scholarly journals Combination of Cladribine, Cytarabine and Topotecan (CLAT) for Relapsed or Refractory Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4897-4897
Author(s):  
Xiaomei Chen ◽  
Jianyu Weng ◽  
Yulian Wang ◽  
Chengxin Deng ◽  
Chengwei Luo ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Natural Science ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Science And Technology ◽  
Technology Planning ◽  
Hematopoietic Stem ◽  
Planning Project ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract Xiaomei Chen and Jianyu Weng contributed equally to this study. The outcomes ofrelapsed or refractory acute myeloid leukemia (RR-AML) are poor and effective salvage regimens are urgently needed. We present a study of 14 patients with RR-AML (median age 42years, range 18-65years; male n=12, female n= 2) treated with CLAT regimen, which consisted of cladribine 5mg/m² per day i.v. 2-3 hour on days 1-5, cytarabine 1.0g/m² per day i.v. 4 hours after cladribine on days 1-5, topotecan 1.25mg/m² per day i.v. 4 hours after cytarabine on days1-5 and G-CSF 300ug per day subcutaneous injection on days until neutrophile granulocyte recovery. Total of fourteen patients were included into the study from June 2013 to June 2015, Two (14.3%) patients were relapsed and twelve (85.7%) patients were refractory, 4 of 14 patients were relapsed or refractory after allogeneic-HSCT. Two patients died of invasive fungal infection before the assessment. Seven patients (58.3%) achieved complete remission (CR), and one patient (8.3%) achieved partial remission (PR), the rest patients (33.3%) did not respond (NR). The overall response rate was 66.7%. Following CLAT treatment, four patients with CR underwent allogeneic hematopoietic stem cell transplantation (HSCT) or microtransplantation. The median relapse-free survival (RFS) for RR-AML patients receiving CLAT regimen was 8.6 (range 2-16) months. Thirteen patients developed grade 4 granulocytopenia and thrombocytopenia, the median duration was 13(range 2 to 21) days and12 (range 2 to 21) days, respectively. The most common non-hematological side effects included nausea, vomiting, diarrhoea, and were grade 1/2. The CLAT regimen seems promising for the treatment of patients, and it was well tolerated. This regimen offers an alternative treatment for those patients with RR-AML who have received severe intensive treatment, especially with anthracycline-containing chemotherapy. The project was sponsored by grants from National Natural Science Foundation of China (No. 30972790; No.81270648; No.81370665; No.81300446) Provincial Natural Science Foundation of Guangdong (No. S2012010009560) Provincial Science and Technology Planning Project of Guangdong (No.2013B021800186; No.2013B021800201), and Science and Technology Planning Project of Guangzhou (No. 201400000003-4, 201400000003-1). Disclosures No relevant conflicts of interest to declare.

