Secondary Chronic Myeloid Leukemia in the Blast Phase With Mixed Phenotype After Radiation Therapy: A Case Report

ABSTRACT

A 55‐year‐old woman underwent hysterectomy and pelvic radiation for cervical cancer, which remains in remission. Forty‐three months later, she developed secondary CML‐BP with CD19+ mixed phenotype (B/myeloid), previously unreported. Following induction therapy, sequential therapy with blinatumomab and ponatinib achieved qualitatively PCR‐negative minor BCR::ABL1 transcripts, indicating that residual transcripts below the qualitative assay's detection limit were undetectable. She received an allogeneic bone marrow transplant and remains well with PCR‐negative minor BCR::ABL1 at 15 months after transplantation. This sequential therapy suggests a potential utility as a bridge to hematopoietic stem cell transplantation for secondary CML‐BP with CD19+ mixed phenotype.

1. Introduction

Myeloid neoplasms, including myelodysplastic neoplasms and acute myeloid leukemia, can develop in patients with a history of cytotoxic therapy such as DNA‐damaging chemotherapy and/or radiation therapy [1]. In this category, secondary CML in the blast phase (CML‐BP) is particularly rare. Secondary CML in chronic phase (CML‐CP) has been reported, and showed similar response to tyrosine kinase inhibitor (TKI) with de novo CML‐CP [2]. But secondary CML‐BP has been reported in three cases, and all of them were B‐lymphoid BP, and treatment was varied from case by case [3, 4, 5]. CML‐BP mixed‐phenotype have not been reported to date. Here we report a case of secondary CML‐BP with CD19+ mixed phenotype (B/myeloid) after radiation therapy for cervical cancer, and sequential therapy with blinatumomab and ponatinib bridged to an allogeneic bone marrow transplant.

2. Case Presentation

A 55‐year‐old woman was referred to our hospital due to acute abdominal pain and underwent an emergency laparotomy. Panperitonitis caused by perforation of the uterus with pyometra resulting from cervical cancer was identified. Pathological and imaging findings of cervical cancer revealed squamous cell carcinoma (stage IIIC2r). Because of the patient's poor condition, chemotherapy was not chosen, and radiation therapy (whole pelvic 40 Gy/20 Fr, central shielding 10 Gy/5 Fr, remote after loading system 24 Gy/6 Fr, right external iliac lymph nodes 10 Gy/5 Fr, and left closed lymph nodes 8 Gy/4 Fr) was administered after her condition stabilized, and remission was achieved. Prior to radiation therapy, she exhibited leukocytosis, anemia, and thrombocytosis likely related to her history of panperitonitis and genital bleeding (white blood cell 13,180/µL, hemoglobin 8.9 g/dL, platelet 506,000/µL). However, at 10 months after radiation therapy, metastasis to the right lower lobe of the lung was confirmed, and tumor resection surgery was performed. Following this treatment, no recurrence of cervical cancer has been observed.

At 31 months after final treatment, she complained of worsening fatigue persisting for several weeks. A hemogram revealed severe anemia (hemoglobin 3.8 g/dL) and a markedly increased white blood cell count (50,500 cells/µL) with blasts (44.0%). Subsequently, she was urgently admitted for suspected hematologic malignancy. A bone marrow examination revealed an increase of blasts (63.5%; Figure 1a), and 11% of blasts were positive for myeloperoxidase cytochemistry staining (Figure 1b), while negative for esterase staining. Flow cytometry analysis revealed that the blasts were positive for CD19 (92.0%), CD10 (71.2%), and CD22 (33.1%), myeloperoxidase (MPO; 8.0%), and negative for cytoplasmic CD3 (Figure 2). The expression of MPO was dim, but confirmed that MPO intensity of blasts was in part exceeded 50% of mature neutrophil level, and CD13/CD33 were highly expressed [6].

FIGURE 1.

Blasts in bone marrow. Bone marrow was occupied by dysplastic blasts (a) May–Grüenwald Giemsa stain, (b) myeloperoxidase stain: original magnification × 1000, 10 µm scale bar.

FIGURE 2.

Flow cytometry analysis of bone marrow. Flow cytometry analysis of bone marrow showed that the blasts were positive for CD10, CD19, CD22, CD13, CD33, CD34, HLA‐DR, and TdT, but negative for myeloperoxidase (MPO) and cytoplasmic CD3.

