Outcomes of Haploidentical Salvage Transplantation Using Post-Transplant Cyclophosphamide for Graft Failure Following Allogeneic Hematopoietic Stem Cell Transplantation

Abstract Introduction: Graft failure (GF) is a fatal complication after allogeneic stem cell transplantation (SCT). Although salvage SCT is the only curative therapy for GF, optimal donors and strategies for this procedure have not yet been established. Although in the last decade haploidentical donors have emerged as alternative donors, only limited data are available regarding the outcomes after haploidentical salvage SCT using post-transplant cyclophosphamide (PTCy). Therefore, this nationwide retrospective study aimed to evaluate the transplant outcomes and risk factors for survival after haploidentical salvage SCT using PTCy on behalf of the Transplant Complications Working Group of the Japan Society for Transplantation and Cellular Therapy. Methods: Clinical data were provided by the nationwide database of the Japanese Data Center for Hematopoietic Cell Transplantation. Patients who were diagnosed with GF and underwent a second or higher allogeneic SCT from the haploidentical related donor (≥2 antigen-mismatch), using PTCy as graft-versus-host disease (GVHD) prophylaxis, between 2011 and 2019 were included. Organ failure was defined as either ejection fraction ≤50%, serum creatinine ≥2 mg/dL, bilirubin ≥1.5 × upper limit of normal, or aspartate aminotransferase/alanine aminotransferase ≥2.5 × upper limit of normal. Overall survival (OS) probabilities were estimated using the Kaplan-Meier method and differences among groups were analyzed using the log-rank test. The multivariate analysis for OS was performed using the Cox proportional hazard regression model. Factors from the univariate analysis that demonstrated significance with P values < 0.1 were included in the multivariate analysis. Results: A total of 33 patients were included in the study. The median age was 34 years (range, 2-67), while performance status (PS) was 0-1 in 21 patients (64%). At salvage transplantation, 12 (36%) were receiving treatment for active infection, and 5 (15%) had organ failure. The median interval from SCT to salvage SCT was 49 days (range, 26-1,468), and 21 patients (68%) underwent salvage SCT within 100 days after previous SCT. Conditioning regimens consisted of fludarabine (Flu)/ cyclophosphamide (Cy)-based in 10 (31%), Flu/melphalan (Mel)-based in 10 (31%), and Flu/busulfan (Bu)-based in 7 (21%). The total dose of PTCy was 75-100 mg/kg in 26 patients (84%) and 40-50 mg/kg in 5 patients (16%). Most patients (84%) received tacrolimus plus mycophenolate mofetil as GVHD prophylaxis in addition to PTCy. Previous SCT was cord blood transplantation in 22 patients (67%) and haploidentical transplantation in 6 patients (19%), of which 4 patients (13%) received PTCy. The median time for neutrophil engraftment was 18 days, and the cumulative incidence of neutrophil engraftment at 30 days was 82%. Specifically, a patient who had donor-specific human-leukocyte antigen-antibody successfully achieved neutrophil engraftment at 22 days after salvage SCT. The median OS was 359 days, while the OS at 1 year was 47% (Figure A). In the univariate analysis, the OS of patients who received 75-100 mg/kg PTCy was significantly better than those who received 40-50 mg/kg PTCy (61% vs. 0% at 1 year, P = 0.022, Figure B). After adjusting for PS and the presence of active infection and organ failure, 75-100 mg/kg PTCy was significantly associated with better OS (hazard ratio, 0.30; P = 0.036). Although the differences were not significant, patients who received Flu/Mel-based conditioning exhibited numerically better OS than those who received Flu/Cy- or Flu/Bu-based conditioning (80% vs. 40% vs. 57%, P = 0.21). Conclusions: Haploidentical salvage SCT using PTCy offers promising survival outcomes and can be a substantial option for GF after allogeneic SCT. An adequate dose of PTCy (i.e., 75-100 mg/kg) needs to be administered to achieve long-term survival. Figure 1 Figure 1. Disclosures Nakamae: PPD-SNBL K.K: Research Funding; Bristol-Myers Squibb　Company: Honoraria, Research Funding; Alexion: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Simon-Kucher & Partners: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; CMIC HOLDINGS Co., Ltd: Research Funding; Novartis: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria. Ichinohe: Celgene: Honoraria; Novartis Pharma K.K.: Honoraria; Repertoire Genesis Inc.: Honoraria, Research Funding; Takara Bio Inc.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Honoraria, Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Nippon Shinyaku Co: Research Funding; Ono Pharmaceutical Co.: Honoraria, Research Funding; Kyowa Kirin Co.: Honoraria, Research Funding; FUJIFILM Wako Chemicals.: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Eisai Co.: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Co.: Honoraria; AbbVie Pharma: Research Funding; Astellas Pharma: Honoraria, Research Funding. Atsuta: Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria. Nakasone: Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Chugai Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria.

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ATG and Post-Transplant Cyclophosphamide Do Not Abrogate the Inferior Outcome Risk Conferred By HLA-Α and HLA-B Mismatched Unrelated Donors

Blood ◽

10.1182/blood-2020-139736 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 31-31

Author(s):

Igor Nicolas Novitzky-Basso ◽

Remberger Mats ◽

Carol Chen ◽

Ivan Pasic ◽

Zeyad Al-Shaibani ◽

...

Keyword(s):

Stem Cells ◽

Research Funding ◽

Graft Failure ◽

Univariate Analysis ◽

Donor Age ◽

Relapse Free Survival ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Donor Factors ◽

