Myeloablative Fractionated Busulfan Conditioning Regimen in Older Patients: Results of a Phase II Study

Background: Traditionally, pre-transplant conditioning regimen is given over 4-6 days before hematopoietic cell transplant (HCT). Delivering higher dose chemotherapy preparative regimen over a longer time period has not been tested previously. We hypothesized that the delivery of myeloablative dose of busulfan over a 3-week period may reduce toxicity and non-relapse mortality (NRM), without affecting relapse, and tested this in a prospective phase II study. Methods: Patients between 18 and 70 years of age with hematological malignancies and adequate organ function, with 8/8-HLA matched related or unrelated donor were eligible. They received a fixed dose of busulfan 80mg/m2 as outpatient on days -20 and -13. Then, fludarabine 40mg/m2 was given on days -6 to -2 followed by busulfan dosed to achieve target area under the curve (AUC) of 20,000 mol/min for the whole course based on pharmacokinetic studies. GVHD prophylaxis was cyclophosphamide (PTCy) 50mg/kg on days 3 and 4 and tacrolimus. Mycophenolate mofetil (MMF) was added to later unrelated donor recipients. All patients received standard supportive care. The primary endpoint was day 100 NRM. Results: We enrolled 52 patients with a median age of 62 (range, 39-69) years. Almost half (n=25, 48%) had AML or MDS and the other half (n=26, 50%) had had CML or MPD; 1 (2%) had multiple myeloma. Low, intermediate, high and very-high disease risk index (DRI) was present in 3 (6%), 34 (65%), 14 (27%) and 1 (2%). HCT-comorbidity index was >3 in 23 (44%) and 1-2 (n=23, 44%). A majority (n=32, 62%) had an unrelated donor. With a median follow up of 14 months (range, 3-23), NRM at day 100 was 1.9% (n=1) and 8% (95% CI, 0-15) at 1 year. Overall survival, progression-free survival and relapse at 1-year were 83% (95% CI, 73-95%), 78% (95% CI, 67-91%), and 14% (95% CI, 4-24%), respectively [Table]. There were no graft failures. The median time to neutrophil engraftment was 17 days (range, 13-33) and that of platelets (> 20K/µL, n=45) was 24 days (range, 9-266). Day 100 grade II-IV and III-IV acute GVHD rates were 37% (95% CI, 23-50%) and 6% (95% CI, 0-12%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 9% (95% CI, 0-17%) and 7% (95% CI, 0-14%), respectively. Overall survival at 1-year differed significantly among patients with low/intermediate DRI (94%; 87-100%) and those with high/very high DRI (53%; 31-91%), P=0.001. Conclusion: Myeloablative fractionated busulfan regimen with PTCy GVHD prophylaxis is feasible in older patients, has low incidence of severe acute GVHD, chronic GVHD, and NRM and results in promising overall survival. Table Disclosures Popat: Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; StemLine: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Ciurea:Miltenyi: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder. Kebriaei:Amgen: Research Funding; Pfizer: Honoraria; Jazz: Consultancy; Kite: Honoraria. Nieto:Astra-Zeneca: Research Funding; Affimed: Research Funding; Affimed: Consultancy; Novartis: Research Funding. Oran:AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Qazilbash:Autolous: Consultancy; Bioclinica: Consultancy; Speaker: Other: Speaker; Amgen: Other: Advisory Board. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties. OffLabel Disclosure: Fludarabine & Busulfan as conditioning agent prior to transplant

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Reduced Severe aGVHD and Improved Survival Using Post Transplant Cyclophosphamide/Tacrolimus/Methotrexate Graft Versus Host Disease Prophylaxis in AML Patients Receiving Myeloablative Fractionated Busulfan Conditioning Regimen

Blood ◽

10.1182/blood-2019-125996 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3296-3296

Author(s):

Uday Popat ◽

Rima M. Saliba ◽

Rohtesh S. Mehta ◽

Amanda L. Olson ◽

Julianne Chen ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Similar Proportion ◽

Myeloablative Conditioning ◽

Advisory Committees ◽

Post Transplant ◽

Gvhd Prophylaxis

Background: Myeloablative conditioning can be given safely to older patients by simply administering busulfan over a longer period (fractionated busulfan regimen) than the standard four day regimen. (Popat et al Lancet Haematology 2018). Subsequently, we added post-transplant cyclophosphamide (PTCy) GVHD prophylaxis to our fractionated regimen with a hypothesis that it will reduce GVHD and improve outcomes. Herein, we report the results of our retrospective analysis comparing outcomes of patients with AML who received fractionated busulfan myeloablative conditioning and PTCy versus standard tacrolimus (Tac) and methotrexate (Mtx) GVHD prophylaxis. Methods: Patients with AML between 18-70 years of age with adequate organ function and 8/8-HLA matched related or unrelated donor, who were treated on 4 consecutive protocols using fractionated busulfan were included in the analysis. All patients received two fixed doses of busulfan 80mg/m2 as outpatient either on days -13 and -12, or on days -20 and-13 followed by busulfan on day -6 to -3 dosed to achieve target area under the curve (AUC) of 20,000 mol/min for the whole course based on pharmacokinetic studies. Fludarabine ± cladribine were given on day -6 to -3. GVHD prophylaxis was PTCy 50mg/kg on days 3 and 4 and Tac ± mycophenolate mofetil in PTCy cohort (n=53), or standard Tac+ Mtx (n=53). Patients in both the cohorts were matched 1:1 by propensity score. Results: Baseline characteristics were similar between the PTCy and Tac/Mtx cohorts. The median age was 60 (range, 18-70) and 58 (range, 24-70) years, respectively, (P=0.3). Forty-nine percent were in CR, and 30% had comorbidity index >3 in each arm. Similar proportion of patients had ELN adverse risk in both arms (43% vs 40%, respectively P=0.7). The median follow up was 19 months (range, 3-36) in the PTCy and 46 months (range, 14-73) in Tac/Mtx cohort. Overall survival at 2-year was 78% vs 58% (P=0.03), non-relapse mortality was 6% vs 13% (P=0.2), incidence of grade 3-4 acute GVHD at 1-year was 6% vs 19% (P=0.07) and chronic GVHD at 2-year was 10% vs 29% (P=0.03) [Table 1 and figure 1]. The median time to neutrophil engraftment was prolonged by 3 days (15 vs 12 days; P<0.001) and platelet engraftment by 9 days (22 vs 13 days; P<0.001) in the PTCy cohort. Full donor chimerism at day 30 was noted in 79% vs 28% in the PTCy and Tac/Mtx cohorts respectively, (P<0.001). Conclusion: As compared to Tac/Mtx, PTCy-based GVHD prophylaxis not only reduced severe acute GVHD and chronic GVHD, but also improved overall survival in AML patients up to the age of 70 years who received myeloablative fractionated busulfan conditioning. Prospective randomized trial is warranted to validate these findings. Disclosures Popat: Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Ciurea:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; MolMed: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding. Kebriaei:Kite: Honoraria; Pfizer: Honoraria; Amgen: Research Funding; Jazz: Consultancy. Nieto:Astra-Zeneca: Research Funding; Affimed: Consultancy; Affimed: Research Funding; Novartis: Research Funding. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding. Qazilbash:Genzyme: Other: Speaker; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy; Bioclinical: Consultancy. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties. Champlin:Johnson and Johnson: Consultancy; Actinium: Consultancy; Sanofi-Genzyme: Research Funding.

