remissions in a selected population of young and heavily pretreated patients with WM. The low RR, the achievement of additional disease responses after DLIs, and the lower RR in patients developing cGVHD suggest the existence of a clinically relevant graft-versus-WM effect

Allogeneic hematopoietic stem cell transplantation for adult patients with t(4;11)(q21;q23) KMT2A/AFF1 B-cell precursor acute lymphoblastic leukemia in first complete remission: impact of pretransplant measurable residual disease (MRD) status: an analysis from the acute leukemia working party of the EBMT

Adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with t(4;11)(q21;q23);KMT2A/AFF1 is a poor-prognosis entity. This registry-based study was aimed to analyze outcome of patients with t(4;11) BCP-ALL treated with allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (CR1) between 2000 and 2017, focusing on the impact of measurable residual disease (MRD) at the time of transplant. Among 151 patients (median age, 38) allotransplanted from either HLA-matched siblings or unrelated donors, leukemia-free survival (LFS) and overall survival (OS) at 2 years were 51% and 60%, whereas relapse incidence (RI) and non-relapse mortality (NRM) were 30% and 20%, respectively. These results were comparable to a cohort of contemporary patients with diploid normal karyotype (NK) BCP-ALL with equivalent inclusion criteria (n = 567). Among patients with evaluable MRD pre-alloHSCT, a negative status was the strongest beneficial factor influencing LFS (hazard ratio [HR] = 0.2, p < 0.001), OS (HR = 0.14, p < 0.001), RI (HR = 0.23, p = 0.001), and NRM (HR = 0.16, p = 0.002), with a similar outcome to MRD-negative NK BCP-ALL patients. In contrast, among patients with detectable pretransplant MRD, outcome in t(4;11) BCP-ALL was inferior to NK BCP-ALL (LFS: 27% vs. 50%, p = 0.02). These results support indication of alloHSCT in CR1 for t(4;11) BCP-ALL patients, provided a negative MRD status is achieved. Conversely, pre-alloHSCT additional therapy is warranted in MRD-positive patients

High-dose imatinib versus high-dose imatinib in combination with intermediate-dose cytarabine in patients with first chronic phase myeloid leukemia:A randomized phase III trial of the Dutch-Belgian HOVON study group

Despite the revolutionary change in the prognosis of chronic myeloid leukemia (CML) patients with the introduction of imatinib, patients with resistant disease still pose a considerable problem. In this multicenter, randomized phase III trial, we investigate whether the combination of high-dose imatinib and intermediate-dose cytarabine compared to high-dose imatinib alone, improves the rate of major molecular response (MMR) in newly diagnosed CML patients. This study was closed prematurely because of declining inclusion due to the introduction of second generation tyrosine kinase inhibitors and only one third of the initially required patients were accrued. One hundred nine patients aged 18-65 years were randomly assigned to either imatinib 800 mg (n = 55) or to imatinib 800 mg in combination with two successive cycles of cytarabine 200 mg/m2 for 7 days (n = 54). After a median follow-up of 41 months, 67 % of patients were still on protocol treatment. The MMR rate at 12 months was 56 % in the imatinib arm and 48 % in the combination arm (p = 0.39). Progression-free survival was 96 % after 1 year and 89 % after 4 years. Four-year overall survival was 97 %. Adverse events grades 3 and 4 were more common in the combination arm. The addition of intermediate-dose of cytarabine to imatinib did not improve the MMR rate at 12 months. However, the underpowering of the study precludes any definitive conclusions. This trial is registered at www.trialregister.nl (NTR674).</p