Unrelated Donors

Background Donor selection for allogeneic stem cell transplant is a complex process, where several factors are considered for potential impact on transplant outcome. Several publications have suggested that 9/10 mismatched unrelated donors (MMUD) may be equivalent to 10/10 MUDs. However, there is debate as to whether all 9/10 mismatches (MM) are equivalent. We sought to examine this in a single centre retrospective study using ATG followed by post transplant cyclophosphamide (ATG PTCy) as standard GvHD prophylaxis and correlated outcomes in terms of donor MM, donor age and CMV serostatus. Patients and methods A total of 414 patients who received HCT from unrelated donors between Jan 2015 and Dec 2019, at Princess Margaret Cancer Centre, Canada, were enrolled in the retrospective study. Patients and disease characteristics, and outcomes are detailed in Tables 1-3. The probability of overall survival (OS) was calculated using the Kaplan Meier product limit method and heterogeneity of time to event distribution functions was compared by the log rank test. The cumulative incidences of chronic and acute GvHD, relapse, and transplant related mortality (TRM) were estimated using the cumulative incidence method considering competing risk, and groups were compared using Gray's test. Death was considered a competing event for relapse, acute and cGvHD, and relapse was considered a competing event for NRM, acute and cGvHD. GvHD outcomes shown in Table 4. Results Median OS at 5y for the whole cohort (n=414) was 45.8% (38.2-53.0), and relapse free survival was 40.2% (32.9-47.4), with TRM at 1y 23.7% (19.6-28.0), Table 5. Compared to the whole cohort (median OS 38.8mo [21.6-NA]), patients who received grafts from MMUD (n=86) had median OS 9.2mo (6.0-17.3), p<0.001, in particular median OS for HLA-A MM was 8.1mo (5.3-18.4), HLA-B MM 5.9 (2.7-11.8) compared to other 9/10 MMUD (n=32) 18.8mo (5.7-NA), p<0.001. This was due to higher TRM at 1y, MMUD 39.1% (24.0-49.4) vs MUD (n=327) 19.2% (15.0-23.8) p<0.001 primarily due to HLA-A MM 39.6% (24.0-54.9) and HLA-B MM 35.7% (11.7-61.1), p=0.001. GVHD-Free Relapse free Survival (GRFS) at 5y for the whole cohort was 36.8% (29.7-43.9). GRFS At 2y for 9/10 MMUD was 25.2% (16.1-35.4), HLA-A MM 21.6% (9.9-36.2) HLA-B MM 15.4% (2.5-38.8) vs MUD 51.4% (45.3-57.2), p<0.001. Median OS for patients who received ATG PTCY (n=298) was 49.2mo (49.2-NA), for 9/10 (n=58) 10.2mo (6.1-19.6), with HLA-A MMUD (n=26) 9.6 mo (5.8-27.4), HLA-B MMUD (n=9) 4.6mo (1-11.8) (p<0.001), Figure. A number of donor factors significant by univariate analysis (incl. donor age, recipient/donor CMV, CD34 dose, presence of HLA MM, type of MM, female donor to male recipient), were selected to determine correlates with all mortality by multivariable analysis (MVA). The only significant factor was 9/10 MMUD HR 2.27 (1.65-3.14), p<0.0001, specifically HLA-A MM HR 2.69 (1.77-4.08), p<0.00001, HLA-B MM HR 3.14 (1.71-5.78) p=0.0002, Table 6. The same donor factors significant by univariate analysis were examined for correlation with TRM and significance was found for HLA MM HR 2.36 (1.57-3.55) p=0.00004, specifically HLA-A MM HR 2.44 (1.42-4.17), p=0.0012, HLA-B MM HR 2.39 (1.03-5.57) p=0.0034. Graft failure (GF) occurred in 4.6% of patients. Significant donor factors for GF were CD34 dose <4.0x106/kg, HR 5.28 (1.11-24.98) p=0.038; and HLA MM 2.78 (1.27-6.05) p=0.01. Of 414 patients, 395 patients (95.4%) received fresh stem cells and 19 (4.6%) received cryopreserved stem cells. Cryopreserved MUD grafts were associated with GF on MVA, HR 5.56 (1.75-17.4, p=0.0034), which may be due to several possible factors including the travel time prior to cryopreservation. Among AML patients, CMV negative patients in receipt of grafts from CMV negative donors (CMV-/-) (n=64) had worse survival (HR 2.05, 1.03-4.09, p=0.04) compared to recipient/donor pairs where any were CMV positive. There was a significantly higher relapse rate in the CMV-/- (15/64, 23.4%), compared to CMV positive (30/236, 12.2%, any combination), p=0.01 by Chi-squared test. Conclusions These data suggest that HLA-A and HLA-B mismatched donors confer a significantly inferior outcome despite the use of ATG PTCy. Cryopreserved stem cells from unrelated donors were associated with graft failure, and CMV-/- were associated with higher incidence of relapse. Further work is required to develop novel conditioning regimens and GvHD prophylaxis to mitigate these risks. Disclosures Lipton: BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Mattsson:Gilead: Honoraria; ITB: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria; Mallinkrodt: Honoraria.

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Novel Prediction Models of Nonrelapse Mortality in Patients Specific to Each Myeloablative Conditioning before Allogeneic Hematopoietic Stem Cell Transplantation: A Multicenter Analysis from the Kanto Study Group for Cell Therapy (KSGCT)

Blood ◽

10.1182/blood-2020-134539 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 28-29

Author(s):

Arata Ishii ◽

Akira Yokota ◽

Emiko Sakaida ◽

Shokichi Tsukamoto ◽

Katsuhiro Shono ◽

...

Keyword(s):

Risk Factors ◽

Stem Cell ◽

Liver Function ◽

Cell Therapy ◽

Cell Transplantation ◽

Research Funding ◽

Prognostic Models ◽

Myeloablative Conditioning ◽

C Statistic ◽

Otsuka Pharmaceutical

Introduction Despite recent developments on various transplantation procedures and supportive therapy, nonrelapse mortality (NRM) after allogeneic stem cell transplantation (allo-SCT) remains an essential issue. In choosing the appropriate regimen for allo-SCT, decision-making information that considers the complexity of different risk factors is vital. The Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), which was initially derived and validated by investigators at the Fred Hutchinson Cancer Research Center to predict NRM, has become a widely validated tool for predicting outcomes in many transplant settings (Sorror et al. Blood. 2005). It can also stratify patients for the risk of other outcomes, including overall survival and graft versus host disease. Patients with a high HCT-CI score tend to prefer allo-SCT with reduced-intensity conditioning. Conversely, for those who prefer allo-SCT with myeloablative conditioning (MAC) and has a low HCT-CI score, a prognostic indicator is unnecessary. Furthermore, the risk factors for NRM may differ among various conditioning regimens. Therefore, the current study aimed to establish a new prognostic model for patients specific to each MAC regimen before allo-SCT. Methods We performed a retrospective cohort study to develop prognostic models of NRM in patients conditioned with cyclophosphamide/total body irradiation (Cy/TBI) or busulfan/cyclophosphamide (Bu/Cy). We selected patients who had leukemia and lymphoma in remission or had untreated or stable myelodysplastic syndrome and experienced initial allo-SCT relapse between 2007 and 2017 in the Kanto Study of Group for Cell Therapy (KSGCT). The primary outcome measure was 2-year NRM. Furthermore, we evaluated variables such as patient age, albumin, liver function, renal function, respiratory function, ejection fraction (EF), C-reactive protein (CRP), stem cell source, donor type, antithymocyte globulin use, performance status, recipient/donor sexes, time interval from diagnosis to transplant, and HCT-CI score. To identify a set of variables for Cox proportional hazards, we used an Akaike Information Criterion (AIC)-based variable selection procedure. We assigned weights to individual parameters according to their prognostic significance in Cox proportional hazard models. The identified model's discriminative ability was assessed by Harrell's C-statistic calculated using the bootstrap method. Results Among the 555 patients analyzed, 338 received Cy/TBI, and 217 received Bu/Cy. In Cy/TBI and Bu/Cy, the median age was 39 (11-60) and 44 (18-62) years, the HCT-CI score ≤ 2 was observed in 82.1% and 87.6%, and 2-year NRM was found in 13.5% and 16.0% of the patients, respectively. Before transplantation, the most dominant parameters in Cy/TBI were abnormal liver function (AST/ALT or bilirubin >upper limit of normal) and albumin value < 4.5g/dL, whereas those in Bu/Cy were age >40 years, EF < 65 %, and CRP ≥ 0.2 mg/dL. Internal validation with bootstrap resampling showed good discrimination, with C-statistic values of 0.70 (95% CI: 0.69-0.71) in Cy/TBI and 0.68 (95% CI: 0.67-0.69) in Bu/Cy. Each of the abovementioned parameters, including age >40 years, was scored as 1 point. To evaluate the 2-year NRM, we divided the total scores into three risk groups. In the Cy/TBI group, the NRM was 6.9% in low (score 0-1, n = 186), 19.5% in intermediate (score 2, n = 127), and 35.3% in high (score 3, n = 25) scores. In the Bu/Cy group, the NRM was 8.3% in low (score 0-1, n = 93), 21.7% in intermediate (score 2, n = 98), and 29.8% in high (score 3, n = 26) scores (Figure). Higher scores were strongly associated with worse NRM and survival. Conclusions Our prognostic models for NRM estimation can distinguish patients with a high NRM risk. To our knowledge, these models are the first prognostic models used to estimate NRM for standard-risk patients specific to each MAC regimen. This new simple index may help predict NRM and choose an appropriate conditioning regimen before allo-SCT. Figure 1 Disclosures Nakasone: Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Janssen Pharmaceutical: Honoraria; Eisai: Honoraria; Chugai Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria. Fujisawa:Takeda Pharmaceutical Company Limited.: Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau; Novartis Pharma KK: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Janssen Pharmaceutical K.K: Speakers Bureau; NIPPON SHINYAKU CO.,LTD.: Research Funding. Nakaseko:Novartis Pharma KK: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau. Kanda:Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Shire: Honoraria; Daiichi Sankyo: Honoraria; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Mochida Pharmaceutical: Honoraria; Mundipharma: Honoraria; Sanofi: Honoraria, Research Funding; Meiji Seika Kaisha: Honoraria; Shionogi: Research Funding; Otsuka: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharma: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Janssen: Honoraria; Astellas Pharma: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Pfizer: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria.

