Targeted Treatment and Survival Following Relapse after Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia and MDS in the Contemporary Era

Introduction: Relapse is the most frequent cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). While transplant-related mortality has decreased substantially over the last few decades, little progress has been made in outcomes and no standard of care exists for patients (pts) with post-alloHCT relapse. In the recent era, several new therapies, including targeted agents, have been approved for ALL, AML, and MDS. We conducted a study to evaluate outcomes of pts with these diseases who relapse after alloHCT in the contemporary period with routine availability of these newer therapeutic agents. Methods: We performed a single-institution retrospective cohort study to review treatment strategies and outcomes of relapse post-alloHCT. We identified 420 adult pts who received their first alloHCT in 2010-2018 using any conditioning regimen or donor source. Overall, 115 (27%) pts experienced relapse (ALL=17/64 [27%], AML=67/242 [28%], MDS=31/114 [27%]) and were included in the analysis. Results: Myeloablative (54%) matched-unrelated donor grafts (50%) were the most common types of HCTs. Peripheral blood stem cell graft (49%) and bone marrow graft (48%) were used the most. Median time from alloHCT to relapse was 5 (range 1-65) months, and 83% of relapses occurred within the first year. Only 24% and 11% of pts experienced grade II-IV acute and any chronic GVHD prior to relapse, respectively. Seven of 17 pts had Philadelphia chromosome positive ALL. Mutation panel was tested in 56% of AML and MDS. Median follow-up period after relapse was 19 (range 6-80) months. The estimated survival after relapse for all diseases was 32% (95% CI 24-41%) at 6 months, 21% (14-28%) at 12 months, and 14% (8-21%) at 24 months (Fig 1). Excluding pts treated with supportive care only, the majority received a combination of different treatments; pts with ALL received median 3 (range 1-5), pts with AML received median 2 (1-4), and pts with MDS received median 1 (1-3) agent. Targeted therapies used for ALL pts included blinatumomab (n=5) and BCR-ABL targeting tyrosine kinase inhibitors with (n=2) or without (n=4) chemotherapy. Among AML pts, targeted agents were used in 15 pts (sorafenib [n=7], 2 each with enasidenib, gemtuzumab ozagamicin, and ivosidenib, and 1 each with venetoclax and SEL24 [a dual pan-PIM/FLT3 inhibitor]). One pt each was treated with enasidenib, gemtuzumab ozagamicin, and PTC299 (an inhibitor of VEGFA mRNA translation) followed by SEL24 for MDS. Second alloHCTs (n=5) were performed median 5 (range 1-16) months after first HCT and median 1 month (range 0-5 months) after relapse. Two pts received no bridging therapy, while 3 pts received chemotherapy (n=2) or donor lymphocyte infusions (DLI [n=1]) prior to the second transplant. DLI without second transplant was used in 25 pts at a median of 20 (range 3-18) months after ALL relapse, median 2 (range 0-13) months after AML relapse, and median 3 (range 1-5) months after MDS relapse. Following DLI, 53% pts developed GVHD. Targeted therapy was associated with a trend towards better survival compared to other therapies (Fig 2, HR 0.65, 95% CI 0.41-1.03, p=0.06). Based on multivariable analysis, matched unrelated (vs. matched sibling, HR 1.70, p=0.027) or haploidentical donor grafts (HR 2.69, p=0.003), presence of grade II-IV acute GVHD before relapse (HR 2.46, p<0.001), and less than 12 months from HCT to relapse (<6 vs. >12 months, HR 6.34, p<0.001; 6-12 vs. >12 months, HR 3.16, p=0.005) were adverse prognostic features with survival after relapse post-alloHCT (Table 1). Conclusion: Outcomes of pts with ALL, AML, and MDS who relapse following alloHCT remain poor in the contemporary era when several newer therapies, including targeted agents, are available for their treatment. Targeted agents were used only in a minority of post-alloHCT relapses likely due to the combination of pt status, absence of the target mutation, the agents' availability, and other factors. Pts who developed grade II-IV acute GVHD and had shorter "disease-free" duration from unrelated or haploidentical donor grafts had the significantly shorter survival following relapse. More innovative treatment strategies to prevent and treat relapse post-alloHCT are needed. Disclosures Hill: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celegene: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding. Anwer:In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Majhail:Atara Bio: Consultancy; Anthem, Inc.: Consultancy; Nkarta: Consultancy; Mallinckrodt: Honoraria; Incyte: Consultancy.