scholarly journals Combination of Homoharringtonine with Venetoclax and Azacitidine Excerts Better Treatment Response in Relapsed /Refractory Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-27
Author(s):  
Guopan Yu ◽  
Na Xu ◽  
Fen Huang ◽  
Zhiping Fan ◽  
Hui Liu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Treatment Response ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Complete Response ◽  
Control Group ◽  
Hematopoietic Stem ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Overexpression of Bcl-2 is known to be an important factor for drug resistance in relapsed /refractory acute myeloid leukemia (R/R-AML). Combination of Bcl-2 inhibitor venetoclax with hypomethylating agents (HMA) has shown promising killing effect in elder patients with newly diagnosed AML, also worked in R/R-AML but with low rate of complete response (CR). High expression of Bcl-XL and/or Mcl-1 is the main reason for resistance to venetoclax. As an inhibitor of both Bcl-XL and Mcl-1, homoharringtonine (HHT) has presented a synegetic effect with venetoclax in inhibition of Mcl-1 and killing of lymphama. In this study, we analyzed the treatment response and safety of combination of HHT (1mg/m2 d1-7) with venetoclax (400mg d1-14) and azacitidine (75mg/m2 d1-7) (HVA) in R/R-AML. From 6, 2019 to 5, 2020, in Nanfang Hopsital, 22 patients with RR-AML were treated with HVA (HVA group), with a median age of 39(16-62) years, previous chemotherapy of 3(1-7) cycles. 15 (68.2%) relapsed within one year after allogenetic hematopoietic stem cell transplantation (allo-HSCT) and 12 (54.5%) previously exposed to HMA treatment. Meanwhile, 7 patients with RR-AML were treated with venetoclax combined with HMA (control group), with a median of 42(31-74) years, previous chemotherapy of 3(1-6) cycles. 2 (28.6%) relapsed after allo-HSCT and 5 (71.4%) had HMA exposure. In HVA group, totally 11/17(64.7%) patients acquired treatment response, and 7/15(46.7%) obtained CR/CRi, of whom 6 presented minimal residual disease (MRD) negative. While in control group, only 2/7(28.6%) acquired treatment response and 1 obtained CR. Subgroup analysis in HVA group showed allover response rate (ORR) was 9/13(69.2%) and CR rate was 6/11(54.5%) (all with MRD negative) in the patients with allo-HSCT. And in the patients without allo-HSCT ORR was 2/4(50.0%) and CR rate was 1/4. With a median follow-up of 6(1-7) months, one patient was bridged to allo-HSCT, 2 out of 7 patients with CR relapsed. All patients were well tolorated to both treatment regimens, showing as a median neutropenia of 9.5(5-14) days, 5 patients with Febrile neutropenia and 4 with pulmonary infection. In conclusion, combination of HHT with venetoclax and azacitidine (HVA) excerts better treatment response in R/R-AML, especially in those with allo-HSCT, and shows well tolorated. A multi-center prospective clinical trial (NCT04424147) has been initiated. Key words: HVA regimen, relapsed /refractory acute myeloid leukemia, treatment response, safety Disclosures No relevant conflicts of interest to declare.

scholarly journals Successful combination chemotherapy involving clofarabine, cyclophosphamide, and etoposide for pediatric relapsed acute myeloid leukemia: A case report

2021 ◽  
Vol 9 ◽  
pp. 2050313X2110155
Author(s):  
Sachio Fujita ◽  
Ryosuke Matsuno ◽  
Naoko Kawabata ◽  
Yumiko Sugishita ◽  
Ryota Kaneko ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Gemtuzumab Ozogamicin ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Positive Effects ◽  
Refractory Acute Myeloid Leukemia ◽  
Relapsed Acute Myeloid Leukemia ◽  
Acute Myeloid

Limited salvage chemotherapies are available for relapsed/refractory acute myeloid leukemia. Herein, we described successful reinduction chemotherapy, involving a combination of clofarabine, cyclophosphamide, and etoposide, in a 12-year-old male with relapsed acute myeloid leukemia prior to allogeneic bone marrow transplantation from his father. Although treatment with a combination of fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin, and gemtuzumab ozogamicin had no positive effects, the aforementioned clofarabine-based chemotherapy induced complete remission and allowed the transplantation to go ahead. The abovementioned regimen may be useful for induction chemotherapy prior to hematopoietic stem cell transplantation for refractory/relapsed acute myeloid leukemia.

