scholarly journals Allogeneic Hematopoietic Cell Transplantation in Patients ≤ 60 Years with Intermediate-Risk Acute Myeloid Leukemia in First Remission - Results of the Randomized Etal-1 Trial-

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 173-173
Author(s):  
Martin Bornhaeuser ◽  
Christoph Schliemann ◽  
Johannes Schetelig ◽  
Christoph Rollig ◽  
Michael Kramer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Allogeneic Hct ◽  
Unrelated Donors ◽  
First Remission ◽  
Related Mortality

Abstract Allogeneic hematopoietic cell transplantation (HCT) offers the highest chance for cure in patients with adverse-risk acute myeloid leukemia (AML) when performed in first remission (CR1). In contrast, patients in CR1 with favorable risk do not seem to benefit from allogeneic HCT due to the inherent risk of transplant-related mortality. Donor vs. no donor comparisons as well as prospective matched-pair analyses have suggested that allogeneic HCT performed in intermediate-risk AML may provide a higher probability of overall survival or relapse-free survival in patients ≤ 60 years of age with an acceptable risk for transplant-related mortality. On the other hand, many intermediate-risk patients relapsing after conventional chemotherapy may be successfully salvaged by allogeneic HCT. The role of allogeneic HCT in cytogenetically defined intermediate-risk AML patients in CR1 was addressed by a prospective randomized trial performed in 16 centers in Germany. Key inclusion criteria were: AML with intermediate-risk cytogenetics, first CR or CRi after conventional induction therapy, age of 18-60 years, and availability of an HLA-matched sibling or unrelated donor. For unrelated donors, a 9 out of 10 HLA allelic match was acceptable except for patients with an NPM1 mutation, for whom full 10/10 allele matching was required. Randomization was stratified according to age (< 40 vs. 40-60), NPM1/FLT3, and CEBP-alpha mutational status and unrelated vs. related donor availability. Endpoints included overall-survival as primary outcome and relapse-free survival (RFS), cumulative incidence of relapse, treatment-related mortality, and quality of life measured according to the short form (36) health status. From 2010 - 2018, 143 patients in CR1 were randomized into Arm A (n=76, allogeneic HCT) and Arm B (n=67, conventional consolidation and allo-HCT only in case of relapse). In July 2018, the trial was stopped prematurely due to slow accrual (143 out of 356 pts. randomized). Median age of the trial cohort was 51 years (range, 19-60), with 42% exhibiting an NPM1 and 25% a FLT3 mutation. A normal karyotype was reported in 84% of the included patients. All mentioned characteristics did not differ between both treatment arms. Sibling donors were available for 44 (31% of patients), matched unrelated donors for 99 (69%) patients. According to the intent-to-treat analysis, the probability of survival at 2 years was 71% (95% CI 60-81%) and 84% (95% CI 73-92%) in Arm A (Transplant) and Arm B (conventional consolidation), respectively (p=0.120, Figure 1A). RFS after allogeneic HCT was 69% (95% CI 57-80%) compared to 41% (95% CI 29-54%) after conventional consolidation (p=0.001, Figure 1B). Primary allogeneic HCT reduced the cumulative incidence of relapse at 2 years from 57% [95%-CI 46-71%] after conventional consolidation to 20% [95%-CI 13-31%] after HCT (p<0.001). Non-relapse mortality at 2 years after primary allogeneic HCT was 9% [95%-CI 5-19%] compared to 2% [95%-CI 0-11%] after consolidation (p=0.017).Most importantly, all 38 patients relapsing in arm B (33 hematologic, 4 molecular and 1 extramedullary) proceeded to allogeneic HCT as salvage therapy. Multivariable Cox regression analysis revealed a status of CRi compared to CR before randomization to be associated with a significantly higher risk of death (HR 3.3, p=0.009). SF (36) scoring suggested a trend towards a lower physical functioning throughout the first 3 months after randomization in the primary HCT arm. No significant differences in vitality, mental health, social and emotional functioning could be documented between both treatment arms. In summary, the results of this first prospective randomized trial did not show that allogeneic HCT performed immediately after achievement of CR1 in patients with cytogenetically defined intermediate-risk AML ≤ 60 years of age conveys an overall survival advantage. However, allogeneic HCT in CR1 significantly reduced the relapse risk and was not associated with relevant impairments in quality of life. Although the limited statistical power of the trial does not allow definitive conclusions, delayed allogeneic transplantation seems to be a potential treatment algorithm in CR1 intermediate-risk AML with an available donor. Figure 1 Figure 1. Disclosures Schliemann: Jazz Pharmaceuticals: Consultancy, Research Funding; Roche: Consultancy; Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; Novartis: Consultancy; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; BMS: Consultancy, Other: travel grants. Schetelig: Roche: Honoraria, Other: lecture fees; Novartis: Honoraria, Other: lecture fees; BMS: Honoraria, Other: lecture fees; Abbvie: Honoraria, Other: lecture fees; AstraZeneca: Honoraria, Other: lecture fees; Gilead: Honoraria, Other: lecture fees; Janssen: Honoraria, Other: lecture fees . Glass: Riemser: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; BMS: Consultancy; Novartis: Consultancy; Helios Klinik Berlin-Buch: Current Employment. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Geron: Honoraria; AbbVie: Honoraria. Burchert: Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Pfizer: Honoraria; Incyte: Honoraria; Gilead: Honoraria; BMS: Honoraria. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Mueller: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; CTI: Membership on an entity's Board of Directors or advisory committees; Gentium: Other: Travel Support; Gilead: Other: Travel Support; Janssen: Other: Travel Support; Novartis: Other: Travel Support; Pfizer: Other: Travel Support; Sanofi: Other: Travel Support. Berdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stelljes: Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

Updated Outcomes of Fludarabine/Melphalan/Bortezomib (Flu/Mel/Vel) Conditioning for Upfront Allogeneic Hematopoietic Cell Transplantation in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5885-5885
Author(s):  
Taiga Nishihori ◽  
Claudio Anasetti ◽  
Rachid Baz ◽  
Jose L Ochoa-Bayona ◽  
Kenneth H. Shain ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Advisory Committees ◽  
Allogeneic Hct ◽  
Genetics Research ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors

