scholarly journals Post-transplantation cyclophosphamide reduces the incidence of acute graft-versus-host disease in patients with acute myeloid leukemia/myelodysplastic syndromes who receive immune checkpoint inhibitors after allogeneic hematopoietic stem cell transplantation

2021 ◽  
Vol 9 (2) ◽  
pp. e001818 ◽  
Author(s):  
Chantal Saberian ◽  
Noha Abdel-Wahab ◽  
Ala Abudayyeh ◽  
Hind Rafei ◽  
Jacinth Joseph ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Acute Gvhd ◽  
Checkpoint Inhibitors ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Acute Myeloid

BackgroundImmune checkpoint inhibitors (ICIs) are being used after allogeneic hematopoietic stem cell transplantation (alloHCT) to reverse immune dysfunction. However, a major concern for the use of ICIs after alloHCT is the increased risk of graft-versus-host disease (GVHD). We analyzed the association between GVHD prophylaxis and frequency of GVHD in patients who had received ICI therapy after alloHCT.MethodsA retrospective study was performed in 21 patients with acute myeloid leukemia (n=16) or myelodysplastic syndromes (n=5) who were treated with antiprogrammed cell death protein 1 (16 patients) or anticytotoxic T lymphocyte-associated antigen 4 (5 patients) therapy for disease relapse after alloHCT. Associations between the type of GVHD prophylaxis and incidence of GVHD were analyzed.ResultsFour patients (19%) developed acute GVHD. The incidence of acute GVHD was associated only with the type of post-transplantation GVHD prophylaxis; none of the other variables included (stem cell source, donor type, age at alloHCT, conditioning regimen and prior history of GVHD) were associated with the frequency of acute GVHD. Twelve patients received post-transplantation cyclophosphamide (PTCy) for GVHD prophylaxis. Patients who received PTCy had a significantly shorter median time to initiation of ICI therapy after alloHCT compared with patients who did not receive PTCy (median 5.1 months compared with 26.6 months). Despite early ICI therapy initiation, patients who received PTCy had a lower observed cumulative incidence of grades 2–4 acute GVHD compared with patients who did not receive PTCy (16% compared with 22%; p=0.7). After controlling for comorbidities and time from alloHCT to ICI therapy initiation, the analysis showed that PTCy was associated with a 90% reduced risk of acute GVHD (HR 0.1, 95% CI 0.02 to 0.6, p=0.01).ConclusionsICI therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after alloHCT may be a safe and feasible option. PTCy appears to decrease the incidence of acute GVHD in this cohort of patients.

scholarly journals The 17-Gene Leukemic Stemess Score Can Predict Treatment Outcomes Following Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3299-3299
Author(s):  
Dennis Dong Hwan Kim ◽  
Taehyung Kim ◽  
Tracy Murphy ◽  
Steven M Chan ◽  
Mark D. Minden ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Allogeneic Hct ◽  
Gvhd Prophylaxis ◽  
Acute Myeloid