Combination of Mitoxantrone,Ara-C and Homoharringtonine In Treatment of Refractory and Relapsed Acute Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4294-4294
Author(s):  
Jianda Hu ◽  
Tingbo Liu ◽  
Chunxia Cai ◽  
Xinji Chen ◽  
Buyuan Chen
Keyword(s):  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Median Time ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Abstract 4294 Advances in effective chemotherapy have improved clinical outcomes in acute leukemia in recent years. 5-year survival rate approaches 50–60% for acute myeloid leukemia (AML). However, the prognosis remains poor for patients who are relapsed or refractory to first-line therapy. Drug resistance and early disease recurrence are major contributing factors in the limited survival of patients with AML. The strategy for treating these patients is through reinduction chemotherapy followed by allogeneic stem cell transplantation. New combinations of different agents were employed in refractory patients to overcome drug resistance. The current study is to evaluate the efficacy of a MAH regimen comprising Mitoxantrone,Ara-C and Homoharringtonine in refractory or relapsed AML. 37 patients aged 14–65 years with refractory or relapsed AML (15 refractory AML patients, 22 relapsed AML patients) were treated with the MAH regimen(Mitoxantrone 10mg qd, iv.gtt, for 2□‘3 days;Ara-C 100mg bid, iv.gtt, for 5□‘7 days; Homoharringtonine 4mg qd iv.gtt, for 5□‘7 days). Chemotherapy duration lasted for 5 or 7days depended on bone marrow cellurarity. 15 (40.5%)and 1 (2.7%) patients achieved complete remission (CR) and partial remission (PR) respectively. The overall response rate was 43.2%. There was no relation between remission duration and previous chemotherapy. All patients who achieved CR received a consolidation and intensification therapy. The median overall survival (OS) for all patients was 97 days (range 18–487 d). For the patients who were in CR or PR,the median relapse-free survival(RFS) was 147 days(range 4 to 341 d). All patients experienced profound myelosuppression. The most common observed side effect of the regimen was infection because of grade ‡W neutropenia, which could be observed in 33 patients(89.1%). 4 patients died in aplasia due to severe infection and brain hemorrhage. In patients achieving remission, the median time to reach absolute neutrophil count (ANC) more than 0.5×109/l was (16.0±6.4)d. Platelet levels of more than 20×109/l were achieved in a median time of (12.7±6.2)d. Nonhematological side effects, consisting mainly of gastrointestinal toxicity(21/37,56.8%) and transient liver ALT and AST increase (4/37), were generally mild to moderate and tolerated. To a conclusion, MAH regimen can be employed in treatment of the refractory or relapsed AML patients who were not responded to other regimen. It is effective and is good tolerant.It could provide some refractory patients the chance to receive hematopoietic stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.

Expression of CD56 Is an Independent Prognostic Factor to Predict Relapse in Acute Myeloid Leukemia with t(8;21): Results of Japan Adult Leukemia Study Group (JALSG) AML97 Protocol.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2511-2511
Author(s):  
Noriyoshi Iriyama ◽  
Yoshihiro Hatta ◽  
Jin Takeuchi ◽  
Yoshiaki Ogawa ◽  
Shigeki Ohtake ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Univariate Analysis ◽  
Rank Test ◽  
Hematopoietic Stem ◽  
Wbc Count ◽  
Adverse Factor ◽  
Acute Myeloid

Abstract Abstract 2511 Background: Although prognosis of acute myeloid leukemia (AML) with t(8;21) is better than other types of AML, outcome of the patients has not been satisfied. Previously, aberrant antigen expression has been reported as risk factor for AML with t(8;21). However, in the reported series, number of cases was not large enough and chemotherapy regimens were variable. We investigated the association of prognosis and several biomarkers including immunophenotype, WBC count, age, and performance status for large number of AML patients with t(8;21) uniformly treated in JALSG AML97 regimen. Patients and Methods: Seven hundred eighty-nine eligible AML patients were evaluated for the multicenter JALSG AML97 study. Adult patients with de novo AML except for APL, ages 15–64 years, were registered consecutively from 103 institutions that participated in JALSG from December 1997 to July 2001. One hundred forty-four patients with AML with t(8;21) were analyzed in this study with a median 1205 days of observation term from diagnosis. Complete remission (CR), relapse-free survival (RFS), and overall survival (OS) rates were analyzed by Fisher's exact test and log-rank test. Factors that would affect clinical outcome were analyzed by multivariate Cox proportional hazard regression model. Results: AML with t(8;21) frequently expressed CD19, CD34, and CD56 compared to other subtypes of AML. CD11b was rarely expressed. Expression of CD19 favorably affected on CR rate (96% in CD19 positive and 87% in negative patients, p<0.05). Univariate analysis showed WBC>20×109/L, CD19 negativity, and CD56 positivity were adverse factors for RFS. CD56 expression was the only independent adverse factor for RFS by multivariate analysis (73.7% in CD56 negative and 48.2% in CD56 positive patients at 3 yrs) although its expression did not affect on OS. There was no difference of age, sex, WBC count, presence or absence of Auer rod, performance status, or CD15 expression between CD56 positive and negative cases. Expression of CD19 was more common in CD56 negative patients (50% in CD56 negative and 30.6% in CD56 positive patients, p<0.05). Conclusions: We demonstrated that the expression of CD56 was a distinctive adverse factor in a large number of AML patients with t(8;21) treated with JALSG AML97 regimen. CD56 positive AML patients with t(8;21) are possible candidates for hematopoietic stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.