Abstract Background: Multiple myeloma remains incurable despite impressive array of available novel agents and therapeutic strategies. Allogeneic hematopoietic cell transplantation (HCT) remains the only potentially curative option for patients with multiple myeloma but it is limited by its toxicities. We previously reported initial result of a phase 2 study of upfront allogeneic HCT in myeloma patients achieving at least very good partial response (VGPR) after initial therapy (Nishihori, et al. ASH 2013 abstract 3390) and here we report more mature results after a median follow up of 3 years. Methods: Twenty seven myeloma patients received allogeneic HCT between 01/2010 and 02/2015 at Moffitt Cancer Center (NCT 00948922). Eligible patients were age ≤ 60, achieving first ≥ VGPR or complete response (CR), and have 8/8 HLA-matched related or unrelated donors. Conditioning regimen consisted of fludarabine 30 mg/m2 for 4 days (days -6, -5, -4, and -3) and melphalan 70 mg/m2 for 2 days (days -4 and -3) followed by a single dose of bortezomib 1.3 mg/m2 on day -3 (Flu/Mel/Vel regimen). GVHD prophylaxis was initially left to the discretion of physicians but later modified to only tacrolimus/methotrexate. No maintenance therapy was prescribed after allogeneic HCT. Results: The median age at transplant was 50 (range, 25-58) years. Disease status at the time of allogeneic HCT was VGPR (n=17: 63%) and CR/stringent CR (n=10: 37%). All patients received unmanipulated peripheral blood stem cell grafts from HLA-matched related donors (n=14) or HLA-matched unrelated donors (n=13). Graft-versus-host disease (GVHD) prophylaxis was tacrolimus plus either methotrexate (n=19: 70%), or mycophenolate mofetil (n=4), or sirolimus (n=4). All patients achieved neutrophil engraftment with a median of 15 (range, 11-19) days. Platelet engraftment was achieved with a median of 17 (range, 13 - 35) days and 2 patients did not recover platelets. The cumulative incidences of grades II-IV and grades III-IV acute GVHD at day 100 were 63.6% (95% confidence interval (CI): 43.1-81.1) and 19.6% (95%CI: 5.4-39.9), respectively. The cumulative incidence of moderate to severe chronic GVHD was 56.4% (95%CI: 36.3-75.5) at 1-year. The cumulative incidences of transplant-related mortality at day 100, 1 year and 2 years were 7.4% (95%CI: 0.8-20.0), 11.1% (95%CI: 2.7-25.4), and 11.1% (95%CI: 2.7-25.4), respectively. Progression-free survival estimates at 1, 2, and 3 years were 74.1% (95%CI: 53.2-86.7), 65.1% (95%CI: 43.3-80.2), and 65.1% (95%CI: 49.9-87.5), respectively. With a median follow up of 39 months for surviving patients, overall survival estimates at 1, 2 and 3 years were 85% (95%CI: 64.9-94.1), 75.4% (95%CI: 52.6-88.3), and 69.1% (95%CI: 53.8-93.5), respectively. Conclusions: The results of the this phase 2 trial of upfront allogeneic HCT with fludarabine/melphalan/bortezomib (Flu/Mel/Vel) conditioning are promising and provide the rationale for reasonable potentially curative option to younger and fit patients who are eligible for upfront intensive consolidation strategy. This approach may be potentially valuable for those with high-risk myeloma and a multicenter study is currently being conducted (BMT CTN protocol 1302:NCT02440464). Disclosures Nishihori: Novartis: Research Funding; Signal Genetics: Research Funding. Baz:Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Bristol-Myers Squibb: Research Funding; Signal Genetics: Research Funding. Shain:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen/Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Signal Genetics: Research Funding; Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Alsina:Signal Genetics: Consultancy; Novartis: Research Funding; Takeda/Millennium: Research Funding; Amgen/Onyx: Consultancy, Speakers Bureau.

scholarly journals Outcome of Autologous Stem Cell Transplantation in Waldenström's Macroglobulinemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2149-2149
Author(s):  
Romil Patel ◽  
Neeraj Y Saini ◽  
Ankur Varma ◽  
Omar Hasan ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Advisory Committees ◽  
First Remission ◽  
Relapsed Disease

Abstract Introduction: The role of autologous hematopoietic stem cell transplantation (auto-HCT) in the management of patients with Waldenström Macroglobulinemia (WM), a rare, indolent lymphoma, has not been established. We had previously published our experience with auto-HCT in a small cohort of WM patients1. Here, we present an updated analysis of auto-HCT with a larger cohort of WM patients. Methods and study population: The study cohort was comprised of 29 patients who underwent high-dose chemotherapy and auto-HCT at MD Anderson Cancer Center (MDACC). The Kaplan-Meier method was used to create survival curves. Overall survival (OS) was defined as the duration from date of transplant to death or last date of follow-up in living patients. Progression-free survival (PFS) was defined as the duration from date of transplant to either progressive disease or death, whichever occurred first. Results: Median age at auto-HCT was 60 (range, 43-75 years). Eight patients (28%) had concurrent light chain amyloidosis (AL). Of the five patients who had MYD88 testing completed, 3 were positive for the MYD88 mutation. Additionally, of these 3 patients, 2 were also positive for CXCR4 mutation. Patients received a median of 2 lines (range 1-6) of therapy prior to auto-HCT; 3(10%) patients had primary refractory disease, 8(28%) were in first remission, and 18 (62%) had relapsed disease. Median time from transplant to last follow-up for the surviving patients was 5.3 years. Preparative regimens received by the patients were: Melphalan (n=20), BEAM-R (n=2), Busulfan/Melphalan (n=1), Cyclophosphomaide/Etoposide/total body irradiation (n=1), Thiotepa/Busulfan/Cyclophosphamide (n=1), and Carmustine/Thiotepa (n=1). Three patients further went on to receive allogeneic transplant either after relapse from auto-HCT or due to disease transformation to aggressive lymphoma. Twenty-eight patients achieved engraftment with a median time to neutrophil engraftment of 11 days (range, 10-15 days). One patient suffered primary graft failure due to progression of disease and died 84 days after transplant. Non-relapse mortality was 3.4% at 1 year. All patients were eligible for response evaluation. The median OS from diagnosis was 12.2 years. Overall response rate was 96%: complete response (n=8, 27.6%), very good partial response (n=5, 17.3%), partial response (n=15, 51.7%), and progressive disease (n=1, 3.4%). PFS and OS at 5 years were 43.3% and 62.9%, respectively. Median PFS and OS from auto-HCT were 4.1 and 7.3 years (Fig. 1A). The median OS from auto-HCT in first remission + primary refractory and relapsed disease was 8.2 years and 4.1 years, respectively.16 patients were alive at the time of censoring while 13 patients had died. Causes of death include relapsed disease (n=6), secondary malignancy (n=2), infection (n=1), chronic graft-versus-host disease (n=1), and unknown (n=3). 8 patients (28%) were positive for concurrent AL amyloidosis. The sites of amyloid involvement were kidneys (n=2), lungs (n=1), bone marrow (n=1), heart(n=1), lymph nodes(n=1), gastrointestinal tract (n=1) and subcutaneous fat aspirate(n=5). The median overall survival for patients with amyloid involvement (n=8) was 12 years. On univariate analyses, the number of chemotherapy regimens prior to transplant (≤ 2 vs >2 lines) was the strongest predictor of overall survival (p=0.03, HR 0.3, CI: 0.09-0.9, log-rank) and PFS (p=0.001, HR 0.24, CI: 0.07-0.85, log-rank). The median PFS in patients with ≤ 2 lines and > 2 lines of therapy was 71 months versus 19 months, respectively (Fig. 1B). Conclusion: Auto-HCT is safe and feasible in selected patients with WM, with a high response rate and durable remission even in patients with relapsed or refractory disease. References: Krina Patel et.al. Autologous Stem Cell Transplantation in Waldenstrom's Macroglobulinemia. Blood 2012 120:4533; Disclosures Thomas: Celgene: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Array Pharma: Research Funding; Amgen Inc: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Takeda: Consultancy; Celgene: Consultancy; Spectrum Pharma: Research Funding; Janssen: Consultancy; Kite Pharma: Consultancy; Sanofi-Aventis: Consultancy; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

