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Offering hope to Elderly, unfit Acute Myeloid Leukemia patients - combining Targeted therapy and chemotherapy

Dr.Reetu Jain1

1Director BMT and Academics, Medical Oncologist and BMT

Jaslok Hospital and Research Center

Email ID: reebun@yahoo.com

Acute myeloid leukemia (AML), the most common leukemia in adults has been associated with poor five-year overall survival (OS) rates (~25%). Treatment options are limited to induction chemotherapy and allogeneic hematopoietic stem cell transplant in a select few. The disease is now witnessing a paradigm shift from chemotherapy-based treatment toward targeted and combination therapies. The recent approvals of CPX-351, venetoclax (VEN), enasidenib, ivosidenib, gilteritinib and midostaurin have improved survival outcomes in AML patients. There remains an unmet need for therapies that provide deeper and durable responses, especially in patients who are unfit and/or relapsed/refractory (R/R). Given the heterogeneity of AML, the treatment landscape will continue to evolve with the approval of newer agents (and their combinations) for the treatment of molecularly defined patient segments.

Venetoclax: A new messiah in the horizon

Amongst the newer targeted drugs,Venetoclax shows promise, especially in the elderly and unfit patients.Venetoclax was granted accelerated approval in November 2018 by the FDA[1] in combination with azacytidine (Aza), decitabine or low-dose cytarabine for the treatment of newly diagnosed AML in adults who are aged 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

VIALE-A:Improvement in overall survival in the trial with azacytidine/venetoclax compared to azacitidine alone for patients with previously untreated acute myeloid leukemia ineligible for intensive chemotherapy

In the VIALE-A[2]trial patients were randomly assigned 2:1 between venetoclax and azacytidine versus azacytidine and placebo. The study enrolled patients who were unfit for intensive chemotherapy, 75 years of age or older, or those with significant comorbidities.

The primary endpoint of the study was overall survival. The overall survival endpoint was reached, with an improvement in median survival from 9.5 months with azacytidine/placebo to 15 months with azacytidine and venetoclax, at 24 months,the Kaplan -Meier curve have not yet met. BCL2 inhibition is one of the options for these group patients who have limited treatment options or get excluded for any newer drug trial.

High rates of minimal residual disease-negative complete remission and excellent tolerability with venetoclax added to cladribine and low-dose ara-C alternating with 5-azacitidine for newly diagnosed AML in older patients.

This is a Phase II study from MD Anderson.[3]The induction consists of cladribine followed by low-dose Ara-C, followed by a maintenance of two cycles with the same at reduced doses alternating with two cycles of azacytidine, and each cycle with up to 21 days of venetoclax.

In the 48 eligible patients, that the complete remission (CR) rate was 77%, with 92% of these patients being MRD negative.This regimen seems to be a less intensive regimen and can be considered in elderly AML patients.

Interim analysis of the Phase Ib/II study of venetoclax with FLAG-IDA for patients with newly diagnosed or relapsed/refractory (R/R) AML

This is another study from MD Anderson [4]combining venetoclax with FLAG-IDA regimen. In newly diagnosed AML as a Phase IIA study and in relapsed/refractory patients as a Phase IIB study.FLAG-IDA is an effective regimen for relapse-refractory AML. Prolonged myelosuppression is the majorconcern for the treating Physician. This study combines Venetoclax with FLAG-IDA (doses in this study differ between this IDA-FLAG regimen and standard IDA-FLAG).The dose of the idarubicin is lower for both the newly diagnosed and the relapsed/refractory patients. The dosages of cytarabine were also reduced from 2 g/m2 to 1.5 g/m2. Venetoclax dose was given for 14 days during induction and subsequently for seven days during consolidation.

The results look impressive with an overall response rate of 82%. In the newly diagnosed patients, overall response rate observed was 97% with 96% of MRD negativity by flow cytometry, very high response rate with deep responses.The newly-diagnosed patients showed a better event-free and overall survival than those in the relapsed/refractory cohorts. Traditionally IDA-FLAG is a very myelosuppressive regimen, and with addition of Venetoclax myelosuppression is the major side effects which should be considered. This myelosuppression can last for 4-6 weeks period. While using this regimen with modified dosages prolonged myelosuppression should be kept in mind.This regimen can be recommended to patients before allogeneic stem cell transplant given the excellent, deeper response rates.