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Alternative Donor Hematopoietic Stem Cell Transplantation for Sickle Cell Disease in Europe

Blood ◽

10.1182/blood-2018-99-111129 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4645-4645 ◽

Cited By ~ 2

Author(s):

Barbara Cappelli ◽

Graziana Maria Scigliuolo ◽

Fernanda Volt ◽

Selim Corbacioglu ◽

Josu de la Fuente ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Graft Failure ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis ◽

Alternative Donor

Abstract Hematopoietic stem cell transplant (HSCT) from an HLA identical sibling is a well-established curative therapy for sickle cell disease (SCD). HSCT from an unrelated donor is a treatment option, but the likelihood of finding a donor varies according to ethnicity and results are still limited. HLA haploidentical relatives can be alternatively used but, to date, only small series of patients have been described. We report outcomes of patients (pts) transplanted with related haploidentical (Haplo) or unrelated (UD) donors grafts and reported to EBMT/EUROCORD databases. Sixty four pts transplanted in 22 EBMT centers between 1991 and 2017 were retrospectively analyzed. Pts were described according to the donor type: haploidentical (n=40) and unrelated (n=24) [adult UD n=19; cord blood (CB) n=5]. The objective of the study was to describe alternative donor transplants for SCD in Europe without performing comparison analyses due to the size and heterogeneity of the groups. Primary endpoint was 3-year overall survival (OS). Median follow-up (FU) was 28 months (range: 1.6-156) [29.5 months (range: 2.1 - 133.5) for Haplo and 24.6 (range: 1.6 - 156) for UD]. Median age at HSCT was 14.2 years (range: 3-31.7) in Haplo and 11.8 (range: 2.1-42.8) in UD, with a predominance of children (<16 years) in both groups (23/40 and 19/24, respectively). Before HSCT, 68% of overall pts were treated with hydroxyurea and 62% received more than 20 red blood cell (RBC) units. RBC alloimmunization occurred in 14% of transfused pts. In both groups, vaso-occlusive crisis and cerebral vasculopathy were the most frequent SCD complications and the main indications for HSCT. Other complications were acute chest syndrome (44%), liver disease (31%) and infection (23%). In Haplo, median year of transplant was 2014 (range: 1991-2017) and in UD 2011 (range: 2004-2015). In Haplo, two major protocols were used: (1) post -transplant cyclophosphamide (PTCY) with G-CSF primed bone marrow (BM) and a fludarabine+ cyclophosphamide+thiotepa+2Gy TBI conditioning regimen [16 pts and 2 centers performing most (n=13) of the transplants]; (2) a protocol (performed in 2 centers) consisting in the use of G-CSF mobilized peripheral blood stem cells (PBSC) with ex-vivo B and T cell depletion (BT depleted) (15 pts) and a fludarabine+thiotepa+ treosulfan conditioning regimen (14/15 pts). Haplo donors were most frequently the parents [mother (50%), father (29%), brother (14%) and cousin (7%)]. ATG was used in 95% of transplants and the most frequent combination for graft versus host disease (GvHD) prophylaxis was mycophenolate mofetil (MMF)+sirolimus in PTCY and MMF+ cyclosporine A (CSA) in BT depleted. In UD, graft source distribution was 14 BM, 5 PBSC and 5 CB. Conditioning regimens were mainly myeloablative (83%) with fludarabine+thiotepa+ treosulfan in 54% of HSCT. ATG was used in 87% and campath in 9% of transplants; GvHD prophylaxis was CSA and methotrexate in 50%. Neutrophil engraftment at 60 days was 95±4% in Haplo and 84±8% in adult UD, after a median engraftment time of 18 and 22 days, respectively. In Haplo, 7 pts experienced graft failure (3 primary and 4 late), of those 3 had a second allogeneic transplant and were alive at last FU, at 16, 16 and 63 months respectively; 1 patient died after rescue with autologous transplant and 3 were alive after autologous reconstitution. In adult UD, 3 pts had a primary and 1 a late graft failure, none of them had a second transplant and were all alive at last FU, at 2, 13, 28, 118 months respectively. Grade II-IV acute GvHD at 100 days was 25±7% in Haplo and 21±9% in adult UD; acute GvHD grade III-IV was observed in 3 pts in Haplo (none in BT depleted) and 2 pts in adult UD. Chronic GvHD was observed in 10 pts in Haplo (5 extensive, 3 of these in PTCY) and 3 pts in adult UD (2 extensive). OS at 3 years was 88±4%; being 89±5% in Haplo (88±8% for PTCY, 92±8% for BT depleted) and 94±5% in adult UD. 3-year event free survival was 58±7%; in detail, 60±9% in Haplo (56±12% for PTCY, 68±13% for BT depleted) and 60±12% in adult UD. Overall, 8 pts died (5 Haplo and 3 UD) due to infections or GVHD. Among the 5 pts receiving CB transplant 3 are alive (1 of which after graft failure and a second allogeneic transplant). Conclusion: This preliminary analysis shows that, despite an acceptable OS, rejection and chronic GvHD are still of concern; therefore alternative donor transplants for SCD should be performed in experienced centers with prospective clinical trials. Disclosures Pondarré: Blue Bird Bio: Honoraria; Novartis: Honoraria; Addmedica: Membership on an entity's Board of Directors or advisory committees. Zecca:Chimerix: Honoraria. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy. Bader:Medac: Patents & Royalties, Research Funding; Riemser: Research Funding; Neovii: Research Funding; Cellgene: Consultancy; Novartis: Consultancy, Speakers Bureau. Bernaudin:AddMedica: Honoraria; Pierre fabre: Research Funding; BlueBirdBio: Consultancy; Cordons de Vie: Research Funding.