Long-Term Survival and Absence of Late Relapses in Patients Who Underwent Allogeneic Stem Cell Transplantation for Advanced Cutaneous T-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5843-5843
Author(s):  
Lori A Leslie ◽  
Lori A. Leslie ◽  
Tatyana A Feldman ◽  
Alan P Skarbnik ◽  
David H. Vesole ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Cell Lymphoma ◽  
Advisory Committees ◽  
Unrelated Donors ◽  
Related Mortality

Abstract Introduction Primary cutaneous T-cell lymphomas (CTCL) are rare subtypes of extranodal non-Hodgkin lymphoma for which no conventional curative therapies are available. Patients (pts) with early-stage, limited disease typically experience an indolent course. Pts with advanced or progressive disease are more likely to experience an aggressive course characterized by short-lived responses to therapy, debilitating symptoms that significantly impact quality of life,and limited overall survival. Prior retrospective studies have shown allogeneic stem cell transplantation (alloSCT) may lead to durable remissions in pts with advanced CTCL, the largest of which included 47 pts and reported an overall survival (OS) of 51% and progression-free survival (PFS) of 26% at 4-years (Hosing et al. Ann Oncol 2015). We performed a retrospective analysis of pts who underwent alloSCT for advanced CTCL at our institution. Methods We performed a retrospective case analysis of 11 pts with CTCL who underwent alloSCT between 1/1/2008 and 3/1/2016. OS and PFS were estimated using Kaplan-Meier analysis. Other endpoints included transplant-related mortality and morbidity as well as CTCL-related mortality. Results Eleven pts were identified including 5 with mycosis fungoides/Sezary syndrome (MF/SS), 2 with CD4+ CTCL not otherwise specified (NOS), and 1 each with CD8+ CTCL-NOS, ALK-negative cutaneous anaplastic large cell lymphoma (cALCL), sub panniculitis-type T-cell lymphoma, and cutaneous smoldering HTLV-1 associated adult T-cell leukemia/lymphoma (ATLL). The median age at diagnosis was 45.4 yr, median time to alloSCT was 2.4 yr. The median follow-up post-alloSCT was 39.2 mo. Prior to alloSCT, pts received a median of 5 lines of therapy (range 2-11). Total skin electron beam radiation (TSEB) was part of the immediate pre-alloSCT regimen for 6 pts (55%), all of whom had persistent disease. Four pts (67%) converted to CR pre-alloSCT with the addition of TSEB. Nine pts (82%) received reduced-intensity and 2 pts (18%) received myeloablative conditioning. Ten pts received peripheral blood stem cells (PBSC) and 1 received bone marrow: 4 pts (36%) received stem cells from HLA-matched unrelated donors, 2 (18%) from mismatched unrelated donors, 4 (36%) from matched sibling donors, and 1 (9%) from a haploidentical sibling. Nine pts (82%) received tacrolimus/mini methotrexate and 2 pts (18%) received tacrolimus/mycophenolate mofetil for graft-versus-host disease (GvHD) prophylaxis. The pt who received haploidentical stem cells also received post-alloSCT cyclophosphamide. At the time of transplantation, disease status included: complete response (CR) in 8/11 pts (73%), partial response (PR) in 2/11 pts (18%), and progressive disease (PD) in 1/11 pts (9%). At day 100, 9/11 pts (82%) were in CR, 1 pt had PD, and 1 pt with CD8+ CTCL-NOS had died on day 26 of PD. Two of the 9 pts (22%) in CR on day 100 relapsed soon thereafter, one on day 105 and one on day 113. Both achieved CR, 1 with withdrawal of immunosuppression, 1 with salvage brentuximab vedotin, bexarotene and donor lymphocyte infusions (DLI). There were no late relapses. Median OS at 36 mo was 72% (Figure 1): 1 pt died of PD on day 26, 2 pts died of non-alloSCT/non-CTCL adverse events (cerebrovascular accident (CVA), suicide). Median PFS at 36 mo was 64% (Figure 2). Fifty percent (2/4) of pts who relapsed/progressed were in CR at time of alloSCT, 86% (6/7) of pts who did not relapse were in CR at time of alloSCT. The incidence of acute cutaneous GvHD was 100%: 30% grade 1, 70% grade 2-3. The incidence of chronic cutaneous GvHD was 50%: 2 pts (20%) have ongoing severe GvHD, 1 pt with severe DLI-induced GvHD died due to CVA, 2 pts (20%) have completed therapy with no further manifestations of chronic GvHD. There were no other significant long-term toxicities of alloSCT identified. Disease-related mortality was 9% (1/11). Transplant-related mortality was 0%. Conclusion AlloSCT is well-tolerated and may result in long-term remissions for pts with various, heavily pretreated subtypes of CTCL. In our experience relapses were uncommon, occurred early, and durable CR could again be achieved with immunomodulatory approaches. Depth of response pre-alloSCT correlated with long term PFS and OS. It is likely that TSEB may be omitted safely in pts in CR, but should be administered immediately pre-alloSCT to deepen responses in patients with persistent disease. Disclosures Leslie: Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Feldman:Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Abbvie/Pharmacyclics/Janssen: Speakers Bureau. Vesole:Novartis: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Goy:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Efficacy of Venetoclax Combination Therapy with Hypomethylating Agents in Patients with Relapsed Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5089-5089 ◽  
Author(s):  
Varun Mittal ◽  
Mimi Lo ◽  
Lloyd E. Damon ◽  
Karin L. Gaensler ◽  
Thomas G. Martin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Hypomethylating Agents ◽  
Advisory Committees ◽  
Allogeneic Hct ◽  
Acute Myeloid

