Response rates in acute myeloid leukemia patients treated with attenuated durations of venetoclax in combination with hypomethylating agents.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19008-e19008
Author(s):  
Dena Blanding ◽  
Bakos Keegan Jonathan ◽  
Christopher Andrew Rangel ◽  
Sarah Pasyar ◽  
Elizabeth Goodwin Hill ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
Response Rate ◽  
Response Rates ◽  
Complete Response ◽  
Cytotoxic Chemotherapy ◽  
Hypomethylating Agents ◽  
Standard Duration ◽  
Composite Response ◽  
Acute Myeloid

e19008 Background: The combination of the Bcl-2 inhibitor, venetoclax, with hypomethylating agents (HMA) recently emerged as an efficacious treatment for older adults with acute myeloid leukemia (AML) who are not eligible for intensive induction therapy. In a phase III randomized controlled trial of HMA +/- venetoclax, DiNardo et al demonstrated impressive composite complete response rate and complete response with incomplete recovery (CR+CRi) of 66% in the venetoclax arm as compared to 28% in the placebo arm. Despite HMA/Venetoclax being lower intensity, 83% of patients developed grade 3 hematologic adverse events, and 42% of patients experienced febrile neutropenia in the venetoclax arm, as compared to 19% in the placebo arm. In the trial, venetoclax was given continually for 28 day cycles, with some patients receiving shortened durations of venetoclax (21 days) due to toxicity. To reduce toxicity, some institutions have further limited the duration of venetoclax in cycle 1. Here, we report response rates with attenuated durations of venetoclax with HMA. Methods: We conducted a retrospective study of AML patients who received venetoclax in combination with HMA, excluding those with prior chemotherapy for AML or MDS, or previous exposure to HMA or venetoclax. Demographic, cytogenetic, pathology, and outcome data were collected including bone marrow biopsy results at diagnosis and after cycle 1 (day +28) or cycle 2 (day +56). The primary outcome was composite response rate (CR+CRi) following cycle 1 or cycle 2 defined by 2017 ELN criteria. Results: 25 patients were identified with median age of 73 (range 63-82). 9 patients received 14 or less days of venetoclax (attenuated duration): < 8 days in 1 patient and 8-14 days in 8 patients. 16 patients received 21 days or more (standard duration): 21 days in 14 patients, and 28 days in 2 patients. Of the patients who received an attenuated duration, the median age was 74 (68-82), 22% had either a TP53 mutation or deletion, 56% had complex karyotype, and 44% had received prior cytotoxic chemotherapy. Of the patients who received standard duration therapy, the median age was 71 (63-81), 44% had either a TP53 mutation or deletion, 75% had complex karyotype, and 6% had received prior cytotoxic chemotherapy. The composite response rate was 78% in the attenuated duration group and 75% in the standard duration group (p > 0.99). Conclusions: Though a limited sample size, this data suggests high response rates can be observed with attenuated courses of venetoclax. With appropriately selected patients, the feasibility of attenuated venetoclax courses could be further explored in larger prospective studies.[Table: see text]

scholarly journals Comparison of High-Dose Cytarabine, Mitoxantrone, and Pegaspargase (HAM-pegA) to High-Dose Cytarabine, Mitoxantrone, Cladribine, and Filgrastim (CLAG-M) as First-Line Salvage Cytotoxic Chemotherapy for Relapsed/Refractory Acute Myeloid Leukemia

2020 ◽  
Vol 9 (2) ◽  
pp. 536
Author(s):  
Ciera L. Patzke ◽  
Alison P. Duffy ◽  
Vu H. Duong ◽  
Firas El Chaer ◽  
James A. Trovato ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Standard Of Care ◽  
Response Rates ◽  
Complete Response ◽  
Cytotoxic Chemotherapy ◽  
High Dose ◽  
High Dose Cytarabine ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Currently, no standard of care exists for the treatment of relapsed or refractory acute myeloid leukemia (AML). We present our institutional experience with using either CLAG-M or HAM-pegA, a novel regimen that includes pegaspargase. This is a retrospective comparison of 34 patients receiving CLAG-M and 10 receiving HAM-pegA as first salvage cytotoxic chemotherapy in the relapsed or refractory setting. Composite complete response rates were 47.1% for CLAG-M and 90% for HAM-pegA (p = 0.027). Event-free survival was significantly different in favor of HAM-pegA (p = 0.045), though overall survival was similar between groups. There were no significant differences in toxicities experienced by patients treated with the two regimens, including adverse events of special interest related to pegaspargase (venous thromboembolism, hemorrhage, hepatotoxicity, pancreatitis, and hypersensitivity reactions). HAM-pegA is a novel regimen for relapsed or refractory AML that resulted in improved response rates and similar toxicities compared to CLAG-M.

