Individualized AML Induction with Venetoclax Based Therapy in Unfit Treatment Naïve Patients Aged ≤ 60 Years: A Real World Perspective from India
Authors: Shaikh Mohd Rizwan Mohamad Anwar , Mehta Pallavi , Mirgh Sumeet Prakash , Halder Rohan , Agrawal Narendra , Khushoo Vishvdeep , Ahmed Rayaz , Folbs Bhaarat , Pratihast Divya , Bansal Nitin , Bhurani Dinesh 
Published: November 2021

Abstract
Introduction:
Although AML outcomes have reportedly improved in the developed world, outcomes continue to be poor in low middle income countries (LMIC). Apart from financial constraints, presence of baseline infections is one of the major reasons for early mortality and treatment deferral. According to an Indian study of 268 patients acute leukemia, more than 54% patients had baseline infections out of which only 40% received induction versus 93 % patients who did not have baseline infections.(Ragesh R et al EHA23 abstract book: Hemasphere; 2018)
Venetoclax has improved outcomes in AML and has been approved in elderly population. There is an unmet need for protocols for younger patients who are unfit for 3+7 due to multi drug resistant baseline infections or ECOG ≥2 or organ dysfunction.
Methods:
This is a single centre prospective observational study of AML patients who received either Azacytidine+Venetoclax or modified 3+7 regimen with Venetoclax.
We recruited 26 AML patients aged 60 or younger who had clinico-radiological evidence of infection or ECOG PS ≥2 or comorbidities from July'19 to March'21. Therapy was individualized based on the nature of infections, ECOG PS and co morbidities into two cohorts by the treating panel.
Cohort A (n=12) received Azacytidine @75mg/m 2 x 7 days with Venetoclax 100mg on day1, 200mg on day 2 and 100mg from day 3 with Voriconazole from day 3 onwards as antifungal prophylaxis and to reduce the cost. This regimen was preferred in patients who were unfit to receive modified 3+7 regimen.
Cohort B (n=14) received modified 3+7. This included backbone of Cytarabine (Ara C) infusion @100mg/m 2 with Venetoclax. Daunorubicin @60mg/m 2 was added based on the clinical status of the patient.Venetoclax was added from day one in the similar ramp up manner as in cohort A. Day 14 bone marrow examination and cytopenias were used to guide the duration of Venetoclax(range 7-14 days).
Daunorubicin doses were individualized as follows: Two doses of Daunorubicin were given to hemodynamically stable patients who showed recovery following antimicrobial therapy. Single dose of Daunorubicin was given to patients with multiple foci of infections or those who required ICU stay either before or during the initiation of therapy. Daunorubicin was omitted in patients on ventilatory support.Ara C infusion was limited to 5 days with 2 doses of Daunorubicin.
Patients who achieved CR and had their infections resolved received standard consolidation like High dose Ara C or HSCT as per ELN risk.
Results:
Baseline data is presented in table 1. Induction mortality was 2/26 (7.6%) till day 56. Median follow up was 6 months. At Day 28 composite CR (CR+CRi) was achieved in 8/12 (66%) in cohort A and 10/14 (71.4%) in cohort B. At day 56 composite CR (CR+CRi) was achieved in 9/12 (75%) in cohort A and 12/14 (85.7%) in cohort B. Overall CR rates at day 28 & day 56 were 69.2% and 80%.
One year OS was 62.8 % for the entire study population. It was 76.2% cohort A and 74 % in cohort B as per Kaplan Meier Curve estimates. RFS was 78.6% at 1 year for entire cohort. RFS was 66.7 % in cohort A and 100 % in cohort B.
In Cohort A, all patients were continued on Azacytidine and Venetoclax as they were not fit for standard consolidation.At the time of analysis 33% patients experienced relapse, 25% patients had refractory disease and 42% patients continue to be in CR. 33% patients were dead at the time of analysis due to disease.
In Cohort B, all patients who achieved CR were consolidated using Ara C @ 9 gm/m 2x 3 cycles. 2 patients underwent HSCT. No relapses were seen in this cohort. At the time of analysis, 3 non relapse mortalities were noted in Cohort B.
Adverse events:
Hematological toxicities were the most common adverse effects in both the arms. Most common infection was colitis. Sepsis due to carbapenem resistant organisms was the most common cause of grade ≥ 3 febrile neutropenia.
On Univariate analysis the outcome was not affected by ICU stay. We report that AML induction using Ara C infusion and Venetoclax backbone with individualized Daunorubicin dose yields non inferior CR rates and durable responses. No patient in cohort B relapsed.We found that by modulating the intensity of induction using Venetoclax we can salvage heavily infected or co-morbid patients.
Conclusion:
Ara C infusion and Venetoclax based AML induction with individualized Daunorubicin dosing is a promising strategy in unfit younger patients. However, it needs to be validated in a larger prospective trial.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.