CXCR4 Invalidation Limits the MLL-ENL Induced Leucemogenesis in Vivo

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4089-4089
Author(s):  
Yanyan Zhang ◽  
Hadjer Abdelouahab ◽  
Aline Betems ◽  
Monika Wittner ◽  
William Vainchenker ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Abstract 4089 The receptor CXCR4 and its ligand SDF-1 play major physiological roles especially on hematopoietic stem cells homing and retention. Many studies have implicated CXCR4 in the invasion by tumor cells of organs that produce SDF-1. In acute myeloid leukemia, the physiological role of CXCR4 is not fully understood. We used retrovirus to express MLL-ENL oncogene in CXCR4+/+ and CXCR4−/− hematopoietic primitive cells (Lin- isolated from fetal liver) and showed that CXCR4 is dispensable for generation of immortalized colonies in vitro. To determine CXCR4 function in vivo, CXCR4+/+ and CXCR4−/− transformed cells were transplanted into lethally irradiated mice. Whatever their phenotype, the recipient developed a myelo-monocytique leukemia characterized by their expression of Gr-1 and Mac-1. As expected, all recipients of MLL-ENL transduced CXCR4+/+ cells were moribund within 35 to 80 days post transplant (median survival time: 50 days). Strikingly, recipients of MLL-ENL transduced CXCR4−/− cells showed significantly increased lifespan, with a median survival time of 90 days. The cellularity of the peripheral blood of recipients of MLL-ENL transduced cells displayed considerable increases over time although this increase was much lower in CXCR4−/− than in CXCR4+/+ chimera. Bone marrow of MLL-ENL transduced CXCR4−/− chimera had moderately decreased numbers of mononuclear cells. There were important numbers of leukemic CD45.2+/Gr1+/Mac1+/c-kit+ cells in spleen from MLL-ENL CXCR4+/+ chimera which suggested that CXCR4 is important for leukemic progenitors cells retention in the bone marrow and especially in the spleen. The homing capacity of transduced CXCR4+/+ cells is comparable to the CXCR4−/− cells. Finally, more DNA damages were found in the BM cells of MLL-ENL CXCR4−/− chimera. All these results were confirmed by treating of MLL-ENL CXCR4+/+ chimera with CXCR4 inhibitor (TN140). These results demonstrated that in absence of CXCR4, the cells transduced by oncogene MLL-ENL are capable of generating leukemia in the recipients. However, mice transplanted with MLL-ENL transduced CXCR4−/− FL cells developed acute myeloid leukemia with reduced aggressiveness and organ infiltration, which is associated with induced differentiation and DNA instability. These results indicated that the MLL-ENL progenitors are dependent on CXCR4 for their maintenance in the BM and spleen suggesting that CXCR4 inhibitors might have potential therapeutic applications. Disclosures: No relevant conflicts of interest to declare.

