scholarly journals Venetoclax Combination Therapy in Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4421-4421
Author(s):  
Jasson Villarreal Hernandez ◽  
Maria Condom ◽  
Helena Pomares ◽  
Susana Vives ◽  
Rosa Coll ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Response Rate ◽  
Hematologic Toxicity ◽  
Hypomethylating Agents ◽  
Advisory Committees ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

Abstract Introduction Venetoclax, a BCL-2 specific inhibitor, used in combination with azacitidine in patients with newly-diagnosed acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy treatment, has shown high response rate and overall survival compared with azacitidine monotherapy (Di Nardo et al. N Engl J Med 2020; 383:617-629). Moreover, venetoclax in combination with hypomethylating agents or with low-dose cytarabine is being explored in other settings being frequently used in relapsed/refractory (R/R) AML. Aims: We performed a retrospective study of patients diagnosed with R/R AML receiving azacitidine combinations in the Catalan Institute of Oncology (ICO) in order to determine the efficacy and safety of the combination. Methods We analyze 35 patients diagnosed with R/R AML at 4 hospitals belonging to ICO in Spain, treated with venetoclax (400mg/24h; initial daily dose of 100mg with a 3-day ramp-up to target dose of 400mg) in combination with hypomethylating agents (azacitidine 75mg/m 2 or decitabine 20mg/m 2) or low-dose cytarabine (20mg/m 2) from May 2019 to Agost 2021. Event was defined as death, refractoriness to treatment or progressive disease. Results Median age was 72 years (range 44-82). Seventeen (43%) patients had high-risk AML according to ELN 2017. Five (14%) patients received venetoclax in combination with decitabine, 20 (57%) patients with azacitidine, and 10 (29%) patients with low-dose cytarabine. The median number of cycles received was 3 (range 1-25). Early mortality in the first 30 days was 5.7% (2 patients). Overall response rate (ORR) was 58%. Complete remission (CR) rate was 48% and 10% partial remission. Seventeen patients (43%) needed venetoclax dosage adjustments due to hematologic toxicity. Median time to response was 2 months. Four patients (10%) were transitioned to allogeneic stem cell transplantation. The median OS was 9.5 months (95% C.I. 2.6-16.2). Response to treatment after 3-4 cycles, discriminate two groups patients with an OS of 13.57 months in those patients who achieved CR or PR vs 2.1 months in non-responders (p<0001). Thirteen patients died as a result of infection (8.2%), disease progression (4.1%), and bleeding (1.3%) Summary/Conclusions Our study showed that real-world experience of treating patients with R/R AML with venetoclax in combination with hypomethylating agents or low-dose cytarabine is feasible, well tolerated with a rapid and promising response rate and low toxicity profile. Moreover, rapid responses shown with the combination, allow us to identify those patients who may benefit from this approach. Figure 1 Figure 1. Disclosures Sureda: Mundipharma: Consultancy; Bluebird: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Support for attending meetings and/or travel; GSK: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: 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; MSD: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau.

scholarly journals The Efficacy and Safety of Decitabine in Combination with ATRA, G-CSF and Low Dose Cytarabine(Dlaag Regimen)in Relapsed/Refractory Acute Myeloid Leukemia Not Suitable for Strong Chemotherapy : A Phase 2, Prospective, Single-Arm, Multicenter Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5108-5108
Author(s):  
Li Yang ◽  
Ligen Liu ◽  
Limin Zhao ◽  
Yingting Lu ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multicenter Study ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Response Rate ◽  
Intensive Therapy ◽  
Significant Difference ◽  
Refractory Acute Myeloid Leukemia ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

