BCL-2 inhibitor–based therapy as an effective bridge to transplant in an older high-risk AML patient

Presentation, medical history and investigations
A 71-year-old woman, previously well, presented with a 3-month history of bilat­eral lower-limb rash. Initial blood test on 22 December 2023 showed leukocytosis with white blood cell (WBC) count 17.8 x 10⁹/L, haemoglobin 10.3 g/dL and plate­lets 172 x 10⁹/L. Peripheral blood analysis found 14 percent blast cells and marked monocytosis (15 percent). She was ad­mitted for further evaluation. Repeat testing on 26 December 2023 showed progressive leukocytosis (WBC, 68.7 x 10⁹/L) with profound monocytosis (abso­lute monocyte count, 22.5 x 10⁹/L). Chest CT revealed a few linear infiltrates and small pulmonary nodules. Bone marrow was hypercellular with 45 percent blasts showing immature myeloid morphology (scant blue cytoplasm, azurophilic gran­ules, irregular nuclei). Cytochemical stains supported myeloid lineage, and flow cy­tometry identified an abnormal myeloid blast population. Cytogenetic and molec­ular studies were pending at presentation. These findings were consistent with high-risk acute myeloid leukaemia (AML), and the patient was admitted for treatment.

Treatment and response
As the patient’s Eastern Cooperative Oncology Group (ECOG) performance sta­tus was 2–3 and she was unfit for intensive chemotherapy, low-intensity venetoclax (VEN; 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3–28) combined with subcutaneous azacitidine (AZA; 132 mg daily on days 1–7) was chosen as the more appropriate treatment for her. Treatment commenced on 8 January 2024. On 16 January 2024, molecular testing reported FLT3-ITD positivity, placing the patient in the intermediate risk category receiving less intensive VEN+AZA therapy, according to the European LeukemiaNet (ELN) 2024 ge­netic risk classification framework for newly diagnosed AML patients receiving less-intensive therapies.¹

Bone marrow aspiration (BMA) on 7 February 2024 found reduced nucleated cell volume, no morphologic blasts, and minimal residual disease (MRD) negativity by flow cytometry; FLT3-ITD was unde­tectable. The patient achieved complete remission (CR) following the first cycle of VEN-based therapy and started the sec­ond cycle on 21 February 2024. Follow-up BMA on 19 March 2024 found sustained blast-free status and MRD negativity.

The patient remained clinically well throughout treatment, with stable appe­tite, sleep, bowel and urinary function, and no significant weight change. Given the sustained morphological and MRD re­sponses as well as her improved physical status, she was evaluated for allogeneic haematopoietic stem cell transplantation (allo-HSCT) according to the Hemato­poietic Cell Transplantation Comorbidity Index (HCT-CI), and underwent the pro­cedure on 15 April 2024 with reduced intensity conditioning. As of May 2026, she remained clinically well with ongoing MRD negativity and was followed up every 3 months.

Discussion
FLT3-ITD mutation occurs in about 20 percent of AML and confers an adverse prognosis with shorter remission duration and higher relapse risk than FLT3-ITD– negative disease.² Allo-HSCT is the most effective curative strategy for intermediate-and high-risk AML, reducing relapse risk by >60 percent vs intensive chemothera­py alone; achieving CR or CR with incom­plete blood count recovery (CRi) with MRD negativity before transplant is associated with better post-transplant outcomes.^3,4

Historically, older or comorbid pa­tients were often ineligible for allo-HSCT because they could not tolerate inten­sive chemotherapy required to attain re­mission.⁴ However, lower intensity treat­ment strategies such as VEN+AZA have demonstrated meaningful remission rates in older or unfit patients, enabling about 10–17 percent to subsequently become candidates for allo-HSCT.^4,5 The clinically meaningful benefits are reflected in the National Comprehensive Cancer Net­work Clinical Practice Guidelines for AML, which recommend transplant-eligible pa­tients with a suitable donor to proceed to allo-HSCT in first remission (category 2A recommendation).⁶ Similarly, the Amer­ican Society of Hematology (ASH) rec­ommends consideration of allo-HSCT in first remission over no transplantation for older adults with newly diagnosed AML who have non-favourable cytogenetic or molecular features and responded to ini­tial anti-leukaemic therapy.⁷

VEN+AZA was first prescribed to our patient in view of her age and poor perfor­mance status (ECOG 2–3). Her condition improved with the treatment and she pro­ceeded with allo-HSCT after multispecial­ity re-assessment of transplant eligibility.

VEN+AZA as an alternative to induc­tion intensive chemotherapy has demon­strated favourable post-transplant out­comes in both clinical trials and real-world practice.

A pooled cohort combined patients ineligible for intensive chemotherapy from the phase III VIALE-A and phase Ib M14-358 studies (n=33; median age, 69 years) who received a median of four cy­cles of VEN plus a hypomethylating agent (HMA) before allo-HSCT. At transplant, 85 percent were in CR/CRi or morphologic leukaemia-free state (MLFS). After a me­dian follow-up of 31.6 months, the medi­an overall survival (OS) was 29.9 months, median duration of remission was not reached, and estimated 12- and 24- month OS rates were 69.1 and 61.6 per­cent, respectively. Among patients who were MRD-negative at the time of trans­plant, median OS after allo-HSCT was not reached (vs 28.2 months for MRD-positive/MRD unevaluable responders), and the estimated post-transplant OS rate was 76.2 percent at 12 months (vs 66.7 percent).⁴ (Figure)

A retrospective study conducted by Mayo Clinic involving 55 patients (median age, 69 years) with newly diagnosed AML (ND-AML) treated with a median of three cycles of VEN+HMA before allo‑HSCT reported that median post‑transplant survival was not reached at a median follow‑up of 25 months, with 1‑, 2‑and 3‑year survival rates of 74, 66 and 62 per­cent, respectively.⁸

A larger study of 111 ND-AML patients (median age, 70 years) who received a median of three cycles of VEN+HMA prior to allo‑HSCT similarly found favourable outcomes. At a median follow‑up of 30 months post‑transplant, 1‑, 2‑and 3‑year survival rates were 69, 60 and 57 percent, respectively, and median post‑transplant OS was not reached.⁹

These datasets collectively support that VEN‑based regimens can enable older or unfit patients who exhibit notable improvements in physical function after achieving remission to reach transplant on a case-by-case evaluation with dura­ble post‑transplant survival.^8,9

Attaining MRD‑negative remission predicts improved post‑transplant sur­vival.⁴ In our older, high-risk patient with FLT3‑ITD AML, VEN‑based induction produced rapid CR and sustained MRD negativity, predicting a favourable out­come after allo‑HSCT. This case illustrates how VEN+AZA may allow patients previ­ously deemed unfit for intensive chemo­therapy to achieve remission, improve physical status, and receive allo-HSCT, highlighting the necessity to re-evaluate fit­ness and transplant suitability in remission on a case-by-case basis.

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