Therapy of refractory or recurrent childhood acute myeloid leukemia using amsacrine and etoposide with or without azacitidine: a Pediatric Oncology Group randomized phase II study.

1996 ◽  
Vol 14 (5) ◽  
pp. 1521-1525 ◽  
Author(s):  
C P Steuber ◽  
J Krischer ◽  
T Holbrook ◽  
B Camitta ◽  
V Land ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Complete Response Rate ◽  
Complete Response ◽  
Drug Regimen ◽  
Childhood Acute Myeloid Leukemia ◽  
Group 2 ◽  
Acute Myeloid ◽  
Group 1

PURPOSE A randomized study compared the combination of amsacrine (100 mg/m2/d on days 1 to 5) and etoposide (200 mg/m2/d on days 1 to 3) with the same two agents plus azacitidine (250 mg/m2/d on days 4 to 50) for the therapy of induction-resistant or relapse childhood acute myeloid leukemia (AML). PATIENTS AND METHODS One hundred sixty-seven assessable children with AML who either had failed to respond to primary induction therapy (group 1, n = 41) or had relapsed (group 2, n = 126) were randomized. RESULTS Overall, there were 56 complete responses (34%; SE 4%). Among primary refractory patients (group 1), the complete response rate was higher with the three-drug regimen (18% vs 53%, P = .03). In the relapsed patients (group 2), there was no difference in complete response rates related to treatment (31% vs 35%, P = .3). There were 17 early deaths. The major toxicities for both regimens were myelosuppression and infection. CONCLUSION The overall complete response rate of 34% in this patient population is indicative of effective antileukemic activity. For patients with relapsed leukemia, the addition of azacitidine to etoposide and amsacrine did not improve response. The suggested advantage of the three-drug regimen for induction failures warrants further investigation.

Chemotherapy Versus Hypomethylating Agents for the Treatment of Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndrome Following Allogeneic Stem Cell Transplant: A Retrospective Review

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3944-3944
Author(s):  
Ibraheem H Motabi ◽  
Jingxia Liu ◽  
Camille N. Abboud ◽  
Amanda F. Cashen ◽  
Keith E. Stockler-Goldstein ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myeloid Leukemia ◽  
Stem Cell Transplant ◽  
Response Rate ◽  
Cell Transplant ◽  
Intensive Chemotherapy ◽  
Hypomethylating Agents ◽  
Allogeneic Stem Cell Transplant ◽  
Chemotherapy Group ◽  
Acute Myeloid

Abstract Allogeneic stem cell transplant (allo-SCT) is a potentially curative option for high risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Disease relapse after transplant is the major cause of treatment failure and is associated with a poor outcome. Intensive chemotherapy followed by donor lymphocytes infusion (DLI) or a second SCT may result in a durable response in some patients, but is associated with increased toxicity. More recently, a less aggressive therapy with hypomethylating agents (HA) has been reported to have activity in treatment of post-SCT relapse. We compared the treatment outcomes of intensive chemotherapy with that of HA. The primary end points were overall response rate (ORR) and overall survival (OS). Secondary endpoints were complete remission (CR) rate and progression free survival (PFS). A total of 100 patients with AML in morphological evidence of relapse were included: 73 patients received chemotherapy and 27 patients received a HA. Fifty-six percent of patients in the chemotherapy group and 33% of patients in the HA group received at least one DLI after treatment. Treatment with chemotherapy resulted in a higher ORR (51% vs. 18.5%, p = 0.004) and a higher CR rate (40% vs. 7%, p= 0.002). The median OS (6 months vs. 4 months, p = 0.024) and PFS (8 months vs. 2.3 months, p = 0.053) were longer in chemotherapy group. The overall survival (OS) at one year was 32% in the chemotherapy group compared with 4% in the HA group (p = 0.024). Similar benefit of chemotherapy over HA was maintained in all treatment outcomes after controlling for the use of DLI. The use of chemotherapy followed by DLI may offer the greatest benefit ( ORR of 68%; 1-year OS of 44%; and median OS of 18 months). Conclusion: our results suggest that intensive chemotherapy may result in a better response rate and a better overall survival compared with hypomethylating therapy in patients with morphological relapse of AML after SCT. We propose prospective studies before the use of hypomethylating agents in this setting for medically fit patients. Disclosures Off Label Use: Rituximab is a genetically engineered monoclonal antibody that targets a specific protein, known as CD20 found on the surface of normal and malignant B-lymphocytes.Use of Rituximab treatment for other than FDA approved indications include a rare condition of acquired factor VIII inhibitors in individuals without inherited hemophilia as an autoimmune phenomenon that may lead to life-threatening bleeding. Due to the low incidence rate of acquired inhibitors, published data consists of only case reports, and reviews.. Vij:celgene: Honoraria, Research Funding.