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Poor Outcomes of HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation and High Ferritin Levels after a Reduced-Intensity Conditioning Regimen in Patients with Advanced Myelofibrosis

Blood ◽

10.1182/blood-2019-130338 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5742-5742

Author(s):

Han Bi Lee ◽

Jae-Ho Yoon ◽

Gi June Min ◽

Sung-Soo Park ◽

Silvia Park ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Reduced Intensity Conditioning ◽

Advisory Committees ◽

Reduced Intensity

Allogeneic hematopoietic cell transplantation (allo-HCT) preconditioning intensity, donor choice, and graft-versus-host disease (GVHD) prophylaxis for advanced myelofibrosis (MF) have not been fully elucidated. Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling (n=16) followed by matched (n=10) or mismatched (n=5) unrelated and familial mismatched donors (n=4). Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation≤ 400cGy. All showed engraftments, but four (11.4%) showed either leukemic relapse (n=3) or delayed graft failure (n=1). Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III-IV acute GVHD was higher with HLA-mismatch (70% vs. 20%, p=0.008). Significant hepatic GVHD was observed in nine patients (5 acute, 4 chronic), and six of them died. Multivariate analysis revealed inferior OS with HLA-mismatch (HR=6.40, 95%CI 1.6-25.7, p=0.009) and in patients with high ferritin level at post-HCT D+21 (HR=7.22, 95%CI 1.9-27.5, p=0.004), which were related to hepatic GVHD and high NRM. RIC allo-HCT can be a valid choice for advanced MF. However, HLA-mismatch and high post-HCT ferritin levels related to significant hepatic GVHD should be regarded as poor-risk parameters. Disclosures Kim: Handok: Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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Sirolimus/Tacrolimus Facilitates Preferential Recovery of Regulatory T Cells (Treg) After Allogeneic Hematopoietic Cell Transplantation (HCT), and Is More Effective Than Methotrexate/Tacrolimus in Preventing Grade II-IV Acute Graft Vs. Host Disease (GVHD) and Moderate to Severe Chronic Gvhd

Blood ◽

10.1182/blood.v118.21.323.323 ◽

2011 ◽

Vol 118 (21) ◽

pp. 323-323 ◽

Cited By ~ 1

Author(s):

Joseph Pidala ◽

Jongphil Kim ◽

Heather Jim ◽

Hugo F. Fernandez ◽

Marcie Tomblyn ◽

...

Keyword(s):

T Cells ◽

Board Of Directors ◽

Research Funding ◽

Causes Of Death ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Advisory Committees ◽