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Fludarabine and Melphalan Compared with Reduced Doses of Busulfan and Flurabine Improves Transplant Outcomes in Older MDS Patients

Blood ◽

10.1182/blood-2019-121970 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 253-253

Author(s):

Betul Oran ◽

Kwang Woo Ahn ◽

Caitrin Fretham ◽

Mithun Vinod Shah ◽

Ryotaro Nakamura ◽

...

Keyword(s):

Total Dose ◽

Board Of Directors ◽

Research Funding ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Sensitivity Analyses ◽

Unrelated Donor ◽

Advisory Committees ◽

Hematopoietic Stem

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only potentially curative therapy in eligible patients with myelodysplastic syndromes (MDS). Reduced-intensity conditioning (RIC) regimens that have been developed to extend HSCT to older patients resulted in encouraging outcomes. However, several retrospective studies have raised concerns about disease control when RIC is used in MDS and the ideal conditioning regimen has not yet been found. In this study, we aimed to compare two most commonly used RIC regimens; intravenous use of fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel). Study population: Through the CIBMTR, after excluding patients with ex-vivo T cell depletion, we identified 1045 MDS patients aged ≥ 60 years and underwent first HSCT with matched related or matched (8/8) unrelated donor (MRD and MUD) using RIC between 2007-2016. RIC was defined via CIBMTR criteria as a regimen that incorporated an IV busulfan (BU) total dose ≤ 7.2 mg/kg or low-dose melphalan (MEL) total dose ≤ 150 mg/m2. By that, we identified 697 MDS patients who received FluBu (BU 6.4 mg/kg: 87%, BU 3.2 mg/kg: 13%) and 448 receiving FluMel (MEL 140 mg/m2: 80%, MEL 100 mg/m2: 20%). Results: The two groups, FluBu and FluMel, were comparable for disease and transplant related characteristics except the more frequent use of ATG or Campath in FluBu group (39% vs. 31%). The median age was 67 in both groups, and 26% and 19% of FluBu and FluMel groups were aged ³70, respectively. Hematopoietic comorbidity index (HCT-CI) was ³3 in 61% and 59% of FluBu and FluMel groups and MDS risk score by CIBMTR at HCT was high/very high in 34% in both groups. FluMel was associated with a reduced relapse incidence (RI) after HSCT compared with FluBu as presented in Table 1 and Table 2. Adjusted RI at 1-year was 43% with FluBu and 25% with FluMel (p=<0.0001). On the other hand, transplant related mortality (TRM) was higher with FluMel compared with FluBu (27% vs. 15%, p=<0.0001). The difference persisted at 2- and 3-years after HSCT as presented in the figure. Since the magnitude of improvement in RI was greater with FluMel than the improvement in TRM with FluBu, disease-free survival (DFS) was improved at 1-year and beyond with FluMel compared with FluBu (48% vs. 41% at 1-year, p=0.030, and 38% vs 28% at 3-years, p=0.0030). These outcome differences remained significant when sensitivity analyses were performed excluding patients who received RIC with either BU 3.2 mg/kg or Mel 100 mg/m2. FluMel, did not lead to higher incidence of severe grade 3-4 aGvHD (HR=1.2, 95%CI, 0.9-1.6, p=0.3) or chronic GvHD (HR=0.9, 95%CI=0.7-1.06, p=0.2). However, grade 2-4 aGVHD was observed more often with FluMel than FluBu (HR=1.3, 95%CI, 1.1-1.6, p=0.006). This led to inferior outcomes of GRFS within the first 2 months with FluMel (HR=1.9, HR=1.4-2.6, p<0.001) but superior outcomes of GRFS beyond 2 months with FluMel compared with FluBu (HR=0.7, 95%CI=0.6-0.8, p<0.001). Conclusion: Our results suggest that between the two most commonly used RIC regimens in older MDS patients, FluMel was associated with superior DFS and overall survival compared with FluBu due to reduced RI despite higher TRM. Disclosures Oran: AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Nakamura:Kirin Kyowa: Other: support for an academic seminar in a university in Japan; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Celgene: Other: support for an academic seminar in a university in Japan; Merck: Membership on an entity's Board of Directors or advisory committees. Scott:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Speakers Bureau. Popat:Jazz: Consultancy; Incyte: Research Funding; Bayer: Research Funding.

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Utilizing Organ-Sparing Marrow Irradiation to Condition Patients Prior to Allogeneic Hematopoietic Cell Transplant with High-Risk Hematologic Malignancies: Results of a Pilot Study

Blood ◽

10.1182/blood-2021-150948 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2856-2856

Author(s):

Sumithira Vasu ◽

Meghan Kromer ◽

Qiuhong Zhao ◽

Hannah Choe ◽

Karilyn Larkin ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Cell Transplant ◽