Cytogenetic analysis demonstrated 46, XX, t(9;22) (q34.1;q11.2) [7]/46, idem, der(5)t(1;5) (q12;q35) [8]. Additional cytogenetic abnormalities, such as der(5)t(1;5) (q12;q35), may indicate clonal evolution and have uncertain prognostic significance in secondary CML‐BP. Real‐time polymerase chain reaction (RT‐PCR) of the BM detected only minor BCR::ABL1 fusion transcripts (1.1 × 10⁵ copies/µg RNA; lower limit: 13.58 copies/µg RNA). Fluorescence in situ hybridization of peripheral blood (PB) neutrophils showed that BCR::ABL1 fusion signals were detected in 83% of segmented nuclei and 94% of round nuclei. Diagnosis of secondary CMP‐BP with CD19+ mixed phenotype (B/myeloid) was made according to WHO 2022 and ICC criteria, based on co‐expression of CD19 and CD10 with myeloid markers including MPO, CD13, and CD33 [6, 9].

The clinical course is shown in Figure 3. Since it is recommended an ALL‐like induction regimen for MPAL, prednisolone (Day 1–21: 60 mg/m², Day 22–28: gradually reduce and discontinued) was started before dasatinib (TKI: Day 8: 140 mg/day) administration. The red blood cell and platelet transfusions were performed according to Japanese guidelines, respectively [8, 10]. And fluconazole, polymyxin B, and inhalation of pentamidine (once a week) were used for infection prophylaxis.

FIGURE 3.

Clinical course of the patient. Following induction therapy, sequential therapy with blinatumomab and ponatinib achieved qualitatively PCR‐negative minor BCR::ABL1 fusion transcripts, and she received bone marrow transplantation from an unrelated donor. She remains well and maintains qualitatively PCR negative minor BCR::ABL1 at 15 months after transplantation. Ara‐C, cytarabine; CY, cyclophosphamide; HD MTX, high‐dose methotrexate; PSL, prednisolone; TBI, total body irradiation.

At 4 weeks after the end of induction therapy, bone marrow suppression persisted with dasatinib, and dasatinib was changed to ponatinib (Day 1‐: 15 mg, Day 2‐: 30 mg) after temporary discontinuation because blasts were found in PB, judging that the effect of dasatinib was insufficient. Subsequently, consolidation therapy with high‐dose methotrexate (1 g/m² × 1)/cytarabine (2 g/m² × 4) was administered. After this treatment, quantitative RT‐PCR showed negative minor BCR::ABL1 fusion transcripts, but qualitative PCR detected minor BCR::ABL1 fusion transcripts.

Next, three courses of the sequential administration of blinatumomab (Days 1–7: 9 µg, Days 8–28: 28 µg) and ponatinib (Day 1‐: 15 mg, Day 2‐: 30 mg) were performed since blasts expressed CD19 and we experienced this sequential therapy for CD19+ MPAL with good results [11]. No adverse events such as cytokine release syndrome or immune effector‐related neurotoxicity syndrome were observed during blinatumomab administration, and treatment was completed as scheduled. And the patient received an allogeneic bone marrow transplant (3.93 × 10⁸ cells/kg) at approximately 11 months after the start of treatment maintaining qualitative PCR negative minor BCR::ABL1 fusion transcripts. The conditioning regimen was total body irradiation (12 Gy) and cyclophosphamide (120 mg/kg), and acute graft versus host disease (aGVHD) prophylaxis was short‐term methotrexate and cyclosporine.

Engraftment was confirmed on Day 16 after transplantation. On Day 20, skin rash (30% of skin), Stage 2 equivalent diarrhea, and elevated aspartate aminotransferase levels were considered to be due to aGVHD, and methylprednisolone (2 mg/kg) was initiated. Methylprednisolone was switched to prednisolone (90 mg/day) on Day 48, and prednisolone was tapered off as the symptoms improved. On Day 80, refractory skin aGVHD recurred, and ruxolitinib (10 mg/day) was added to prednisolone. She was discharged on Day 155. She remains well and has qualitatively PCR negative minor BCR::ABL1 fusion transcripts at 15 months after bone marrow transplantation, keeping performance status zero.