Background. Patients with relapsed or refractory acute myeloid leukemia (R/R AML)who are intolerant of strong regimen chemotherapy have poor responsibility to chemotherapy and clinic remission is lower. The DNMT is depleted to reactivate the silencing tumor suppressor gene to exert anti-tumor effects. Vitro experiments confirmed that ATRA has an anti-leukemia effect on non-M3-AML cell lines. We perform the 2 phase, single-arm, multicenter study of Decitabine in Combination with ATRA, G-CSF and low dose cytarabine(DLAAG Regimen)in R/R AML not suitable for strong chemotherapy (NCT03356080). Methods. R/R AML patients aged more than 18 years not suitable for strong chemotherapy were eligible to enroll on this study. The objective was to assess the responses and safety of this therapy. All patients received subcutaneous decitabine injection 0.1-0.2mg/kg on days 1-3 ,8-10,15-17 .ATRA was taken orally at 45mg/m2 on day 4-6 and 15mg/m2on days 7-20. Subcutaneous injection cytarabine 15mg/m2 every 12 hours on days 1-10 and G-CSF 300ug/d on day 0 until disease remission or absolute neutrophils count ≥ 0.5×109/L were administered. The FLT3 inhibitor, arsenious acid, and the JAK-2 inhibitor, rotectinib, were allowed to be combined.All patients received one or two courses of induction treatments. Results. During the period from December 1, 2017 to July 2019, a total of 33 patients were recruited, including 17 women and 16 men. The median age is 64 years (range 46-82). In 33 patients, the overall response rate (ORR = CR + PR) was 36.3%, and the complete response rate (CRR = CR + CRi) was 33.3%. The early treatment-related mortality rate was 6.0%. One died of infection and one died of organ bleeding. Of the 26 patients with karyotype data, 11 received CR. Seven patients (63.6%) in CR showed normal karyotype, 2 patients (18.1%) in CR, and 1 patient (9.0%) in PR showed other moderate karyotypes. One case (9.0%) of the CR group had a poor karyotype. Statistical analysis showed that there was a statistically significant difference between the different karyotype groups (P < 0.05). Only 2 of the 10 FLT3 mutant patients achieved CR (20%). Two patients with abnormal MLL gene did not receive CR. Conclusions DLAAG regimen is effective and tolerated in patients with R/R AML who are not suitable for intensive therapy and could be as a bridging therapy regimen followed by HSCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Efficacy of Venetoclax Combination Therapy with Hypomethylating Agents in Patients with Relapsed Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5089-5089 ◽  
Author(s):  
Varun Mittal ◽  
Mimi Lo ◽  
Lloyd E. Damon ◽  
Karin L. Gaensler ◽  
Thomas G. Martin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Hypomethylating Agents ◽  
Advisory Committees ◽  
Allogeneic Hct ◽  
Acute Myeloid

Introduction: Venetoclax (VEN), a selective BCL-2 inhibitor, in combination with hypomethylating agents (HMA) has high efficacy in treatment-naïve elderly patients with acute myeloid leukemia (AML). The role for VEN in patients with relapsed/refractory (R/R) AML, myelodysplastic syndrome (MDS), or other myeloproliferative neoplasms remains incompletely defined. In particular, the efficacy of VEN+HMA has not been studied systematically in patients who experience AML relapse following allogeneic hematopoietic cell transplantation (HCT). Method: All patients treated with VEN+HMA (azacitidine or decitabine) for R/R de novo or secondary AML or progressive MDS following allogeneic HCT were identified and reviewed retrospectively. All included AML patients had overt clinical relapse with ≥ 5% bone marrow blasts or extramedullary disease biopsy proven to be AML. Patients were included in this analysis if they received at least 14 days of VEN therapy. Results: Eleven patients with median age 66 (range 25-75) were treated for R/R AML post-allogeneic HCT. Transplant characteristics included use of reduced intensity conditioning in 10/11 (91%), matched sibling donors in 5/11 (45%), matched unrelated donors in 5/11 (45%), and cord blood in 1/11 patients. The median time from HCT to relapse/disease progression was 7 months (range 3-36). Two patients had extramedullary relapse only, and the remainder had marrow involvement. Eight patients (73%) received azacitidine and 3 (27%) received decitabine in combination with VEN. All but two patients (82%) had prior HMA exposure and most received VEN+HMA as initial post-transplant salvage therapy (64%). Only one patient received donor lymphocyte infusion in conjunction with VEN+HMA therapy, and none proceeded to a second allotransplant. Nine patients (82%) experienced an objective response, which included 4 CR/CRi (36%) and 5 PR/SD (45%). In patients with CR/CRi, three patients had adverse risk cytogenetics and one had a favorable risk profile at diagnosis consisting of normal cytogenetics with an isolated NPM1 mutation. All patients who failed to remit with VEN+HMA had intermediate- or high-risk genetic features. The median number of treatment cycles given was 3 (range 1-20). Median survival was 11 months and estimated 6-month and 12-month survival was 82% and 36%, respectively. Three patients remain alive with median 16.5 months follow-up (range 2.5-32). Conclusion: Venetoclax in combination with HMA is a viable salvage option in patients with relapsed AML or progressive MDS after allogeneic HCT, including those with prior exposure to HMA. Although one patient in this cohort sustained long term complete remission, overall prognosis remains dismal in this high-risk patient population and improved treatment options for relapsed/refractory AML following alloHCT remain needed. Disclosures Damon: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Martin:Amgen, Sanofi, Seattle Genetics: Research Funding; Roche and Juno: Consultancy. Olin:MedImmune: Research Funding; Ignyta: Research Funding; Clovis: Research Funding; AstraZeneca: Research Funding; Revolution Medicine: Consultancy; Daiichi Sankyo: Research Funding; Astellas: Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria; Novartis: Research Funding; Mirati Therapeutics: Research Funding; Spectrum: Research Funding. Smith:Astellas Pharma: Research Funding; Abbvie: Research Funding; fujiFilm: Research Funding; Revolution Medicines: Research Funding. Logan:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pharmacyclics: Research Funding; Astellas: Research Funding; Jazz: Research Funding; Kite: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; TeneoBio: Consultancy; Kiadis: Consultancy; Kadmon: Research Funding; Abbvie: Consultancy.