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Maximally Tolerated Busulfan Area Under the Concentration-Time Curve (AUC) In Combination with Fludarabine as Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation.

Blood ◽

10.1182/blood.v116.21.3499.3499 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3499-3499

Author(s):

Janelle Perkins ◽

Teresa Field ◽

Jongphil Kim ◽

Hugo F. Fernandez ◽

Lia Perez ◽

...

Keyword(s):

Cell Transplantation ◽

Cumulative Incidence ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Systemic Exposure ◽

Hematopoietic Cell ◽

Time Curve ◽

Concentration Time ◽

Gvhd Prophylaxis ◽

Dose Limiting Toxicity

Abstract Abstract 3499 Intravenous busulfan (IV Bu) dosing in hematopoietic cell transplantation (HCT) conditioning regimens has been based largely on bioequivalence studies done with the oral dosage form. As systemic exposure to Bu has been correlated to both efficacy and toxicity, we used area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to IV Bu when given daily in combination with fludarabine as HCT conditioning. Three AUC levels were planned: 6000, 7500, and 9000 micromole*min/L, in cohorts of 20 patients (pts) each, with an additional 10 pts to be enrolled at the maximally tolerated AUC. To be included, pts had be 16–65 years old and have a hematologic malignancy, an HLA A, B, C, DRB1 8/8 or 7/8 matched related or unrelated donor, Karnofsky performance status 70–100%, and adequate organ function. The initial dose of IV Bu for the first AUC level was 170mg/m2/day on day -6 and day -5 then, on day -4 and day -3 doses were adjusted based on pharmacokinetic modeling after the first dose to achieve an average daily AUC of 6000. First doses for the subsequent cohorts were based on the linear correlation between AUC and dose in the previous cohort: 180mg/m2/day for AUC 7500 and 220mg/m2/day for AUC 9000, with dose adjustment on days -4 and -3 as described. Pharmacokinetic analysis was done after the day -3 dose to verify the accuracy of the dose adjustments. The first 20 pts in the AUC 6000 cohort (DL1) were coenrolled onto a randomized trial of GVHD prophylaxis (tacrolimus and methotrexate vs tacrolimus and mycophenolate mofetil) and were analyzed separately from a second cohort of 20 pts receiving an AUC 6000 (DL1A) and GVHD prophylaxis with tacrolimus and methotrexate. 20 pts were then enrolled onto AUC 7500 (DL2), followed by 3 pts on AUC 9000 (DL3). All DL3 pts had dose limiting toxicity so accrual to that level was stopped. An additional 9 pts have been treated to date on DL2 (5 of these are <100 days posttransplant and are not evaluable for toxicity or GVHD). The median (and range) average daily AUC for each of the cohorts were: DL1 5955 (5375-6557); DL1A 6145 (4846-7018); DL2 7555 (5920-8682); DL3 8899 (8784-8955). There were no primary engraftment failures and median times to neutrophil engraftment were: DL1 15 days, DL1A 16 days, DL2 14 days, and DL3 12 days (p=0.01). The dose-limiting toxicity seen at DL3 was hepatic venoocclusive disease (VOD) which developed in all 3 pts; two of these pts died. There were no seizures attributable to IV Bu seen at any dose level. NCI CTCAE toxicities (observed in the first 100 days unrelated to infection or GVHD) that were significantly different between the dose level groups were dermatitis and VOD with more severe toxicity seen in DL2 and DL3. Diarrhea and the use of total parenteral nutrition appeared to be more common on DL2 and DL3 but not significantly so. The cumulative incidence of acute GVHD was similar across the cohorts (p=0.11). There was no difference between the dose levels in cumulative incidence of relapse (p=0.54) or event-free survival (p=0.4). Nonrelapse mortality at 6 months was significantly different: DL1 20%, DL1A 0%, DL2 17.5% and DL3 67% (p=0.008) as was overall survival at 6 months: DL1 75%, DL1A 90%, DL2 80%, DL3 33% (p=0.04). We conclude that in the pts studied, 7500 micromole*min/L is the maximally tolerated AUC based on protocol-defined criteria but exceeding an AUC of 6000 may not provide any survival benefit. Disclosures: Perkins: PDL BioPharma: Research Funding. Off Label Use: IV busulfan was used in combination with fludarabine as conditioning prior to allogeneic hematopoietic cell transplantation in patients with a variety of hematologic malignancies. Field:PDL BioPharma: Research Funding.