3. Discussion

As mentioned above, only three cases of secondary CML‐BP, whose phenotypes were all B‐lymphoid BP, have been reported to date [3, 4, 5]. Mixed‐phenotype BP cases have not been reported. Furthermore, although these three cases harbored a major BCR::ABL1 fusion gene, our case was secondary CML‐BP with a mixed phenotype and solely harbored a minor BCR::ABL1 fusion gene. A minor BCR::ABL1 fusion gene is found in approximately 1% of de novo CML cases, and these cases are considered to have a poor response to TKIs and a poor prognosis [12]. Biologically, the p190 protein possesses a shorter structure than the p210 protein, resulting in higher constitutive tyrosine kinase (TK) activity [7]. Consequently, p190‐positive leukemia typically follows a much more rapidly progressive clinical course than p210‐positive leukemia, characterized by rapid disease progression [13]. In addition, three cases received cytotoxic chemotherapy, but our case did not undergo it and received only radiation therapy.

Exposure to isolated radiation preferentially causes the BCR::ABL1 translocation and is necessary and sufficient to cause CML [14, 15]. Regarding the relationship between radiation therapy for primary cancer and the onset of CML, the median interval is 53 months (range 27–109 months) [16], and similarly 43 months in our case.

Secondary CML‐CP is considered to have a similar response to TKIs and clinical course as de novo CML [2]. However, no standardized treatment for secondary CML‐BP has been established. Practical guidelines by the Japanese Society of Hematology recommend combination treatment with anticancer drugs and TKIs for CML‐BP, followed by early allogeneic hematopoietic stem cell transplantation with myeloablative conditioning after achieving remission [17]. Our treatment strategy was performing transplantation with lower leukemia burden as possible to molecular remission and regular checking of molecular markers to lead a high quality of life.

Previously, we treated a case of de novo CD19+ mixed phenotype (B/myeloid) CML‐BP, in which sequential therapy with blinatumomab and ponatinib was effective for achieving remission [11]. In the present case, sequential therapy using blinatumomab and ponatinib also achieved qualitatively PCR‐negative minor BCR::ABL1 fusion transcripts, and received an allogeneic bone marrow transplant.

This report has some limitations. (1) Findings are limited to a single patient. (2) No consensus has been reached regarding the risk of CML after radiation therapy alone for cervical cancer due to the low frequency of CML and the limited number of CML cases analyzed. One study indicated that the standardized incidence ratio of CML is not increased in patients who receive radiation therapy alone for cervical cancer [18]. Some reports suggest that radiation therapy increases the risk of CML compared to patients without prior radiation therapy or chemotherapy [19, 20]. (3) Regarding treatment, sequential therapy with blinatumomab and ponatinib was effective and a bridge to hematopoietic stem cell transplantation. As mentioned above, blinatumomab has recently administered for CD19+ MPAL patients; this is the first case of secondary CML‐BP with CD19+ mixed phenotype. (4) The patient is being followed for 15 months after bone marrow transplantation with qualitatively PCR‐negative minor BCR::ABL1 fusion transcripts, but long‐term observation is necessary to confirm the therapeutic effect.

In summary, we reported a first case of secondary CML in BP with mixed phenotype after radiation therapy for cervical cancer. Sequential therapy using blinatumomab and ponatinib also achieved qualitatively PCR‐negative minor BCR::ABL1 fusion transcripts, and received an allogeneic bone marrow transplant. After transplantation, the patient has maintained qualitatively PCR‐negative minor BCR::ABL1 fusion transcripts, suggesting that sequential therapy with blinatumomab and ponatinib may be a potential approach as a bridge to hematopoietic stem cell transplantation for patients with secondary CML‐BP with CD19+ mixed phenotype.

Author Contributions

M.A., T.M., and Y.E. designed the study. M.A., H.K., and Y.T. performed the laboratory examinations. T.M., D.S., and N.T. were responsible for the patient care. M.A. and Y.E. wrote the manuscript.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

Dr. Maeda declares lecture fees (Bristol‐Myers Squibb Co., Ltd.) and scholarship donations (Chugai Pharmaceutical Co., Ltd.). The other authors declare no conflicts of interest.

Aoki M., Maeda T., Kinoshita H., et al. “Secondary Chronic Myeloid Leukemia in the Blast Phase With Mixed Phenotype After Radiation Therapy: A Case Report.” eJHaem 7, no. 1 (2026): e70249. 10.1002/jha2.70249

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.