Graft Vs Host Disease ◽

Grade Ii

Abstract Abstract 323 Sirolimus/Tacrolimus Facilitates Preferential Recovery of Regulatory T cells (Treg) after Allogeneic Hematopoietic Cell Transplantation (HCT), and is More Effective than Methotrexate/Tacrolimus in Preventing Grade II-IV Acute Graft vs. Host Disease (GVHD) and Moderate to Severe Chronic GVHD Background: Clinical translation of the Treg suppressive potential will require definition of a pharmacologic immune suppressive platform conducive to preferential Treg reconstitution post-HCT. Sirolimus has differential impact on Treg and conventional T cells. Patients and Methods: We performed a prospective, randomized phase II trial of sirolimus (SIR) and tacrolimus (TAC) vs. methotrexate (MTX) and TAC. From 9/2008 to 5/2011, a total of 74 patients were randomized 1:1 to SIR/TAC vs. MTX/TAC, stratified by age (> or ≤ 50) and donor relation (related vs. unrelated). SIR was administered as a 9 mg oral loading dose on day -1, followed by maintenance with 4 mg daily adjusted to target 8–12 ng/ml; SIR was continued for at least 1 year. MTX was 15 mg/m2 on day +1, then 10 mg/m2on days +3, 6, and 11. TAC was administered at 0.02 mg/kg/day IV or equivalent oral dosing starting on day -3. Target TAC levels were 3–7 ng/ml for the SIR arm versus 10–15 ng/ml for the MTX arm and were maintained through day 60. TAC was tapered thereafter in the absence of acute GVHD. Patient age for the whole study was 23 to 69 (median 49) years, and disease diagnoses included AML (23), ALL (15), MDS (9), MM (8), NHL (8), CLL (7), CML (2), and MPD (2). Patients received peripheral blood mobilized stem cells from HLA-A, B, C, and DRB1 matched sibling (n=35) or unrelated donors (n=39). Age, diagnosis, disease risk and donor relation were balanced across the two study arms. Serial peripheral blood samples were obtained at baseline pre-HCT, day 0, and days 30, 90, 180, and 360 post-HCT. Treg were defined by the surface CD4+CD25brightCD127negative phenotype. The reciprocal relationship between negative surface CD127 and high intracellular FoxP3 expression was confirmed in a subset (n=15) of day 30 patient samples (r=0.94). Results: Median percent Tregs among blood CD4 T cells at day 30 was 16.3 (range 12.5–17.9) for SIR versus 9.9 (8.6–13.5) for MTX, p < 0.0001, and 14.6 (10.8–18.1) for SIR and 9.7 (7.5–11.6) for MTX at day 90 post-HCT, p = 0.0009. SIR-treated patients had increased absolute numbers of Treg, and decreased absolute numbers of non-Treg CD4+ cells on days 30 and 90. The 100-day cumulative incidence of grade 2–4 acute GVHD for SIR was 43% (95% CI 30–63%), and 89% (95% CI 80–100%) for MTX, p<0.0001. Grade 3–4 acute GVHD for SIR was 16% (95% CI 7–36%) and 13% (95% CI 5–33%) for MTX, p=0.16. The incidence of any grade chronic GVHD for SIR was 51% (95% CI 34–78%) and 67% (95% CI 52–85%) for MTX, p=0.56. The cumulative incidence of NIH consensus-defined moderate to severe chronic GVHD was 20% (95% CI 9–43%) following SIR, and 63% (95% CI 47–83%) for MTX, p=0.013. Median time to neutrophil engraftment was comparable (SIR 16, range 11–22 days; MTX 16, range 12–28, p=0.57), and platelet engraftment was improved with SIR (SIR 12, range 6–20; MTX 16, range 10–33, p=0.012). No significant differences in peak mucositis, hepatic veno-occlusive disease (VOD), or thrombotic microangiopathy were observed between SIR and MTX. Overall survival did not significantly differ, log-rank p=0.55. Causes of death in SIR included relapse (n=2), and non-relapse death (septicemia 2, acute GVHD 1, chronic GVHD 1, influenza pneumonia 1, RSV pneumonia 1, VOD 1, multi-organ failure 1). Causes of death in the MTX arm were relapse (n=7), and non-relapse death (diffuse alveolar hemorrhage 1, GVHD 1). We performed serial assessment of patient-reported quality of life (QOL) with the FACT-BMT. While those patients in the MTX group had significantly better mean FWB and FACT-G scores at baseline pre-HCT, we did not detect significant differences in any FACT-BMT domain or summary score at day 30 or 90 post-HCT. Further follow up is needed to study longer term recovery of QOL in SIR and MTX treated patients. Conclusions: These results of a randomized, controlled study provide evidence that the combination of SIR/TAC favors Treg recovery and more effectively prevents acute GVHD and moderate to severe chronic GVHD after allogeneic HCT. Disclosures: Alsina: Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding.

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Impact of Specific Adverse Cytogenetic Features on Outcomes after Allogeneic Hematopoietic Cell Transplantation in Myelodysplastic Syndrome with Very Poor Risk Cytogenetics: A Study from the Chronic Malignancies Working Party of EBMT

Blood ◽

10.1182/blood-2021-150892 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3953-3953

Author(s):

Xavier Poiré ◽

Diderik-jan Eikeman ◽

Linda Koster ◽

Johan A. Maertens ◽

Jan J. Cornelissen ◽

...

Keyword(s):

