Search

Introduction:Even in the era of novel targeted therapies for the treatment of Chronic Lymphocytic Leukemia (CLL) patients, such as BTK, PI3K and BCL2 inhibitors, allogeneic hematopoietic stem cell transplantations (alloHCT) will remain an important treatment option for a subset of patients with very high risk CLL. The current study focused on the impact of center and procedure-related factors on outcomes after alloHCT, taking into account the impact of patient- and disease-related risk factors. Patients and Methods:Data of 684 CLL patients who received a first alloHCT between 2000 and 2011 were analyzed. Their data were collected as part of the EBMT CLL Data Quality Initiative. Outcomes of interest were Event-Free Survival (EFS) up to 5 years after transplantation and mortality in the first 100 days after alloHCT. Outcomes were analyzed by means of the Kaplan-Meier method and Cox proportional hazards models with a frailty (random effects) component to take into account unexplained center heterogeneity. The following factors describing center characteristics or the transplant procedure were analyzed: experience in alloHCT in general and, for CLL specifically, accreditation by the Joint Accreditation Committee-ISCT & EBMT (JACIE), Gross National Income (GNI)/capita based on purchasing power parity (PPP) (GNI/cap), donor type, donor-patient sex-match, type of conditioning, stem cell source and T-cell depletion (TCD). Results:Five-year EFS of the whole cohort was 37% (95% Confidence Interval, 33%-42%), Day-100 survival was 90% (88%-92%). Experience of the transplant center was measured by the number of all alloHCTs, and alloHCTs for patients with CLL respectively. The median total number of alloHCTs per center per year was 45 (range 0-169) and the median number of CLL alloHCTs was only 2 per center per year (range 0-19). Greater experience with transplantation of patients with CLL (Hazard Ratio (HR) 0.96 per additional transplant, p=0.002), JACIE accreditation (HR 0.7, p=0.045) and a higher GNI/cap (HR 0.4, 95% CI 0.2-0.96, p=0.04) showed a protective impact on 5-year EFS in the Cox model. In vivo TCD with alemtuzumab (HR 1.5 compared to no TCD, p=0.03) and a female donor for a male patient (HR 1.4 compared to a male donor for a male patient, p=0.02) were the only procedure-related factors significantly associated with EFS. Event-Free Survival after in vivo TCD with Anti-Thymocyte-Globulin or after ex vivo TCD was comparable to EFS without TCD (HR 0.9, 0.7-1.3, p=0.6; HR 0.9, 0.5-1.6, p=0.8). Non-myeloablative conditioning did not have a negative impact on 5-year EFS, and exposed patients to a lower risk of non-relapse mortality. Measured and unmeasured center characteristics did not have a significant impact on 100-day mortality. Even when correcting for patient-, procedure- and center-related characteristics, there was still significant variation in center outcome, expressed by center-specific HRs derived from the frailty models, ranging from 0.6 to 1.2. Their impact is illustrated in a model-based plot for EFS (see Figure) which shows outcomes for three reference patients with the same characteristics who would be transplanted in three centers with the same measured characteristics but with the highest, average and lowest HRs in the dataset. These unexplained center effects likely represent a mixture of differences which could apply to the location of the transplant center, unmeasured characteristics of the patient population transplanted at this center, selection criteria which were not reported and factors determining the success of the transplant procedure which might differ between centers. Conclusion: We have confirmed that both center- and procedure-related factors have a significant impact on the EFS of patients with CLL undergoing alloHCT. Our results may help to interpret outcomes of single or multicenter studies better. Since non-myeloablative conditioning did not have a negative impact on EFS and exposed patients to a lower risk of non-relapse mortality, this approach should be favored for future alloHCT for CLL. Probability of Event-Free Survival up to Five Years Post-HCT for three Reference Patients Contribution: J.S. designed the research and wrote the paper. L.C.d.W conducted the statistical analysis and produced the figure. Figure Figure. Disclosures Schetelig: Sanofi: Honoraria. Gramatzki:Janssen: Other: Travel/Accommodation/Expenses, Research Funding. Dreger:Gilead: Consultancy; Gilead: Speakers Bureau; Janssen: Consultancy; Novartis: Speakers Bureau; Novartis: Consultancy; Roche: Consultancy.