Advisory Committees ◽

High Incidence ◽

Grade Ii

Abstract Background: Total body irradiation (TBI) has long been incorporated as part of the conditioning regimen prior to hematopoietic stem cell transplant (HSCT). While the myeloablative TBI conditioning is associated with a lower relapse rate in high risk diseases such as Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Acute Lymphoblastic Leukemia (ALL), it is also associated with substantial toxicities, and increased NRM so use of this regimen is limited to young patients with excellent performance status. In this study, we used a linac-based volumetric modulated arc therapy (VMAT) technique to deliver standard myeloablative radiation to high risk body sites while sparing radiation sensitive organs (Organ Sparing Marrow Targeted Irradiation, OSMI). We hypothesized that this technique would be feasible and safe in patients who are older or who have higher transplant specific comorbidity index (HCT-CI), typically ineligible for standard TBI conditioning. Methods: This is a single-arm prospective study. Patients from age 18-75 with high risk AML, MDS or ALL were eligible. There are 3 cohorts: (1) age 18-50 with HCT-CI of 3/4; (2) age 51-65 with HCT-CI of ≤ 3; and (3) age 66-75 with HCT-CI of ≤ 2. Patients receive OSMI to a total dose of 1200 cGy delivered twice daily for 6 fractions for a total of 7200 cGy. Clinical tumor volume includes total skeletal bone marrow and any sanctuary or high-risk areas. Graft-versus-host disease (GVHD) prophylaxis originally was tacrolimus and methotrexate. Given high incidence of bacterial infections related to mucositis, prophylaxis was changed to tacrolimus and sirolimus without methotrexate. All patients received Keratinocyte growth factor for prevention of mucositis. The primary objective was to assess feasibility and tolerability of OSMI based HSCT as defined by transplant-related mortality (TRM) at day 30 (D30) as well as rate of grade II/III organ toxicity (defined by Bearman Regimen-Related Toxicities Scale) attributable to conditioning occurring within 30 days. Results: Patient demographics for the 24 patients are shown in Table 1. Median age of recipients was 56.5 years. No graft failures were observed. The most common grade II or III Bearman toxicities include mucositis (grade 2: n=4), and diarrhea (grade 2: n=4). Clinical outcomes are shown in Figure 2. With a median follow-up of 3.3 years, overall survival (OS) and relapse-free survival (RFS) at 2 years was 78% and 74% respectively. Among the 5 patients who were not in complete remission at the time of transplant, 2-year OS and RFS rate was 40%. Incidence of Grades II-IV acute GVHD was 79% and Grades III-IV GVHD was 30%. Relapse incidence was 4% at 2 years. Incidence of Thrombotic microangiopathy by day 100 (TMA) as defined by Jodele's criteria was 17%. Incidence of chronic GVHD was 45% and severe chronic GVHD was 16%. One year non-relapse mortality was 22%, likely due to higher incidence of GVHD. Conclusions: Selected patients who are older or with higher HCT-CI, who are typically not candidates for standard TBI conditioning, were able to receive a radiation-based myeloablative conditioning regimen with 2 year overall survival rates of 78%. We observed a high incidence of TMA, possibly related to use of tacrolimus and sirolimus as GVHD prophylaxis, and a high incidence of Grade II-IV acute GVHD. Low incidence of relapse was observed. OSMI-based conditioning was feasible in this cohort with median age of 56 years and was associated with low rates of relapse and favorable 2 year overall survival. Figure 1 Figure 1. Disclosures Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Jaglowski: Novartis: Consultancy, Research Funding; Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. de Lima: Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding.

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Low Incidence of Chronic Graft-Versus-Host Disease in Myeloablative Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide Using Matched Related or Unrelated Donors: Phase II Study Interim Analysis

Blood ◽

10.1182/blood-2021-147569 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1811-1811

Author(s):

Najla H El Jurdi ◽

Daniel O'Leary ◽

Fiona He ◽

Todd E. DeFor ◽

Armin Rashidi ◽

...

Keyword(s):

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Advisory Committees ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

Preparative Regimen

Abstract Introduction Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative treatment for many high-risk hematologic malignancies. Myeloablative conditioning is currently the standard of care for young and fit patients; however, graft-versus-host disease (GVHD) continues to be a major limitation to the success of HCT, increasing post-transplant morbidity and mortality. An ideal HCT is one combining strategies that reduce incidence and severity of GVHD, without compromising graft-versus-tumor effect. We hypothesized that GVHD prophylaxis regimen consisting of post-transplant cyclophosphamide (PTCy), tacrolimus (Tac) and mycophenolate mofetil (MMF) will reduce the incidence of chronic GVHD in patients receiving a standard hematopoietic myeloablative HCT without an increase in risk of malignant relapse. Methods This is an interim analysis of a phase II study using a myeloablative preparative regimen of either: 1. total body irradiation (TBI, total dose 1320 cGy administered twice a day from days -4 to -1) or 2. Busulfan 3.2mg/kg daily (cumulative AUC 19,000 - 21,000 µmol/min/L) plus fludarabine 160mg/m 2 days -5 to -2 for patients unable to receive further radiation, followed by a GVHD prophylaxis regimen of PTCy (50mg/kg days +3 and +4), Tac and MMF (beginning day +5). The primary endpoint is cumulative incidence of chronic GVHD requiring systemic immunosuppressive treatment at 1 year post-transplant. Patient and disease characteristics are detailed in Table 1. Eligibility included: age ≤ 60 years, malignant or non-malignant diagnosis, matched related (MRD) or unrelated (MUD) donor with either a bone marrow (BM) or filgrastim-mobilized peripheral blood (PB) graft. Results Through October 2020 we treated 63 patients with a median follow up of 502 days post-transplant. Of those, 48% were female and n=11 (17%) younger than 18 with median age at HCT of 36 years (range, 2-55; Interquartile range [IQR], 20-48). Donor source was 8/8 MRD in 44 patients (70%), 8/8 MUD in 18 (29%), and one with 7/8 MUD. Graft source was BM in n=28 (44%) and PB in n=35 (56%). Preparative regimen was TBI in 94% of patients. All patients achieved primary neutrophil engraftment by 42 days, median 16 days (range, 13-27). Overall, 94% achieved platelet engraftment by 6 months, median 25 days (range, 16-98). At day 100, 48 patients (86%) achieved full donor bone marrow chimerism (>95% donor DNA); 29 (52%) and 52 (95%) achieved full donor peripheral blood CD3 and CD33 chimerism (defined as >95% donor). 42 patients (66%) required total parenteral nutrition (TPN) for oral mucositis and regimen-related toxicities during their initial transplant admission. Cumulative incidence of Grade II-IV acute GVHD by 100 days post-transplant was 14% overall (95% confidence interval CI: 6-23%), 7% for MRD and 32% for the MUD group; Grade III-IV acute GVHD was 5% overall (CI: 0-10%), similar for both MRD and MUD group. At 1 year, only two patients receiving a PBSC graft developed chronic GVHD requiring immune suppression, for a cumulative incidence of 3% overall, one in the MRD group and one in the MUD group. Two-year cumulative incidence of relapse was estimated at 21% overall, 22% and 16% for the MRD and MUD groups, respectively. Two year cumulative incidence of non-relapse mortality was 13% overall, 15% and 5% for MRD and MUD, respectively. Estimated 2-year overall survival was 79% overall (CI: 65-88%), 75% for the MRD group and 95% for MUD. Estimated 2-year GVHD-free relapse free survival (GRFS) was 57% overall (CI: 42-69%), 56% and 63% in the MRD and MUD groups, respectively. Discussion Myeloablative transplantation with a TBI preparative regimen, followed by a GVHD prophylaxis regimen of PTCy, Tac, and MMF results in very low incidence of chronic GVHD. Importantly, this regimen is feasible and effective for pediatric and adult patients. Further improvement in outcomes can be achieved by incorporating post-transplant relapse mitigating strategies as well as supportive care measures to decrease regimen-related toxicities. Figure 1 Figure 1. Disclosures Arora: Kadmom: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding. Janakiram: Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria; FATE, Nektar Therapeutics: Research Funding. Smith: Astellas Gene Therapies: Current Employment. Bachanova: Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Brunstein: BlueRock: Research Funding; AlloVir: Consultancy; FATE: Research Funding; NANT: Research Funding; GamidaCell: Research Funding. MacMillan: Equilium: Other: DSMB member; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. Miller: Sanofi: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vycellix: Consultancy; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; Wugen: Membership on an entity's Board of Directors or advisory committees. Betts: Patent Disclosures: Patents & Royalties: B.C.B. holds a patent (WO2015120436A2) related to CD4+ T cell pSTAT3 as a marker and therapeutic target of acute GVHD. B.C.B. additionally holds a provisional patent (WO2017058950A1) related to the use of JAK inhibitors for rejection and GVHD prevention. . Vercellotti: Mitobridge, an Astellas Company: Consultancy, Research Funding; CSL Behring: Research Funding. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Holtan: Generon: Consultancy; Incyte: Consultancy, Research Funding.