CPX-351 (Liposomal Daunorubicin) versus 7 + 3 for older adults with newly diagnosed high-risk or secondary AML

CPX-351 (Liposomal Daunorubicin) was studied in the relapsed/refractory AML with CPX-351 in combination with venetoclax.[5]This study included patients who were previously untreated with high-risk AML or secondary AML. Patients aged 60 to 75 years, received either CPX-351 daily on days 1, 3, and 5, or 7 + 3. They could go on to receive two cycles of consolidation with the same or go on to transplant.

The updated five years results look impressive as presented by Jeff Lancet, with plateauing of the curve in this high-risk group of patients. The median survival was six months with 7 + 3 and nine months with CPX-351. At five years, 20% of patients were still alive and disease free in the CPX-351 arm and less than 10% in the 7 + 3 arm.In the CPX-351 arm one third were able to go on to transplantation which looks impressive, with improvement in survival in younger and older patients, a small number of older patients 70-75 years could undergo allo-transplant.

Phase II study of CPX-351 (Liposomal Daunorubicin with venetoclax for patients with AML in Rel/Ref AML

In this study of 16 patients, CPX351 44 mg/m2 (induction) day 1, 3, 5 and Venetoclax 300 mg Day 2-21 was given. Venetoclax was reduced to 300 mg day 2-8 due to DLT (neutropenia, thrombocytopenia).[6]All but 1 of the 16 patients had relapsed/refractory disease. All 16 patients were evaluable for response. Only 6%, one patient, had a CR. The majority of responses were CRi or morphologic leukemia-free state, which indicates that the regimen does clear blasts from the marrow, but count recovery is an issue.

A new study (V-FAST)venetoclax with CPX-351 is also being tested in newly-diagnosed patients without AML with myelodysplasia-related changes or therapy-related AML.

Delays in Time to Deterioration of Health-Related Quality of Life Were Observed in Patients with Acute Myeloid Leukaemia Receiving Venetoclax in Combination with Azacytidine or in Combination with Low-Dose Cytarabine. (Abstract # 589)

Quality of life is important for those ineligibles for intensive treatment with a high-risk disease.

Viale-A[7]and Viale-C evaluated health related quality of life (HRQoL) in patients with AML receiving venetoclax (VEN) co-administered with azacytidine (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C). Both trials included treatment-naïve patients who are ineligible to receive intensive chemotherapy.

The results show VEN+AZA patient had a non-statistically significant trend to longer time to deterioration (TTD) in Global Health Status/Quality of Life (GHS/QoL) (median in months) fatigue, longer TTD in physical functioning (PF),and health status.In the Viale-C [VEN+ LDAC ( low dose cytarabine)], 55% patients with a median age of 76 years significantly longer TTD in GHS/QoL fatigue and PF, and a trend in health status visual analog scale (VAS).

These results suggest that VEN conveys meaningful benefit in terms of HRQoL. Overall, the improvements in patient reported outcomes (PRO) with VEN are consistent with previous efficacy reports. Venetoclax appears to have a positive impact on the HRQoL of patients with AML who are ineligible for intensive chemotherapy, leading to a longer preservation of functioning and overall health status.

Venetoclax and azacitidine for chemotherapy-ineligible patients with untreated AML

In this randomized, phase-3, double-blind, multi-center trial, DiNardo [8]and colleagues randomly assigned 431 patients with AML (median age, 76 years; range, 49-91) to azacitidine in combination with venetoclax (n = 286) or with placebo (n = 145). Patients received subcutaneous or IV azacitidine dosed at 75 mg/m2 on days one to seven of each 28-day cycle. Those in the venetoclax group received oral venetoclax dosed at 400 mg daily on days 1 to 28 with a 3-day ramp up to cycle one. Patients received a median seven cycles (range, 1-30) of azacitidine in the venetoclax group and a median 4.5 cycles (range, 1-26) in the placebo group. Median follow-up was 20.5 months. Using the Kaplan-Meier method and comparing between groups using the log-rank test stratified by age and cytogenetic risk, showed median OS of 14.7 months in the venetoclax group and 9.6 months in the placebo group (HR = 0.66; 95% CI, 0.52-0.85). Composite complete remission observed were 66.4% in the venetoclax group and 28.3% in the placebo group (P < .001). Patients in the venetoclax group had a shorter median time to first complete response with or without incomplete count recovery (1.3 months vs. 2.8 months) and longer duration of composite complete remission (17.5 months vs. 13.4 months) than those in the placebo group. Higher response rates were observed in thevenetoclax combination among patients with poor cytogenetic risk (53% vs. 23%), intermediate cytogenetic risk (74% vs. 32%), de novo AML (66% vs. 30%) and secondary AML (67% vs. 23%). Longer event-free survival (EFS) was observed in the venetoclax group (9.8 months; 95% CI, 8.4-11.8) compared with the placebo group (7 months; 95% CI, 5.6-9.5; P < .001).

