Chemo-Free Triple Therapy Puts 78-Year-Old With Rare Mixed-Lineage Leukemia Into Complete Remission

A 78-year-old man with one of the rarest and most aggressive forms of acute leukemia has achieved a complete remission without receiving a single dose of conventional chemotherapy, according to a case report published in Frontiers in Hematology. The treatment combined azacitidine, a hypomethylating agent, with short-course sonrotoclax, a next-generation BCL-2 inhibitor, followed by the immunotherapy blinatumomab. Within 28 days, the patient’s blood counts had normalized, his bone marrow showed no detectable residual leukemic cells, and the variant allele frequency of his TP53 mutation had collapsed from 68.67 percent to 2.46 percent.

The case is notable because the patient had B-lymphoid/myeloid mixed phenotype acute leukemia, or MPAL, a biologically heterogeneous malignancy in which leukemic blasts simultaneously display features of both B-cell and myeloid lineages. MPAL accounts for only a small fraction of acute leukemias and carries an unfavorable prognosis. Standard treatment for younger adults typically involves intensive combination chemotherapy followed by consolidation, with or without allogeneic hematopoietic stem cell transplantation. But advanced age, comorbidities, and poor performance status often render older adults ineligible for both intensive chemotherapy and transplantation, leaving lower-intensity and targeted regimens as a critical unmet need.

The patient arrived at the Affiliated People’s Hospital of Ningbo University in March 2026 with a two-week history of fatigue and anorexia. His medical history was already formidable: chronic hepatitis B virus infection managed with long-term oral antiviral therapy, and lung adenocarcinoma initially treated with surgical resection followed by platinum-based chemotherapy. After the lung cancer relapsed, he underwent a second resection and received maintenance pembrolizumab for two years, ending in May 2025.

Laboratory investigations on admission revealed pancytopenia, a dangerous depletion of all three major blood cell lines. His leukocyte count was 0.6 × 10^9 per liter, his absolute neutrophil count 0.2 × 10^9 per liter, his hemoglobin 96 grams per liter, and his platelet count 73 × 10^9 per liter. Lactate dehydrogenase was elevated at 464 units per liter, fibrinogen was markedly elevated at 55.64 grams per liter, and D-dimer was significantly increased at 12,719 nanograms per milliliter, confirming disseminated intravascular coagulation, a life-threatening disorder in which the blood’s clotting system becomes catastrophically dysregulated.

Bone marrow aspiration morphology initially suggested acute myeloid leukemia, but multiparameter flow cytometry told a more complex story. Two distinct abnormal blast populations were identified. The first, comprising 38 percent of total nucleated cells, showed an aberrant B-cell precursor phenotype with expression of CD19, CD22, CD123, CD138, bright CD34, nuclear terminal deoxynucleotidyl transferase, and cytoplasmic CD79a. The second, at 21 percent, displayed an aberrant myeloid phenotype expressing CD19, CD123, CD38, CD34, CD117, and HLA-DR. Cytogenetic analysis revealed a complex karyotype with 78 to 83 chromosomes and multiple losses and structural abnormalities. Next-generation sequencing identified a TP53 missense mutation in exon 6 with a variant allele frequency of 68.67 percent, and a KIT missense mutation in exon 2 with a variant allele frequency of 72 percent. Both alterations were subsequently confirmed by whole transcriptome sequencing. Critically, the molecular test results were not available until day 10 after induction began, so they could not guide the initial therapeutic decision.

The team initiated a chemotherapy-free induction regimen: azacitidine at 100 milligrams intravenously daily for five days, dexamethasone at 10 milligrams intravenously daily for 14 days with subsequent tapering, and sonrotoclax with dose escalation beginning on day 4, stepping from 5 milligrams through 10, 20, 40, and 80 up to 160 milligrams. During this period, D-dimer levels peaked at 47,261 nanograms per milliliter, reflecting progressive disseminated intravascular coagulation 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 the chemotherapy-free treatment, bone marrow evaluation revealed severe myelosuppression but no detectable residual leukemic cells. Blinatumomab was started on day 15 at 9 micrograms intravenously daily for one week, with planned dose escalation to 28 micrograms daily for the following week to deepen the remission. Supportive management included granulocyte colony-stimulating factor. No significant infections occurred during this period. Serial monitoring of HBV-DNA viral load showed no evidence of hepatitis B reactivation, a real concern given the patient’s chronic infection and the immunomodulatory nature of the treatment.

By day 28, complete hematologic recovery had been achieved, with normalization of leukocyte and platelet counts. Bone marrow examination confirmed remission with measurable residual disease negativity. The TP53 variant allele frequency had fallen to 2.460 percent, while the KIT variant allele frequency stood at 43.068 percent. The patient remains alive and has received consolidation therapy with the initial regimen. The authors note that given the previous platinum-based chemotherapy, the complex karyotype, and the TP53 mutation, therapy-related leukemia should be considered, but because pre-treatment peripheral blood or bone marrow samples from the lung-cancer phase were unavailable, further laboratory investigations to confirm the relationship could not be carried out.

The rationale for the triple-agent strategy draws on converging evidence from recent literature. Venetoclax combined with hypomethylating agents has demonstrated encouraging efficacy while sparing older patients the toxicity of intensive chemotherapy. Immunotherapeutic approaches are increasingly being explored in MPAL, and blinatumomab, a CD19/CD3 bispecific T-cell engager that physically links cytotoxic T cells to CD19-expressing leukemic cells, is effective in relapsed or refractory B-cell lineage MPAL, particularly when combined with venetoclax. Sonrotoclax, a novel second-generation BCL-2 inhibitor, offers superior BCL-2 binding affinity and selectivity and a lower risk of tumor lysis syndrome than venetoclax, potentially improving both efficacy and safety in hematological malignancies.

The authors emphasize that novel targeted agents and immunotherapies, alone or in combination, offer effective and tolerable alternatives for patients who cannot withstand conventional treatment. They call for prospective trials integrating genomic profiling, measurable residual disease-adapted therapy, and immunotherapeutic combinations to establish evidence-based standards for this population. As a single case report, the findings cannot establish the regimen as standard of care, and the durability of the remission remains to be seen. But for a disease where elderly patients have historically had few options beyond palliative care, the rapid, chemotherapy-free remission documented here offers a striking proof of principle that rational combinations of targeted and immune therapies can subdue even a genetically complex, dual-lineage leukemia.

Subject of Research: Chemotherapy-free targeted and immunotherapy combination for mixed phenotype acute leukemia in an elderly patient

Article Title: 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

Article References: 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. (n.d.). https://doi.org/10.3389/frhem.2026.1970481

Image Credits: AI Generated

DOI: 10.3389/frhem.2026.1970481

Keywords: mixed phenotype acute leukemia, azacitidine, sonrotoclax, blinatumomab, BCL-2 inhibitor, chemotherapy-free treatment, TP53 mutation, disseminated intravascular coagulation, measurable residual disease, elderly patient, case report, hematology