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Higher Grade Cytokine Release Syndrome Is a Predictive Factor for Gvhd in Haploidentical Stem Cell Transplantation with Peripheral Blood Cell

Blood ◽

10.1182/blood-2021-151187 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2881-2881

Author(s):

Benjamin Bouchacourt ◽

Valerio Maisano ◽

Ana Benzaquen ◽

Angela Granata ◽

Sabine Furst ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Advisory Committees ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Grade Ii

Abstract Background: Early Cytokine Release Syndrome (CRS) is a common complication following haploidentical stem cell transplantation (Haplo-HSCT) induced by the proliferation of alloreactive T-Cells. CRS is occurring more frequently in patients receiving peripheral blood stem cells (PBSC) comparatively to bone marrow transplant, however its impact on outcome, notably graft versus host disease (GVHD) remain unclear. The main objective was to evaluate the impact of severity of CRS on the risk of GVHD. Patients and Methods: This retrospective single-center study included patients who had received a first haplo-HSCT for hematological malignancies, with PBSC as graft source. All patients received either a reduced-intensity conditioning (RIC) based on thiotepa (5mg/kg), busulfan (260 mg/m²) and fludarabine (120 mg/m²) [TBF], or a non-myeloablative conditioning (NMAC) based on fludarabine (150 mg/m²), cyclophosphamide (29 mg/kg) and 2 Gy TBI [CyFluTBI]. GVHD prophylaxis was based on PT-Cy 50 mg/kg (day+3 and +4) and cyclosporine A plus mycophenolate mofetil starting at day+5. All patients were given GSCF from day+5 to neutrophil recovery. Results: 241 consecutive patients were analyzed. One hundred patients (54%) had myeloid malignancies, and 111 (46%) had lymphoid malignancies. Most patients had intermediate or low risk DRI (n = 180, 75%) and HCT-CI was ≥ 3 for 159 patients (66%). Using ASTCT consensus criteria, 226 patients (94%) developed CRS, including 183 grade 1 and 43 grade ≥ 2. Transplantation and patient characteristics were not significantly different between patients with CRS grade 0-1 vs. ≥ 2, except for age. Indeed, patients with CRS grade ≥ 2 were significantly older than patients with CRS grade 0-1 (median 65 vs 60 yo respectively, p = 0.01). Patients with grade ≥ 2CRS had significantly higher cumulative incidence of day-100 grade II-IV acute GVHD (grade 0-1 vs. ≥ 2 : 28% and 44%, p = 0.028) and 4-year moderate to severe chronic GVHD (grade 0-1 vs. ≥ 2 : 16% and 30%, p = 0.024) compared to patients with grade 0-1 CRS (Figure 1). No difference in the cumulative incidence of relapse was observed between CRS groups (grade 0-1 vs. ≥ 2 : 22% and 21%, p = 0.802). By multivariate analysis, CRS grade ≥ 2 was the only factor associated with grade II-IV acute GVHD (HR = 1.99; 95%CI = [1.17-3.39], p = 0.011). CRS grade ≥ 2 was significantly associated with a higher risk of moderate to severe chronic GVHD (HR = 2.67; 95%CI = [1.36-5.21], p = 0.004) and poorer GVHD- and relapse-free survival (GRFS) (HR = 1.78 ; 95%CI = [1.19-2.67], p = 0.005). Progression free survival, overall survival and non-relapse mortality were not influenced by the severity of CRS. Conclusion: In the context of PBSC haplo-HSCT, the occurrence of grade ≥ 2 CRS following graft infusion is significantly associated with an increased risk of both acute and chronic GVHD. This may improve the early identification of patients with high risk of GVHD for whom specific enhanced GVHD prophylaxis should be investigated. Figure 1 Figure 1. Disclosures Chabannon: Sanofi SA: Other: Travel Support, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Novartis: Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Speakers Bureau; Miltenyi Biotech: Research Funding; Fresenius Kabi: Research Funding; EBMT: Membership on an entity's Board of Directors or advisory committees. Blaise: Jazz Pharmaceuticals: Honoraria.

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Profound Lymphopenia at the Time of ATG Administration Is Not Predictive of Survivals after Allotransplant Using Purine Analogue/Busulfan-Based Conditioning Regimen

Blood ◽

10.1182/blood-2019-122013 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1985-1985

Author(s):

Maxime Jullien ◽

Thierry Guillaume ◽

Pierre Peterlin ◽

Alice Garnier ◽

Amandine Le Bourgeois ◽

...

Keyword(s):

Board Of Directors ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Routine Practice ◽

