Maintenance Therapy in AML

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.

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Outcomes and Predictors of Relapse with Use of Hypomethylating Agents in Combination with Venetoclax Prior to Allogeneic Transplant in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-150815 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2327-2327

Author(s):

Imran Nizamuddin ◽

Timothy Seijung Oh ◽

Yazan Numan ◽

Max Farber Kelsten ◽

Madelyn Burkart ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Maintenance Therapy ◽

Myeloid Leukemia ◽

Research Funding ◽

Advisory Board ◽

Intermediate Risk ◽

Hypomethylating Agents ◽

Significant Difference ◽

Acute Myeloid

Abstract Introduction The treatment of acute myeloid leukemia (AML) has evolved tremendously. Recently, venetoclax with hypomethylating agents (HMA/ven) demonstrated durable responses in the frontline and relapsed/refractory (R/R) settings. This regimen is now standard of care for older adults or those unfit for intensive induction chemotherapy (DiNardo CD, N Engl J Med, 2020). Our institution also often uses HMA/ven to treat fit patients (pts) with high risk disease characteristics. Because HMA/ven was studied in transplant-ineligible pts, outcomes following potentially curative allogeneic hematopoietic stem cell transplantation (HSCT) remain unknown. This retrospective study aims to describe characteristics and outcomes of pts treated with HMA/ven who proceeded to HSCT. Methods Adult pts diagnosed with AML and treated with HMA/ven either in the frontline or R/R setting between 1/2010 and 2/2020 at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University were identified. Hypomethylating agents included either azacitadine or decitabine. Data were collected and analyzed based on demographics, laboratory and clinical characteristics, and disease and toxicity outcomes. Efficacy endpoints included complete remission (CR), CR with incomplete hematologic recovery (CRi), and CR with incomplete platelet recovery (CRp). Survival curves for overall survival (OS) and leukemia-free survival (LFS) were calculated using the Kaplan-Meier method. Univariate analyses were performed to determine impact of clinical variables on outcomes (significance defined as p≤0.05). Cohorts were compared using χ 2 or Fisher's exact test for categorical variables and the unpaired t-test for continuous variables. Results Clinical and demographic features at time of diagnosis are listed in Table 1. In total, 257 pts received HMA/ven. Of these, 36 pts received a HSCT, which was the population analyzed in this study. In the front-line setting 11 (31%) pts received HMA/ven and 25 (69%) pts received HMA/ven for R/R disease. 25 (69%) pts received azacitadine and 11 (31%) pts received decitabine (5 days, n=5, 14%; 10 days, n=6, 17%). Based on ELN guidelines, 23 (64%) pts had adverse risk disease at diagnosis. Response to HMA/ven in the pre-transplant setting is shown in Table 2. Of 35 evaluable pts, 34 achieved remission (CR, n=32, 91%; CRi, n=1, 3%; CRp, n=1, 3%). Table 3 shows outcomes following HSCT. 14 (39%) pts relapsed post HSCT and 13 (36%) pts received treatment for relapse. With a median follow-up of 11.6 months, median LFS from time of transplantation was 11.2 months. Median OS was not reached over follow up period but estimated to be 25.4 months. There was a significant difference in rates of relapse based on ELN classification at diagnosis (p=0.0296). In comparison, presence of complex/monosomal karyotypes (p=0.593), blast percentage at diagnosis (p=0.456), donor type (p=0.484), and number of previous lines of therapy (p=0.822) did not predict for relapse. Median LFS in adverse and favorable/intermediate risk ELN groups was 5.8 and 19.8 months, respectively. Median OS in adverse and favorable/intermediate risk ELN groups was 25.4 and 29.5 months, respectively. Following transplant, 10 (28%) pts received maintenance therapy with a median of 5 cycles (range 1-14); 8 pts (22%) received HMA/ven maintenance following HSCT. There was no significant difference in relapse rates between those who received maintenance therapy (n=6, 43%) and those who did not (n=8, 57%) (p = 0.107). Median time to relapse from HSCT was 4.42 months in those who received maintenance therapy compared to 2.98 months in those who did not receive maintenance therapy (p=0.370). Following relapse, 10 (28%) pts were retreated with HMA/ven, but less than half (n=4, 40%) had a response. To date, 22 (61%) pts are alive with the majority (n=19, 86%) in remission. 14 (39%) pts died with half in remission at the time of death. Conclusions Our study showed that HMA/ven can feasibly be used not only to bridge to transplant, but to achieve durable remissions post HSCT. For those pts that relapsed post HSCT, duration of remission was very short. ELN classification was the only factor that informed relapse risk. Prospective studies must be done to understand which cytogenetic and molecular subgroups benefit the most from HMA/ven prior to transplant. Figure 1 Figure 1. Disclosures Abaza: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Altman: Biosight: Consultancy, Other: Travel fees, Research Funding; Fujifilm: Research Funding; Kura: Research Funding; Immunogen: Research Funding; Kartos: Research Funding; Daiichi Sankyo: Consultancy; ALZ Oncology: Research Funding; Theradex: Consultancy, Other: Advisory boards; Syros: Consultancy; Amgen: Research Funding; Aprea: Research Funding; Boehringer Ingelheim: Research Funding; Astellas: Consultancy, Other: Advisory Board, Research Funding; GlycoMimetics: Other: Participation on an advisory board; AbbVie: Consultancy, Other: Advisory Board, Research Funding; BMS: Research Funding; Kura Oncology: Consultancy. Dinner: Pfizer: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria.

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

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e19008 ◽

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]

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