Introduction: A 17-gene stemness score (LSC17 score) had been reported to determine the risk of therapy resistance in acute myeloid leukemia (Nature 2016), and this was replicated successfully in 5 independent cohorts (n=908). When the patients were stratified according to the median value of the LSC17 score, allogeneic hematopoietic stem cell transplantation (HCT) did not affect overall survival (OS) from initial diagnosis for either high- or low-score patients (p=0.2 for high and p=0.06 for low LSC17 score groups). In the present study, we aimed to further perform a subgroup analysis confined to the patients receiving allogeneic HCT and determine whether the LSC17 score at leukemia diagnosis was associated with treatment outcomes including OS, leukemia-free survival (LFS), non-relapse mortality (NRM), relapse incidence (RI), and acute/chronic GVHD following allogeneic HCT. Methods and patients: Out of 452 patients with available LSC17 scores, 123 patients were included into the final analysis who received allogeneic HCT using matched (n=104, 84.6%) or mismatched/haploidentical donors (n=19, 15.4%). 80 patients were from the previous study (Nature 2016), while 43 patients were a prospectively accrued cohort during 2016-2018. Patients and transplant characteristics were: male/female (n=61/62); median age, 51 (17-73); CR status prior to HCT, CR1 (n=93, 75.6%), CR2 (n=30, 24.4%); Conditioning regimen, reduced intensity/myeloablative conditioning (n=59, 48.0% vs n=64, 52.0%); GVHD prophylaxis using post-transplant cyclophosphamide (PTCy; n=45, 36.6%) or T cell depletion (n=62, 50.4%); Cytogenetic risk, favorable (n=10, 8.1%), intermediate (n=70, 56.9%), adverse (n=26, 21.1%), inconclusive or not done (n=17, 13.8%). The LSC17 score for each patient was measured in a diagnostic sample using a NanoString assay and compared to the high/low threshold of a reference AML cohort (Ng et al, Nature 2016 and unpublished data). Transplant outcomes were compared according to the LSC17 risk group for OS, LFS, NRM and RI. Univariate and multivariate analyses were conducted for OS and LFS using Cox's proportional hazard model or for NRM and RI using Fine-Gray model, respectively. The following variables were included in the model: the LSC17 score group (high vs low LSC17 score), chronic GVHD, CR status (CR2 vs CR1), Cytogenetic risk (adverse vs favorable/intermediate/inconclusive), GVHD prophylaxis (PTCy vs others, T-cell depletion vs others), Age (above 60 vs others), donor type (mismatched/haploidentical vs matched donors). Results: With a median follow-up duration of 22 months among survivors after HCT, 23 patients experienced relapse (n=23, 18.7%) while 63 deaths (51.2%) were noted. Out of 123 patients, 58 (47.1%) had a low LSC17 score and 65 (52.9%) had a high LSC17 score. There was no difference in the distribution of LSC17 scores between the group who received HCT (n=123; 0.479±0.026) vs not (n=229; 0.456±0.019; p=0.491). LFS survival was significantly better in the low LSC17 score group (51.5 vs 32.4% for 2-year LFS rate, p=0.0219), and there was a trend to higher OS rate in the low LSC17 group (48.1%) compared to the high LSC17 group at 2 years (34.2%, p=0.09). Furthermore, patients with a low LSC17 score had a significantly lower RI (14.9% vs 27.3% for 2-year relapse incidence, p=0.028). There is no difference of NRM between the groups (37.2% vs 38.2% at 2 years, p=0.647). Multivariate analysis confirmed that the high LSC17 score group was associated with worse LFS (HR 1.874 [1.080-3.249], p=0.025). However, it was not confirmed with respect to OS or relapse incidence. As expected, it was not associated with NRM. Conclusion: A low 17-gene stemness score is associated with better leukemia-free survival and lower relapse incidence after allogeneic HCT, and is suggested to be associated with OS. The high LSC17 score group may be considered for novel therapeutic strategies to reduce the risk of relapse after allogeneic HCT. Figure Disclosures Chan: Celgene: Honoraria, Research Funding; AbbVie Pharmaceuticals: Research Funding; Agios: Honoraria. Minden:Trillium Therapetuics: Other: licensing agreement. Michelis:CSL Behring: Other: Financial Support. Mattsson:Gilead: Honoraria; Celgene: Honoraria; Therakos: Honoraria. Wang:Pfizer AG Switzerland: Honoraria, Other: Travel and accommodation; Pfizer International: Honoraria, Other: Travel and accommodation; Trilium therapeutics: Other: licensing agreement, Research Funding; NanoString: Other: Travel and accommodation.

scholarly journals Maintenance therapy in acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Li Xuan ◽  
Qifa Liu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Maintenance Therapy ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Acute Myeloid

AbstractRelapse remains the main cause of treatment failure in acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Emerging evidence has demonstrated that AML patients might benefit from maintenance therapy post-transplantation, especially for high-risk AML patients. In this mini-review, we will summarize targeted drugs, such as hypomethylating agents, FLT3 inhibitors and isocitrate dehydrogenase inhibitors, as maintenance therapy post-transplantation in AML patients undergoing allo-HSCT.