Unrelated Donor ◽

Roc Curve Analysis ◽

Advisory Committees ◽

Purine Analogue ◽

Gvhd Prophylaxis ◽

The Impact

Introduction: Prophylactic T cell depletion with antithymocyte globulin (ATG) remains a standard of care for GVHD prophylaxis during allotransplant (ASCT). Although the optimal ATG dosing strategy is still unknown, recent studies have reported that recipient absolute lymphocyte counts (ALC) at the time of ATG administration may predict survivals in ASCT with unrelated donors, suggesting that the dose (especially at the cut off of <0.1x109/L) and timing of ATG administration must be taken into account (Soiffer et al, JCO 2017; Kennedy et al, BBMT 2018). Our experience on the impact of lymphopenia at the time of ATG administration during allotransplant is reported here. Materials & Methods: All adults transplanted in our department between 01/2009 and 03/2019 with a Purine analogue/Busulfan/ATG based conditioning regimen and PBSC as source of graft from a matched or 9/10 mismatched donor were eligible. Reduced-intensity conditioning (RIC) regimen consisted of fludarabine 30mg/m²/day (d) from d-6 to d-2, busulfan 3,4 mg/kg/d from d-4 to d-3 and ATG (Thymoglobuline, Sanofi, Lyon, France) 2,5 mg/Kg/d, d-2 and d-1 (FB2A2) or the same but with clofarabine 30mg/m²/d in replacement of fludarabine with 1 or 2 d of ATG (CloB2A2/CloB2A1). Reduced-toxicity myeloablative conditioning regimens (RT-MAC) consisted of the same as FB2A2 but with 3 or 4 d of busulfan instead of 2 (FB3A2/FB4A2). All grafts were administered freshly on the day of the collection while patients (pts) had already received ATG. GVHD prophylaxis was ciclosporine alone for pts with a sibling donor while pts grafted with a matched (MUD) or a 9/10 mismatch (mmUD) unrelated donor received ciclosporine+MMF. We exhaustively looked at pts for whom a blood differential was available at the time of ATG administration in order to study the impact on OS, DFS and GRFS (no grade 3-4 acute GVHD, no moderate/severe chronic GVHD and no relapse) of a profound lymphopenia vs not. Results: Of 395 eligible pts, 116 (median follow-up for alive pts: 49 months) were documented with a differential at time of ATG administration, confirming that this analysis is not a routine practice in our department and probably in many centers. RIC was administered in 80 (69%) of the pts including 39 FB2A2, 12 CLOB2A2 and 29 CLOB2A1. RT-MAC was administered in 36 (31%) pts, including 27 FB3A2 and 9 FB4A2. Seventy-six pts had a myeloid disease while 40 had a lymphoid disease. Donor types were siblings (n=33), MUD (n=70) or 9/10 mmUD (n=13). For the entire cohort, 4y OS, DFS and GRFS were 56.2% (47-66), 40.9% (32-51) and 34.5% (26-45), respectively. No difference in survivals was observed between lymphoid vs myeloid pts, pts transplanted with sibling vs other donors, pts receiving a RIC vs a MAC or a CloB2 vs a FB2 RIC regimen. Median ALC at time of start of conditioning was .915x109/L (range: .010-15.780). No difference in terms of survivals was observed when considering pts under this threshold vs others. ROC curve analysis failed to identify a cut-off allowing to predict better survivals according to ALC at the time of ATG administration (ALC/ATG). Median ALC/ATG was .070x109/L (range: 0-2.300). No difference in terms of survivals was observed when considering pts under this threshold vs others. The same was true when considering .100x109/L as ALC/ATG cut-off. Regarding MAC, the median ALC/ATG was .100x109/L with no difference in survivals between pts under or above this value. The same was true for RIC with ALC/ATG cut-offs < median (.055x109/L) or <.100 x109/L. Interestingly, considering pts with ALC/ATG <.100 x109/L within the RIC setting, survivals were similar between those who received 1d (n=25) vs 2d (n=28) of ATG. This analysis was not performed for pts with ALC/ATG >.100 x109/L as only 4 of them received 1d of ATG vs 23 2d. The dose of CD34+ and CD3+ T cells infused had no impact also on survivals. Conclusion: This study demonstrates that profound lymphopenia at the time of ATG administration as part of a RIC as well as a RT-MAC Purine analogue/Busulfan/ATG based conditioning regimen has no impact on outcomes. Moreover, a reduced dose of ATG in RIC pts with profound lymphopenia at the time of ATG administration did not translate into better survivals. Other unknown factors rather than recipient lymphopenia remain to be discovered to optimize individualized dosing of ATG. Disclosures Peterlin: AbbVie Inc: Consultancy; Astellas: Consultancy; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Le Gouill:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Chevallier:Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria.

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Thiotepa-Fludarabine-Treosulfan (TFT) Conditioning for 2nd Allogeneic Peripheral Blood Hematopoietic Cell Transplantation (HCT) from a Second Unrelated Donor in Patients with Acute Myeloid Leukemia (AML) Relapsed after Prior Allogeneic HCT: A Prospective Multicenter Phase II Trial

Blood ◽

10.1182/blood-2018-99-118999 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 210-210

Author(s):

Jürgen Finke ◽

Claudia Schmoor ◽

Matthias Stelljes ◽

Andreas Burchert ◽

Peter Dreger ◽

...

Keyword(s):

Primary Endpoint ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Allogeneic Hct ◽

