Boy Beats Leukemia, Then a Different One Emerges With the Same Chromosomal Hallmark

In one of the rarest leukemia sequences ever documented, physicians in Iran report that a boy who recovered from Philadelphia-positive pre-B acute lymphoblastic leukemia in childhood went on to develop chronic myeloid leukemia roughly a decade later, carrying a completely different BCR::ABL1 fusion transcript and a rare kinase-domain variant that blunted his response to two generations of targeted drugs. The case, published as a detailed clinical report, describes how the same chromosomal hallmark, the Philadelphia chromosome, appeared at both presentations while the molecular signature of the disease shifted from the p190 isoform typical of acute lymphoblastic leukemia to the p210 isoform that defines chronic myeloid leukemia. The report raises fundamental questions about whether the two malignancies evolved from a single hidden precursor, whether the second leukemia was triggered by the very chemotherapy that cured the first, or whether they were independent cancers that happened to share the same chromosomal translocation.

The story began in February 2015, when a 4-year-old boy arrived at Amirkabir Hospital in Arak with four weeks of fever, malaise, and a palpable mass in his left abdomen. Examination revealed nontender cervical lymphadenopathy and a spleen extending five centimeters below the costal margin. Blood counts showed leukocytosis, anemia, and thrombocytopenia, with a white cell count of 16,000 per microliter, hemoglobin of 6.5 grams per deciliter, and platelets of just 6,000 per microliter. Bone marrow aspirate contained approximately 90 percent blasts. Flow cytometry confirmed B-lineage commitment: the blasts expressed CD10, CD19, CD22, CD79a, and TdT while lacking myeloid and T-cell markers, excluding mixed-phenotype acute leukemia. Reverse-transcription PCR detected the BCR::ABL1 p190 transcript, and cytogenetic analysis demonstrated an isolated t(9;22)(q34;q11) without additional abnormalities, confirming Philadelphia-positive pre-B ALL.

The Philadelphia chromosome arises from a reciprocal translocation between chromosomes 9 and 22, fusing BCR and ABL1 into an oncogenic tyrosine kinase. The breakpoint within BCR determines the resulting isoform: p210 is the hallmark of chronic myeloid leukemia but appears in a minority of Philadelphia-positive ALL cases, whereas p190 predominates in Philadelphia-positive ALL. Tyrosine kinase inhibitors, which specifically block BCR::ABL1, are the cornerstone of therapy in these leukemias. The boy received a Children’s Oncology Group AALL0232-based high-risk B-ALL protocol combined with imatinib at 340 milligrams per square meter per day. Within one month, next-generation sequencing-based minimal residual disease testing fell below 0.001 percent. By six months he had achieved a complete cytogenetic response, with BCR::ABL1 PCR declining to 0.46 percent, and at twelve months the level had dropped further to 0.08 percent.

Therapy continued for three years, by which time deep molecular remission had been achieved, with BCR::ABL1 undetectable by PCR and minimal residual disease below 0.001 percent. Imatinib monotherapy was then continued for an additional three years, during which clinical assessments remained unremarkable and BCR::ABL1 stayed undetectable. No hematopoietic stem cell transplant was performed, consistent with standard practice for pediatric Philadelphia-positive pre-B ALL in first remission without adverse features. Imatinib was planned for five to ten years after chemotherapy completion. During monotherapy, however, follow-up became irregular because of socioeconomic constraints, with visits occurring only annually. According to the family, the patient discontinued imatinib approximately three years into monotherapy without physician supervision and outside any planned treatment-free remission strategy. He then stopped attending follow-up entirely, and the exact duration of the interruption could not be reconstructed because the discontinuation date rested solely on family report.

Approximately five years after his last visit, the boy re-presented with malaise and a progressively enlarging abdominal mass over three months. Examination revealed massive splenomegaly, fifteen centimeters below the costal margin, and blood tests showed a white cell count of 451,000 per microliter with a full spectrum of myeloid precursors, basophilia, and a platelet count of 1,282,000 per microliter. Bone marrow examination showed hypercellularity with marked myeloid expansion, and flow cytometry revealed a maturing myeloid pattern with strong expression of CD13, CD33, and CD117, minimal B-cell markers, and low-level T-lineage antigens. PCR detected BCR::ABL1 p210 with both b2a2 and b3a2 transcripts, while p190 was absent, confirming chronic-phase CML. Karyotyping demonstrated isolated t(9;22)(q34;q11), unchanged from the ALL phase, meaning the same translocation now drove a biologically distinct disease.

Imatinib was restarted at 340 milligrams per square meter per day, and the patient achieved a complete hematologic response at one month and a complete cytogenetic response at three months, with BCR::ABL1 falling to 1.7 percent on the International Scale. At six months, however, the PCR rose to 5.3 percent, placing him in the European LeukemiaNet-defined warning category and prompting a switch to dasatinib at 70 milligrams per square meter per day once daily. On dasatinib, BCR::ABL1 initially decreased to 3.2 percent at three months but subsequently climbed to 8.9 percent at six months, a second warning-category response. Bidirectional Sanger sequencing of the BCR::ABL1 kinase domain, performed on cDNA generated from bone marrow RNA, revealed no common resistance-associated mutations, including T315I, E255K/V, Y253H, V299L, F359V/C/I, and F317L/V/I/C, but detected a rare heterozygous missense variant, c.1159T>A, p.Leu387Met, within the ABL1 kinase domain.