scholarly journals What Is the Optimal Time to Initiate Hypomethylating Agents (HMA) in Higher Risk Myelodysplastic Syndromes (MDS)?

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3098-3098 ◽  
Author(s):  
Rami S. Komrokji ◽  
Najla Al Ali ◽  
David A Sallman ◽  
Eric Padron ◽  
Aziz Nazha ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Disease Risk ◽  
Response Rates ◽  
Complete Response ◽  
Optimal Time ◽  
Hypomethylating Agents ◽  
Advisory Committees ◽  
Baseline Characteristics

Abstract Background: Hypomethylating agents (HMA) are the standard of care for higher risk MDS patients (pts). Fewer than one-half will respond to therapy for an average duration of one year, thereby emphasizing the necessity to optimize the use of these disease modifying agents. HMA clinical trials have not addressed the optimal time in the disease course to initiate treatment to maximize disease-modifying potential. The current dogma is to begin HMA therapy in all higher risk MDS pts at the time of initial diagnosis. Nevertheless, a subset of higher risk MDS pts will have adequate hematopoiesis at the time of diagnosis regardless of disease risk, and for these pts therapy may be delayed and reserved for a later time when symptomatic cytopenias develop. We investigated the impact of the timing of HMA initiation on outcomes among higher risk MDS pts presenting with adequate blood counts to discern the possible benefit of early treatment based solely on disease risk. Methods: We identified MDS pts with intermediate-2 and high risk IPSS (higher risk) MDS treated with HMA among the Moffitt Cancer Center database. We included patients with adequate hematopoiesis defined for the purpose of this study as platelets >50 x 109/L, Hgb > 9 g/dl and ANC > 0.5 x 109/L and being transfusion independent to exclude those pts in need of HMA treatment for cytopenias. We divided patients into 4 groups based on the time of HMA initiation (within 30, 31-60 , 61-90 and greater than 90 days from time of diagnosis). We compared baseline characteristics, best response rate to treatment using international working group criteria (IWG 2006), leukemia free survival (LFS) and overall survival (OS) among the 4 groups. Results: We identified 320 higher risk MDS pts with adequate hematopoiesis who were treated with HMA. Baseline characteristics for the 4 groups based upon time of HMA therapy initiation are summarized in Table-1. Pts receiving treatment within 30 days had higher marrow myeloblast percentage at time of diagnosis. There was no difference in mean blood counts at time of diagnosis between the 4 groups; however, mean platelet count was lower at time of initiating HMA therapy in patients treated after 90 days from diagnosis. Table-2 summarizes somatic gene mutation data among 110 patients tested. TET-2 mutations were more common among those treated within 60 days, whereas U2AF1 mutations were more common among those treated after 60 days from diagnosis. The complete response rates were 21%, 26%, 23% and 7%, respectively for pts treated within 30 , 31-60 , 61-90 and greater than 90 days from time of diagnosis (p=0.046). The overall response rates (defined as hematological improvement or better) were 43%, 41%, 43% and 34%, respectively for pts treated within 30, 31-60 , 61-90 and greater than 90 days from date of diagnosis (p .70). There was no difference in mean duration of treatment with HMA among the groups with mean durations of 267, 204, 224 and 215 days, respectively, (p .35). The median OS from the date of diagnosis was 641, 550, 979 and 806 days, respectively for pts treated within 30, 31-60, 61-90 and greater than 90 days from date of diagnosis (p .2). There was no impact of timing for HMA initiation when adjusted for Revised-IPSS risk groups in Cox regression analysis. There was no difference in OS based on HMA initiation time when adjusted for myeloblasts % or karyotype. Further, there was no difference between groups in rate of AML transformation or LFS (p =.7 and .16, respectively). Conclusions A delay in initiating HMA therapy in higher risk MDS pts with adequate blood counts is not associated with worsened overall survival or increased frequency of leukemia transformation. Complete response rates were higher when treatment was started earlier in the disease course, however, there was no difference in overall response rate. Close observation to initiate treatment upon development of clinically significant cytopenias appears to be a safe and equally effective strategy among pts with higher risk MDS. Disclosures Komrokji: Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding. Sallman:Celgene: Research Funding, Speakers Bureau. Nazha:MEI: Consultancy. Steensma:Takeda: Consultancy; Syros: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Janssen: Consultancy, Research Funding; H3 Biosciences: Research Funding; Celgene: Research Funding; Amphivena: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy. Roboz:AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Cellectis: Research Funding; Novartis: Consultancy; Celltrion: Consultancy; Astex Pharmaceuticals: Consultancy; Sandoz: Consultancy; Celgene Corporation: Consultancy; Otsuka: Consultancy; Janssen Pharmaceuticals: Consultancy; Aphivena Therapeutics: Consultancy; Daiichi Sankyo: Consultancy; Orsenix: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; Orsenix: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; Roche/Genentech: Consultancy; Cellectis: Research Funding; Otsuka: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Celltrion: Consultancy; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Eisai: Consultancy; Roche/Genentech: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. List:Celgene: Research Funding.