Gvhd Prophylaxis ◽

Secondary Endpoints ◽

Full Analysis

Abstract Introduction: Relapse of AML after allogeneic HCT has a dismal prognosis. Long-term survival after 2nd allogeneic HCT has been described in selected patients. Here we tested a specific protocol with a fixed drug combination for myeloablative conditioning and GvHD prophylaxis for 2nd allogeneic HCT from a different unrelated donor. (EudraCT no.: 2012-005414-18, German Clinical Trials Registry no.: DRKS00005126) Methods : Aim of the trial was to show efficacy and safety of a 2nd alloHCT from an unrelated donor after a uniform conditioning with Treosulfan 3x12gm/m2, Fludarabin 3x30mg/m2, and Thiotepa 3x 5mg/kg (TFT), and GvHD prophylaxis with cyclosporine A (CyA) /Mycophenolate and ATG-F (Neovii) 3x10mg/kg. Eligible were adult patients with AML, ECOG ≤ 2, with sensitive or refractory hematologic relapse (≥ 20% blasts) > 6 months after a prior allogeneic HCT , including secondary (s) and/ or tAML. CR prior 2nd HCT was no prerequisite. The primary endpoint of the study was disease-free survival (DFS) defined as being alive and free of disease at 1 year post 2nd HCT. Secondary endpoints were relapse, relapse mortality (RM), NRM, overall survival (OS), acute GvHD, chronic GvHD, engraftment, and adverse events. According to the Fleming one-stage design, 50 evaluable patients had to be included. If 16 or more patients were alive and free of disease at 1 year post 2nd SCT, the regimen could be considered as successful for evaluation in further trials. With this decision rule, it can be shown at one-sided α=0.1 that the probability of DFS at 1 year post 2nd HCT is higher than 23% with a power of 90%, when it is at least 40%. This is a first analysis of the study covering the first year after 2nd HCT of each patient. The analysis is based on the full analysis set, which includes all patients, for whom the conditioning regimen TFT and the GvHD prophylaxis regimen CyA, MPA/MMF, ATG-F has started, and for whom allogeneic HCT from an unrelated donor has been performed. Results: Fifty-two patients were registered for the study from 25th March 2014 up to 10th March 2017 from 9 German centres. The full analysis set includes 50 patients (median age 53.5 years). ECOG was median 1. Donors for 1st allo HCT had been related (n=11 (22.0%)) or unrelated (n=39 (78.0%)) (n=48 PBSCT, n=2 bone marrow). Conditioning for 1st HCT was myeloablative in 23 (46.0%) patients. After 1st HCT, the rate of acute GvHD I-IV was 34.0%, and of chronic GvHD was 40.0%. Median time from 1st HCT to relapse was 17.2 months and from relapse after 1st HCT to 2nd HCT 2.5 months. Thirty-six (72%) patients had received induction chemotherapy for relapse prior to 2nd HCT, 11 (22.0%) patients had received azacytidine or decitabine, and 11 (22.0%) had received donor lymphocyte infusions (DLI). Remission status prior to 2nd HCT was complete remission in 16 (32.0%) patients, chemo-refractory relapse in 33 (66.0%), one patient was in partial remission. With regard to the primary endpoint, 23 (46%, 95%-CI (31.8-60.7%) of the patients were alive and free of relapse at 1 year after 2nd SCT. With regard to the secondary endpoints at 1 year, the cumulative incidence of relapse (95%-CI) was 26 (17-42)%, 9/50 patients (18 (10-33)%) died after relapse of AML, NRM was 14/50 patients (28 (18-44)%, cause: infection n=6, infection after aGvHD n=6, PTLD n=2), OS was 54 (39-66)%. Four patients are alive after relapse. aGvHD rate was 54 (42-70)%, aGvHD III-IV 26 (16-42)%, cGvHD 26 (16-42)%, extensive cGvHD 20 (12-35)%, engraftment rate with ANC > 1.0 x 103/µl was 92 (85-100)%, with platelets > 20 x 103/µl was 80 (70-92)%, and with platelets > 100 x 103/µl was 66 (54-81)%. After 1 year, 4 patients had received DLI for prophylaxis, and 5 patients for mixed chimerism as per protocol. Conclusion: Second alloHCT with an ablative double alkylator containing conditioning regimen with Thiotepa, Fludarabine, and Treosulfan is feasible and can result in sustained disease control in patients with AML relapse after a first alloHCT, and therefore seems to be a valid option in this otherwise detrimental setting. Disclosures Finke: Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding. Stelljes:Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy; Novartis: Honoraria; Amgen: Honoraria; JAZZ: Honoraria. Burchert:Novartis: Research Funding; Bayer: Research Funding; AOP Orphan: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Schub:Affimed: Research Funding. Kobbe:Celgene: Honoraria, Other: Travel Support, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.

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Secondary Graft-Versus-Host Disease (GVHD) Prophylaxis with Oral Proteasome Inhibitor Ixazomib Is Associated with Low Incidence of Recurrent, Late Acute and Chronic GVHD and Facilitated Calcineurin Inhibitor Taper within the First Year Post Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood-2020-139666 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 41-42

Author(s):

Natasia Rodriguez ◽

Jasme Lee ◽

Lisa Flynn ◽

Fiona Murray ◽

Sean Devlin ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Calcineurin Inhibitor ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Overlap Syndrome ◽

Advisory Committees ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

Low Incidence

Background. GVHD is a frequent complication within the 1st year after allogeneic stem cell transplantation (allo-HCT). Recipients of reduced intensity (RI) and non-myeloablative (NMA) conditioning combined with calcineurin inhibitor (CNI)-based GVHD prophylaxis, frequently develop GVHD in the context of immunosuppression taper. Ixazomib is an oral proteasome inhibitor (PI) that has demonstrated immunomodulatory properties, inhibition of pro-inflammatory cytokines, anti-tumor activity, and has a wide safety profile. We hypothesized that secondary GVHD prophylaxis using ixazomib, will facilitate CNI taper without increase in GVHD frequency and severity, maintaining graft-versus-tumor (GVT) effect, and a safety profile. Methods. We conducted an open label, prospective, single-center pilot study between 11/16 and 03/19. Eligible patients were > 18 yrs old, had a hematologic malignancy treated with RI or NMA conditioning allo-HCT, received CNI-based GVHD prophylaxis, and were within day 100 to 150 post-HCT. Patients with active acute and/or chronic GVHD were excluded. Patients were treated with ixazomib 4 mg orally once weekly, each cycle consisting of 3 weeks on and 1 week off therapy, until completion of taper from prophylactic CNI or 1-year post-HCT was reached, whichever occurred first. Patients who developed grade II-IV acute GVHD, chronic GVHD, or died of transplant-related mortality (TRM) were deemed treatment failure. The primary endpoint was the efficacy of ixazomib for the prevention of recurrent or late grade II-IV acute GVHD or chronic GVHD at 1-year post-HCT. Additional endpoints included TRM, relapse rate, survival analysis, safety evaluation, and immune reconstitution. Results. A total of 18 patients (median age of 58 yrs) were accrued in the study. The majority were male, had a diagnosis of NHL, and received RI conditioning (Table 1). All patients had a PBSC graft, and 16 (89%) were 10/10 HLA-matched. The median time for initiation of ixazomib was 141.5 days post-HCT. Fourteen patients had no GVHD during the study period. The 4 patients who developed GVHD had severe overlap syndrome (n = 2), mild de novo chronic GVHD (n = 1), and recurrent grade II acute GVHD (n = 1). Notably, patients with severe overlap syndrome had limited chronic GVHD involvement affecting the mouth and/or eyes, and the severity score was driven by acute manifestations affecting the skin and GI tract. Six patients successfully discontinued CNI and 4 patients were tapering immunosuppression close to the end of study at 1-year post-HCT. The cumulative incidence (CI) of grade II-IV acute and chronic GVHD at 1-year post-HCT was 25% (95%CI: 7.2-48.1) (Fig. 1A). No patients died during the study and therefore, the CI of TRM at 1-year was 0%, and only 1 patient had malignant relapse (NHL). The CI of PFS and the composite endpoint GVHD-free/relapse-free survival (GRFS) at 1-year were 83% (95%CI: 58-100) and 73% (95%CI: 49-100, Fig 1B), respectively. All patients experienced at least 1 TEAE of any grade. Most AEs were grade 1 or 2, with the most common being cytopenia and elevation in ALT/AST. Drug-related SAEs were reported in 9 patients and included neutrophil and decreased WBC. Seven patients required ixazomib dose reduction due to side effects, and 5 patients were removed from the study due to toxicity (1 neutropenia, 3 GI, 1 skin rash). Of those, 1 had subsequent GVHD by day 365 post-HCT. Immune recovery at 3, 6 and 12 months post-HCT was evaluated. There was a rapid and sustained recovery in T-cell subpopulations and B cell reconstitution Fig 2. Conclusions. Secondary GVHD prophylaxis with ixazomib was associated with low incidence of recurrent and late acute and chronic GVHD within the 1st year post-HCT. This approach allowed CNI taper while preserving GVT effect without aggravating GVHD. No deaths occurred during the study period and the 1-year GRFS was high. Ixazomib was overall well tolerated and favored immune reconstitution post-HCT. Our findings support further development of this approach and provide a proof-of-concept for secondary GVHD prophylaxis. Disclosures Dahi: Kite: Consultancy. Giralt:TAKEDA: Research Funding; JAZZ: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; MILTENYI: Consultancy, Research Funding; KITE: Consultancy; NOVARTIS: Consultancy, Honoraria, Research Funding; OMEROS: Consultancy, Honoraria; ACTINUUM: Consultancy, Research Funding. Sauter:Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Celgene: Consultancy, Research Funding; Kite - a Gilead Company: Consultancy; Precision Biosciences: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Consultancy; Spectrum Pharamaceuticals: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding. Perales:Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Cidara Therapeutics: Other; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ponce:Ceramedix: Membership on an entity's Board of Directors or advisory committees; Generon: Membership on an entity's Board of Directors or advisory committees; Kadmon: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding.

