scholarly journals Low-Dose Decitabine Plus Venetoclax Maintenance Therapy Can Decrease the Relapse after Allogeneic Stem Cell Transplantation for MRD Positive High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-33
Author(s):  
Yunxiong Wei ◽  
Yaqing Cao ◽  
Xin Jin ◽  
Xiaoyuan He ◽  
Rui Sun ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
High Risk ◽  
Adverse Events ◽  
Maintenance Therapy ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Post Transplantation ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) and myelodysplasia (MDS) are usually associated with poor outcomes, especially in high-risk AML/MDS. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curable option for patients suffering from high-risk AML/MDS. However, there were still many patients relapsed after allo-HSCT, especially for some patients are MRD positive before transplantation. Novel therapy to prevent replase is urgently needed. Both BCL-2 inhibitor, venetoclax (VEN) and hypomethylating agent, decitabine (DEC) possess significant antitumor activity effects against AML/MDS. Administration DEC has been shown to ameliorate GVHD and boost GVL post-transplantation. Several clinical trials have also shown that venetoclax plus decitabine can be a safety and effective salvage treatment for patients with AML/MDS relapsing after allo-HSCT. We therefore conducted a prospective study (ChiCTR1900025374) to exam the tolerability and efficacy of a maintenance therapy low-dose decitabine (LDEC) plus VEN to prevent relapse after allo-HSCT for MRD positive high-risk AML/MDS patients. To our knowledge, this is the first report of venetoclax combined decitabine in this setting. Methods: Six patients with MRD positive high-risk AML (n=5) /MDS(n=1) post transplantation were recruited. Around day 100 post transplantation, all patients received LDEC (15mg/m2 for 3 days) followed by VEN (200mg) on day 1 to 21. Two months is a cycle. The primary end points of this study were rates of Overall survival (OS) and event-free survival (EFS). The secondary endpoints included adverse events (AEs), incidence of cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), incidences of acute GVHD (aGVHD) and chronic GVHD (cGVHD) and incidences of viral infection after allo-HSCT. Survival outcomes were analyzed using Kaplan-Meier analysis Results: Two of the six patients were partial remission (PR) before transplantation, and the remaining 4 patients were MRD+ before transplantation. The median follow-up was 16 (11-26.5) months. Both 2-year OS and 2-year EFS were 83%. The median 2-year EFS time was 16(9-26.5) months, and five patients still EFS alive at the time of this writing. The 2-year cumulative incidence of relapse after LDEC+VEN was 17% and 2-year non-relapse mortality was 0%. No tumor lysis syndrome (TLS) was observed. The most common AEs were neutropenia, anemia, thrombocytopenia, neutropenic fever, and fatigue. Grade 2 or 3 adverse events were observed in 33% (2/6). No grade>3 AEs were observed. Acute (any grade) and chronic (limited or extensive) graft-versus-host disease occurred in 67% and 17% of patients, respectively. The 2-year cumulative incidence of CMV viremia and EBV viremia were 33.3% and 16.7%, respectively. Conclusion: We conclude LDEC+VEN can be administered safely after allo-HSCT, without evidence for increased incidence of GVHD, and this combination demonstrates decreased relapse for MRD positive high-risk AML/MDS patients. This novel maintenance therapy may be a promising way to prevent replase for MRD positive high-risk AML/MDS patients, and the clinical benefits need to be assessed in a comparative prospective trial. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals Azacitidine Maintenance after Allogeneic Stem Cell Transplantation Is Feasible in Patients with Acute Myeloid Leukemia and Myelodysplasia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5884-5884 ◽  
Author(s):  
Ahmad Antar ◽  
Mohamed A Kharfan-Dabaja ◽  
Hussein Abou Ghaddara ◽  
Rami Mahfouz ◽  
Ali Bazarbachi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
High Risk ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
Abnormal Karyotype ◽  
Acute Myeloid