Response to Hypomethylating Agent Therapy in Acute Myeloid Leukemia Based upon Mutations in the DNA Methylation Pathway

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2522-2522
Author(s):  
Catherine C. Coombs ◽  
Sean Devlin ◽  
Shweta Dixit ◽  
Abhinita Mohanty ◽  
Kristina Marie Knapp ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Dna Modification ◽  
Advisory Committees ◽  
Methylation Pathway ◽  
Mutational Profiling ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis, especially in the elderly for whom hypomethylating agent therapy may be the only standard treatment option. Data from The Cancer Genome Atlas Research Network indicates 44% of patients with de novo AML carry mutations in genes that regulate DNA modifications, such as IDH1/2, DNMT3A, and TET2. Small retrospective series have reported differential response to hypomethylating agents (HMAs) in patients with mutations in the DNA modification pathway. For example, Itzykson et al. reported an increased response rate with azacitidine in MDS and AML patients with TET2 mutations compared with those without (82% vs 45%, p = 0.007). Next, Metzeler et al. reported an increase in CR rate with decitabine therapy in patients with DNMT3A mutations as compared with those without (75% vs 34% CR, p = 0.05). Emadi et al. noted a higher response rate in AML patients with IDH1/2 mutations compared to those without (71% vs 23%, p = 0.01) in patients receiving either decitabine or azacitidine. In contrast, Dinardo et al. did not find an association between responses to HMAs in patients with IDH1/2 and DNMT3A mutations in a retrospective analysis of 68 elderly AML patients. Recent evidence demonstrates that WT1 mutations lead to loss of TET2 function, suggesting thatAML pts with WT1 mutations may also be sensitive to HMAs. These findings suggest that mutations in the TET/IDH/WT1/DNMT3A pathway might confer increased sensitivity to HMAs. We aimed to determine if there was an association between response and mutations in the DNA methylation pathway in AML patients treated with HMAs at our institution. Methods: This is a single institution, retrospective study. Of a cohort of 288 molecularly characterized AML patients, 76 patients were treated with HMAs; either alone (n= 59) or in combination with another agent (n= 17). In our cohort, 39 patients were treated with HMA in the frontline setting and 37 were treated in the relapsed/refractory setting. DNA was obtained from peripheral blood or bone marrow aspiration samples. Testing was performed using a targeted enrichment NGS assay designed with the RainDance DeepSeq system, covering clinically relevant regions in 30 genes known to be mutated in myeloid malignancies. Samples were subjected to microdroplet emulsion PCR and sequenced on an Illumina MiSeq to an average depth of at least 500X. 51.3% of patients had mutational profiling at time of diagnosis, and the remainder had mutational profiling at time of relapse/refractory disease. Genes affecting DNA modification pathway (DNMT3A, IDH1/2, TET2, WT1) were analyzed as a composite (present/absent). Results: Among patients receiving HMA for AML, the mean age was 67.1 years and 68% of patients were male. Using the NCCN cytogenetic/molecular risk categories, 7/76 had "better" risk, 35/76 had "intermediate" risk, 28/76 had "poor" risk and 6/76 patients' risk status could not be determined. Four of the 76 patients had incomplete molecular data available and were excluded from analysis; therefore, the final cohort under study was 72 patients. 34/39 of the frontline HMA patients were evaluable for response and 32/37 of the relapsed/refractory patients were evaluable for response. Among the 34 patients treated with HMAs in the frontline setting, 16 had mutations affecting DNA methylation and 18 patients did not. The CR rate (CR + CRi) in patients with DNA pathway mutations was 8/18 (44%) vs. 3/16 (19%) in patients without mutations (p = 0.15). Among the patients treated with HMAs in the relapsed/refractory setting, responses were rare with only 3 patients (9.4%) achieving CR. Responses were too few to demonstrate statistical relationships. Conclusions: We noted a trend toward an improved CR rate in patients with DNA modification mutations. However, the difference was not statistically significant in this small study cohort. Given the rarity of mutations and size of published cohorts, including ours, it has been difficult to demonstrate statistically significant associations between mutations and response to HMAs. A meta-analysis of existing data may overcome barriers of small numbers in individual studies, though retrospective nature of studies and publication bias may influence these results. A prospective trial with comprehensive molecular profiling of all patients is warranted to determine true associations. Disclosures Levine: Foundation Medicine: Consultancy; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Real-World Outcomes of Patients with Refractory or Relapsed FLT3-ITD Acute Myeloid Leukemia: A Toulouse-Bordeaux DATAML Registry Study