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Comparison of Reduced-Intensity Conditioning (RIC) Regimens for Allogeneic Hematopoietic Cell Transplantation (alloHCT) in Non-Hodgkin Lymphomas (NHL)-a Center for International Blood & Marrow Transplant Research (CIBMTR) Analysis

Blood ◽

10.1182/blood-2019-121849 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 319-319

Author(s):

Nilanjan Ghosh ◽

Sairah Ahmed ◽

Carlos Litovich ◽

Kwang Woo Ahn ◽

Manoj Khanal ◽

...

Keyword(s):

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Advisory Committees ◽

Gvhd Prophylaxis ◽

Conditioning Regimens ◽

The Impact ◽

Reduced Intensity

Introduction: Reduced-intensity and non-myeloablative (RIC/NMA) conditioning regimens are frequently used in alloHCT for NHL, because they are associated with decreased non-relapse mortality (NRM) risk in comparison with myeloablative conditioning regimens and allow older patients and patients with comorbidities to receive alloHCT. However, the optimal RIC/NMA regimen in allo-HCT for NHL is not known. Using the CIBMTR database we compared the transplant outcomes between the commonly used RIC/NMA regimens in NHL. Methods: 1823 adult (≥18 years) NHL patients in CIBMTR registry undergoing alloHCT using matched related or unrelated donors, between 2008-2016 were included. Analysis was limited to patients receiving four commonly used RIC/NMA regimens: fludarabine/ i.v. busulfan (6.4mg/kg) (Flu/Bu), fludarabine/melphalan (140mg/m^2) (Flu/Mel 140), fludarabine/cyclophosphamide (Fly/Cy) and Flu/Cy with 2Gy Total Body Irradiation (Flu/Cy/TBI). Graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor-based regimens. Patients who received post transplantation cyclophosphamide for GVHD prophylaxis were excluded. The primary outcome was overall survival (OS). Secondary outcomes included cumulative incidence of NRM, relapse, progression-free survival (PFS) and cumulative incidence of acute and chronic GVHD. Probabilities of OS and PFS were calculated using the Kaplan-Meier estimator. Multivariable regression analysis was performed for GVHD, relapse/progression, NRM, PFS, and OS. Covariates with a p<0.01 were considered significant. Results: The study cohort was divided into 4 groups; Flu/Bu (n=458), Flu/Cy/TBI (n=89), Flu/Mel 140 (n=885) and Flu/Cy (n=391). The baseline characteristics are shown in Table 1. The 4 cohorts were comparable with respect to median patient age, gender, donor type, remission status at alloHCT, and use of prior auto HCT. There was no interaction between NHL histological subtype and type of conditioning regimen. Results of multivariate analysis are shown in Table 2. The Flu/Mel 140 regimen was associated with a higher NRM (HR 1.78, 95% CI 1.37-2.31; p<0.001) when compared to Flu/Bu. Although the risk of relapse with Flu/Mel 140 was lower when compared to Flu/Bu (HR 0.79, 95% CI 0.66-0.94); p=0.007), this did not result in an improvement in PFS. Moreover, the Flu/Mel 140 cohort had an inferior OS (HR 1.34, 95% CI 1.13-1.59; p<0.001) when compared to Flu/Bu. There was no significant difference in terms of OS, PFS, relapse and NRM between Flu/Bu, Flu/Cy and Flu/Cy/TBI. There was no difference in risk of grade 3-4 acute GVHD across the four cohorts and compared to Flu/Cy/TBI, Flu/Mel 140 had a higher risk of chronic GVHD (HR 1.38, 95% CI 1.15-1.65; p<0.001). Four year adjusted PFS was 38% for Flu/Bu, 51% for Flu/Cy/TBI, 39% for Flu/Mel 140 and 35% for Flu/Cy (p=0.07). Four year adjusted OS was 58% for Flu/Bu, 67% for Flu/Cy/TBI, 49% for Flu/Mel 140 and 63% for Flu/Cy (p<0.001). Disease relapse was the most common cause of death across all 4 cohorts. Conclusion: This is the largest analysis comparing the impact of various RIC/NMA conditioning regimens on the outcomes of NHL patients undergoing alloHCT. We report that the choice of RIC/NMA conditioning regimen significantly impacted OS. The most commonly used conditioning regimen, Flu/Mel 140 was associated with a higher NRM and an inferior OS. The Flu/Bu, Flu/Cy, and Flu/CY/TBI conditioning regimens appear to provide comparable OS. Disclosures Ghosh: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; SGN: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; Forty Seven Inc: Research Funding; AstraZeneca: Honoraria, Speakers Bureau. Kharfan-Dabaja:Pharmacyclics: Consultancy; Daiichi Sankyo: Consultancy. Sureda:Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Novartis: Honoraria; Roche: Honoraria. Hamadani:Merck: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Otsuka: Research Funding; Medimmune: Consultancy, Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Sanofi Genzyme: Research Funding, Speakers Bureau.

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