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Advisory Committees ◽

Free Survival ◽

Grade Ii

Abstract INTRODUCTION: Myelodysplastic Syndrome (MDS) is a heterogenous disease which is almost incurable without an allogeneic hematopoietic cell transplantation (allo-HCT). Within the revised international scoring system (R-IPSS), MDS with poor and very poor cytogenetics have a much worse outcome after allo-HCT. The very poor cytogenetic subgroup refers to patients harboring more than 3 abnormalities and is therefore a highly heterogenous group. We have shown in acute myeloid leukemia (AML) that beyond complex karyotype, specific adverse cytogenetic features such as 7q abnormalities (abn7q), 5q abnormalities (abn5q), 17p abnormalities (abn17p) and monosomal karyotype (MK) worsen the outcomes after allo-HCT. We have therefore retrospectively reviewed MDS with very poor cytogenetics and studied the impact of adverse cytogenetic features on outcomes after transplant. METHODS: We selected MDS patients who underwent allo-HCT between 2001 and 2018 from a matched related or unrelated donor, for whom a full cytogenetic report was available in the EBMT registry. We then stratified them according to the presence of abn7q, abn5q, abn17p, MK and the number of abnormalities (≤5, 6-9 and ≥10). Graft-versus-host disease (GvHD) and relapse-free survival (GRFS) was defined as survival without grade II-IV acute GvHD, extensive chronic GvHD or relapse. RESULTS: A total of 154 patients were identified in the registry. One hundred twenty-three patients (81%) had MDS with excess of blasts and 4 (3%) had secondary AML. Median age was 59 years (interquartile range (IQR), 51-64) and the median follow-up was 38 months (95% confidence interval (CI), 34-60). The time from diagnosis to allo-HCT was a median of 6 months (IQR, 4-8). Two thirds of patients received a reduced-intensity conditioning regimen (N = 103, 67%) and 87 patients had a matched unrelated donor (57%). Almost all patients were in first complete remission at time of transplant (N= 149, 97%). Regarding specific cytogenetic features, 87 patients had abn7q (57%), 99 abn5q (64%), 59 abn17p (38%) and 120 MK (78%) with considerable overlap between groups. The 2-year overall survival (OS) and progression-free survival (PFS) was 34% (95% CI 26-42%) and 24% (95% CI 17-31%), respectively. The 2-year cumulative incidence of relapse and non-relapse mortality (NRM) was 59% (95% CI 51-67%) and 18% (95% CI 12-24%), respectively. The cumulative incidence of grade II-IV acute GvHD and chronic GvHD was 33% (95% CI 25-40%) and 44% (95% CI 36-53%) by day 100 and 2 years respectively. The 2-year GRFS was 12% (95% CI 6-17%). The presence of abn5q was associated with a significantly decreased PFS of 17% (95% CI 9-25%) versus 36% (95% CI 23-49%); p=0.05) and GRFS (6% (95% CI 1-11%) versus 23% (95% CI 11-34%); p=0.04). The presence of abn7q was associated with significantly increased NRM (25% (15-34%) versus 9% (2-16%); p=0.02) which did not translate into OS. There were no specific cytogenetic features that had an independent impact on the cumulative incidence of relapse, but age over 55 years did increase the relapse risk (<55: 45% (95% CI 31-59%); 55-65: 65% (95% CI 54-77%); >65: 66% (95% CI 50-83%); p=0.03). A continuous effect was also observed (per decade increase: HR=1.24, 95%CI 1.02-1.52; p=0.03). Patients with an interval of more than 6 months from diagnosis to allo-HCT had almost double the OS (45% (95% CI 32-58%)) compared to patients with an interval less than 6 months (27% (95% CI 17-37%); p=0.04), however a continuous effect was not observed. CONCLUSION: MDS with very poor cytogenetics according to R-IPSS is a very bad group with dismal outcomes after allo-HCT. Within this high-risk group, specific adverse cytogenetic features such as the number of abnormalities, abn7q, abn5q, abn17p or MK did not stratify outcomes further, except for abn5q which was associated with a decreased PFS. Our results might be explained in part by the low number patients and by the over-representation of adverse features within this cohort. Despite that, advancing age was associated with increased relapse. Whilst allo-HCT remains the best therapeutic option for this very high-risk patient group, efforts should focus on post-transplant preemptive intervention strategies to prevent relapse. Disclosures Byrne: Incyte: Honoraria. Schroeder: Celgene: Honoraria, Other: Travel support, Research Funding. Blaise: Jazz Pharmaceuticals: Honoraria. Hayden: Jansen, Takeda: Other: Travel, Accomodation, Expenses; Amgen: Honoraria. Scheid: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria; Roche: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.

