Discussion

Background (history, epidemiology, and risk factors)

Chronic myeloid leukemia (CML) is an uncommon myeloproliferative neoplasm defined by the Philadelphia chromosome and the resulting BCR::ABL1 fusion gene [1-3]. In the United States, the overall age-adjusted incidence of CML is approximately 2.1 cases per 100,000 persons per year, and CML accounts for a small fraction of all new cancer diagnoses [1-3]. The disease is strongly age-associated: population-based data show that CML is most frequently diagnosed between 65 and 74 years of age, with a median age at diagnosis of approximately 67 years [1-3]. By contrast, diagnosis in younger adults is uncommon; SEER data indicate that patients aged 20-34 years account for only 6.7% of new CML cases, while those younger than 20 years account for 1.6% [4,6,7].

CML in adolescents and young adults is increasingly recognized as a clinically important subgroup because younger patients may present with distinct disease features [4,6,7]. Several studies have reported that younger patients can present with higher leukocyte counts, larger spleen size, and greater disease burden at diagnosis compared with older adults [4,6,7]. Despite this, outcomes have improved substantially in the tyrosine kinase inhibitor era, and long-term survival can approach that of the general population when optimal molecular responses are achieved [1,3,4,6,7].

Few established risk factors for CML have been identified. Ionizing radiation remains the most consistently recognized environmental risk factor, whereas hereditary predisposition and lifestyle-related exposures have not been definitively linked to disease development [1,2]. Because CML is rarely diagnosed in young adults, cases with prolonged disease course, persistent high disease burden, and unusual cytogenetic features provide important insight into the clinical heterogeneity and long-term management challenges of CML in this population.

Pathology/pathophysiology

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm driven by the BCR::ABL1 fusion gene, most commonly generated by the Philadelphia chromosome translocation t(9;22)(q34;q11.2) [1-3]. Constitutive BCR::ABL1 tyrosine kinase activity activates multiple downstream signaling pathways, promoting uncontrolled myeloid proliferation and producing the characteristic features of CML, including leukocytosis, left-shifted granulopoiesis, basophilia, and splenomegaly [1,3,15].

Variant Philadelphia chromosome translocations occur in approximately 5-10% of patients and involve one or more chromosomes in addition to chromosomes 9 and 22 while preserving formation of the BCR::ABL1 fusion gene [8-10]. Although most patients respond similarly to tyrosine kinase inhibitor therapy, the biologic significance of many rare variant rearrangements remains incompletely understood [8-10].

In this case, a rare three-way translocation, t(6;9;22)(p21;q34;q11.2), was associated with persistent BCR::ABL1-positive chronic-phase CML. Marked leukocytosis, basophilia, massive splenomegaly, and a hypercellular marrow reflected ongoing myeloproliferative activity, while low blast counts on bone marrow examination and flow cytometry confirmed persistent chronic-phase disease without transformation to accelerated- or blast-phase CML [1,3].

Comparative analysis of this case with the existing literature

Clinical Presentation

The patient's initial presentation with incidental leukocytosis detected in 2017 during a routine blood donation screening is consistent with reports indicating that many patients with CML are 50% asymptomatic at diagnosis [5]. However, the degree of leukocytosis observed in this case being 187.8 ×10³/µL at diagnosis and >500 ×10³/µL during recurrence, and the presence of massive splenomegaly measuring 31.9cm demonstrates a high disease burden. CML most commonly presents in middle-aged and older adults, with a median age of onset around 60-65 [5]. Initial diagnosis of our patient was when he was 24, placing him within a small subset of cases.

CML found in individuals under 30 is extremely rare, with an incidence estimated at approximately 0.025 cases per 100,000 [5]. Identification of a complex variant Ph (vPh) chromosome, t(6;9;22)(q34;q11.2;p21), distinguishes our patient's case from most CML cases having the traditional t(9;22) translocation. Only 5-8% of CML cases have complex variant translocations, and chromosome 6 involvement is particularly uncommon [5,12-14]. Strikingly, the patient presented with a CML diagnosis at 24 with a vPH chromosome t(6;9;22) estimated to be approximately 0.025-0.08 cases per 100,000 population per year, noting the rarity of this presentation. Additionally, despite the nine-year disease course this patient had along with remarkable hematologic levels, the patient had no evidence of accelerated-phase or blast-phase transformation considering the uncommon nature of this case.

