Abstract
Introduction:
AML is a heterogenous group of hematological neoplasms with morphological, cytogenetic and molecular abnormalities resulting in maturation arrest of myeloid cell lines. This translates into clinical symptoms and signs resulting from neutropenia, anemia and thrombocytopenia.
Although the knowledge of the underlying biology and molecular abnormalities has evolved tremendously, this has not been accompanied as quickly by translational changes in the early management of AML patients. The intensive induction therapy (combination of anthracycline and cytarabine) for young patients with good performance status has remained static since the first description in 1973 (Yates et al, Cancer Chemother Rep. 1973; 57(4):485-8). Older adults and patients with comorbidities had inferior treatment choices limited to hypomethylating (HMA) agents.
The activity of Venetoclax R (Ven) with either HMA or Low dose Cytarabine (LDAC) has improved the outcome of patients who are not candidates for intensive induction therapy. In this report we describe our experience with HMA alone or the combination of HMA and Ven in patients not fit for intensive induction therapy in a real-world setting.
Method:
We conducted a retrospective chart review of AML patients diagnosed between January 2020 and July 2021. Data collected included patient demographics, karyotype, treatment and response to treatment. Older adults were defined as patients greater than 60 years of age. Patients with comorbidities (renal failure, active cardiac, pulmonary and hepatic disease) active opportunistic infections and poor performance status (ECOG >2) were also deemed not suitable for intensive induction therapy.
Results:
Alternative induction was given with HMA (5 Azacitidine) alone or in combination with Ven. HMA dose (75mg/m 2 was calculated over a period of 7 days and given during workdays of the week. Ven was given 100 mg (with CYP3A4 inhibitor) - 400 mg per day for 21 days. Patients were evaluated for treatment response after 2 - 4 cycles.
Between January 2019 and June 2021, 66 patients were diagnosed with AML. The median age was 45 years (range 16-95years). Older adults (>60 years of age) have increased from < 10 % to 28 % (n=19) in the current cohort (Alam A et al Blood 2014; 124 (21).
Treatment was as follows: Intensive induction n= 29, alternative induction n=19 and no therapy n=18 (refused treatment, age and poor performance status).
The median age of patients given alternative induction was 55 years (range 26-80 years). Karyotype analysis showed good risk n=3, intermediate risk n= 9 poor risk n=3, metaphase failure n=4.
Alternative induction reasons included age (n=9), co-morbidities (n=10) (Obesity, respiratory failure, cardiomyopathy, pulmonary embolism, renal failure, acute hepatitis, active infection (mucormycosis) and 2ndry AML).
The response to HMA and Ven consisted of CR 60 % (9/15) with 4 patients ineligible for evaluation (2 early death (day + 3 and day + 8), the other 2 < 28 days post induction). The progression free survival is 149 days (range 41-517 days). 3 patients have relapsed after achieving complete remission. The median overall survival (OS) for the cohort is 120 days (range 3 to 517 days) while the median OS for non-responders is 103 days (range 3 to 375 days).
Conclusion:
The combination of HMA and Ven is an effective treatment modality in newly diagnosed patients with AML who are not eligible for intensive induction. The response to treatment has improved from < 10 % (HMA alone) to 60 % with HMA + Ven in an older cohort or those with comorbidities.
The treatment is given in outpatient setting with increased patient satisfaction and minimal toxicities. However, this is complicated by increasing issues with access due to insurance coverage and co pay for Ven.
Standardization of HMA and Ven with or without CYP3A4 inhibitors may improve the CR rates. Consolidation strategies in younger patients (especially good risk disease) who are other wise ineligible for intensive induction may improve progression free survival.
Disclosures
McCarthy: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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