Introduction: Venetoclax (VEN), a selective BCL-2 inhibitor, in combination with hypomethylating agents (HMA) has high efficacy in treatment-naïve elderly patients with acute myeloid leukemia (AML). The role for VEN in patients with relapsed/refractory (R/R) AML, myelodysplastic syndrome (MDS), or other myeloproliferative neoplasms remains incompletely defined. In particular, the efficacy of VEN+HMA has not been studied systematically in patients who experience AML relapse following allogeneic hematopoietic cell transplantation (HCT). Method: All patients treated with VEN+HMA (azacitidine or decitabine) for R/R de novo or secondary AML or progressive MDS following allogeneic HCT were identified and reviewed retrospectively. All included AML patients had overt clinical relapse with ≥ 5% bone marrow blasts or extramedullary disease biopsy proven to be AML. Patients were included in this analysis if they received at least 14 days of VEN therapy. Results: Eleven patients with median age 66 (range 25-75) were treated for R/R AML post-allogeneic HCT. Transplant characteristics included use of reduced intensity conditioning in 10/11 (91%), matched sibling donors in 5/11 (45%), matched unrelated donors in 5/11 (45%), and cord blood in 1/11 patients. The median time from HCT to relapse/disease progression was 7 months (range 3-36). Two patients had extramedullary relapse only, and the remainder had marrow involvement. Eight patients (73%) received azacitidine and 3 (27%) received decitabine in combination with VEN. All but two patients (82%) had prior HMA exposure and most received VEN+HMA as initial post-transplant salvage therapy (64%). Only one patient received donor lymphocyte infusion in conjunction with VEN+HMA therapy, and none proceeded to a second allotransplant. Nine patients (82%) experienced an objective response, which included 4 CR/CRi (36%) and 5 PR/SD (45%). In patients with CR/CRi, three patients had adverse risk cytogenetics and one had a favorable risk profile at diagnosis consisting of normal cytogenetics with an isolated NPM1 mutation. All patients who failed to remit with VEN+HMA had intermediate- or high-risk genetic features. The median number of treatment cycles given was 3 (range 1-20). Median survival was 11 months and estimated 6-month and 12-month survival was 82% and 36%, respectively. Three patients remain alive with median 16.5 months follow-up (range 2.5-32). Conclusion: Venetoclax in combination with HMA is a viable salvage option in patients with relapsed AML or progressive MDS after allogeneic HCT, including those with prior exposure to HMA. Although one patient in this cohort sustained long term complete remission, overall prognosis remains dismal in this high-risk patient population and improved treatment options for relapsed/refractory AML following alloHCT remain needed. Disclosures Damon: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Martin:Amgen, Sanofi, Seattle Genetics: Research Funding; Roche and Juno: Consultancy. Olin:MedImmune: Research Funding; Ignyta: Research Funding; Clovis: Research Funding; AstraZeneca: Research Funding; Revolution Medicine: Consultancy; Daiichi Sankyo: Research Funding; Astellas: Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria; Novartis: Research Funding; Mirati Therapeutics: Research Funding; Spectrum: Research Funding. Smith:Astellas Pharma: Research Funding; Abbvie: Research Funding; fujiFilm: Research Funding; Revolution Medicines: Research Funding. Logan:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pharmacyclics: Research Funding; Astellas: Research Funding; Jazz: Research Funding; Kite: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; TeneoBio: Consultancy; Kiadis: Consultancy; Kadmon: Research Funding; Abbvie: Consultancy.

scholarly journals Risk-Adapted Intensive Chemotherapy for Primary ACUTE Myeloid Leukemia during the Last 25 YEARS: Increase in Complete Remission RATE, Hematopoietic Cell Transplantation Access and Decrease in Relapse Incidence Have LED to Improved Survival

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-14
Author(s):  
Ana Garrido ◽  
Montserrat Hoyos ◽  
Marina Diaz-Beyá ◽  
Montserrat Arnan ◽  
Susana Vives ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
High Dose ◽  
Prognostic Impact ◽  
Intensive Chemotherapy ◽  
Advisory Committees ◽  
Allogeneic Hct