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Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽

10.1182/blood-2019-130419 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4619-4619

Author(s):

Jee Yon Shin ◽

Sung-Soo Park ◽

Gi June Min ◽

Silvia Park ◽

Sung-Eun Lee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Advisory Committees ◽

Sibling Donor ◽

Alternative Donor ◽

Matched Sibling ◽

Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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Prediction of Graft-Versus-Host Disease in Recipients of Single Mismatched Unrelated Hematopoietic Cell Transplantation Donor Using a Highly Multiplexed Proteomic Assay, MHC-Pepseq

Blood ◽

10.1182/blood-2021-153597 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1808-1808

Author(s):

Karamjeet S. Sandhu ◽

Ketevan Gendzekhadze ◽

Dongyun Yang ◽

Ryotaro Nakamura ◽

Sally Mokhtari ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Graft Versus Host Disease ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Advisory Committees ◽

Graft Versus Host ◽

Mismatched Donor

Abstract Graft-versus-host disease (GVHD) remains a major cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). In HLA-mismatched donor setting, indirect presentation of allogeneic peptides from recipient's mismatched HLA class I or II proteins by donor or recipient antigen presenting cells can be an immunogenic driver of GVHD. However, the potential diversity of such antigens is large, and predicting them in a systematic manner has proven challenging. Using a novel, highly-multiplexed peptide-MHC binding assay (MHC-PepSeq) we sought to 1) identify allogeneic peptides derived from mismatched HLA protein that can be efficiently presented by HLA-DR, and 2) explore the possibility that the frequency of these HLA-DRB1 binding allopeptides may be predictive of clinical GVHD in HLA-DPB1 mismatched donor/recipient pairs. Using publicly-available population allele frequency data (allelefrequencies.net), we identified a set of class I and II sequences that cover >95% of alleles at each of 9 human HLA-loci (-A, -B, -C, -DRA1,-DRB1, -DQA1, -DQB1, -DPA1, -DPB1) in 3 major US populations (European Caucasian, African American, Mexican Chicano). When represented in the form of densely overlapping tiled 15-mer peptides, 7,744 unique 15mers were identified. We encoded these peptides into DNA oligonucleotides and used the PepSeq parallel synthesis protocol to generate a library of the corresponding DNA-barcoded peptides. The library was incubated with recombinantly-expressed full-length HLA proteins, washed, eluted, amplified, and sequenced to identify the various HLA-derived peptides that bind to the assayed HLA proteins (Figure 1). In the current study, DPB1-derived allopeptides in the setting of HLA-A, B, C, DRB1, and DQB1 (10/10) matched unrelated (MUD) HCT donors with a mismatch in DPB1 were investigated. The peptide library was assayed for binding to the DRB1*07:01 protein, selected since it was the common allele in this cohort. We identified 327 patients who were transplanted at our center and met these criteria. For each case, we used comprehensive in silico tiling to identify HLA-DPA and DPB-derived peptides present in the recipient but absent in the donor. This set was intersected with the peptides identified as binders to HLA-DRB1*07:01 in the 7,744-plex MHC-PepSeq assay, to arrive at a donor-recipient pair-specific set of 'allopeptides' Overall, we identified such allopeptide at the median of 0 (range: 0-8) across the 327 cases. Next, we examined an association between the number of allopeptides and acute GVHD in the cohort of 94 patients with positive HLA-DRB1*07:01. Median age at alloHCT was 60 years (range: 19-78), 53% males, 1.% bone marrow graft and only 7% female to male donors. Ablative (TBI) conditioning was delivered to 34%) pts. 83% received Tacrolimus/Sirolimus-based, and 9% received post-transplant cyclophosphamide-based GVHD prophylaxis. Patient/HCT characteristics are summarized in Table 1. In this cohort, 18% had no DPB1 mismatch, 54% had a single and 28% had double mismatches, with 21% pts carrying non-permissive DPB1 mismatches. Allopeptide score was 0 in 75% of pts. Non-permissive mismatch 9 (39%) vs. 11 (16%) were more likely to have allopeptide score ≥1 and similarly double mismatches 11 (48%) vs. 15 (21%) were more likely to have allopeptide score of ≥1. Among pts with ≥1 allopeptide score 14 (61%) had DPB1 matched or permissive mismatch. The cumulative incidence of grade 2-4 acute GVHD was 40.8% (range: 29-52) in pts with no allopeptides from DPB1 compared with 56% (range: 34-74) in those with ≥1 allopeptides (p=0.259) (Figure 2). The cumulative incidence of grade 3-4 acute GVHD and chronic GVHD were similar between allopeptide 0 vs. ≥1. Together, we show that the "MHC-PepSeq" assay can identify novel candidate HLA-derived allopeptides in 10/10 MUD HCTs. The number of such peptides are relatively low - with a majority having no allopeptide. In an exploratory analysis in a selected cohort of patients with HLA-DRB1*0701 in the setting of 10/10 MUD HCT, the number of allopeptides in our assay may be predictive of GVHD. The expanded analyses on other HLA-DRB1 restriction elements are underway. Figure 1 Figure 1. Disclosures Al Malki: CareDx: Consultancy; Hansa Biopharma: Consultancy; Neximmune: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Rigel Pharma: Consultancy. Ali: BMS: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy.