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2044
Author(s):  
Pierre-Yves Dumas ◽  
Sarah Bertoli ◽  
Emilie Bérard ◽  
Laetitia Largeaud ◽  
Audrey Bidet ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Real World ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Hypomethylating Agents ◽  
First Line ◽  
Phase 3 ◽  
Free Treatment ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

Two recent phase 3 trials showed that outcomes for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) patients may be improved by a single-agent tyrosine kinase inhibitor (TKI) (i.e., quizartinib or gilteritinib). In the current study, we retrospectively investigated the characteristics and real-world outcomes of R/R FLT3-internal tandem duplication (ITD) acute myeloid leukemia (AML) patients in the Toulouse-Bordeaux DATAML registry. In the study, we included 316 patients with FLT3-ITD AML that received intensive chemotherapy as a first-line treatment. The rate of complete remission (CR) or CR without hematological recovery (CRi) was 75.2%, and 160 patients were R/R after a first-line TKI-free treatment (n = 294). Within the subgroup of R/R patients that fulfilled the main criteria of the QUANTUM-R study, 48.9% received an intensive salvage regimen; none received hypomethylating agents or low-dose cytarabine. Among the R/R FLT3-ITD AML patients with CR1 durations < 6 months who received intensive TKI-free treatment, the rate of CR or CRi after salvage chemotherapy was 52.8%, and these results allowed a bridge to be transplanted in 39.6% of cases. Finally, in this QUANTUM-R standard arm-matched cohort, the median overall survival (OS) was 7.0 months and 1-, 3- and 5-year OS were 30.2%, 23.7% and 21.4%, respectively. To conclude, these real-world data show that the intensity of the second-line treatment likely affects response and transplantation rates. Furthermore, the results indicate that including patients with low-intensity regimens, such as low-dose cytarabine or hypomethylating agents, in the control arm of a phase 3 trial may be counterproductive and could compromise the results of the study.

scholarly journals TREATMENT WITH LOW-DOSE CYTARABINE IN ELDERLY PATIENTS (AGE 70 YEARS OR OLDER) WITH ACUTE MYELOID LEUKEMIA: A SINGLE INSTITUTION EXPERIENCE

2016 ◽  
Vol 8 ◽  
pp. 2016009 ◽  
Author(s):  
Maël Heiblig ◽  
Mohamed Elhamri ◽  
Isabelle Tigaud ◽  
Adriana Plesa ◽  
Fiorenza Barraco ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Intensive Chemotherapy ◽  
Hypomethylating Agents ◽  
Single Institution ◽  
Low Dose Cytarabine ◽  
Acute Myeloid ◽  
Better Than

Objectives: Low-dose cytarabine (LD-AraC) is still regarded as the standard of care in elderly patients with acute myeloid leukemia (AML) ‘unfit’ for intensive chemotherapy. In this study, we compared the efficacy of LD-AraC, in patients ≥ 70 years old, with that of intensive chemotherapy, best supportive care (BSC), or hypomethylating agents in a single institution experience.Methods: Between 2000 and 2014, 60 patients received LD-AraC at 20 mg once or twice daily by subcutaneous injection for 10 consecutive days every 4-6 weeks. 85 patients were treated by intensive chemotherapy, 34 patients by hypomethylating agents, and 43 patients only by BSC.Results: Complete remission rate with LD-AraC was 7% versus 56% with intensive chemotherapy and 21% with hypomethylating agents. Median overall survival (OS) of patients treated with LD-AraC was 9.6 months with 3-year OS of 12%. Survival with LD-AraC was better than with BSC only (P = 0.001). Although not statistically significant, intensive chemotherapy and hypomethylating agents tended to be better than LD-AraC in terms of OS (median: 12.4 months and 16.1 months, respectively). There was no clear evidence that a beneficial effect of LD-AraC was restricted to any particular subtype of patients, except for cytogenetics.Conclusions: Despite a trend in favor of intensive chemotherapy and hypomethylating agents over LD-AraC, no real significant advantage could be demonstrated, while LD-AraC showed a significant advantage comparatively to BSC. This tends to confirm that LD-AraC can still represent a baseline against which new promising agents may be compared either alone or in combination.

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