BACKGROUND: The progress in the understanding of pathophysiology of AML has allowed the identification of genetic and immune abnormalities with prognostic impact on outcome and suitable as therapeutic targets. The genetic abnormalities are essential for risk allocation and risk-adapted treatment included the indication of hematopoietic cell transplantation. In the last decade, several studies have shown that persistence of measurable residual disease (MRD) after chemotherapy increases relapse incidence and the probability of leukemia recurrence and survival. Therefore, MRD has been progressively incorporated in prognosis estimation. In the last 25 years the CETLAM cooperative group has promoted 4 consecutive trials for AML patients fit for intensive chemotherapy and eventually HCT. Post-remission treatment was based on genetics of the disease and more recently on MRD. The aim of this study has been to investigate if the survival of patients has improved and, if so, to identify the factors that have influenced on the better outcome. METHODS: We included all patients with primary AML up to the age of 60 years enrolled in 4 consecutive Spanish CETLAM group trials. In brief, induction chemotherapy included idarubicin, cytarabine and etoposide in AML-94, AML-99 and AML-03 protocols and without etoposide in the AML-12. G-CSF priming was allowed in the two more recent trials. Post remission therapy included 1 to 3 consolidations including intermediate or high dose cytarabine. Hematopoietic transplantation indication was based on availability of an HLA-compatible donor, genetic findings and more recently MRD. Follow-up was extended to June 2020. The survival and relapse incidence analyses were censored at 5 years. Informed consent was obtained in all cases and the institutional review boards approved the protocols. RESULTS: Between 1994 and 2019, 1755 primary AML patients between 18 and 60 years-old fulfilled the inclusion criteria. The main characteristics of patients appear in table 1. Median age of the whole group was 46 years old. Overall survival (OS) in the whole group was 45% at 5 years, being significantly better in AML-03 and AML-12 than in AML-94 and AML-99 (image 1). Event free survival (EFS) in the whole group was 37% at 5 years, with also significant differences between trials. Also, the cumulative incidence of relapse (CIR) was 39% in the whole group with less relapses in the two more recent trials (image 2). To understand these findings, we analyzed first the CR rate over time that was higher in the AML-03 and AML-12 protocols (table 2). The results were different depending on genetics of AML with highest CR rate in patients with CBF AML and in those with intermediate-risk cytogenetics and favorable molecular findings; in contrast, patients with adverse cytogenetics had the lowest CR rate mainly because frequent refractoriness to therapy. According to outcomes in each MRC cytogenetic group 5y-OS was: 69±3% (63-76) in favorable group, 46±2% (43-49) in intermediate and 21±3% (16-27) in adverse group (p<0.001). 5y-EFS was 57±3% (51-64), 38±1% (35-41) and 15±2% (11-20) (p<0.001), and 5y-CIR was 30±3% (24-37), 39±2% (36-43) and 51±4% (43-59) (p<0.001), respectively (table 3). Referent to feasibility of allogeneic HCT, there was an increased access to the procedure over the years. A higher proportion of patients allografted in AML-03 and AML-12, 32% and 41% of patients in CR, respectively, compared to 16% in AML-94 and 19% in AML-99. A shortening of the interval between CR and transplantation has been observed in recent years; 3.9 months (mo) in AML-94, 2.7 mo in AML-99, 2.9 mo in AML-03 and 2.2 mo in AML-12. CONCLUSIONS: In adults with primary AML and age up to 60 years-old have improved over the last 25 years. During this period, the CETLAM group has refined the biological characterization of AML patients and tailored the post-remission therapy based on genetic markers with prognostic impact. The increased feasibility of allogeneic HCT may also justify the better results in more recent trials. Even though, there is substantial room for improvement, particularly in patients with AML and adverse genetic features. Disclosures Salamero: Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria; Daichii Sankyo: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Moraleda:Takeda: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Novartis: Consultancy, Other: Travel Expenses; Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding. Tormo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; MSD: Honoraria; Daiichi Sankyo: Honoraria; Servier: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Ribera:Pfizer, Amgen: Research Funding; Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau. Sureda Balari:Roche: Honoraria; Incyte: Consultancy; Janssen: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Speakers Bureau; Celgene: Consultancy, Honoraria. Sierra:Jazz Pharmaceuticals: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals An IDO1-Related 3-Gene Signature Predicts Overall Survival in Intermediate-Risk Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5193-5193
Author(s):  
Simone Ragaini ◽  
Sarah Wagner ◽  
Giovanni Marconi ◽  
Sarah Parisi ◽  
Chiara Sartor ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Mrna Expression ◽  
Board Of Directors ◽  
Research Funding ◽  
Gene Signature ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Expression Score ◽  
Gene Expression Score

Introduction: ELN intermediate-risk AML poses considerable challenges to clinicians both in terms of accurate prognostication and optimal treatment. Indoleamine 2,3-dioxygenase 1 (IDO1) plays a central role as a mediator of immune tolerance in AML through the increase of Treg cells. IDO1 activity is negatively regulated by the BIN1 proto-oncogene. Herein, we analyzed the correlation between BIN1 and IDO1 expression in AML, also focusing on IDO1-interacting genes, with the aim to identify a predictive gene signature for OS. Methods: Biological and clinical data of 732 patients with de novo AML were retrieved from public TCGA and HOVON datasets. Since details on chemotherapy regimens were not available in the HOVON dataset, we decided to exclude patients >= 65 years from survival analyses. IDO1-interacting genes were selected through a co-expression analysis performed on TCGA RNA-sequencing data accessed through cBioPortal. The best genes combination predicting overall survival was plotted in a gene expression score. Patients were split in three different groups using score quartiles as cut-off. Results: In the HOVON dataset, IDO1 and BIN1 mRNA expression were negatively correlated (r = -0.40, P<0.0001). Our analysis of TCGA data identified PLXNC1 as an IDO1-interacting gene and a predictor of patient survival (median split of mRNA expression, P<0.001, survival analysis performed on the BloodSpot online portal). The correlation between PLXNC1 and IDO1 was validated in the HOVON dataset (r=-0.24, P<0.0001). PLXNC1 expression was combined with IDO1 and BIN1 expression to obtain the gene expression score. The 3-gene score predicted survival in ELN intermediate-risk patients who did not receive allogeneic HSCT both in the HOVON dataset (P<0.0001) and the TCGA dataset (P<0.05). In particular, the highest score values predicted the shortest OS. Conclusions: Our study shows a negative correlation between IDO1 and BIN1 in AML, suggesting IDO1 inhibition by BIN1, and identifies for the first time PLXNC1, a receptor for semaphorines, as an IDO1-interacting gene potentially implicated in immune response regulation. This finding corroborates the role of IDO1 and its interacting genes in the promotion of a tolerogenic microenvironment in AML. Lastly, our gene expression score predicted OS in intermediate-risk AML patients not undergoing HSCT, a finding which has clinical implications for accurate patient stratification and for clinical decision making, i.e., bridging these patients to transplant. Figure Disclosures Papayannidis: Pfizer: Honoraria; Amgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Shire: Honoraria; Teva: Honoraria. Cavo:celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rutella:MacroGenics, Inc.: Research Funding; NanoString Technologies, Inc.: Research Funding; Kura Oncology: Research Funding.

scholarly journals Survival and Time to Response with Frontline Hypomethylating Agents in AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4035-4035
Author(s):  
Jing Ai ◽  
Danielle Boselli ◽  
Lauren M. Bohannon ◽  
Thomas G. Knight ◽  
Brittany Ragon ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Rank Test ◽  
Hypomethylating Agents ◽  
Advisory Committees ◽  
Curative Intent ◽  
Npm1 Mutation ◽  
Platelet Recovery