Abstract Background: 5-Azacidine (5-AZA) is a DNA hypomethylating agent with proven clinical activity in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). A recent non-randomized study reported promising results with the use of lower doses of 5-AZA as maintenance therapy after hematopoietic stem cell transplantation (HSCT). It is important to note that 5-AZA has an immunomodulatory effect and might enhance the graft-versus-leukemia (GVL) effect. Here, we report the successful use of 5-AZA maintenance following allogeneic HSCT in patients with high risk AML and MDS. Patients and methods: Nine patients (M=6, F=3; median age=49 (36-65) years ) with high-risk AML (n=6 including 2 abnormal karyotypes) or MDS (n=3 including 1 abnormal karyotype) received 5-AZA as post-transplant maintenance at a dose of 32mg/m2 daily for 5 days every 4 weeks starting at a median time of 100 (30-210) days post-transplant. All patients were in complete remission at initiation of 5-AZA. A median of 12 cycles (1-18) were delivered. Patients’ characteristics, treatment details, response and side effects are summarized in Table I. Results: After a median follow-up of 19 months post HSCT and 15 months after starting 5-AZA treatment, five patients with normal karyotype are still in CR. Conversely, all three patients with abnormal karyotype rapidly developed disease recurrence while they were receiving 5-AZA after a median of 3 months. Overall, the actuarial 1-year progression free and overall survival rates were 65% and 90%, respectively. 5-AZA was generally well tolerated with only mild thrombocytopenia observed in 2 patients. No clinically evident graft-versus-host disease exacerbation was observed. Conclusion: These results suggest that Low-dose 5-AZA is an effective maintenance therapy post- allogeneic SCT in high-risk AML and MDS particularly when a normal diploid karyotype is present. The relative lack of efficacy in the presence of an abnormal karyotype is intriguing and questions whether these subjects might benefit from higher doses of 5-AZA or other novel therapies within the context of a well-designed clinical trial. Prospective clinical trials and longer follow-up are needed to confirm these observations. Abstract 5884 TABLE I.Patients characteristics and Outcomes After Azacitidine maintenanceSubject #123456789Age at transplant655848433649495851genderMMFMFMFMMDiseaseAMLAMLAMLAMLSecondary AMLSecondary AMLMPD/MDSMDS (RAEB-2)MDS (RAEB-2)cytogeneticnormalnormalT(6,9)normalDel 5normalnormalnormalHypoploidy(43-45)Molecular abnormalityNoneNoneNoneFLT3 ITDNoneNoneNoneNoneNoneDisease status at HSCTCR2CR3CR1CR1RefractoryCR1PRPRCR1Donor typeMRDMRDMRDMRDMUDMRDMRDMRDMRDConditioningFB2+ATGFB3+ATGFB3+ATGFB4+ATGFB3+ATG+ TBI (4Gy)FB4+ATGFB4+ATGFB3+ATGFB2+ATGGVHD prophylaxisCSACSACSACSACSACSACSACSACSA, mycophenolate mofetilTime from HSCT to 5-AZA (days)37701001503021010055104Disease status at 5-AZACRCRCRCRCRCRCRCRCRnb of cycles12131241218129ToxicityNoneNoneNoneNoneGrade II thrombocytopeniaGrade II thrombocytopeniaNoneNoneNoneGVHD after 5-AZANoNoYesYesYesNoYesNoNoDisease recurrencenonoyesnoyesnononoyesSalvage therapy if recurrenceN/AN/AChemotherapy followed by DLIN/ANoneN/AN/AN/AChemotherapy followed by DLIProgression free survival, months13+24+124+319+21+18+10Status at last follow upCRCRCRCRdiedCRCRCRCRSurvival, months13+24+18+24+519+21+18+34+ Stem cell source for all patients: peripheral blood; CR: complete remission; PR: partial remission; CSA: cyclosporine A; MRD: matched related donor; MUD: matched unrelated donor; PBSC: peripheral blood stem cell; CCR: continuous complete remission; FB4: 5 days fludarabine plus 4 days busulfan (130 mg/m2/day); FB3: 5 days fludarabine plus 3 days busulfan (130 mg/m2/day); FB2: 5 days fludarabine plus 2 days busulfan (130 mg/m2/day) ATG: anti-thymoglobuline; DLI: donor lymphocyte infusion. Disclosures Off Label Use: Azacitidine maitenance post HSCT.

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.