Successful Salvage Treatment With Clofarabine and Cytarabine In Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5039-5039
Author(s):  
Alessandra Malato ◽  
Francesco Acquaviva ◽  
Alessandra Santoro ◽  
Rosaria Felice ◽  
Silvana Magrin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Stem Cell Transplant ◽  
Remission Rate ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract Objectives Relapsed/refractory AML patients  have a poor prognosis; allogeneic hematopoietic stem cell transplantation (HSCT) is the only chance in this setting to achieve long-term disease-free survival (1). It was previously established the activity of clofarabine plus cytarabine in AML relapse (clofarabine dosed once daily for 5 days with 40 mg/m2  followed 4 hours later by ara-C at 1 g/m2 per day)(2).However, modifications of this combination in AML therapy of relapsed/refractory patients warrant further evaluation. Therefore, our goal was to determine the efficacy and safety of clofarabine at lower dosage followed by  cytarabine (Ara-C) in adult patients with relapsed or refractory acute myeloid leukemia (AML) and to evaluate the capacity of this regimen as a bridge for HSCT. Methods Patients aged 18-65 years with refractory/relapsed AML were treated at the dose of clofarabine 30 mg/mq on days 1-5 and cytarabine 1000 mg/mq gg on days 1-5. We evaluated the complete remission rate (CRR), duration of remission (DOR) and overall survival (OS). Minimal residual disease (MRD) by molecular targeting was considered in all patients. Results Twenty-five (25) patients aged 29-64 years (median 47), who were fit for allogenetic HCT,  received one cycle of 30 minutes infusion of  clofarabine 30 mg/mq, followed 4 hours later by 3 hours infusion of  intermediate dose cytarabine 1000 mg/mq  days 1-5. Only in the first three patients this schedule was followed by gentuzumab. Nine (36%) patients had refractory disease (seven after one induction regimen, one after two previous regimes, one after a prior hematopoietic stem cell transplant (HSCT);  16 (64%) patients  were in their first (12 patients) or second relapse (4 patients); among the 12 patients in first relapse, 5 were from an allogeneic stem cell transplant.  Fourteen patients (56%)  achieved a complete remission (CR), seven (28%) was refractory and 4 (16%) died of treatment related mortality. Eleven (44%) patients  underwent (9 in CR) to allogeneic transplants or DLI infusion (3 patients refractory, and 8 patients relapsed), only one  patient underwent to autologous transplant. One patient, who was relapsed after prior HSCT, obtained a CR but he developed acute  graft vs host disease after therapy  and died in molecular CR*.  Among all patients underwent HSCT after Clofa/Ara-c salvage, six patients (50%) are still alive and in complete remission, six patients (50%) died because of  HSCT complications or AML relapse. The complete remission rate (CRR) was  (56,00 %), the median  Overall Survival  was 5 months for all patients (range 1-38 M), 11 Months for those underwent to tranplantation and 1,5 Months for non transplanted group. Treatment was complicated by neutropenic fever (n=17), grade III-IV mucositis (n=2) , skin rush  (n=4) grade II- III, hepatic transaminase elevations (n=2).  Two (n=5) patient died before their disease status could be evaluated. Conclusions These preliminary results suggest that combination treatment with clofarabine 30 mg/mq and ARA-C 1000 mg/mq is effective in this particularly poor prognosis category of patients, resulting in an ORR very favorably,  representing a potential “bridge” toward bone marrow transplant procedures (among the 14 patients who achieved a CR, twelve (85%) proceeded to HSCT, and six are still alive). The safety profile is acceptable in this relapsed/refractory population, and our results are very similar to previous regimes using higher clofarabine dosages.  More studies with this combination in adults are warranted. References 1 Estey E. Treatment of relapsed and refractory acute myeloid leukemia. Leukemia. 2000;14:476-479. 2. Faderl S et al, “Results of a pase 1-2 study of clofarabine in combination with cytarabine (ara-C)”Blood 2005 Disclosures: No relevant conflicts of interest to declare.

Inhibition of HDAC8 Reactivates p53 and Abrogates Leukemia Stem Cell Activity in CBFβ-SMMHC Associated Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 363-363
Author(s):  
Jing Qi ◽  
Qi Cai ◽  
Sandeep Singh ◽  
Ling Li ◽  
Hongjun Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Cell Activity ◽  
Disease Free Survival ◽  
Hematopoietic Stem ◽  
The Impact ◽  
Acute Myeloid