scholarly journals Maintenance Therapy in AML

2021 ◽  
Vol 10 ◽  
Author(s):  
Patrick K. Reville ◽  
Tapan M. Kadia
Keyword(s):  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
Initial Therapy ◽  
Cytotoxic Chemotherapy ◽  
Hypomethylating Agents ◽  
Therapy Options ◽  
Future Studies ◽  
Improved Outcomes ◽  
Clinical Dilemma ◽  
Acute Myeloid

Recent advances in therapeutics coupled with steady improvements in supportive care for patients with acute myeloid leukemia (AML) have led to improved outcomes. Despite these advances, even in patients that achieve a complete remission with initial therapy high rates of relapse remain a clinical dilemma. For decades, investigators have attempted strategies of maintenance therapy to prolong both remission duration and overall survival in patients with AML. These approaches have included cytotoxic chemotherapy, immunotherapy, hypomethylating agents, and targeted small molecule therapy. Overall, the evidence in favor of maintenance therapy is limited. Recent strategies, especially with hypomethylating agents have begun to show promise as maintenance therapy in improving clinical outcomes. Ongoing and future studies will continue to elucidate the true role for maintenance therapy options in patients with AML. In this review we summarize prior and ongoing maintenance therapy approaches in AML and highlight some of the most promising strategies.

scholarly journals Hematopoietic growth factors as adjuncts to the treatment of acute myeloid leukemia

Blood ◽  
1996 ◽  
Vol 88 (10) ◽  
pp. 3675-3685 ◽  
Author(s):  
CA Schiffer
Keyword(s):  
Acute Myeloid Leukemia ◽  
Growth Factors ◽  
Growth Factor ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Complete Response ◽  
Colony Stimulating Factor ◽  
Hematopoietic Growth Factors ◽  
Stimulating Factor ◽  
Acute Myeloid

A number of randomized trials have recently been completed evaluating the effect of hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor) as adjuncts to the treatment of patients with acute myeloid leukemia. Most studies used the growth factors to decrease the duration of neutropenia with the hope of reducing infectious morbidity and mortality. The results of these trials are generally quite consistent. Virtually all trials showed a modest reduction in the duration of severe neutropenia with a variable effect on the incidence of severe infections, antibiotic usage, and the duration of hospitalization. There was no consistent benefit in terms of improvements in complete response rate, complete response duration, or overall survival. However, it is important that there does not appear to be an increase in the incidence of drug-resistant leukemia in trials in which the growth factor was begun after completion of the chemotherapy. Other trials administered growth factors either before or simultaneous with the chemotherapy in an attempt to enhance chemosensitivity and decrease drug resistance. None of these trials, whether conducted as part of initial induction therapy or in relapse, showed improvements in response rate or survival. Lastly, some anecdotal reports have suggested that occasional patients who receive growth factors as the only therapy for overt leukemia can achieve remission, possibly through a differentiating effect of the growth factor. However, there are very few such reports, and growth factor use in this situation is potentially dangerous and should be performed only in the context of a clinical trial. In summary, there appears to be no role at this time for priming of leukemia cells by growth factors to enhance the effect of chemotherapy, and more in vitro studies should be performed before further clinical trials of this approach. It is clear that growth factors administered after induction and possibly consolidation chemotherapy can shorten the duration of neutropenia, without a significant effect on treatment outcome. It is as yet unclear whether the use of growth factors in this fashion is cost effective.