The L387M variant sits within the activation loop of the kinase, is absent from population databases such as gnomAD and ClinVar, and appears in COSMIC and CIViC as a variant of uncertain significance with mixed resistance data. Experimental Ba/F3 models have demonstrated modest imatinib resistance with preserved dasatinib and nilotinib sensitivity, and L387M has been identified among kinase-domain variants in patients with imatinib-resistant CML, although its independent contribution to treatment response remains uncertain. Unexpectedly, this case showed suboptimal responses to both imatinib and dasatinib, a clinical pattern not entirely concordant with the previously reported sensitivity profile of L387M. Because Sanger sequencing may not reliably detect variants present below approximately 15 percent frequency, low-level subclones harboring additional resistance mutations cannot be excluded, and the variant allele frequency of L387M could not be quantified. The authors caution that clinical behavior of rare kinase-domain variants may not always align with experimental data.

Given the suboptimal molecular responses, the patient underwent allogeneic hematopoietic stem cell transplantation from a fully HLA-matched related donor following myeloablative conditioning with intravenous busulfan and cyclophosphamide. Graft-versus-host disease prophylaxis consisted of cyclosporine adjusted by therapeutic drug monitoring and short-course methotrexate. Engraftment was successfully achieved with recovery of peripheral blood counts, and Day +100 chimerism demonstrated 99 percent donor cells. No significant acute or chronic graft-versus-host disease or transplant-related complications have been observed during follow-up. After engraftment, nilotinib was initiated at 230 milligrams per square meter twice daily because ponatinib was unavailable locally and L387M-associated resistance to nilotinib had not been established. Treatment has been well tolerated, and posttransplant qualitative PCR for BCR::ABL1 remains negative, closing a remarkable molecular arc that spanned two Philadelphia-positive diseases with discordant fusion transcripts.

Whether the two malignancies share a clonal origin cannot be determined from the discordant transcripts alone, and several possibilities remain. One is evolution from a shared Philadelphia-positive precursor, through selection of a subclone with different biological characteristics, acquisition of additional genomic alterations, or altered transcript processing such as alternative splicing. Prior molecular analyses have established that transcript and phenotypic divergence can occur within a single BCR::ABL1 genomic rearrangement, supporting the biological plausibility of this route. A second possibility is therapy-related CML following cytotoxic exposure. Therapy-related CML has been reported after treatment for other malignancies, notably ALL, with alkylating agents and topoisosmerase II inhibitors most strongly implicated, and it typically develops four to seven years after treatment, closely resembling de novo CML with isolated t(9;22) and comparable TKI responses. This patient received cyclophosphamide, daunorubicin, and doxorubicin, and the latency interval was consistent with published data. A third possibility is an independent Philadelphia-positive malignancy unrelated to the initial ALL.

The authors also emphasize that the initial presentation was highly consistent with de novo Philadelphia-positive pre-B ALL rather than lymphoid blast-phase CML, which can mimic de novo ALL and has likely accounted for several reported cases of apparent ALL followed by CML. The absence of significant leukocytosis, basophilia, eosinophilia, or granulocytic left shift, a purely lymphoid immunophenotype, isolated t(9;22), exclusive p190 expression, and a rapid sustained deep remission after ALL-directed therapy all supported de novo ALL, since sustained remissions are uncommon in lymphoid blast-phase CML. Archived diagnostic material was unavailable for paired high-sensitivity genomic analysis across disease phases, so the clonal relationship could not be established, and the unsupervised imatinib interruption means neither the timing of the later disease nor any effect of TKI withdrawal on clonal dynamics can be determined. The temporal association does not establish that discontinuation caused the subsequent CML or that continued therapy would have prevented it, but it reinforces that treatment-free remission should occur only under specialist supervision with close molecular monitoring. The case ultimately highlights that a subsequent Philadelphia-positive disease should undergo complete morphologic, immunophenotypic, cytogenetic, and molecular reassessment rather than automatically being assumed to represent relapse, and that the clinical significance of rare variants such as L387M may be context-dependent, warranting further functional investigation.

Subject of Research: Sequential Philadelphia‐Positive Pre‐B Acute Lymphoblastic Leukemia and Chronic Myeloid Leukemia With Distinct BCR::ABL1 Fusion Transcripts

Article Title: Sequential Philadelphia‐Positive Pre‐B Acute Lymphoblastic Leukemia and Chronic Myeloid Leukemia With Distinct BCR::ABL1 Fusion Transcripts

Article References: Latifi, A., & Yousefian, S. (2026). Sequential Philadelphia‐Positive Pre‐B Acute Lymphoblastic Leukemia and Chronic Myeloid Leukemia With Distinct BCR :: ABL1 Fusion Transcripts. Cancer Reports, 9(10), Article e70694. https://doi.org/10.1002/cnr2.70694

Image Credits: AI Generated

DOI: 10.1002/cnr2.70694

Keywords: leukemia, chronic myeloid leukemia, BCR::ABL1, tyrosine kinase inhibitor, case report, Sequential, Philadelphia, Positive, Acute, Lymphoblastic, Chronic, Myeloid