Optimizing management of AML with a BCL-2 inhibitor in an elderly patient unfit for intensive chemotherapy

Presentation, medical history and investigations
A 77-year-old man with multiple well-controlled comorbidities, includ­ing hypertension, diabetes mellitus, benign prostatic hyperplasia (BPH) and atrial fibrillation (AF), presented with fatigue and pancytopenia on 4 November 2022, with white blood cell (WBC) count 2.69 x 10⁹/L, neutrophils 28 percent, haemoglobin (Hb) 11 g/dL and platelets 96 x 10⁹/L. He reported no other symptoms. Repeat blood test on 25 November 2022 showed wors­ening cytopenia: WBC 1.79 x 10⁹/L, neutrophils 23 percent, Hb 9.4 g/dL and platelets 78 x 10⁹/L.

Bone marrow aspiration showed a leukaemic picture with high blast bur­den and morphology consistent with acute myeloid leukaemia (AML)-M2a. Next-generation sequencing identified IDH2 (33.48 percent), SRSF2 (35.81 percent) and NPM1 (3.1 percent). The diagnosis of AML‑M2a (low risk) was established on 1 December 2022.

Treatment and response
In view of his advanced age and in­eligibility for allogeneic haematopoietic stem cell transplantation (allo-HSCT), oral venetoclax (VEN; 100 mg on day 1, 200 mg on day 2 and 400 mg on days 3–28) + subcutaneous azaciti­dine (AZA; 135 mg on days 1–7) thera­py was initiated on 5 December 2022. Tumour lysis syndrome prophylaxis in­cluded adequate hydration and antihy­peruricaemic agents starting 24 hours prior to VEN initiation.

After cycle 1, the patient achieved complete remission (CR) with mini­mal residual disease (MRD) negativity; NPM1 and IDH2 became undetect­able. VEN+AZA treatment was contin­ued, and granulocyte-colony stimulat­ing factor (G-CSF) was given post-CR when the absolute neutrophil count (ANC) fell to <0.5 x 10⁹/L, and stopped once ANC recovered to at least 1.0 x 10⁹/L.

The patient did not receive antifun­gal prophylaxis due to the absence of predisposing high-risk factors.

During cycle 7 (16 August 2023), VEN was interrupted on day 13 due to COVID‑19. After recovery, the regimen was adjusted to VEN 400 mg on days 1–21 + AZA 135 mg on days 1–5, while CR with MRD negativity were maintained. On 18 December 2023, VEN was reverted to full 28-day dosing following re-detection of IDH2. Despite IDH2 positivity, the patient remained in CR with undetectable NPM1 and was clinically stable. Subsequent dose adjustments of AZA were made for tolerability.

The patient tolerated VEN+AZA without major adverse events (AEs) or infections. As of May 2026, he remained in CR with sustained MRD negativity, re­ported good quality of life, and contin­ued follow-up every 3 months.

Discussion
AML predominantly affects older adults (median age at diagnosis, about 68 years) and the estimated 5-year survival for patients >60 years of age is <10 per­cent.¹ Intensive chemotherapy followed by allo-HSCT remains the standard cu­rative approach for fit patients. Howev­er, as in our case, many older patients with comorbidities or poor performance status are often considered unfit for this approach.¹

VEN (a BCL-2 inhibitor) + AZA is rec­ommended by international and Chinese national guidelines as first-line (1L) therapy for newly diagnosed AML patients unfit for intensive chemotherapy, based on surviv­al benefit in randomized trials.^1-4 In the phase III VIALE-A trial (n=431), VEN+AZA significantly prolonged median overall sur­vival (mOS) vs placebo + AZA (14.7 vs 9.6 months; p<0.001) and increased the es­timated 24-month OS rate (37.5 vs 16.9 percent) after a median follow-up of 43.2 months.¹

Optimizing VEN-based therapy
Emerging real-world evidence and expert consensus support the use of an optimized VEN schedule (full dose, full duration – typically 400 mg daily for 28 days/cycle) + AZA to achieve deeper and more durable response.^5-8 Multiple real-world studies indicate that early re­ductions in dose intensity (<400 mg, <21 days before a response is achieved) may compromise response rates, MRD neg­ativity rates and long-term outcomes, and could increase early mortality.^9-12

Managing haematologic AEs with G-CSF
Cytopenias are invariably present in AML due to compromised bone mar­row function and severe myelosuppres­sion.¹³ In VIALE-A, 69 percent of patients had grade ≥3 neutropenia and 51 per­cent had grade ≥3 thrombocytopenia at baseline.¹⁴ Cytopenias often improve as targeted therapy induces remission; post-CR, normal haematopoiesis is re­stored and haematologic AEs decline.¹⁴

Supportive care, such as blood transfusions, should be used to man­age severe cytopenias during induction, and cytopenia alone should not routinely prompt interruption of VEN+AZA before response.¹⁵ After achieving CR, G-CSF can be used to improve neutropenia, as in our patient. In VIALE-A responders, neutropenia recovery was achieved at a median of 14 days, with narrower re­covery ranges reported with G-CSF use (8–22 vs 8.5–30.5 days). A trend toward longer duration of response and OS with G-CSF use was observed in these re­sponders.¹⁶ (Table)

Antifungal prophylaxis during targeted therapy
I do not routinely administer anti­fungal prophylaxis to all patients, but reserve it for patients at high risk of in­vasive fungal disease (eg, those with chronic obstructive pulmonary disease or prolonged profound neutropenia).¹⁷ Routine monitoring is recommended during VEN+AZA treatment for all newly diagnosed AML patients.^17-18 Unlike in­tensive chemotherapy, VEN+AZA does not induce gastrointestinal mucositis and may be associated with a lower risk of fungal infections.¹⁹ Concomitant use of strong CYP3A4-inhibiting azole antifungals introduces drug–drug inter­actions that require VEN dose modifi­cations, and might be associated with lower composite CR rates and delayed neutrophil and platelet recovery.^20-22 Therefore, in my practice, echinocan­dins are used for prophylaxis in high-risk patients, and azoles are used in cases of resistance to echinocandin or when they would be more effective in controlling the infection.

Conclusion
VEN+AZA represents an effective, well-tolerated option that can produce durable remission in patients with newly diagnosed AML who are older or con­sidered unfit for intensive induction chemotherapy. Our patient was on 1L VEN+AZA for >3 years, well exceeding the mOS reported in VIALE-A.¹

Related MIMS Drugs

VENCLEXTA