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Post-Transplant Cyclophosphamide for Graft vs Host Disease Prophylaxis in Multiple Myeloma Patients Who Underwent Allogeneic Hematopoietic Cell Transplantation: First Comparison by Donor Type: A Study from the Chronic Malignancies Working Party of the EBMT
Sahebi, F., Eikema, D. J., Koster, L., Kroger, N., Meijer, E., van Doesum, J. A., Rovira, M., Koc, Y., Angelucci, E., Blaise, D., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Graft-versus-host disease (GVHD), non-relapse mortality (NRM), and relapse are among major causes of treatment failure in multiple myeloma (MM) patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Use of post-transplant cyclophosphamide (PT-CY) is now a well-established and widely used method for GVHD prophylaxis after HLA haplo-identical HCT. However, the rationale for using PT-CY in the setting of matched donor transplant is less apparent, as the degree of bidirectional alloreactivity is less. OBJECTIVE Evaluate the cumulative incidence of acute and chronic GVHD, engraftment, progression-free survival (PFS), GVHD free/relapse free survival (GRFS) and overall survival (OS), as well as NRM by 2 years, using PT-CY as GVHD prophylaxis among 4 different donor types. STUDY DESIGN We analyzed PT-CY as GVHD prophylaxis in MM patients (n=295) who underwent allo-HCT using matched related (MRD, n=67), matched unrelated (MUD, n=72), mismatched related or unrelated (MMRD/MMUD, one antigen, n=27), and haploidentical (haplo; n=129) donors between 2012-2018. In addition to PT-CY, GVHD prophylaxis included calcineurin inhibitors (n=239, 81%), and mycophenolate in 184/239 (77%). OS and PFS were estimated using the Kaplan-Meier product limit estimation method, and differences in subgroups were assessed by the Log-Rank test. The cumulative incidence of relapse and non-relapse mortality were analysed together in a competing risks framework. Competing risks analyses were also applied to estimate the incidences of acute grade II-IV GVHD and limited and extensive chronic, by day 100 and one and two years, respectively. The competing events were relapse and death. Subgroup differences in cumulative incidences were assessed using Gray's test. Multivariable Cox regression was applied to investigate the simultaneous impact of multiple covariates on outcomes, when a sufficient number of patients and subsequent events were available. RESULTS Cumulative incidence of acute GVHD grade II-IV at +100 d was 30% (95%CI:25-36%), grade III-IV 9% (95%CI:5-12%), and chronic GVHD was 27% (95%CI:21-32%), limited 21% and extensive 6%, without difference among donor types. Median platelet engraftment was delayed in haplo donors (27 versus 21 d, p<0.001). Two-year OS, PFS, GRFS, and NRM were 51% (95%CI:45-58%), 26% (95%CI:20-32%), 24% (95%CI:18-30%) and 19% (95%CI:14-24%), respectively, with no significant difference between different donor types. In multivariable analyses compared to haplo, MRD was associated with significantly improved OS (HR 0.6 [0.38-0.95], p=0.029) and MUD had a significantly higher GRFS (HR 0.63 [0.42-0.97], p=0.034). There was a trend toward improved PFS with use of MUD (HR 0.69 [0.46-1.04, p=0.08]). CONCLUSION PT-CY in MM patients undergoing allo-HCT resulted in low rates of acute and chronic GVHD and led to favorable survival, especially in the matched setting.
2.
Graft-Versus-Host Disease in Multiple Myeloma Patients Treated With Daratumumab After Allogeneic Transplantation
Nikolaenko, L., Chhabra, S., Biran, N., Chowdhury, A., Hari, P. N., Krishnan, A., Richter, J.
Clinical lymphoma, myeloma & leukemia. 2020
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Abstract
INTRODUCTION Allogeneic hematopoietic cell transplantation (allo-HCT) represents an adoptive immunotherapy strategy for eliciting a graft-versus-myeloma, the effect for high-risk or relapsed multiple myeloma (MM). Allo-HCT recipients are at risk for graft-versus-host disease (GVHD) as well as associated increases in morbidity and mortality. Daratumumab, an anti-CD38 human immunoglobulin G1 kappa humanized monoclonal antibody, is used for treatment of MM. Daratumumab also affects CD38(+) nonmyeloma cells, including T cells, which mediate GVHD. The use of daratumumab after allo-HCT has not been well described, and its potential impact on GVHD is unknown. PATIENTS AND METHODS In a multicenter retrospective study, we evaluated incidence of GVHD in 34 patients with relapsed MM treated with daratumumab after allo-HCT. RESULTS Overall response to daratumumab (partial response or better) was 41% (95% confidence interval, 24-59). Five patients (15%) developed acute GVHD after daratumumab therapy; no chronic GVHD events were observed after daratumumab therapy. One of these 5 patients had a history of chronic GVHD and developed a flare of acute GVHD during daratumumab therapy. The remaining 4 patients did not have a history of GVHD before daratumumab. CONCLUSION The incidence of GVHD after daratumumab was low and did not result in increased exacerbation of GVHD in patients with a history of GVHD.
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Haploidentical Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma Using Post-Transplantation Cyclophosphamide Graft-versus-Host Disease Prophylaxis
Castagna, L., Mussetti, A., Devillier, R., Dominietto, A., Marcatti, M., Milone, G., Maura, F., de Philippis, C., Bruno, B., Furst, S., et al
Biology of Blood & Marrow Transplantation. 2017;23(9):1549-1554
Abstract
Allogeneic (allo) hematopoietic cell transplantation (HCT) currently represents the only potentially curative therapy for patients affected by multiple myeloma (MM). Up to 30% of patients in western countries do not have a matched donor. Haploidentical HCT (haplo-HCT) may be an option, but currently, there are little available data regarding this treatment. We analyzed survival outcomes of 30 heavily pretreated MM patients who received haplo-HCT with post-transplantation cyclophosphamide as graft-versus-host-disease (GVHD) prophylaxis. Median neutrophil and platelet engraftments at day +30 were 87% (95% confidence interval [CI], 66% to 95%) and 60% (95% CI, 40% to 75%), respectively. The cumulative incidences of relapse or progression of disease (PD) and nonrelapse mortality at 18 months were 42% (95% CI, 23% to 59%) and 10% (95% CI, 2% to 24%), respectively. The cumulative incidence of grade II to IV acute GVHD at day +100 was 29% (95% CI, 14% to 47%). The cumulative incidence of chronic GVHD at 18 months was 7% (95% CI, 1% to 21%). With a median follow-up in survivors of 25 months (range, 15 to 73 months), the 18-month progression-free survival (PFS) and overall survival (OS) were 33% (95% CI, 17% to 50%) and 63% (95% CI, 44% to 78%), respectively. No differences were observed between peripheral blood and bone marrow graft in terms of engraftment, GVHD, or PD incidence. Chemorefractory disease at transplantation was associated with a lower/reduced 18-month PFS (9% versus 47%, P=.01) and OS (45% versus 74%, P=.03). This was explained by a higher PD incidence (55% versus 33%, P=.05). In this multicenter study, we report encouraging results with haplo-HCT for patients with heavily pretreated MM.