Abstract Background: The hypomethylating agents (HMAs) azacitidine and decitabine have been increasingly used in the frontline setting for elderly and/or unfit patients with acute myeloid leukemia (AML). While these therapies are oftentimes used in the palliative setting, HMAs have also been used with curative intent in some patients, as a bridge to allogeneic hematopoietic cell transplantation (HCT). It is well known that 4-6 cycles of HMA therapy can be necessary to achieve a response; however, it is still common in practice for treating physicians to stop HMAs earlier when a rapid response is not observed. Few studies have investigated time to response in the setting of frontline HMA treatment for AML. Methods: We retrospectively evaluated all patients who were initiated on frontline HMAs for AML at our institution from September 2013 to April 2018. HMAs were administered without dose reduction or treatment delays. Responses were evaluated and categorized as hematologic response (HR; defined by neutrophils > 1000/µL, platelets > 100k/µL, transfusion independence, and no peripheral blasts), complete remission (CR), CR with incomplete platelet recovery (CRp), CR with incomplete hematologic recovery (CRi), and no response. Patient, cytogenetic, and treatment characteristics were summarized and described. We evaluated patients exhibiting a response before receiving 4 cycles of HMA therapy ("early" responders) and compared these patients to those achieving a response after receiving at least 4 cycles of HMA ("late" responders). The Kaplan-Meier method estimated overall survival (OS). Odds of early response were estimated with logistic regression models. Results: During the study period, 137 patients received frontline HMAs. 122 (89.1%) patients received azacitidine, and 15 (10.9%) were treated with decitabine. Mean age at HMA start was 70.1 years (range 39.8-94.3). Most patients (62.8%) were male, and most (77.4%) were Caucasian. 21 (15.3%) patients were NCCN favorable-risk, 52 (38.0%) were intermediate-risk, and 64 (46.7%) were poor-risk. At first testing, 21.4% of the patients were positive for the FLT3/ITD mutation, 0.8% the FLT3/TKD mutation, and 21.4% the NPM1 mutation. Some patients received concomitant therapies along with the HMA; these included hydroxyurea, lenalidomide, and sorafenib. Median survival in the entire population was 11.6 (95% CI 8.3, 15.2) months. Overall response rate (ORR) was 60.6%. Among responders, 80.7% achieved HR as their first response; 19.3% were first noted to have marrow responses (1.2% CR, 4.8% CRp, and 13.3% CRi). Most patients did not undergo bone marrow evaluation to assess response. Among responding patients, 60.2% responded "early", whereas 39.8% responded "late". Median overall survival was 15.2 (9.3, 17.7) months in early responders, and 22.2 (11.7, 38.9) months in late responders. There was no difference in survival between the groups (p=0.108, log-rank test; Figure 1), although there was a trend toward improved survival in late responders. Nineteen patients underwent allogeneic HCT. Time to response was not associated with odds of receiving HCT (p=0.812). Conclusions: HMAs have a high ORR as frontline therapy in elderly and unfit AML patients. Among AML patients receiving frontline HMAs, later responders have equivalent survival to earlier responders. Physicians should consider exercising patience when treating AML patients with HMAs. These findings warrant validation in a larger, prospective study. Figure. Figure. Disclosures Avalos: Juno: Membership on an entity's Board of Directors or advisory committees. Grunwald:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Janssen: Research Funding; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medtronic: Equity Ownership.

scholarly journals De-Escalation of Antimicrobials in Adult Hematopoietic Cell Transplantation Recipients with Febrile Neutropenia of Unknown Origin

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2079-2079 ◽  
Author(s):  
Megan M. Petteys ◽  
Ekaterina Kachur ◽  
Kelly E. Pillinger ◽  
Jiaxian He ◽  
James T. Symanowski ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Unknown Origin ◽  
Recurrent Fever ◽  
Inpatient Mortality ◽  
Advisory Committees ◽  
Allogeneic Hct ◽  
Icu Admission ◽  
Hematopoietic Recovery

Abstract Background: Guideline recommendations from the Infectious Diseases Society of America (IDSA) and the 4th European Conference on Infections in Leukemia (ECIL-4) for the optimal duration of empiric antimicrobial therapy in patients with hematological malignancies and febrile neutropenia (FN) of unknown origin (FUO) vary given limited available evidence. Recent studies involving hematology patients and hematopoietic cell transplantation (HCT) recipients with FN have demonstrated that de-escalation of broad-spectrum antimicrobials (BSA) prior to hematopoietic recovery is associated with greater antibiotic-free days, but without increased risks, such as recurrent fever, bacteremia, intensive care unit (ICU) admission, or inpatient mortality. However, the safety of this de-escalation approach has not been extensively studied in autologous and haploidentical HCT recipients within the United States as most prior studies were conducted in Europe. The main purpose of this study was to compare rates of recurrent fever, re-escalation of therapy, and Clostridium difficile-associated infection (CDI) in autologous and allogeneic HCT recipients with FUO who received early de-escalation of BSA prior to hematopoietic recovery versus those who continued BSA until hematopoietic recovery. Methods: This retrospective, observational study assessed HCT recipients with FN admitted to Carolinas Medical Center in Charlotte, North Carolina between March 2014 to April 2018. Patients were included if they were ≥ 18 years of age, had an active hematologic malignancy and underwent allogeneic or autologous HCT, experienced their first episode of FN after HCT, and were initiated on appropriate BSA for ≥ 48 hours. Patients were excluded if they had microbiological or radiological diagnosis of active bacterial, fungal, or viral infection during the FN episode. Patients were enrolled into either cohort 1, which represented patients who were de-escalated to prophylactic antimicrobials prior to hematopoietic recovery (early de-escalation group), or cohort 2, which represented patients who continued BSA until hematopoietic recovery (hematopoietic recovery de-escalation group). Fisher's exact test was conducted to make cohort comparisons for categorical patient characteristics, while Mann-Whitney U test was employed for continuous variables. Multivariate logistic regression was utilized to evaluate rates of recurrent fever, re-escalation of therapy, and CDI between the 2 cohorts. Results: A total of 107 patients were included with 24 (22.4%) in cohort 1 and 83 (77.6%) in cohort 2. Most patients (87.5%) in cohort 1 received haploidentical HCT, whereas 84.3% of patients in cohort 2 received autologous HCT (P < 0.001). The median duration of neutropenia following the first FN episode was significantly shorter in cohort 2 (15 vs 4 days in cohorts 1 and 2, respectively, P < 0.001). There were no significant differences in rates of recurrent fever (4.2% vs 7.2%, adjusted OR (AOR) = 0.63,P = 0.684) and re-escalation of therapy (4.2% vs 4.8%, AOR = 1.26, P = 0.853) within 72 hours following de-escalation between the 2 cohorts. Rates of CDI within 30 days from hematopoietic recovery were also similar (4.2% vs 2.4%, AOR = 2.25, P = 0.582). No patients experienced inpatient mortality, ICU admission, or bacteremia. There were no significant differences in days of antimicrobial use per 1000 transplant days (P = 0.071). In a subgroup analysis of only allogeneic HCT recipients, haploidentical was the most common transplant type with 91.3% (n = 21/23) in cohort 1 and 69.2% (n = 9/13) in cohort 2. Recurrent fever was very infrequent among allogeneic HCT recipients (n = 1 in cohort 1 vs n = 0 in cohort 2, P > 0.999). However, a significant reduction in days of antimicrobial use per 1000 transplant days (P = 0.002) was observed in cohort 1 compared to cohort 2. Conclusion: HCT recipients with FUO who received de-escalation of BSA prior to hematopoietic recovery did not experience increased rates of recurrent fever, re-escalation of therapy, CDI, bacteremia, ICU admission, or inpatient mortality. These results concur with recently published studies and the ECIL-4 guidelines. An early de-escalation approach in haploidentical HCT recipients specifically appears to be safe and may result in a reduction in antimicrobial utilization. Disclosures Grunwald: Forma Therapeutics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medtronic: Equity Ownership; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Avalos:Juno: Membership on an entity's Board of Directors or advisory committees. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy.