Abstract The inv(16)-created CBFβ-SMMHC fusion protein inhibits differentiation of hematopoietic stem and progenitor cells (HSPCs) and creates pre-leukemic populations predisposed to acute myeloid leukemia (AML) transformation. However, the molecular mechanism underlying the leukemogenic function of CBFβ-SMMHC has been elusive. Given the low TP53 mutation rate in AML, alternative mechanisms disrupting p53 function are expected. We showed thatCBFβ-SMMHC impairs p53 acetylation and p53 target gene activation through formation of an aberrant protein complex with p53 and HDAC8 (Blood, 120: A772; 122(21): 224). We now show that CBFβ-SMMHC binds to p53 and HDAC8 independently through distinct regions and that HDAC8 mediates the deacetylation of p53 associated with CBFβ-SMMHC. In addition, we generated mice carrying a floxed Hdac8 (Hdac8f) allele and crossed with Cbfb56M/+/Mx1-Cre (Kuo YH et al, Cancer Cell 2006). Deletion of Hdac8 signifiacntly (p<0.0001) reduced the incidence of AML and prolonged disease-free survival. Pharmacologic inhibition of HDAC8 activity with HDAC8-selective inhibitors (HDAC8i) reactivates p53 and selectively induces apoptosis of inv(16)+ AML CD34+ cells while sparing normal HSPCs. To test the effect of HDAC8i on LSC engraftment and leukemia-initiating capacity, we generated Cbfb56M/+/Mx1-Cre mice with a Cre-reporter line expressing tdTomato fluorescence protein following Cre-mediated recombination. AML cells (dTomato+/cKit+) treated with HDAC8i (22d) ex vivo showed reduced engraftment (p=0.025) and enhanced survival (p=0.025) in transplanted mice. To examine whether HDAC8i 22d treatment affects the engraftment capacity on surviving cells, we transplanted equal number (2 x 106) of AML cells treated with either 22d or vehicle in another cohort of mice (n=4). We show that HDAC8i 22d treatment reduced the engraftment of dTomato+/cKit+ AML cells and enhanced survival, suggesting that the engraftment capacity is altered in addition to reducing AML cell survival. We next performed preclinical studies to determine the efficacy of in vivo administration of HDAC8i 22d. AML transplanted mice were randomized into two groups, one group treated with vehicle and the other treated with HDAC8i 22d for 2 weeks. Flow cytometry analysis revealed significantly reduced frequency (p=0.0097) and number (p=0.0101) of dTomato+/cKit+ AML cells in the bone marrow and spleen of 22d treated mice compared to vehicle treated group. To further assess the impact on LSC activity, we transplanted bone marrow cells from these treated mice into secondary recipients and analyzed for AML engraftment. Significant reduction in the frequency (p<0.0001) and the number (p=0.0006) of dTomato+/cKit+ AML cells was observed in the bone marrow and spleen. Furthermore, HDAC8i 22d treated transplants showed no signs of leukemia while vehicle treated transplants are moribund with aggressive AML. These results indicate that HDAC8 inhibition by 22d treatment effectively eliminates engraftment and leukemia-initiating capacity of AML LSCs. In conclusion, our studies identify a novel post-translational p53-inactivating mechanism and demonstrate selective HDAC8 inhibition as a promising approach to target inv(16)+ AML LSCs. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Retrospective Observation of Treatment Outcomes Using Decitabine-Combined Standard Conditioning Regimens Before Transplantation in Patients With Relapsed or Refractory Acute Myeloid Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuhang Li ◽  
Longcan Cheng ◽  
Chen Xu ◽  
Jianlin Chen ◽  
Jiangwei Hu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Hematopoietic Reconstitution ◽  
Conditioning Regimens ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid ◽  
Refractory Aml

Hypomethylating agents, decitabine (DAC) and azacitidine, can act as prophylactic and pre-emptive approaches after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a non-intensive bridging approach before allo-HSCT. However, they are rarely used as a part of conditioning regimens in patients with relapsed or refractory acute myeloid leukemia (AML). This retrospectively study included a total of 65 patients (median, 37; range, 13–63) with relapsed or refractory AML who were treated by allo-HSCT after myeloablative conditioning regimens without or with DAC (high-dose DAC schedule, 75 mg/m2 on day −9 and 50 mg/m2 on day −8; low-dose DAC schedule, 25 mg/m2/day on day −10 to −8). DAC exerted no impact on hematopoietic reconstitution. However, patients who were treated with the high-dose DAC schedule had significantly higher incidence of overall survival (OS, 50.0%) and leukemia-free survival (LFS, 35.0%), and lower incidence of relapse (41.1%) and grade II–IV acute graft versus host disease (aGVHD, 10.0%) at 3 years, when compared with those treated with standard conditioning regimens or with the low-dose DAC schedule. In conclusion, high-dose DAC combined with standard conditioning regimens before allo-HSCT is feasible and efficient and might improve outcomes of patients with relapsed or refractory AML, which provides a potential approach to treat these patients.

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