Background. The combination of melphalan and dexamethasone (MDex) is considered standard treatment for patients with AL amyloidosis who are not eligible for autologous stem cell transplant at most referral centers. When full-dose (40 mg) dexamethasone can be combined with melphalan, hematologic response is achieved in three fourths of patients, with complete remissions (CRs) in 30% of cases and prolonged survival (median >7 years). Several studies showed that bortezomib is highly effective in AL amyloidosis with response rates as high as 80-90%, with 50-60% CRs, when used in combinations with alkylating agents and dexamethasone, suggesting that these regimens could replace current standard of care in AL amyloidosis. A recent case-control study indicated that the addition of bortezomib to MDex (BMDex) does not overcome the poor prognosis of patients with advanced cardiac involvement. Here we report the first interim analysis of a multicenter randomized phase III trial comparing MDex and MDex with the addition of bortezomib (BMDex) in newly-diagnosed AL amyloidosis ongoing in Europe and Australia (EMN-03 study, NCT01277016). Patients and Methods. Main eligibility criteria included measurable disease (M-protein >10 g/L or dFLC >50 mg/L), estimated glomerular filtration rate (eGFR) ³30 mL/min, and adequate liver function. Previously treated patients, those who had >30% bone marrow plasma cell or lytic bone lesions, NYHA class >II heart failure, grade 3 sensory or grade 1 painful peripheral neuropathy, or ECOG performance status >2 were excluded. In January 2013 the protocol was amended to include Mayo stage III patients, provided their NT-proBNP was Results. Heart and renal involvement were present in 26 (74%) and 22 (63%) patients in the MDex arm, and in 25 (71%) and 24 (69%) in the BMDex arm, respectively. Five patients in each arm were stage III. In the MDex arm 15 patients (43%) experienced grade 3-4 adverse events [cytopenia (6), fluid retention (4), fatigue (2), need for a coronary stent (1), diarrhea (1), and renal failure (1)]. In the BMDex arm grade 3-4 adverse events were reported in 21 patients (63%, P=0.151 compared to MDex): cytopenia (12, febrile in 1 case), fluid retention (3), insomnia (2), transient troponin increase (1), peripheral neuropathy (1), renal failure (1), and injection site reaction (1). Three patients died in the first three months, 1 was treated with MDex and 2 with BMDex. Response was evaluated by intent to treat. Fifty-one patients, 26 treated with MDex and 25 who received BMDex, completed cycle 3 or died before completion and are evaluable for response. Overall, 15 patients (58%) responded in the MDex arm, and 19 (76%) in the BMDex arm (P=0.166). After cycle 3, nine patients (35%) in the MDex group and 16 (65%) in the BMDex group achieved at least very good partial response (P=0.036). Renal response was achieved in 2 of 8 evaluable patients in the MDex group and in 2 out of 10 subjects in the BMDex arm. Cardiac response was reached in 4 of 15 evaluable patients in the MDex arm and in 2 out of 12 in the BMDex arm. After a median follow-up of 14 months, 9 patients (13%) died, 4 in the MDex arm and 5 in the BMDex arm (Figure 1). Conclusion. This is the first prospective randomized trial of novel agents in AL amyloidosis. The present interim analysis indicates that the addition of bortezomib to MDex grants more profound hematologic responses that should be balanced with relative increase in toxicity. Longer follow-up is required to demonstrate a benefit in terms of organ improvement and of overall survival. Updated data will be presented at the meeting. We would like to acknowledge the European Myeloma Network and the Leukaemia Foundation of Australia for their ongoing support, and Janssen-Cilag for partially funding the trial and providing the study drug. Figure 1 Patients’ survival Figure 1. Patients’ survival Disclosures Leleu: Janssen, Celgene, leopharma, Takeda, Amgen, Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zamagni:Janssen and Celgene: Honoraria. Cibeira:Janssen and Celgene: Honoraria. Schönland:Janssen: Honoraria. Moreau:Millenium and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hajek:Merck and Celgene: Consultancy, Honoraria; Janssen: Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Celgene and Orthobiotech: Honoraria. Sonneveld:Celgene, Janssen, Onyx, Millennium: Research Funding; Celgene, Janssen, Onyx, Millennium: Membership on an entity's Board of Directors or advisory committees. Merlini:Millennium Takeda: Honoraria. Off Label Use: Bortezomib in AL amyloidosis.

Acute graft-versus-host disease (aGvHD) remains a major threat to successful outcome following allogeneic hematopoietic cell transplantation though advances in prophylaxis and supportive care have been made. The aim of this study is to test whether the incidence and mortality of aGvHD have decreased over time. 102,557 patients with a median age of 47.6 years and with malignancies after first allogeneic sibling or unrelated donor (URD) transplant were studied in the following periods: 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2011-2015. Findings: 100-day incidences of aGvHD grades II-IV decreased from 40% to 38%, 32%, 29% and 28%, respectively, over calendar time (P