Chemotherapy-free treatment with azacitidine, short-course sonrotoclax and blinatumomab produces acute complete remission in B-lymphoid/myeloid mixed phenotype acute leukemia in an elderly patient: case report

Introduction

Mixed phenotype acute leukemia (MPAL) is a rare, biological heterogeneous hematologic malignancy with unfavorable outcomes (1). Current therapeutic strategies for younger adult patients comprise intensive combination chemotherapy followed by consolidation therapy with or without allogeneic hematopoietic stem cell transplantation (allo-HSCT) (2, 3). By contrast, for pediatric patients with MPAL, those achieving an early favorable response to chemotherapy are generally not candidates for allo-HSCT (4). Advanced age, comorbidities, and poor performance status render older adults ineligible for both chemotherapy and subsequent allo-HSCT. Consequently, lower-intensity and targeted regimens represent a critical unmet need.

In this case, a chemotherapy-free induction regimen combining sonrotoclax and azacitidine followed by sequential blinatumomab, induce rapid complete remission in a patient with B/myeloid MPAL and a complex karyotype.

Case presentation

A 78-year-old man presented to our institute in March 2026 with a 2-week history of fatigue and anorexia. His medical history included chronic hepatitis B virus (HBV) infection on long-term oral antiviral therapy and lung adenocarcinoma initial treated with surgical resection followed by platinum-based chemotherapy. Following disease relapse, he underwent a second surgical resection and received maintenance pembrolizumab therapy for 2 years until May 2025.

On admission, laboratory investigations revealed pancytopenia, with a leukocyte count of 0.6 × 10⁹/L, absolute neutrophil count of 0.2 × 10⁹/L, hemoglobin of 96 g/L, and platelet count of 73 × 10⁹/L. Additional findings included elevated lactate dehydrogenase (464 U/L), markedly elevated fibrinogen (55.64 g/L), and significantly increased D-dimer (12,719 ng/mL), which was confirmed with disseminated intravascular coagulation (DIC). Bone marrow aspiration morphology showed acute myeloid leukemia. However, multiparameter flow cytometric was consistent with mixed phenotype acute leukemia (MPAL), with two distinct abnormal blast populations. The first population (38% of total nucleated cells) demonstrated an aberrant B-cell precursor phenotype with expression of CD19, CD22, CD123, CD138, bright CD34, nuclear terminal deoxynucleotidyl transferase, and cytoplasmic CD79a. The second population (21% of total nucleated cells) displayed an aberrant myeloid phenotype, expressing CD19, CD123, CD38, CD34, CD117, and HLA-DR. Cytogenetic analysis revealed a complex karyotype: 78~83,XXY,-Y,-2,-3,-5,-7,-11,-12,-16,-16,add(17)(p13)×2,-18,-19,-20,-20,-21,-22[CP19]/46,XY (1). Next-generation sequencing (NGS) identified a TP53 missense mutation in exon 6 (NM_000546.6: c.569C>T, p.Pro190Leu) with a variant allele frequency (VAF) of 68.67%. A KIT missense mutation in exon 2 (NM_000222.3: c.154G>A, p.Asp52Asn) was also detected by NGS with a VAF of 72%. Both alterations were subsequently confirmed by whole transcriptome sequencing. Reports of the two molecular biology test were unavailable until day 10 following the start of induction therapy, and thus could not guide the initial therapeutic decision-making.

The patient received azacitidine at 100mg intravenously daily for 5 days, dexamethasone at 10mg intravenously daily for 14 days with subsequent tapering, and sonrotoclax with dose escalation initiated on day 4 (5mg, 10mg, 20mg, 40mg, 80mg and 160mg). During this period, D-dimer levels peaked at 47,261 ng/mL, reflecting progressive DIC with a markedly elevated hemorrhagic risk. Given this life-threatening complication, sonrotoclax was discontinued and supportive care with blood component transfusion was initiated. On day 14 of chemotherapy-free treatment, bone marrow evaluation revealed severe myelosuppression, no detectable residual leukemic cells. Blinatumomab was initiated on day 15 at 9μg intravenously daily for 1 week, with planned dose escalation to 28μg intravenously daily for the subsequent week to deepen remission. Concurrently, supportive management comprised granulocyte colony-stimulating factor administration. No significant infections occurred during this period. Serial monitoring of HBV-DNA viral load was performed, and no evidence of HBV reactivation was detected. By day 28, complete hematologic recovery was achieved, with normalization of leukocyte and platelet counts (Figure 1). Bone marrow examination confirmed remission with measurable residual disease negativity. The TP53 VAF decreased to 2.460%, whereas the KIT VAF was 43.068%. Up to the present, the patient remains alive after consolidation therapy with the initial regimen.

In view of previous platinum-based chemotherapy, complex karyotype and TP53 mutation in this patient, a therapy-related-leukemia should be considered. However, since pre-treatment peripheral blood or bone marrow samples from the lung-cancer phase were unavailable, further laboratory investigations to confirm their relationship could not be carried out.

Owing to advanced age and poor performance, an effectively and well tolerated therapeutic intervention was urgently required in patients with MPAL. Recently, venetoclax combined with hypomethylating agents has demonstrated encouraging efficacy while sparing older patients the toxicity of intensive chemotherapy (5). Immunotherapeutic approaches are being increasingly explored in MPAL. Blinatumomab, a CD19/CD3 bispecific T-cell engager, is effective in relapsed/refractory B-cell lineage MPAL, particularly when combined with venetoclax (6). Notably, sonrotoclax, a novel second-generation BCL-2 inhibitor, has a superior BCL-2 binding affinity and selectivity and a lower risk of tumor lysis syndrome than venetoclax, offering improved efficacy and safety in hematological malignancies (7). Taking these published findings into consideration, we initiated this triple-agent strategy for the patient, and a rapid remission was successfully achieved following this chemo-free therapeutic regimen.

In summary, novel targeted agents and immunotherapies—alone or in combination—offer effective and tolerable alternatives. Prospective trials integrating genomic profiling, MRD-adapted therapy, and immunotherapeutic combinations are urgently needed to establish evidence-based standards for this population.

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Footnotes

Edited by: Bhavana Bhatnagar, West Virginia University, United States

Reviewed by: Meike Kaehler, University Hospital Schleswig-Holstein, Germany

Gazmend Temaj, College UBT, Albania