Improvement in overall survival with ivosidenib compared to standard therapies for relapsed or refractory AML with IDH1 mutation

Isocitrate dehydrogenase (IDH) mutations occur in ~20% of acute myeloid leukemia (AML) patients (pts) and are frequently identified in older pts. This study evaluated the efficacy and safety of Ven+Aza among treatment-naïve AML pts with IDH1/2mut unfit for intensive treatment either due to comorbidities and/or age ≥ 75 yrs.[9]

Data were pooled from patients enrolled in an ongoing phase III study(NCT02993523, data cut-off: 04Jan2020) comparing patients treated with Ven+Aza or placebo (Pbo)+Aza, and a phase 1b study (NCT02203773, data cut-off: 19Jun2019) where pts were treated with Ven+Aza. Patients on Ven+Aza received Ven 400 mg daily orally (days 1–28) and Aza (75 mg/m2; days 1-7/28-day cycle).

Ven+Aza compared to Aza monotherapy resulted in higher response rates, longer duration of response (DoR), and mOS among treatment-naïve pts with IDH1/2mut ineligible for intensive chemotherapy. The safety profile was acceptable.

To conclude,future clinical research will be directed on deepening the responses provided by HMA + venetoclax with other targeted agents, like ivosidenib in IDH1 mutated AML, FLT3 inhibitors, and novel pathways inhibitors to eventually cure a greater fraction of newly diagnosed elderly,unfit AML patients and to explore new strategies to deal with relapses after venetoclax-based therapies.

References:
  • 1. FDA grants regular approval to venetoclax in combination for untreated acute myeloid leukemia [Internet]. 2020 [updated 2020; cited 2021 Jun 6]. Available from https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-regular-approval-venetoclax-combination-untreated-acute-myeloid-leukemia
  • 2. Chua CC, Roberts AW, Reynolds J, Fong CY, Ting SB, Salmon JM et al. Chemotherapy and venetoclax in elderly acute myeloid leukemia trial (CAVEAT): a phase ib dose-escalation study of venetoclax combined with modified intensive chemotherapy. Journal of Clinical Oncology. 2020 Oct 20;38(30):3506-17.
  • 3. Tapan M. Kadia, MD. Phase II Study of Venetoclax Added to Cladribine + Low Dose AraC (LDAC) Alternating with 5-Azacytidine Demonstrates High Rates of Minimal Residual Disease (MRD) Negative Complete Remissions (CR) and Excellent Tolerability in Older Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)[abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA): ASH; 2020. Abstract nr 28 Available from:ash/2020/webprogram/Paper142092
  • 4. Curtis Lachowiez, MD. Interim Analysis of the Phase 1b/2 Study of the BCL-2 Inhibitor Venetoclax in Combination with Standard Intensive AML Induction/Consolidation Therapy with FLAG-IDA in Patients with Newly Diagnosed or Relapsed/Refractory AML [abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA): ASH; 2020. Abstract nr 28 Available from:ash/2020/webprogram/Paper134300
  • 5. Jeffrey E. Lancet, Geoffrey L. Uy, Laura F. Newell, Tara L. Lin, Ellen K. Ritchie, Robert K. Stuart, Stephen Anthony Strickland et al : Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 7510-7510.
  • 6. Tapan M. Kadia, MD.Phase II Study of CPX-351 Plus Venetoclax in Patients with Acute Myeloid Leukemia (AML) [abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA): ASH; 2020. Abstract nr 28 Available from: ash/2020/webprogram/Paper142074
  • 7. Keith W. Pratz, MD. Delays in Time to Deterioration of Health-Related Quality of Life Were Observed in Patients with Acute Myeloid Leukemia Receiving Venetoclax in Combination with Azacitidine or in Combination with Low-Dose Cytarabine [abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA): ASH; 2020. Abstract nr 589 Available from: ash/2020/webprogram/Paper133912
  • 8. DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. New England Journal of Medicine. 2020 Aug 13;383(7):617-29.
  • 9. Peter Paschka, MD.Lymphoma: Pre-Clinical—Chemotherapy and Biologic Agents: Poster I[abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA): ASH; 2020. Abstract nr 625 Available from: ash/2020/webprogram/Session19680

  • Courtesy - Indian Journal of Medical and Paediatric Oncology (IJMPO)
    Editor-in-Chief - Dr. Padmaj Kulkarni
    Section Editor -Dr. Sneha Bothra
    Assistant - Devika Joshi