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Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation Following Fludarabine Plus 2 Gy TBI or ATG Plus 8 Gy TLI: A Phase II Randomized Study from the Belgian Hematological Society

Blood ◽

10.1182/blood.v124.21.542.542 ◽

2014 ◽

Vol 124 (21) ◽

pp. 542-542

Author(s):

Yves Beguin ◽

Pierre Zachee ◽

Johan Maertens ◽

Tessa Kerre ◽

Aurelie Ory ◽

...

Keyword(s):

Total Dose ◽

Cell Transplantation ◽

Research Funding ◽

Hematological Malignancies ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Randomized Study ◽

Inclusion Criteria ◽

Grade Ii

Abstract Background. Allogeneic hematopoietic cell transplantation (allo-HCT) following nonmyeloablative conditioning is increasingly used as treatment for hematological malignancies in older patients or those with comorbidities. One of the most widely used nonmyeloablative conditioning associates fludarabine (90 mg/m² total dose) and 2 Gy total body irradiation (TBI) (Flu-TBI). This regimen can be safely performed in an outpatient setting but is associated with a relatively high incidence of graft-versus-host disease (GVHD). In an effort to prevent GVHD, the Stanford group have developed another nonmyeloablative conditioning that combines total lymphoid irradiation (TLI, 8 Gy total dose) with ATG (7.5 mg/kg Thymoglobulin® total dose) (TLI-ATG). As these 2 conditioning regimens have not been compared head to head, the Belgian Hematological Society (BHS)-transplantation committee initiated a phase II multicenter randomized study comparing nonmyeloablative allo-HCT with PBSC with either Flu-TBI (TBI arm) or TLI-ATG (TLI arm), and postgrafting immunosuppression with tacrolimus and mycophenolate mofetil. Here, we report the final analysis of the study. Methods. Patients were randomized 1/1 between TBI or TLI arm. Main inclusion criteria consisted of hematological malignancies not rapidly progressing, age ≤ 75 years of age, and having a HLA-identical sibling donor or 10/10 HLA-matched related or unrelated donors who is fit to donate PBSC. The primary endpoint was the 6-month incidence of grade II-IV acute GVHD. Results. 107 patients were randomized in the TBI (n=55) or TLI (n=52) arms between January 2008 and March 2011 in one of the 9 participating centers. Thirteen patients (6 in the TBI and 7 in the TLI arm) were excluded from the analyses because they did not meet the inclusion criteria at the time of the start of the conditioning (disease relapse before the start of the conditioning (n=5), ineligible for further irradiation (n=3), donor refusal to give PBSC (n=2), HLA-mismatched donor (n=2), and poor performance status (PS) precluding transplantation (n=1)). One patient randomized in the TBI arm received the TLI conditioning (and was analyzed in intention to treat in the TBI arm). Thus, the analysis includes data from 94 patients randomized to the TBI (n=49) or TLI (n=45) arm. The 2 groups were well balanced. Median follow-up for surviving patients was 45 (range, 19-65) months. The 180-day cumulative incidences of grade II-IV acute GVHD were 12.2% versus 8.9% in TBI and TLI patients, respectively (P=0.5). Two-year cumulative incidences of moderate/severe chronic GVHD were 40.8% versus 17.8% in TBI and TLI patients, respectively (P=0.017). Four-year cumulative incidences of relapse/progression were 22% and 50% in TBI and TLI patients, respectively (P=0.017). The difference remained statistically significant in multivariate analysis (HR=2.3, P=0.02). Four-year cumulative incidences of nonrelapse mortality were 24% and 13% in TBI and TLI patients, respectively (P=0.5). Finally, 4-year overall (OS) and progression-free survivals (PFS) were 53% and 54%, respectively, in the TBI arm, versus 54% (P=0.9) and 37% (P=0.12), respectively, in the TLI arm. Conclusions. In comparison to patients included in the TBI arm, patients included in the TLI arm had lower incidence of chronic GVHD, higher incidence of relapse and similar OS. The study was registered on ClinicalTrial.gov (NCT00603954). Disclosures Beguin: Genzyme / Sanofi: Research Funding. Baron:Genzyme / Sanofi: Honoraria, Research Funding.