Maintenance Therapy With Decitabine After Allogeneic Hematopoietic Stem Cell Transplantation For Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4638-4638 ◽  
Author(s):  
Iskra Pusic ◽  
Jaebok Choi ◽  
Noel Bernabe ◽  
Camille N. Abboud ◽  
Peter Westervelt ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
To Receive ◽  
Acute Myeloid

Introduction Disease recurrence is the major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (alloHSCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Graft-versus-host disease (GVHD) is the major cause of non-relapse morbidity and mortality after alloHSCT. Decitabine (DAC) is a hypomethylating agent that irreversibly binds to and inhibits DNA methyltransferase-1, leading to loss of DNA methylation. DAC maintenance may help eradicate minimal residual disease and facilitate a graft-versus-leukemia effect. Lower DAC doses are expected to be better tolerated after alloHSCT and equally effective in promoting hypomethylation. Additionally, DAC maintenance may have a favorable effect on the incidence of GVHD by enhancing the effect of T-regulatory lymphocytes (Choi et al, Blood, 2012). Methods Patients (pts) with AML/MDS in complete remission (CR) after alloHSCT, with ANC> 1,500/mm3, platelets> 50,000/mm3, and without grade III-IV acute GVHD were eligible to receive DAC, starting between day +50 and +100 after alloHSCT. We investigated 4 DAC doses: 5, 7.5, 10 and 15 mg/m2/day IV x 5 days of a 6-week cycle, for a total of 8 cycles. Each cohort contained 4-8 evaluable patients. The Maximum Tolerated Dose (MTD) was defined as the maximum dose at which< 20% of patients experience hematologic or non-hematologic dose limiting toxicities (DLT) during the 1st cycle of treatment. GVHD prophylaxis was at the physician discretion. Results 19 pts were enrolled to date; the median age was 60 y (22-66); 14 pts had AML and 5 MDS. All conditioning regimens were myeloablative; 14 donors were unrelated and 5 related. 3 cohorts have been completed and a final 4th cohort is currently enrolling. Median follow-up from alloHSCT is 24 mo (7-36). 8 pts (44%) completed all 8 cycles: 7 pts remain in CR with stable counts and full donor chimerism and 1 pt developed CNS-only relapse 26 mo after alloHSCT. 9 pts went off study before cycle 6: 1 pt for poor compliance after 6 cycles, 3 pts for relapsed disease (after 1, 2 and 5 cycles, respectively), 2 pts for sepsis, and 2 pts after physician decision. 6 pts have died: 3 from relapse, 2 from sepsis after 3 cycles of DAC (they were not neutropenic at a time), and 1 form sepsis >1 y after getting off study. 2 pts are still on study passed 3rd cycle. DAC maintenance was well tolerated. Associated hematological toxicities were mostly grade I/II leukopenia and thrombocytopenia. There was one occurrence of hematological DLT. No MTD has been reached. Non-hematological toxicities were grade I/II nausea, fatigue, neuropathy, and transaminase elevation. 2 pts had grade I-II acute GVHD prior to starting DAC and both resolved while on DAC; 1 pt developed grade IV gut GVHD coinciding with first cycle of DAC that completely resolved on DAC; 1 pt developed late acute GVHD of skin and liver around 6th cycle of DAC that resolved after few wks. 2/8 pts who completed 8 cycles of DAC developed very mild skin and oral chronic GVHD not requiring any systemic therapy, 1/8 pt developed late acute GVHD responding to therapy, and 1 pt developed overlap GVHD syndrome. 4/7 pts who went off study prior cycle 6, and did not have an early relapse, developed severe chronic GVHD requiring intensive immunosuppressive therapy. Conclusion To our knowledge this is the first report of DAC as maintenance therapy after alloHSCT. DAC at the dose of 15 mg/m2 for 5 days every 6 weeks is safe and can be administered in heavily pretreated pts in the post-alloHSCT setting. Approximately 43% of pts were able to receive all 8 cycles. The lack of toxicities and low incidence of GVHD indicate that a longer period of administration should be investigated. Although there is a trend of increased FOXP3 expression, results were not statistically significant. Further correlative studies, including genome-wide methylation studies, are ongoing. Disclosures: Off Label Use: Decitabine maintenance after alloHSCT.