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Outcomes of Mismatched Related Allogeneic Stem Cell Transplantation for Chronic Lymphocytic Leukemia: A Retrospective Study on Behalf of the Chronic Malignancies Working Party of the EBMT

Blood ◽

10.1182/blood.v128.22.3504.3504 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3504-3504

Author(s):

Gwendolyn van Gorkom ◽

Michel van Gelder ◽

Dimitris Ziagkos ◽

Henric-Jan Blok ◽

Maria Teresa van Lint ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Gvhd Prophylaxis ◽

Related Donor ◽

Support Research

Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (HCT) is a treatment for CLL that can give long disease control. Even with the availability of kinase and BCL2 inhibitors, HCT is still performed in fit patients (pts) with high-risk CLL. Almost exclusively, outcomes on matched related and unrelated donor transplantations in CLL have been published. Recently, mismatched related donors are gaining interest because of the better outcome of haploidentical HCT with post-transplantation cyclophosphamide (PTCY). Methods: All pts with CLL who received a first allogeneic HCT with a mismatched related donor and whose data were available in the EBMT registry were analyzed. Median values and ranges are reported for continuous variables and percentages for categorical variables. The probabilities of overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method and the log-rank test for univariate comparisons. Relapse/progression and nonrelapse mortality (NRM) were analyzed together in a competing risk framework. Statistical analyses were performed using SPSS and R. Results: One-hundred-seventeen pts with CLL (74% males) underwent a mismatched related donor transplantation between 1984 and 2015 (1984-1999: 10, 2000-2004: 18, 2005-2009: 23, 2010-2016: 66). Median follow-up after HCT was 8 months (range 0-187 months). Median age at transplantation was 54 years (yrs) (range 27-71 yrs). Median time from diagnosis to HCT was 67 months (range 4-207 months). Eighteen pts (17%) had previously undergone autologous stem cell transplantation (ASCT). Disease status at HCT was CR in 16% of pts, PR in 39% and SD/PD in 45%. The Karnofsky score was known for 98 pts; 96% had a score of 70% or more at the time of HCT. Fifty-eight percent of pts received reduced-intensity conditioning, 42% myeloablative conditioning. Peripheral blood stem cells were used in 68% of pts, bone marrow in 32%. The HCT was sex matched in 41% of recipient-donor pairs. The relationship of the donor to the patient was known for 34 pts; in 53% the donor was a child, in 38% a sibling and in 6% a parent. Forty pts (38%) received PTCY as GVHD prophylaxis. In the other 77 pts various methods of T-cell depletion (TCD) were used, but not all methods were specified. At least 56% of those pts had in vivo TCD. For the whole cohort of pts OS at 2 and 5 yrs was 46% and 37%, respectively. PFS at 2 and 5 yrs was 38% and 30%, respectively. The use of PTCY did not have a significant impact on OS (49% vs. 42% at 2 yrs, 44% vs. 33% at 5 yrs, p=0.35) and PFS (45% vs. 31% at 2 yrs, 40% vs. 22% at 5 yrs, p=0.15). CI of NRM in the whole group at 2 and 5 yrs were 41% and 45%, respectively. CI of relapse at 2 and 5 yrs were 21% and 25%, respectively. The CI of NRM and relapse at 2 and 5 yrs were not statistically different in pts who received PTCY compared to other types of TCD (NRM: 38% vs. 45% at 2 yrs, 43% vs. 49% at 5 yrs, p=0.45; relapse: 17% vs. 25% at 2 yrs, 17% vs. 29% at 5 yrs, p=0.33). For the whole cohort, the incidence of acute graft-versus-host disease (aGVHD) at 100 days was 34% for grade II-IV and 16% for grade III-IV with a median time of onset of 23 days (range 4-57 days). Conclusions: Mismatched related donor HCT resulted in a 5-year PFS in 30% of the pts. This result seems only slightly inferior to matched donor transplant (5 yrs PFS 37%1). NRM was higher than expected in this cohort, but comparable to other studies on haploSCT with in vivo T-cell depleted grafts. In conclusion, a mismatched related donor HCT may be considered for high-risk chemoimmunotherapy-refractory or 17p deleted/TP53 mutated CLL pts without options for kinase and BCL2 inhibitor therapy. More data are needed to assess the value of PTCY for GVHD prophylaxis in this specific context. References: 1. Schetelig J, de Wreede L, Moreno C, et al. Risk factors for adverse outcome in patients with Chronic Lymphocytic Leukemia (CLL) undergoing Allogeneic Hematopoietic Cell transplantation (alloSCT): a Retrospective EBMT Analysis. Abstract WP024, EBMT meeting 2015. Figure 1 Figure 1. Disclosures Ciceri: MolMed SpA: Consultancy. Foà:Ariad: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Janssen-Cilag: Consultancy, Speakers Bureau; Genetech: Consultancy; Roche: Consultancy, Speakers Bureau. Hallek:Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Schetelig:Sanofi: Honoraria. Kröger:Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

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Improved GvHD-Free, Relapse-Free Survival (GRFS) with Post-Transplant Cyclophosphamide and Tacrolimus for GvHD Prevention in Older Adults Undergoing Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2021-153366 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2760-2760

Author(s):

Paola Andrea Charry ◽

Maria Queralt Salas ◽

Alexandra Pedraza ◽

María Suárez-Lledó ◽

Nuria Martínez-Cibrian ◽

...

Keyword(s):

Older Adults ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Older Patients ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Free Survival ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

Relapse Rates

Abstract INTRODUCTION The continuous refinement of transplant techniques has lead to a reduction of transplant-related toxicity resulting on an increasing number of allogeneic hematopoietic cell transplantation (alloHCT) performed in older patients. Since 2014, post-transplant cyclophosphamide (PTCy) with tacrolimus (PTCy-TK), alone, has been progressively implemented at our Institution as GvHD prophylaxis for related, matched and mismatched unrelated donor transplantation (MRD, MUD, MMUD). The experience has proved that the use of this prophylaxis induces effective GvHD prevention without increased relapsed rates (Pedraza et al, 2021). Secondary to the encouraging results obtained from the use of PTCy-TK at our Institution, and considering that older patients with hematological disorders are a group of patients with higher risk to develop transplant-related toxicity, this study compares, as far as we know, the results provided by the use of PTCy-TK with conventional GVHD prophylaxis in a consecutive cohort of patients older than 50 years. METHODS Between January 2014 and June 2020, 147 adults with hematological malignancies and > 50 years underwent alloHCT either from MRD or UD at our Institution. Seventy-two (48.9%) patients received PTCy 50 mg/kg/day IV on day +3 and +4, followed by TK, initiated at a dose of 0.03/kg/24h IV on day +5 and titrated to achieve a therapeutic level of 5-15mg/mL. Other GvHD prophylaxes combined calcineurine inhibitors combined with methotrexate, mycophenolate mofetil, or sirolimus, and anti-thymocyte globulin was added especially when MMUD were selected. Data were collected retrospectively and updated in June 2021. Overall survival (OS) and GvHD-Free/Relapsed free survival (GRFS) were considered the main outcome variables, and the cumulative incidence of GvHD was calculated accounting relapse and dead as competing events. In order to analyze the independent impact of PTCy-TK prophylaxis on OS and GRFS, a multivariate Cox regression analysis was performed including GvHD prophylaxis, Disease Risk Index, and transplant year (dichotomized with a cut-off in 2017, given the marked increase of PTCy-TK after this year) as explanatory variables together with other variables with prognostic value in the univariate analysis. RESULTS Baseline characteristics of patients classified according to the GvHD prophylaxis are reported in Figure 1. The two cohorts of patients according to GvHD prophylaxis are well balanced. Peripheral blood was the predominant stem cell source in the vast majority (97%). Of note, 53 out of 72 patients receiving PTCy-TK were transplanted between July 2017 and December 2020. And UD was used in more than 90% of PTCy-TK alloHCT, compared to 44% of alloHCT with other prophylaxes. The median of days for neutrophil (20 vs 16, p<0.01) and platelet (19 vs 11, p<0.01) engraftment were higher for patients receiving PTCy-TK, while the differences between the incidences of viral reactivations and infections were not statistically significant between the two groups. The cumulative incidence of grade II-IV aGvHD (day +100: 21.9% vs 21.5%, p=0.88) and grade III-IV aGvHD (day +100: 9.2% vs 9.3%, p=0.88) were comparable between both cohorts, but the use of PTCY-TK resulted on a significant reduction on the incidence of moderate/severe cGvHD (1-y: 9% vs 31.5%, p<0.01) (Figure 1). OS (1-y: 72.1% vs 66.7%, HR 0.98; p=0.91), NRM (1-y: 18.1% vs 13.3%, HR 1.20; p=0.63), and relapse rates (1-y: 18.1% vs 22.9%, HR 0.86, P=0.65) were similar in both groups (PTCy-TK and other GvHD prophylaxis, respectively). However, PTCy-TK significantly resulted into an improved GRFS (1-y: 52.6% vs 30.7%, HR 1.68, p=0.01). A multivariate analysis confirmed the independent favorable impact of PTCy-TK prophylaxis on GRFS (HR 0.58, p=0.01), but not on OS (Figure 1). CONCLUSIONS PTCy-TK, alone, is an effective GVHD prophylaxis for alloHCT when related and UD are selected. The use of this innovative combination provides superior GRFS than the use of conventional GvHD prophylaxis in older adults undergoing alloHCT, with comparable transplant-related mortality and relapse rates. GRFS is a composite endpoint considered a surrogate outcome of health-related quality of life, and the improvement of this parameter is remarkable in PTCy-TK alloHCT, especially for older patients. Figure 1 Figure 1. Disclosures Lozano: Grifols: Honoraria; Terumo BCT: Honoraria, Research Funding; Macopharma: Research Funding. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Esteve: Novartis: Consultancy, Research Funding; Abbvie: Consultancy; Astellas: Consultancy; Jazz: Consultancy; Novartis: Research Funding; Pfizer: Consultancy; Bristol Myers Squibb/Celgene: Consultancy.