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The Effect of JAK 1/2 Inhibitors on Outcomes of Allogeneic Stem Cell Transplantation for Patients with Myelofibrosis

Blood ◽

10.1182/blood-2018-99-112769 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5784-5784

Author(s):

Guido Lancman ◽

Kathleen Miller ◽

Shuli Li ◽

Vincent T. Ho ◽

Amir T. Fathi ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Research Funding ◽

Acute Gvhd ◽

Advisory Committees ◽

Free Survival ◽

Donor Type

Abstract Introduction: Ruxolitinib was the first JAK 1/2 inhibitor (JAKi) approved for myelofibrosis (MF), with several other JAKi in development. Ruxolitinib was approved on the basis of reducing splenomegaly and improving constitutional symptoms, but its effect on subsequent allogeneic stem cell transplantation (SCT) is not well understood. Retrospective studies to date have reported mixed outcomes after SCT for MF patients with previous exposure to JAKi. In this multicenter retrospective study, we report on outcomes of patients with MF treated with SCT at our institutions. Methods: We analyzed outcomes for 184 consecutive patients at three institutions who underwent SCT for primary or secondary MF. Primary outcomes included overall survival (OS), progression free survival (PFS), and graft-versus-host-disease (GVHD)-free and relapse-free survival (GRFS), all measured from the time of SCT. Cox proportional hazard regressions were fit to estimate the association between the use of JAK 1/2 inhibitors prior to SCT and OS, PFS, and GRFS, adjusting for donor type and DIPSS-plus status. p<0.05 was considered statistically significant. Results: 72 patients received a JAKi prior to SCT, while 112 did not. Patients in these two groups were well-matched with respect to age, sex, DIPSS plus score, conditioning, and donor type (Table 1). Median follow-up was 31.2 months (range: 0.8-146.3 months). In univariate analysis, there was no difference in OS (JAKi: 4-yr OS 56.7% [95% CI 40.9-69.8%] vs. no JAKi: 43.6% [95% CI 32.9-53.9%], p=0.49), PFS (JAKi: 4 yr PFS 54.1% [95% CI 40.8-65.7%] vs. no JAKi: 43.9% [95% CI 33.4-53.9%], p=0.77), or GRFS (JAKi: 8-month GRFS 56.6% [95% CI 44.1-67.4%] vs. no JAKi: 50.4% [95% CI 40.4-59.5%], p=0.62) in the overall population; there was similarly no difference when comparing only intermediate-risk or only high-risk patients. In multivariate analysis, there was no difference in these outcomes for patients based on previous JAKi exposure when accounting for DIPSS plus score and donor type (related vs unrelated). Rates of acute GVHD were similar between the two groups (JAKi: 53.5% vs. no JAKi: 55.0%, p=0.88), including grade 3 or 4 acute GVHD (JAKi: 16.9% vs no JAKi: 19.8%, p=0.70). Conclusions: Our data suggest that there is no statistically significant difference in OS, PFS, GRFS, or rates of acute GVHD after SCT for MF patients based on previous JAKi treatment. This was true overall and after adjusting for DIPSS plus risk score or donor type. Given the retrospective design of our study, we were not able to assess prior response to JAKi or splenomegaly at SCT, which may influence outcomes. Given mixed results in the literature to date, we eagerly await the results of ongoing phase 2 trials of JAKi prior to SCT for MF. Disclosures Ho: Jazz Pharmaceuticals: Consultancy. Fathi:Astellas: Honoraria; Jazz: Honoraria; Boston Biomedical: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria. Chen:Takeda Pharmaceuticals: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy. Hoffman:Formation Biologics: Research Funding; Incyte: Research Funding; Janssen: Research Funding; Merus: Research Funding; Summer Road: Research Funding. Mascarenhas:Novartis: Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Promedior: Research Funding; Janssen: Research Funding; Roche: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Establishment of Subspecialized Care in Hematologic Malignancies and a Hematopoietic Cell Transplantation Program

Blood ◽

10.1182/blood.v128.22.3580.3580 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3580-3580

Author(s):

Edward A. Copelan ◽

Jonathan M. Gerber ◽

Saad Z Usmani ◽

Michael R. Grunwald ◽

Nilanjan Ghosh ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Hematologic Malignancies ◽