scholarly journals Effect of Vancomycin-Resistance Enterococci Colonization Status Prior to Allogeneic Hematopoietic Cell Transplantation on Transplant Outcomes: A Single Center Retrospective Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3386-3386
Author(s):  
Amandeep Salhotra ◽  
Dongyun Yang ◽  
Bernard Tegtmeier ◽  
Sally Mokhtari ◽  
Justine Abella Ross ◽  
...  
Keyword(s):  
Overall Survival ◽  
Risk Factor ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Advisory Committees

Abstract The prevalence of vancomycin-resistance Enterococci colonization (VRE-C) in patients undergoing allogeneic hematopoietic cell transplantation (aHCT) is between 23-40%. Pre-HCT VRE-C is shown to be associated with high risks of VRE bloodstream infection (VRE-BSI), non-relapse mortality (NRM) and lower overall survival. Recent studies investigating the association between VRE-C and risk of acute graft-versus-host disease (aGVHD) after aHCT has demonstrated conflicting results, possibly due to the heterogeneous transplant conditioning and GVHD prophylactic regimens. Here, we sought to examine the VRE-C prevalence and determine its impact on aHCT outcomes, in patients receiving tacrolimus and sirolimus (T/S) as aGVHD prophylaxis. To explore the association between pre-HCT VRE-C and transplant outcomes, we retrospectively reviewed medical records of a cohort of 1074 consecutive patients who underwent aHCT at City of Hope from 2014 to 2017. Patients with stool culture screening within 30 days pre-aHCT (n=862) were identified from the microbiology database and were grouped as VRE-C and non-colonized (VRE-NC). Data was not available on VRE-C in 185 patients and they were not included in analysis. Overall survival (OS) and progression-free survival (PFS) were examined by Kaplan-Meier curves and log-rank tests. Non-relapse mortality (NRM), VRE-BSI, and GVHD rates of the 2 groups were compared by cumulative incidence rates and Gray's test. Multivariate analyses were performed when adjusting for prognostic factors. Two-sided P value of ≤0.05 was considered significant. Of the 862 evaluated patients, 68 had VRE-C (7.9% prevalence). Median age of patients in VRE-C and VRE-NC groups were 53 and 55 years, respectively. Gender distribution, transplant indications, stem cell source, proportion of unrelated donors, GVHD prophylaxis with T/S and other clinical variables including intensity of conditioning regimen and HCT-CI were similar between the two groups (Table 1) . Karnofsky performance status (KPS) of 90-100 and 70-80 were seen in 40% and 53% of patients with VRE-C compared to 47% and 48% of VRE-NC patients (p=0.12). Overall, VRE-BSI episodes were rare (n=7) with 4 patients in VRE-C (6.1%) and 3 patients in VRE-NC (0.4 %); p <0.001. All 3 patients in the VRE-NC group developed bacteremia within the first 100 days (range 2-97) but VRE-BSI was not the eventual cause of death. The median onset of VRE-BSI in the VRE-C group (n=4) was only 6 days (range: 2-12) with 1 surviving patient and 3 who died of non VRE-BSI related causes. No statistical significance was detected in rates of non-VRE BSI (24.1% in VRE-C Vs. 19.2% in VRE-NC; p=0.30) and fungemia (1.5% in VRE-C vs 1.2% VRE-NC; p=0.77). At a median follow-up duration of 19.4 months (range: 2.7-48.4), similar 1-year OS was achieved in both groups (67.4% in VRE-C and 76.5% in VRE-NC; p=0.11) but 1 year PFS was significantly lower in the VRE-C cohort (55.6% Vs. 69.4%; p=0.038). Higher NRM was achieved in the VRE-C cohorts on days +100 and +365 (11.8% Vs. 7.2% and 25.1% Vs. 14.4%, respectively, p=0.041). (Figure 1) There were no differences in rates of day 100 aGVHD (grades II-IV) (Figure 2) and relapse rates at 12 months between the two groups. Conditioning regimen intensity, donor type, KPS, and primary diagnosis were significantly associated with NRM. When these variables were included in the multivariate model, VRE-C was found to be independently associated with higher NRM (HR=1.82, 95%CI: 1.12-2.93; p=0.015). In conclusion, in our cohort of patients receiving predominantly T/S-based aGVHD prophylaxis, no association was detected between VRE-C and aGVHD incidence. Higher rate of VRE-BSI in the VRE-C group is in accordance with published data, albeit lower rates of VRE-BSI was seen in our cohort. VRE-C contributed to higher NRM at days 100 and 365 post-aHCT and was an independent risk factor for poor HCT outcomes Since VRE-C is a potentially modifiable risk factor, our data supports continued efforts for specific interventional strategies (i.e. antimicrobial stewardship) to reduce drug resistant bacterial colonization, and for clinical research to reverse the impact of VRE-C, such as the use of agents, which may modulate gut microbiome. Disclosures Salhotra: Kadmon Corporation, LLC: Consultancy. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Dadwal:AiCuris: Research Funding; Gilead: Research Funding; MERK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Research Funding.