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Frequency and Risk Factors of Cord Graft Failure (CGF) Following Reduced Intensity Conditioning Haplo-Cord Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v124.21.2463.2463 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2463-2463

Author(s):

Stephanie B. Tsai ◽

Hongtao Liu ◽

Tsiporah B. Shore ◽

Michael R Bishop ◽

Melissa M. Cushing ◽

...

Keyword(s):

Risk Factors ◽

Cord Blood ◽

Cell Transplantation ◽

Research Funding ◽

Graft Failure ◽

Mean Value ◽

Reduced Intensity Conditioning ◽

Univariate Analyses ◽

Reduced Intensity

Abstract PURPOSE: Delayed engraftment and cord graft failure (CGF) are serious and often fatal complications after unrelated cord blood (UCB) hematopoietic cell transplantation (HCT), precluding use of low cell dose UCB. The haplo-cord HCT approach allows the use of a lower dose single UCB unit by co-infusion of a CD34+ selected haploidentical graft. Although haplo-cord HCT aims to achieve durable UCB hematopoiesis, the haplo graft provides early temporary engraftment. We describe the frequency, complications and risk factors of CGF after haplo-cord HCT after reduced-intensity conditioning (RIC). PATIENTS AND METHODS: Adult hematologic malignancy patients from the University of Chicago or the Weil Cornell medical centers who underwent haplo-cord HCT between 2007 and 2013 were included. Conditioning consisted of fludarabine, melphalan, and rATG (and TBI 400 cGY if high CNS relapse risk), followed by infusion of a CD34+ selected G-CSF mobilized haploidentical graft and the best HLA matched single UCB unit of at least 0.5 or 1.0 x 10^7 total nucleated cells (TNC)/kg, depending on the protocol. CGF was defined as <5% cord blood chimerism by Day 60 in the unfractionated or CD3 compartments irrespective of neutrophil or platelet counts. Death before Day 60 excluded patients from the primary outcome of CGF at Day 60. Univariate analyses were performed to identify potential risk factors for CGF: Fisher's Exact test for dichotomous and logistic regression for continuous predictor variables. RESULTS: 107 patients were evaluated. Chimerism data were not available on two, and 11 (10.3%) died before Day 60, leaving 94 evaluable patients for CGF. Diseases indications were: AML (51%), ALL, (12%), MDS (11%), and other (25%). Median age of patients was 50 years (range 18-73) and many had active disease at HCT (47%). The mean UCB collected dose was 2.1x10^7 TNC/kg (range 0.77-8.3x10^7 TNC/kg) and HLA cord match was 4/6 in 24% and 5/6 or 6/6 in 73%. Few patients had UCB doses below 1x10^7 TNC/kg (N=5). CGF occurred in 14 of 94 (15%) evaluable patients. Of these, 7 died within 1 year of transplant date. The causes of deaths were: poor graft function (N=2), infection (N=2), relapse or progressive disease (N=2) and unknown (N=1). The other 7 remain alive (range: 7 months to 5.5 years) with haplo-derived or mixed haplo-recipient hematopoiesis. Four are in remission and three have relapsed disease. Median survival for the CGF group was 12.7 months. In univariate analyses, no UCB factor, including cell doses, major ABO mismatch, donor specific antibodies, CMV status, and HLA-match, was associated with CGF. (Table) However, higher haploidentical TNC and CD34+ doses were associated with greater risk of CGF. CONCLUSION: Approximately 15% of patients experienced CGF after haplo-cord HCT. Most have died or relapsed, but some have had relatively long-term survival due to sustained haploidentical hematopoiesis. Avoidance of high haploidentical cell doses may reduce risk of CGF. We were unable to identify other determinants of CGF. In ongoing studies, we have limited the haplo graft to <5 x10^6 CD34+/kg and are testing the use of lower UCB cell doses when large units can not be identified. Additional follow-up is needed to determine if sustained or greater cord chimerism improves long-term outcomes compared to haplo chimerism after RIC haplo-cord SCT. Table: Graft Composition and Association with Cord Graft Failure (CGF) at Day 60 No CGF CGF p-value Evaluable Patients, N=94 N=80 N=14 Cord Blood Unit: Mean/Value (+/-SD or %) Mean/Value (+/-SD or %) Cord Bank Reported (post-processing): TNC/kg x 10^7 2.1 (+/-1.1) 1.9 (+/-0.63) 0.61 TNC/kg<1.5x10^7, N=92 27 (35%) 3 (21%) 0.54 CD34+/kg x 10^5 0.88 (+/- 0.71) 0.98 (+/- 0.80) 0.65 Viability (%) 95.6 (+/-4.7) 96.9 (+/-4.6) 0.38 Viability <85%, N=82 1 (1.5%) 1 (7%) 0.31 Post Wash: TNC/kg x 10^7 1.5 (+/-0.72) 1.4 (+/-0.43) 0.72 TNC/Kg<1.5x10^7, N=92 47 (60%) 8 (57%) 1.0 Viability (%) 91.8 (+/-5.3) 91.9 (+/-5.3) 0.96 Viability <85%, N=92 6 (8%) 2 (14%) 0.3 Haploidentical Graft: TNC/kg x 10^6 3.8 (+/-1.6) 5.0 (+/-2.2) 0.03 CD34+/kg x 10^6 3.8 (+/-1.6) 4.8 (+/-2.2) 0.055 CD34+/kg <3.0 x 10^6, N=92 30 (38%) 2 (14%) 0.13 CD3/kg x 10^4 1.2 (+/-3) 0.53 (+/-0.6) 0.29 Disclosures Larson: Novartis: Consultancy, Research Funding. Stock:Sigma-Tau: Membership on an entity's Board of Directors or advisory committees, Research Funding. Artz:Miltenyi: Research Funding.