Hematopoietic Cell ◽

Advisory Committees ◽

Transplantation Program ◽

Disease Specific

Abstract Introduction Access to appropriate healthcare close to home is a national and global problem with huge geographic variation in availability of subspecialized care and specific therapies, as illustrated by hematopoietic cell transplantation rates [Gratwohl, et al. Lancet Hematol, 2015]. Disease-specific physician specialization appears to improve outcomes in hematologic malignancies [Go, et al. Mayo Clin Proc, 2015]. Charlotte is the 2nd largest city in the Southeastern United States and 17th largest in the US, yet subspecialized care in hematologic malignancies including a leukemia unit and hematopoietic cell transplantation (HCT) program were non-existent 3 years ago. The closest HCT program was a 90-minute drive from Charlotte. Many patients lacked the resources or willingness to travel to a transplant center and died of potentially curable diseases. Establishment of a transplantation program, in particular, requires a substantial upfront investment, broad infrastructure and highly specialized interdisciplinary care. Better transplant outcomes have been associated with higher numbers of procedures [Loberiza, et al. Blood, 2005], but programs established over the last decade have struggled to attract adequate numbers of patients to support the required investment. Methods In 2011 Carolinas HealthCare System (CHS), which serves as a healthcare safety net for the region, decided to develop the Levine Cancer Institute as a primary through quaternary referral and treatment center, integrated through more than 12 sites, with a key focus being a program in HCT. The Department of Hematologic Malignancies and Blood Disorders was established in September 2012. We envisioned that the development of specialized care in leukemia, lymphoma, and plasma cell disorders, as well as more complex non-malignant hematologic disorders, would improve the quality of care for patients with those diseases, attract larger volumes of patients, and serve to identify patients appropriate for HCT in a timely manner. A 16 bed hematologic malignancies unit housed in a protected environment was constructed and completed in January 2014. Results Starting with 4 general hematologists, the department has grown over 4 years to include 23 faculty members, 14 of whom provide subspecialized care in hematologic malignancies and HCT. Patient volumes have grown more than six-fold during this time. The HCT Program performed its first transplant in March 2014, with a total of 60 transplants performed in 2014 and 81 in 2015. The HCT Program is on pace to perform over 100 transplants in 2016. The program received FACT accreditation in 2016, a little more than 2 years after the first HCT was performed. The age range of patients undergoing transplantation is from 22 to 76 (median 58) years. Sixty-nine percent of transplants have been autologous and 31% allogeneic, of which 65% were from haploidentical related donors. The proportion of transplants which are allogeneic is steadily increasing. More than 90% of patients who have undergone transplantation were referred through a disease-specific section. Non-relapse mortality (NRM) at 1 year is 1.8% for autologous transplants and 9.4% for allogeneic transplants, with survival rates at 1 year of 95.6% and 80.8% respectively. Notably, there is no difference in NRM (P=0.86), relapse-free survival (P=0.85), or overall survival (P=0.47) between HLA-identical and haploidentical transplant recipients. Conclusions Three years ago, for patients in Charlotte, access to subspecialized care in hematologic malignancies and HCT required significant travel. The development and growth of a program that provides disease-specific care in hematologic malignancies has overcome this barrier and has provided a base for growth of a newly established program in HCT. These developments have elevated the quality of care in hematologic malignancies in the Charlotte area and permit patients to receive appropriate and complex care close to home. Disclosures Gerber: Janssen: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Usmani:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Novartis: Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Array: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Britsol-Myers Squibb: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Grunwald:Amgen: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Medtronic: Equity Ownership; Janssen: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees. Ghosh:Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SGN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Research Funding. Bhutani:Prothena: Research Funding; Takeda Oncology: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Onyx, an Amgen subsidiary: Speakers Bureau. Symanowski:Endocyte: Consultancy; Eli Lilly & Co: Consultancy; Ra Pharma: Consultancy; Caris Life Sciences: Consultancy. Raghavan:Gerson Lehrman: Consultancy; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees. Avalos:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽

10.1182/blood-2020-140680 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 13-14

Author(s):

Ana Garrido ◽

Montserrat Hoyos ◽

Marina Diaz-Beyá ◽

Montserrat Arnan ◽

Susana Vives ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

High Dose ◽

Prognostic Impact ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

Allogeneic Hct

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

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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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