Flamsa Sequential Chemotherapy Followed By Reduced Intensity Conditioning and Allogeneic Hematopoietic Transplantation for High Risk Acute Myeloid Leukemia Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3892-3892 ◽  
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Marie Y. Detrait ◽  
Helene Labussiere-Wallet ◽  
Sandrine Hayette ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
High Risk ◽  
Confidence Interval ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Reduced Intensity Conditioning ◽  
Secondary Aml ◽  
Reduced Intensity ◽  
Acute Myeloid

Abstract Advances in chemotherapy have improved the prognosis of patients with acute myeloid leukemia (AML), however, high-risk patients still have a poor outcome. In this category of patients, the only therapeutic strategy with curative potential remains allogeneic hematopoietic stem cell transplantation (allo-HSCT). With the aim to improve the effect of allo-HSCT by sequential use of chemotherapy followed by reduced intensity conditioning (RIC), we conducted a prospective study in high-risk AML patient. The high-risk population included intermediate II [t(9;11)(p22;q23); MLLT3-MLL, cytogenetic abnormalities not classified as favorable or adverse] and unfavourable patients [inv(3)(q21q26.2) or t(3;3)(q21;q26.2); t(6;9)(p23;q34); t(v;11)(v;q23); MLL rearranged, -5 or del(5q); -7; abnl(17p); complex karyotype] (Dohner et al. Blood 2010), secondary AML, and patients requiring 2 induction courses to obtain CR. The chemotherapy sequential regimen consisted in fludarabine 30 mg/m², high-dose cytarabine 2 g/m², and amsacrine 100 mg/m² from days -12 to -9 (FLAMSA). After 3 days of rest, RIC consisted of 4 Gy total-body irradiation (TBI) on day -5, cyclophosphamide (40 mg/kg with HLA-identical sibling, 60 mg/kg for unrelated or mismatched donors) on days -4 and -3, and rabbit antithymocyte globulin (ATG, Genzyme) (5 mg/kg total dose) from day -3 to day -1. In a group of patients, TBI was replaced by iv. busulfan (BU) (Busilvex, Pierre Fabre) 3.2 mg/kg/d during either 4 or 2 days according to patient age (>55 years) (from day -7 to -4 or from day -5 to -4). Peripheral-blood stem cells (PBSC) were preferred; bone marrow (BM) and cord blood (CB) were also accepted. Graft-versus-host disease (GvHD) prophylaxis consisted in cyclosporine from day -1, and mycophenolate mofetil (15 mg/kg bid), starting from day 0. In the absence of GvHD, MMF was discontinued by day+50 and cyclosporine was tapered from day +60 to +90. Except for CB transplantation, patients received 3 prophylactic increased doses of donor lymphocyte infusions (DLI) if they were in CR and GvHD-free at day +120 or 30 days after discontinuation of immunosuppressive agents starting at 1x106 CD3+ cells/kg. Between January 2007 and December 2013, 66 consecutive AML patients were included; 33 males and 33 females with a median age at allo-HSCT of 52 years (range: 19-66), 59 (89%) were de novo AML and 7 (11%) secondary AML. At transplantation, 22 (33%) patients were in CR (20 CR1 and 2 CR2) and 44 (67%) were in less than CR. Stem cell source was PBSC for 52 (79%) patients, CB for 6 (9%) and BM for 2 patients. Donors were 10/10 HLA matched siblings in 24 (36%) patients, 10/10 HLA matched unrelated in 18 (27%) patients and HLA mismatched for the rest of patients [unrelated 9/10 (n=18), CB 4/6 (n=6)]. For ABO compatibility, 32 (48%) were compatible, 13 (20%) had minor incompatibility and 21 (32%) had major incompatibility. For conditioning, 49 (74%) patients received TBI, 17 (26%) received BU. After transplantation, 59 (89%) patients engrafted, 7 patients did not engraft and died early (2 from relapse and 5 from infection). At day 90 post-allo-HSCT, among evaluated patients (N=52), 37 (71%) showed total donor chimerism, 15 (29%) had mixed chimerism. There were 24 patients with acute GvHD [10 gr I, 3 gr II and 7 gr III and 4 gr IV] with a cumulative incidence of 27% for grade ≥II; and 17 chronic GvHD [10 limited and 7 extensive], among them 5 after DLI, with a cumulative incidence of 48% at 2 years. After a median follow-up of 7 months (range: 0.1-76), the 2-years probability of overall survival (OS) and progression-free survival for the whole population were 30% (confidence interval: 24-36) and 40% (confidence interval: 37-52) respectively with a cumulative incidence of transplant-related mortality of 30% at 2 years. When stratifying on disease status at transplantation, patients in CR had significantly better OS and PFS at 2 years compared to patients in less than CR with 45% versus 18% (p=0.013) and 73% versus 22% (p=0.001) respectively. No statistical difference was found in outcomes of TBI compared to BU conditioning. Patients in CR showed very promising results and could benefit the most from this strategy. A high rate of deadly infections was observed, thus an efficient prophylactic anti-infectious strategy is recommended. Patients not in CR remain having poor outcome and maybe new transplantation strategy using haploidentical donors could be interesting to evaluate in this population. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Efficacy of clofarabine and low-dose cytarabine combination for genetically high-risk acute myeloid leukemia prior to allogeneic stem cell transplantation.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18515-e18515
Author(s):  
Carlos Enrique Vigil ◽  
Nusrat Jahan ◽  
Oana Valeria Paun ◽  
Jennifer Weis ◽  
Kevin Heckman ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
High Risk ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