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Functional Status Is Associated with Outcomes after Allogeneic Stem Cell Transplantation for Older Patients with Hematologic Malignancies

Blood ◽

10.1182/blood-2018-99-112025 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3599-3599 ◽

Cited By ~ 3

Author(s):

Li-Wen Huang ◽

Chiung-Yu Huang ◽

Charalambos Andreadis ◽

Aaron C. Logan ◽

Gabriel N. Mannis ◽

...

Keyword(s):

Physical Health ◽

Functional Status ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Univariate Analysis ◽

Health Score ◽

Post Transplant ◽

Transplant Outcomes ◽

Physical Health Score

Abstract Introduction: Allogeneic hematopoietic cell transplantation (alloHCT) has historically been reserved for younger, fit patients with hematologic malignancies. With the introduction of non-myeloablative conditioning regimens and improved supportive care, alloHCT has been increasingly offered to older adults. Objectives: To determine the association between functional status as measured by a cancer-specific comprehensive geriatric assessment (CGA) and post-transplant outcomes in an older alloHCT patient population. Methods: We conducted a prospective cohort study of patients aged 50 or older who underwent alloHCT at the University of California San Francisco between October 2011 and September 2017. A cancer-specific CGA (1) was administered prior to alloHCT, which included measures of functional status such as Lawton Instrumental Activities of Daily Living (IADL), Medical Outcomes Study (MOS) Physical Health scale, and patient-reported Karnofsky Performance Status (KPS). Post-transplant outcomes included length of hospital stay (LOS), non-relapse mortality (NRM), progression-free survival (PFS), and overall survival (OS). Results: A total of 148 patients were included in the analysis. The median age at transplant was 62 (range 50-76). Disease types included acute myeloid leukemia (43%), myelodysplastic syndrome (26%), myeloproliferative neoplasm (12%), acute lymphoblastic leukemia (10%), non-Hodgkin lymphoma (5%), multiple myeloma (1%), and other (3%); 68% received non-myeloablative conditioning. Median follow-up was 16.3 months (range 0.9-72.7 months). Median PFS and OS were 22.9 months and 47.6 months, respectively. At baseline, 39% had at least one IADL deficit, and 88% had at least one MOS Physical Health scale deficit. The mean patient-KPS was 82.4 and mean provider-KPS was 91.6; these were weakly correlated (Spearman's r=0.39, p<0.001). In univariate analysis, the presence of any IADL deficit was associated with inferior PFS (HR 1.78, p=0.01) and OS (HR 1.68, p=0.04) (Figure). MOS Physical Health score was associated with increased NRM (HR 1.06 per 1-point change in 20-point scale, p=0.04), inferior OS (HR 1.05, p=0.04), increased LOS (difference 0.63 days, p=0.007), but not with PFS (HR 1.04, p=0.06). Neither patient- nor provider-KPS was associated with NRM, PFS, or OS, but lower patient-KPS was associated with increased LOS (difference 1.94 days, p=0.01). In this study, the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), disease risk by American Society for Blood and Marrow Transplantation (ASBMT) classification, and conditioning intensity were not associated with NRM, PFS, or OS. Notably, chronologic age was not associated with NRM, PFS, or OS (Figure). In addition, age was not associated with baseline IADL score (r=-0.02, p=0.26) or MOS Physical Health score (r=-0.13, p=0.06). Conclusion: IADL impairment was associated with inferior PFS and OS, supporting previous studies (2, 3) identifying IADL as an important predictor for alloHCT. In univariate analysis, IADL was a stronger predictor of post-transplant outcomes than traditional prognostication tools such as age, HCT-CI, and provider-KPS. MOS Physical Health score was associated with multiple poor outcomes including NRM and LOS, suggesting a primary impact on alloHCT toxicity. Multivariate analyses, as well as examination of other CGA variables, are ongoing. References:J Clin Oncol. 2011 Apr 1;29(10):1290-6.Haematologica. 2014 Aug;99(8):1373-9.Bone Marrow Transplant. 2018 May;53(5):565-575. Figure. Figure. Disclosures Andreadis: Genentech: Consultancy, Employment; Gilead: Consultancy; Juno: Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; Kite: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Astellas: Consultancy. Logan:Napajen: Consultancy; Adaptive Biotech: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding. Mannis:Agios: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; NKarta: Membership on an entity's Board of Directors or advisory committees. Smith:Astellas Pharma: Research Funding. Martin:Roche: Consultancy; Amgen: Research Funding; Sanofi: Research Funding. Damon:Novartis: Other: spouse's relationship with company; Boston Scientific: Other: spouse's relationship with company; Actelion: Other: spouse's relationship with company; Gilead Sciences Inc: Other: spouse's relationship with company. Olin:Synapse: Honoraria; Astellas: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding.

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From Ex-Vivo T-Cell Depletion to Post-Transplant Cyclophosphamide: Improved GvHD-Free & Relapse-Free Survival but Comparable Chronic GvHD Incidence in Haploidentical Transplantation. A 15 Years EBMT Registry Analysis on Behalf of the TCWP-EBMT

Blood ◽

10.1182/blood-2019-129105 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 876-876

Author(s):

Maria Teresa Lupo-Stanghellini ◽

Christophe Peczynski ◽

Hildegard T. Greinix ◽

Emmanuelle Polge ◽

Mohamad Mohty ◽

...

Keyword(s):