scholarly journals A phase 1/2 study of the oral FLT3 inhibitor pexidartinib in relapsed/refractory FLT3-ITD–mutant acute myeloid leukemia

2020 ◽  
Vol 4 (8) ◽  
pp. 1711-1721 ◽  
Author(s):  
Catherine C. Smith ◽  
Mark J. Levis ◽  
Olga Frankfurt ◽  
John M. Pagel ◽  
Gail J. Roboz ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Drug Exposure ◽  
Kinase Inhibitors ◽  
Response Rate ◽  
Phase 1 ◽  
Complete Response ◽  
Flt3 Inhibitor ◽  
Acute Myeloid

Abstract FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitors (TKIs) have activity in acute myeloid leukemia (AML) patients with FLT3 internal tandem duplication (ITD) mutations, but efficacy is limited by resistance-conferring kinase domain mutations. This phase 1/2 study evaluated the safety, tolerability, and efficacy of the oral FLT3 inhibitor PLX3397 (pexidartinib), which has activity against the FLT3 TKI–resistant F691L gatekeeper mutation in relapsed/refractory FLT3-ITD–mutant AML. Ninety patients were treated: 34 in dose escalation (part 1) and 56 in dose expansion (part 2). Doses of 800 to 5000 mg per day in divided doses were tested. No maximally tolerated dose was reached. Plasma inhibitory assay demonstrated that patients dosed with ≥3000 mg had sufficient levels of active drug in their trough plasma samples to achieve 95% inhibition of FLT3 phosphorylation in an FLT3-ITD AML cell line. Based on a plateau in drug exposure, the 3000-mg dose was chosen as the recommended phase 2 dose. The most frequently reported treatment-emergent adverse events were diarrhea (50%), fatigue (47%), and nausea (46%). Based on modified response criteria, the overall response rate to pexidartinib among all patients was 21%. Twenty-three percent of patients treated at ≥2000 mg responded. The overall composite complete response rate for the study was 11%. Six patients were successfully bridged to transplantation. Median overall survival (OS) of patients treated in dose expansion was 112 days (90% confidence interval [CI], 77-150 days), and median OS of responders with complete remission with or without recovery of blood counts was 265 days (90% CI, 170-422 days). This trial was registered at www.clinicaltrials.gov as #NCT01349049.

scholarly journals A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia

Blood ◽  
2013 ◽  
Vol 121 (24) ◽  
pp. 4854-4860 ◽  
Author(s):  
Stephen H. Petersdorf ◽  
Kenneth J. Kopecky ◽  
Marilyn Slovak ◽  
Cheryl Willman ◽  
Thomas Nevill ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Complete Response Rate ◽  
Complete Response ◽  
Gemtuzumab Ozogamicin ◽  
Phase 3 ◽  
Younger Patients ◽  
Key Points ◽  
Acute Myeloid

Key Points The addition of gemtuzumab ozogamicin to induction or maintenance therapy failed to improve the complete response rate or overall survival in patients with acute myeloid leukemia.

scholarly journals Impact of Smoking and TP53 Mutations in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-35
Author(s):  
Xia Bi ◽  
Zachary French ◽  
Margaret Kasner ◽  
Gina Keiffer ◽  
Lindsay Wilde ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Cigarette Smoking ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Response Rate ◽  
Tp53 Mutations ◽  
History Of ◽  
Acute Myeloid