scholarly journals Association of Ikir-Mismatching and Donor Akirs with Better Outcomes in Haploidentical Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2904-2904
Author(s):  
Yu Zhang ◽  
Shaozhen Chen ◽  
Jinhua Ren ◽  
Xiaofeng Luo ◽  
Jianda Hu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Selection Strategy ◽  
Receptor Ligand ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Acute Myeloid

Abstract Objectives: Natural killer (NK) cells are the first donor-derived lymphocytes to be reconstituted after transplantation and play a critical role in improving transplantation outcomes. Their surface receptor, killer cell immunoglobulin like receptor (KIR), can trigger the alloreactivity of NK cells and have been shown to be protective for acute and chronic graft-versus-host disease (aGVHD, cGVHD) while retaining graft-versus-leukemia (GVL) effect. However, different results have been reported about KIR matching models and KIR alleles based on patient, donor and transplant characteristics, resulting in significant controversy about the best donor selection strategy. Here, we investigated the potential influence of KIR matching and KIR alleles on GVHD prophylaxis, overall survival (OS) and relapse rate (RR) of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in acute myeloid leukemia (AML) patients. Methods：Data from 79 patients with AML treated with haplo-HSCT between May 2015 and May 2021 in the transplantation unit of the Fujian Medical University Union Hospital were retrospectively analyzed. The cohort included 49 male patients (62.0%) and 30 female (38.0%), with a median age of 25 years (1-68 years). KIR genotyping was performed by the PCR-SSO method. The amplicons were quantified on the Luminex 200 flow analyzer and analyzed using the Quick-Type for Lifecodes software for generating KIR data. HLA-A and -B alleles were typed by polymerase chain reaction using sequence-specific primers (PCR-SSP) (TBG, Taipei, Taiwan). HLA-C genotyping was determined by reverse hybridization with sequence specific oligonucleotides probes (rSSO) Line probe assay. Cox proportional hazards model and Kaplan-Meier survival curves were used for analysis. Results：At the time of transplantation, 49 cases (62.0%) were at CR1, while 30 (38.0%) were not. aGVHD occurred in 16 patients (20.3%) and recurrence arose in 10 patients (12.7%), 4 (5.1%) cases cGVHD was observed. After adjusting for age, disease-risk, disease-status, HLA-match, donor gender, conditioning regimen intensity and type of post-grafting GVHD prophylaxis, Cox regression analysis revealed that both KIR ligand-ligand mismatching (KLM) and KIR receptor-ligand matching (RLM) was associated with an decreased risk of aGVHD and relapse compared to KIR ligand-ligand matching and receptor-ligand matching group, respectively (aGVHD: KLM: p=0.047, RLM: p＜0.001; RR: KLM: p=0.049, RLM: p=0.017). Furthermore, RLM shows more accurate in prediction of relapse and aGVHD compared with KLM in both aGVHD and relapse. (aGHVD: p=0.009; RR: p=0.039). After taking activating KIR (aKIR) into consideration to compensate the defect of only inhibitory KIR (iKIR) dominant model, we found that patients with more donor activating KIRs can reach the lower incidence of aGVHD and relapse, and the benefit can gradually increase parallel with the increase in donor activating KIRs. (aGVHD：p=0.019；RR：p=0.037). Patients with both receptor-ligand mismatch and the most donor aKIRs can reach the lowest relapse, lowest incidence of aGVHD and best overall survival (OS). Conclusions: KIR-mismatch, both KLM and RLM significantly reduced the risk of aGVHD and relapse after halpo-HSCT in AML patients and RLM show more superiority in the prediction of HSCT outcome. The synergistic effects of receptor-ligand mismatch and more donor aKIRs can provide a better clinically applicable donor selection strategy to improve haplo-HSCT outcome in AML patients. Disclosures Hu: Astellas Pharma, Inc.: Research Funding.

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