e18515 Background: The outcome of genetically high risk acute myeloid leukemia (AML) patients (pts) remains poor, with a median overall survival (OS) of a few months after the failure of regimens. Long-term survival requires complete remission followed by allogeneic stem cell transplantation (ASCT).Clofarabine, a deoxyadenosine analog, at 20mg/m2 days 1-5, in combination with low-dose cytarabine (LDAC) has reported efficacy and tolerability in older newly diagnosed AML pts (Cancer 2015;121:2375). We have therefore prioritized this combination for relapsed/refractory(R/R) pts. Aims:Determine the efficacy of Clofarabine and low dose cytarabine in R/R AML pts who are eligible for ASCT. Methods: Using Holden Comprehensive Cancer Center database, we performed a retrospective chart review on 16 pts of R/R AML who were treated with Clofarabine and LDAC between January 2014 and Dec 2016. Each patient received Clofarabine 20mg/m2on days 1-5 IV and LDAC on days 1-10 subcutaneous. The primary endpoint was complete remission (CR) or complete remission with incomplete marrow recovery (CRi). Secondary endpoint was median OS. Results: Sixteen pts were analyzed. The median age was 58 years (range 27-78). Nine pts (56%) had AML with high risk characteristics (complex karyotype and/or presence of FLT3-ITD). Nine pts achieved either a CR or CRi. Responses were observed in 7of 9 pts with genetically high-risk features. 2 pts had mutated TP53, and both of them achieved CR. The median OS time was 13.25 months (range 3.6-19.2 months). 4 pts received ASCT after treatment combination. Conclusions: These results suggest that Clofarabine is well-tolerated and effective in the treatment of R/R AML pts, especially those with high-risk genetics. Clofarabine and LDAC could be used as a bridging therapy prior to ASCT for high-risk R/R AML pts. Future clinical trials are warranted to explore additional modifications to this combination in order to optimize therapy for this group of high-risk and heavily treated R/R AML pts.

scholarly journals Maintenance Therapy with Decitabine after Allogeneic Hematopoietic Stem Cell Transplantation to Prevent Relapse of High Risk Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3306-3306
Author(s):  
Yunju Ma ◽  
Changju Qu ◽  
Haiping Dai ◽  
Jia Yin ◽  
Zheng Li ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Median Number ◽  
Control Group ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Background: Relapse remains the main cause of treatment failure post transplantation. Relapse prevention is an important strategy for acute myeloid leukemia (AML) patients. M ethods: We retrospectively analyzed the results of21 high risk AML patients who received a median number of 3 courses (range, 2 - 8) of decitabine (DAC) maintenance treatment (20mg/m2/d ×5d every 3 months for 1 year). Meanwhile, another 63 high risk AML patients without any prophylactic treatment after transplantation were included as a control group for 1:3 pair matched study. Results: With median follow-up of 23 months, 20 out of 21 (95.2%) patients maintained complete molecular remission (CMR) in DAC group, while 35 out of 63 (55.6%) patients maintained CMR in control group. Comparing with control group, the patients of DAC group had higher 3-year overall survival (OS) rates and 3-year leukemia free survival (LFS) rates (92.9% vs 51.8%, P =0.003; 94.1% vs 54.7%, P=0.002 respectively). Moreover, DAC maintenance was well tolerated in all patients and grade 3/4 or 4/4 hematological toxicities were observed in 11 of 21 (52.4%) patients. Conclusion: Our results suggested that DAC maintenance therapy was an effective and safe treatment option to prevent relapse after transplantation for high risk AML patients. Disclosures No relevant conflicts of interest to declare.

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