Objective: With the routine use of next generation sequencing (NGS) for diagnosis and prognosis, a growing number of pathogenic mutations have been discovered in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). TP53 is the most frequently mutated gene in human cancer. Mutations in TP53 are found in approximately 8% of de novo AML, but occur more frequently, up to 30% in secondary-AML (s-AML) and therapy-related AML (t-AML), as well as 5-20% of patients with MDS. They are associated with older age, chemotherapy resistance, and worse overall survival. Previous studies have shown potent carcinogens in tobacco smoke can induce transversion mutations along the p53 gene in patients with lung cancers, laryngeal cancers, and head and neck cancers. The association between cigarette smoking and TP53 mutations and its prognostic implications in AML and MDS have not been characterized before. Methods: We performed a retrospective review of AML and MDS patients with or without TP53 mutations at Thomas Jefferson University Hospital between April 2016 and December 2018. Data on patient age, gender, smoking status (current or past history of smoking), disease type, induction regimen, cytogenetics, and genetic mutations via NGS from bone marrow or peripheral blood were collected. Overall response rate (ORR) defined as complete remission and partial response and overall survival (OS) were analyzed. Kaplan-Meier method was used to estimate OS and compared using the log-rank test. Chi-square test was used where appropriate in comparison. P&lt;0.05 was considered as statistically significant. Results: From April 2016 to December 2018, 50 and 74 patients were identified with AML or MDS with and without a TP53 mutation, respectively. In patients with a TP53 mutation, median age at diagnosis was 70 years (range 51 to 91). 27 patients were diagnosed with AML (including 4 with s-AML, 3 with t-AML), 22 with MDS (including 2 with t-MDS), and 1 with acute leukemia with ambiguous lineage. A past or current history of smoking was found in 70% of patients with a TP53 mutation and 51% of patients without a TP53 mutation (p=0.006). Complex karyotype was observed in 54% of smokers with a TP53 mutation, and 73% of non-smokers with a TP53 mutation (p=0.21). In smokers with TP53 mutation, the most common co-occurring mutations were DNMT3A (6 patients), ASXL1 (5 patients), and TET2 (4 patients). In non-smokers with TP53 mutation, the most common co-occurring mutation was TET2 (3 patients). 26% of patients received intensive chemotherapy (IC), 38% of patients received a hypomethylating agent (HMA), 6% of patients received lenalidomide, and 22% of patients received supportive care only. 8% of patients were lost to follow-up. ORR was 40% in smokers with a TP53 mutation, compared to 20% in non-smokers (p=0.26). Response rate was 27% in patients who received IC and 75% in patients who received HMA (p=0.01). All patients with a TP53 mutation had died at the time of analysis, with a median OS 7.1 months (range 0.0 - 55.9) in smokers, and 6.3 months (range 0.2 - 30.3) in non-smokers (p=0.40). Conclusion: A higher prevalence of smoking was found in patients with AML or MDS with a TP53 mutation. Response rate was higher in patients who received HMA compared to IC. Overall survival was poor in all patients with a TP53 mutation, but the difference was not statistically significant in smokers versus non-smokers. Limitations of the study include its retrospective nature, small number of patients, and single institution experience. More studies are needed to elucidate the effect of cigarette smoking on TP53 mutations in patients with AML and MDS, especially in the setting of evolving treatment paradigms using newer agents. Disclosures Palmisiano: AbbVie: Research Funding; Genentech: Research Funding.

scholarly journals Comparison of Induction Strategies and Responses for Acute Myeloid Leukemia Patients after Resistance to Hypomethylating Agents for Antecedent Myeloid Malignancy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 665-665 ◽  
Author(s):  
Chetasi Talati ◽  
Aaron D Goldberg ◽  
Amanda Przespolewski ◽  
Onyee Chan ◽  
Najla Al Ali ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Response Rates ◽  
Advisory Board ◽  
Cancer Center ◽  
Hypomethylating Agents ◽  
Advisory Committees ◽  
Induction Regimen ◽  
Acute Myeloid