Research Funding ◽

Ex Vivo ◽

Chronic Gvhd ◽

Univariate Analysis ◽

Disease Status ◽

Free Survival ◽

Patient Gender ◽

Gvhd Prophylaxis ◽

Grade 3

Background: Haploidentical stem cell transplantation (Haplo HSCT) has emerged in the past three decades as an alternative curative option when an HLA match donor is not available. Over time, the use of Haplo has increased dramatically, reaching superimposable results when compared to unrelated and related HSCT strategies, confirming its validity. The widespread use of Haplo mainly relies upon technical advances, control of alloreactivity through graft-versus-host disease (GvHD) prophylaxis combined with a rapid and almost universal probability to find an Haplo donor for any candidate patient. The aim of our study was to provide a picture of acute (aGvHD) and chronic GvHD (cGvHD) incidence in Haplo HSCT across different platform in the past 15 years, where Haplo moved from ex-vivo T-cell depleted (TCD) platform to in-vivo TCD platform to the post-transplantation cyclophosphamide (PTCy). Methods: We compared the outcomes of adult patients receiving a 1st Haplo HSCT for any hematological malignancy according to GvHD prophylaxis - ex-vivo + in-vivo TCD (n=160), in-vivo only TCD (n=507) or PTCy (n=2593) - and reported to the EBMT registry in 2004-2016. Patients with missing data on disease status at last follow-up and GvHD information were excluded. Primary endpoint was GvHD-free & Relapse-free survival (GRFS) with events defined by death or relapse or grade ≥3 aGvHD or extensive (ext) cGvHD. Secondary endpoints were progression-free survival (PFS), overall survival (OS), aGvHD and cGvHD, incidence of relapse (IR) and non-relapse-mortality (NRM). Due to sample size in the first cohort of ex-vivo TCD, multivariate analysis compared only in-vivo TCD vs PTCy cohorts. Table 1 illustrates patients' characteristics. Results: Univariate analysis for 3-year outcomes are reported on table 2. PTCy provides better GRFS, OS, PFS, NRM versus ex-vivo or in-vivo. IR was not significantly different. Likewise, the 3-year CI of cGvHD and ext cGvHD were similar between PTCy, in vivo TCD and ex-vivo TCD (cGvHD 27% [25-29%], 25% [21-29%], 18% [12-25%], p 0.03; ext cGvHD 11% [10-12%], 10% [8-13%], 8% [4-13%], p 0.45). On the contrary the 100-day CI of grade ≥2 aGvHD were lower in the ex-vivo TCD vs PTCy and in-vivo TCD (19% [14-26%], 28% [26-30%], 32% [28-36%], p 0.002) while grade ≥3 aGvHD were lower in the PTCy group vs ex-vivo and in-vivo TCD (9% [8-10%], 11% [7-17%], 14% [11-18%], p <0.001). After adjustment for diagnosis, patient age, disease status, Karnofsky PS, donor/patient gender and CMV, cell source, conditioning intensity, previous auto and year of transplant, the multivariable model comparing in-vivo TCD and PTCy showed better outcome for PTCy. Compared to in-vivo TCD, the hazards for GRFS was 0.76 for PTCy (p 0.004), the HR for PFS was 0.71 (p 0.001) and the HR for OS was 0.7 (p 0.0008), the HR for NRM was 0.63 (p 0.001). Moreover, compared to in-vivo TCD, PTCy yielded similar hazards for grade≥2 aGvHD (HR: 1.02, p 0.89), grade≥3 aGvHD (HR 0.79, p 0.27), cGvHD (HR 1.17, p 0.37), ext cGvHD (HR 1.18, p 0.52) and relapse (HR 0.8, p 0.1). Variables associated with GRFS were active disease, Karnofsky PS ≥90%, diagnosis, donor/patient gender and CMV. An ancillary analysis evaluating the stem cell source effect in the PTCy cohort only, demonstrates comparable outcome endpoints (OS, PFS, NRM, IR) at 2-year between bone marrow (BM) and peripheral blood (PB) PTCy. In univariate analysis GRFS and the 2-year CI of cGvHD were not different between BM and PB (GRFS 47% [45-50%], 46% [44-49%], p 0.085; 2-year CI of cGvHD 25% [23-28%], 27% [25-30%], p 0.2) while ext cGvHD, 100-day CI of grade ≥2 aGvHD and grade ≥3 aGvHD were lower in BM PTCy vs PB PTCy (ext cGvHD 8% [7-10%], 12% [10-14%], p <0.001; grade ≥2 aGvHD 20% [18-22%], 36% [33-38%], p <0.001; grade ≥3 aGvHD 6% [5-7%], 12% [10-14%], p <0.001). Compared to BM PTCy, the HR for cGvHD was 1.55 for PB PTCy (p 0.001), the HR for ext cGvHD was 2.04 (p 0.0003), the HR for grade ≥2 aGvHD was 1,94 (p <0.0001), the HR for grade ≥3 aGvHD was 2.01 (p 0.0001). Conclusions: In the present EBMT registry study on more than 3000 patients transplanted from an Haplo donor, we report improved outcome (better GRFS - in spite of comparable chronic GvHD - OS and PFS, lower NRM) and widespread use in different diagnosis setting other than acute leukemia in PTCy platform. PTCy strategy provides a concrete progress into the field: even if cGvHD still represent a major issue, exploitation of BM PTCy seems to protect against most severe GvHD manifestation. Disclosures Mohty: Jazz Pharmaceuticals: Honoraria, Research Funding. Kröger:Sanofi-Aventis: Honoraria; Riemser: Research Funding; Novartis: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Medac: Honoraria; JAZZ: Honoraria; DKMS: Research Funding; Celgene: Honoraria, Research Funding. Basak:Celgene: Honoraria; Teva: Honoraria.

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Comparison of Tacrolimus Versus Cyclosporine with Methotrexate for Immunosuppression after Allogeneic Hematopoietic Cell Transplantation for Severe Aplastic Anemia: A CIBMTR Analysis

Blood ◽

10.1182/blood.v124.21.4383.4383 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4383-4383

Author(s):

Yoshihiro Inamoto ◽

Paul J. Martin ◽

Mary E. Flowers ◽

Alvaro Urbano-Ispizua ◽

Tao Wang ◽

...

Keyword(s):

Cell Transplantation ◽

Graft Failure ◽

Causes Of Death ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Neutrophil Recovery ◽

Center Effect ◽

Gvhd Prophylaxis ◽

Overall Mortality

Abstract Background: Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for patients with severe aplastic anemia (SAA), but graft-versus-host disease (GVHD) has been a major impediment to success. Cyclosporine (CSP) has been widely used as GVHD prophylaxis after HCT for SAA, while both CSP and tacrolimus (TAC) have been used after HCT for hematological malignancies. The aim of this study was to compare transplant outcomes according to TAC+methotrexate (MTX) vs. CSP+MTX as GVHD prophylaxis after HCT for SAA using large registry data. Patients and methods:The retrospective cohort included 949 patients who had a first allogeneic bone marrow or growth factor-mobilized peripheral blood cell transplantation from HLA-identical siblings (SIB) or unrelated donors (URD) for treatment of SAA using GVHD prophylaxis with MTX in combination with either TAC or CSP from 2001 to 2011. Patients who had ex-vivo T cell depletion were excluded. Study endpoints included grades II-IV acute GVHD, grades III-IV acute GVHD, chronic GVHD, overall mortality, hematopoietic recovery and graft failure. Multivariate Cox regression models were used to evaluate hazard ratios for endpoints with TAC+MTX as compared with CSP+MTX. A stepwise procedure was used in developing models for each outcome, using a P value threshold of 0.05, with GVHD prophylaxis and year of HCT forced in all models. Analyses were performed separately in SIB (n=631) and URD (n=318) recipients. Results: The median age of patients was 19 (range, 0.5 to 70) years. TAC+MTX was used in 62 SIB recipients (10%) and in 120 (38%) URD recipients, and was used more frequently in older patents than in younger patients in both groups. Multivariate analysis showed a decreased risk of overall mortality with TAC+MTX in URD group and an increased probability of neutrophil recovery with TAC+MTX in SIB group, but other outcomes did not differ statistically between TAC and CSP prophylaxis (Table). Center effect was not statistically associated with overall mortality, and results were similar even after adjustment for center effect. Causes of death were similar between CSP and TAC prophylaxis in both SIB and URD recipients. Conclusion: Based on adjusted multivariate analyses, the use of TAC+MTX was associated with a decreased risk of mortality among URD recipients and with earlier neutrophil recovery among SIB recipients. Results showed no statistically significant differences in other outcomes with the 2 prophylaxis regimens, although power was limited by the number of patients treated with TAC. Our results support the use of either prophylaxis regimen for SIB recipients. TAC+MTX may be favored for URD recipients, but the interpretation of the survival difference remains uncertain, since TAC was not associated with a reduction in the risk of GVHD, causes of death were similar between the 2 prophylaxis regimens, and the actual difference in survival was small between the 2 prophylaxis regimens. Table. Multivariate analysis of outcomes with TAC+MTX compared to CSP+MTX Outcome Identical Sibling (n=631) Unrelated (n=318) HR* (95% CI) P HR* (95% CI) P Grades II-IV acute GVHD 1.79 (0.92-3.47) 0.09 1.17 (0.76-1.80) 0.48 Grades III-IV acute GVHD 0.79 (0.19-3.34) 0.75 1.52 (0.81-2.86) 0.19 Chronic GVHD 1.79 (0.92-3.47) 0.09 1.23 (0.80-1.88) 0.35 Overall mortality 1.38 (0.74-2.55) 0.31 0.45 (0.25-0.81) 0.008 ANC recovery 1.47 (1.04-2.08) 0.03 1.29 (0.95-1.75) 0.10 Platelet recovery 1.26 (0.93-1.71) 0.13 0.89 (0.66-1.20) 0.44 Graft failure 1.08 (0.45-2.56) 0.87 0.48 (0.16-1.48) 0.20 *Adjusted for other covariates. Disclosures No relevant conflicts of interest to declare.