scholarly journals A Phase II Study of Dasatinib and Dexamethasone As Primary Therapy Followed By Hematopoietic Cell Transplantation for Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: CALGB Study 10701 (Alliance)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2782-2782 ◽  
Author(s):  
Matthew J. Wieduwilt ◽  
Jun Yin ◽  
Meir Wetzler ◽  
Geoffrey L. Uy ◽  
Bayard L Powell ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Advisory Committees ◽  
Allogeneic Hct ◽  
Cns Prophylaxis ◽  
Autologous Hct

Abstract Background: Potent inhibitors of BCR-ABL1have improved remission results and altered post-remission therapy for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Dasatinib plus dexamethasone followed by hematopoietic cell transplantation (HCT) promises high response rates, reduced toxicity, and durable remissions. Methods: We conducted a Phase II trial at 17 U.S. centers with the primary objective being to estimate the 3-year overall survival and disease-free survival of patients with Ph+ ALL treated with dasatinib and dexamethasone for remission induction and intensification, central nervous system (CNS) prophylaxis, consolidation with reduced-intensity conditioning (RIC) allogeneic HCT, autologous HCT, or etoposide and cytarabine, and dasatinib-based maintenance. Eligible patients had untreated Ph+ ALL, were ≥18 years old, and had normal cardiac function. Induction (Course I) used dasatinib 140 mg oral daily and dexamethasone 10 mg/m2/day oral or intravenous (IV) days 1-7. For patients with ≤20% blasts in the Course I, Day 15 bone marrow biopsy, intensification (course II) continued daily dasatinib with another 7 days of dexamethasone. Those with >20% lymphoblasts also received vincristine (VCR) and daunorubicin (DNR). Patients (n=3) not in CR/CRi after Course II received a second induction (Course III) with dasatinib, cyclophosphamide, VCR, DNR, and dexamethasone. After Course II or III, CNS prophylaxis (Course IV) consisted of IV VCR and IV, oral, and intrathecal methotrexate (MTX). Dasatinib was restarted at serum [MTX] <0.05 microM. Course V consisted of HCT or chemotherapy. Patients aged 18-70 years with an HLA-matched donor underwent RIC allogeneic HCT; otherwise they underwent autologous HCT. Allogeneic HCT conditioning used fludarabine 30 mg/m2/day IV day -7 through -3, alemtuzumab 20 mg/day IV day -7 through -3, and melphalan 140 mg/m2 once on day -2. GVHD prophylaxis with tacrolimus began day -2. Patients undergoing autologous HCT received etoposide 10 mg/kg/day (age >65 years, 5 mg/kg/day) continuous IV for 4 days and cytarabine 2 g/m2 (age >65 years, 1 g/m2) IV every 12 hours for 8 doses (EA) then G-CSF for mobilization. Autologous HCT conditioning used melphalan 100 mg/m2/day on days -2 and -1. Patients >70 years or unable to undergo HCT received EA alone. Dasatinib maintenance (Course VI) began on day 30 of Course V and continued for 12 months and until 2 consecutively negative bone marrow BCR-ABL1RT-PCR assays 3 months apart or until relapse. Dasatinib levels were measured on day 15 of induction. Results: Sixty-six patients enrolled from 12/15/2010 to 11/14/2014; 65 received dasatinib and are evaluable. Median age was 60 years (22-87); 49% were male. Median presenting WBC count was 23.1 x 103/ul (0.3-453.6). No deaths occurred during induction or intensification. CR or CRi occurred 31 patients (48%) by Day 15 of induction and in 62 patients overall (95%; CR 86%). Median dasatinib levels in serum and CSF on Day 15 of induction were 30.3 ng/mL (<3-308) and 0.29 ng/mL (<0.2-1.37), respectively suggesting approximately 1% of plasma dasatinib penetrates into the CSF, less than the unbound fraction (6%). Fifty-four patients started Course IV, 38 Course V, and 37 Course VI. Fourteen patients continue on protocol therapy. Of 38 patients receiving Course V, 22 had allogeneic HCT, 6 had autologous HCT, and 10 had EA chemotherapy. Median age of allogeneic HCT recipients was 61 years (31-69). Robust autologous stem cell mobilization was observed [median CD34+ cell count, 90 x 106/kg (31-166, n=6)]. Dasatinib maintenance was feasible after allogeneic HCT, autologous HCT, and chemotherapy alone with no missed doses in 59%, 83%, and 63% of cycles, respectively. Ten patients have relapsed with one isolated CNS relapse. No relapses have occurred after allogeneic HCT with 3 relapses after autologous HCT and one after Course V EA alone. Median follow up for survivors is 22.8 months (longest, 51 months). There have been 23 deaths: 5 treatment-related (4 after allogeneic HCT, 1 after course V EA), 16 disease-related and 2 unrelated. Conclusions: Dasatinib with dexamethasone yields CR rates comparable to those reported with tyrosine kinase inhibitors combined with conventional chemotherapy. Post-remission therapy with reduced-intensity allogeneic HCT, autologous HCT, or chemotherapy followed by dasatinib maintenance is feasible. Survival follow up is maturing. Disclosures Stock: Sigma-Tau: Honoraria, Research Funding; Royalties for a chapter in Up to Date: Patents & Royalties; ADC Therapeutics: Honoraria; Amgen: Honoraria; Gilead Sciences: Honoraria. Beumer:Bristol-Myers Squibb: Research Funding. Stone:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Juno Therapeutics: Consultancy; Karyopharm: Consultancy; Sunesis Pharmaceuticals: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Jansen: Consultancy; Merck: Consultancy; ONO: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Xenetic Biosciences: Consultancy. Larson:Bristol-Myers Squibb: Consultancy; Astellas: Consultancy, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document