Abstract Background Outcomes in patients (pts) with secondary acute myeloid leukemia (sAML) (therapy related myeloid neoplasms and AML with myelodysplasia related changes (MRC) per WHO 2016 classification (Arber et al, Blood 2016)) are poor. Pts treated with hypomethylating agents (HMAs) have suboptimal responses to induction chemotherapy (IC) upon transformation to AML. Previously, it was retrospectively demonstrated that the IC with cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) yields significantly higher response rates (64%) than 7+3 (cytarabine and anthracycline) (29%) in pts with prior HMA exposure (Jaglal et al, Leukemia Research 2014). Following the recent approval of CPX-351 for induction in sAML subgroup, we investigated outcomes after CPX-351 to cladribine based regimens and 7+3 in pts with sAML with prior HMA exposure. Methods We identified pts with sAML who had prior HMA treatment for an antecedent hematologic malignancy (AHM) and later received induction chemotherapy upon AML transformation from Moffitt Cancer Center (MCC) (n=229), Memorial Sloan Kettering Cancer Center (n=11) and Roswell Park Comprehensive Cancer Center (n=2). Patients were divided into 3 cohorts based on induction regimen: (A) cladribine based (CLA+/-G+/-M) (B) standard 7+3 and (C) CPX-351. Demographics, disease-specific variables, and outcomes were collected in accordance with the institutional review board approved protocol. Responders (R) were defined as pts achieving CR or CRi as defined by the 2003 International Working Group (IWG) criteria after 1 or 2 cycles of the either induction regimen whereas non-responders (NR) were defined as responses other than CR/CRi. Pts receiving a second induction with a different regimen were considered NR. Fisher's exact test and the ANOVA test were used to determine significance for continuous and categorical variables. Kaplan-Meier analysis with log-rank test was performed to estimate overall survival (OS). Results Among 242 pts who received IC for AML after HMA failure for prior AHM, 114 were treated with (A) cladribine based regimen (B) 94 pts with standard 3+7 and (C) 34 pts with CPX-351 (Cohort C). Baseline characteristics for all 3 cohorts are outlined in Table 1A. Median age for cohort A, B, and C were 65 (33-82), 66 (26-81), and 69 (36-82), respectively. Males comprised of 68.4%, 63% and 52.9% of the cohorts A, B and C, respectively. No pts had favorable-risk karyotype as defined by European LeukemiaNet (ELN) 2017 criteria. Adverse risk karyotype was noted in 42.1% of cohort A, 34.6% of cohort B and 22.7% of cohort C (p=.337). The majority of pts received azacitidine as their HMA for their AHM (88.7%, 84.9% and 82.4% in cohorts A, B, C, respectively) and median number of cycles administered prior to transformation to AML were 6, 4 and 5 for cohorts A, B, and C, respectively. Response rates in each cohort are summarized in Table 1B. The CR/CRi rate was 53% in cohort A, 32% in cohort B and 41.1% in cohort C (p=.005 between cohort A and B) (p=.329 between cohorts A and C) (p=.526 between cohorts B and C). The early death rates (<60 days of induction) were not significantly different among the 3 cohorts, at 12%, 8% and 2.9% in cohorts A, B and C respectively (p=.200). In pts who received ≤ 4 cycles of HMAs prior to AML transformation, response rates to CPX-351 were higher (64.3%) than in pts who received >4 cycles of HMAs (25.0%) (p=.0397). Cohort A (56.5% vs. 50.0%, p=.288) and B (39.1% vs. 25.5%, p=.175) did not demonstrate such a difference (Table 1C and 1D). There was a trend towards better OS (19.9 vs. 5.5mo) with CPX-351 treated pts with ≤ 4 cycles of HMAs compared to >4 cycles (p=.092) (Figure 1). To date, 70.0% of responding pts in cohort A have undergone an allogeneic stem cell transplant compared to 31.0% in cohort B and 28.6% in cohort C (p=.15). There was no significant difference in median OS among the 3 groups, cohort A (7.27 months), cohort B (7.63 months) and cohort C (7.07 months) (p=.887). Among responders, the mOS did not differ (12.93, 21.7, and 19.9 months for cohorts A, B, and C respectively, p=.635). Conclusions We demonstrate that cladribine-based induction regimens and CPX-351 yield higher CR/CRi rates compared to 7+3 in pts with sAML after HMA failure. Prolonged duration of HMA exposure may lower response potential with CPX-351 upon AML transformation. Median OS remains poor and did not differ among the 3 groups illustrating the unmet need for therapy for sAML pts after HMA failure. Disclosures Goldberg: AROG: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Pfizer: Research Funding. Sallman:Celgene: Research Funding, Speakers Bureau. List:Celgene: Research Funding. Wang:Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau. Tallman:AROG: Research Funding; Cellerant: Research Funding; AbbVie: Research Funding; ADC Therapeutics: Research Funding; Orsenix: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; BioSight: Other: Advisory board. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sweet:Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Agios: Consultancy; Astellas: Consultancy; Phizer: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Phizer: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Jazz: Speakers Bureau; BMS: Honoraria; Agios: Consultancy; Celgene: Honoraria, Speakers Bureau; BMS: Honoraria.

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