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Post-Transplant Cyclophosphamide (PT-Cy) Based Haploidentical Cell Transplantation (Haplo) Versus Rabbit Anti-Thymocyte Globulin (r-ATG) Based HLA Matched Unrelated Donor (MUD) Transplantation in Patients (pts) with Relapsed/Refractory Lymphoma

Blood ◽

10.1182/blood-2019-125876 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4530-4530

Author(s):

Akash Mukherjee ◽

Denái R. Milton ◽

Alison Gulbis ◽

Celina Ledesma ◽

Elias Jabbour ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Hemorrhagic Cystitis ◽

Chronic Gvhd ◽

Univariate Analysis ◽

Advisory Committees ◽

Gvhd Prophylaxis ◽

Comorbidity Index ◽

Similar Survival

Background PT-Cy has emerged as an effective strategy for graft-versus-host disease (GVHD) prophylaxis in Haplo. The reported risk of GVHD with non-PT-Cy in pts receiving MUDs varies between centers. In this report, we compared the engraftment rates, survival, risk of GVHD and comorbidities between PT-Cy Haplo and r-ATG-based MUDs approach in pts with relapse/refractory lymphoma receiving an allogeneic transplantation. Method We retrospectively evaluated 160 adult pts with lymphoma who received Haplo (n=35) or r-ATG-MUDs (n=125) at our center between 2012 and 2018. Pts received GVHD prophylaxis of r-ATG (2-4 mg/kg total on days -3 to -1), tacrolimus and methotrexate if MUD, and tacrolimus and mycophenolate mofetil in addition to PT-Cy (50 mg/kg on days+3, +4) if Haplo. Tacrolimus taper was initiated at 6 months after transplantation in pts with no active GVHD. The study was IRB-approved. Results Haplo pts were more likely to be younger (median age 47 vs 55 yrs; P=0.032), have a lower HCT-Comorbidity Index (median 2 vs 3; P=0.048), and to include more diffuse large b-cell lymphoma (31% vs 22%, and Hodgkins disease (29% vs 16%) (P=0.015). Significant differences were also observed in the conditioning intensity and cell source of transplants between the 2 groups. The majority of Haplo pts (80%) received a reduced intensity-conditioning (RIC) of melphalan/fludarabine +/- 2Gy TBI; the remaining received a myeloablative (MA) busulfan-based regimen (9%) or nonmyeloablative (NMA) (11%) conditioning. In comparison, the percentage of MUDs pts receiving RIC, MA and NMA [bendamustine, fludarabine, rituximab or fludarabine, cyclophophamide, rituximab were 31%, 22% and 46%, respectively (P<0.001). The percentage of pts receiving bone marrow as a source of cells in the Haplo and MUDs groups were 74% vs 14%, respectively (P<0.001). There was no difference in the # of prior therapies received (median = 3, in both), the # of pts who failed a prior autologous (37% vs 26%; P=0.21), disease status (CR vs PR vs refractory; P=0.3), IPI >2 (25% vs 19%, P=0.73) or PET-positive status (55% vs 44%, P=0.33) at study entry between the 2 groups. PT-Cy Halplo group had a significantly higher incidence of symptomatic BK- induced hemorrhagic cystitis compared to r-ATG MUD group (49% vs 10%, P< 0.001). Delayed engraftment was noted in PT-Cy Haplo group compared to r-ATG MUD group with median time to achieve ANC > 500 (18 days vs 10 days; P<0.001), and platelets > 20k were 25.5 days vs 10 days (P<0.001), respectively. The median follow-up time for pts treated with PT-Cy Haplo and r-ATG MUD pts was 12.1 and 20.8 months, respectively. Similar survival and non-relapse mortality (NRM) rates were observed between the 2 groups. The 1-year OS rates were 64% vs 67% (P=0.76) and the 1-year PFS rates were 52% vs 58% (P=0.67). The cumulative incidence (CI) of 1-year NRM was 30% vs 26%, respectively (P=0.66). Chemo-sensitivity (Figure 1), NMA conditioning (Figure 2), and HCT-Comorbidity Index of < 4 were associated with a better OS and PFS in univariate and multivariable analyses. Among histologies, pts with follicular lymphomas had the best OS and PFS. T-cell lymphoma had the worse outcomes. In addition, cystitis was associated with a lower survival rate by univariate analysis (P=0.036). The CI of acute 2-4 GVHD (26% vs 33%, P=0.43), acute 3-4 GVHD (14% vs 12%, P=0.66), and 1-year CI of chronic GVHD (6% vs 15%, P=0.19) were not statistically different between PT-Cy Haplo and r-ATG MUD. By univariate analysis, bone marrow source of graft was the only factor that was found to be significantly associated with a lower risk of chronic GVHD (HR 0.34; P=0.041) (Figure 3). Conclusion Our data show similar survival rates and risk of acute and chronic GVHD in pts with lymphoma who received PT-Cy Haplo and r-ATG MUD. The use of bone marrow graft was the only predictor of a lower incidence of chronic GVHD. Considering the statistically significant delayed time to engraftment and the higher risk of hemorrhagic cystitis, a MUD remains the donor of choice in lymphoma pts who have this option. Disclosures Jabbour: Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Cyclacel LTD: Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding. 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. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding. Kebriaei:Kite: Honoraria; Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Champlin:Johnson and Johnson: Consultancy; Sanofi-Genzyme: Research Funding; Actinium: Consultancy.

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