Diagnosis

The diagnostic evaluation in our patient was consistent with routine diagnostic workup for CML. This included complete blood count, peripheral blood smear, bone marrow biopsy, flow cytometry, cytogenetics, and Fluorescence In Situ Hybridization (FISH) analysis. Bone marrow examination demonstrated hypercellularity with granulocytic hyperplasia. Cytogenetic analysis identified vPh chromosome translocation, t(6;9;22)(q34;q11.2;p21). Additionally, FISH confirmed BCR-ABL fusion positivity in 94.5% of the analyzed cells. Comparable studies of CML and vPh chromosome CML have noted cytogenetic and FISH analysis confirmation along with molecular confirmation [5,12,13]. Re-evaluation in 2026 consisted of acknowledging that the chronic-phase of CML was maintained without blast transformation, demonstrating moderate reticulin fibrosis (MF-2) and CD34-positive blasts approximately 1% on immunohistochemistry.

In addition to standard protocol testing, advanced imaging was utilized to evaluate disease burden in our patient. Contrast-enhanced CT imaging of the abdomen displayed massive splenomegaly measuring approximately 31.9cm with significant mass effect.

Splenomegaly is a common manifestation of CML and reflects extramedullary hematopoiesis and leukemic cell sequestration [5,6,13]. However, the degree of enlargement noted in this patient is more pronounced than that described in most reported cases, reflecting persistent disease activity.

Management

Young adults with CML often present with a higher disease burden than older patients, including greater leukocytosis and splenomegaly. In recent studies, tyrosine-kinase inhibitors (TKI) therapy has improved the prognosis of all age groups diagnosed with CML. Our patient was initiated with dasatinib 100 mg daily during his 2026 re-evaluation. Other documented cases of young adults with CML and/or vPH chromosome t(6;9;22) have been treated with first-generation TKIs, such as Imatinib [6,7]. Compared with Imatinib, Dasatinib is more potent and is commonly utilized for its ability to induce faster and deeper molecular responses for chronic-phase CML. Furthermore, hydroxyurea was initiated prior to TKI therapy for rapid cytoreduction in the setting of extreme hyperleukocytosis, as seen in our patient, prior to definitive therapy with dasatinib.

Current studies have shown no significant difference in survival rates between young adults and older patients diagnosed with CML [6,7]. Early initiation and compliance with TKIs aid in long-term disease control and improved quality of life for patients diagnosed under the age of 30 with higher leukocyte counts and more pronounced organomegaly [5,7]. In this case, the patient presented at a young age for initial diagnosis, with marked leukocytosis, massive splenomegaly measuring approximately 31.9 cm, despite high disease burden. Notably, despite a nine-year disease course, marked leukocytosis, massive splenomegaly, persistent BCR::ABL1 positivity, and moderate marrow fibrosis, the patient remained in chronic phase without evidence of accelerated-phase or blast-phase transformation.

Outcome and Follow-up

The patient demonstrated significant clinical and hematologic improvement following cytoreduction and initiation of dasatinib therapy, with a marked decline in leukocyte count and resolution of his presenting symptoms. He was discharged with plans for close hematology follow-up, including serial complete blood count monitoring, comprehensive metabolic panels, lactate dehydrogenase, uric acid, and serial quantitative BCR::ABL1 transcript monitoring by real-time polymerase chain reaction (RT-qPCR) using the International Scale (IS) to evaluate treatment response and long-term disease control. Although longitudinal quantitative BCR::ABL1 transcript results were unavailable for inclusion in this report, continued molecular monitoring was recommended to determine treatment response and achievement of standardized molecular milestones, including major molecular response (MMR; BCR::ABL1 ≤0.1% IS), MR4 (≤0.01% IS), and MR4.5 (≤0.0032% IS), during long-term follow-up.

This case highlights several features described in the current literature on chronic myeloid leukemia (CML) in adolescents and young adults (AYA). Although CML is predominantly diagnosed in older adults, younger patients frequently present with higher leukocyte counts, more pronounced splenomegaly, and greater disease burden at diagnosis [4,6,7]. Consistent with these observations, our patient was diagnosed at 24 years of age and subsequently presented with extreme leukocytosis and massive splenomegaly. Notably, despite persistent disease nearly nine years after diagnosis and the presence of a rare variant Philadelphia chromosome, t(6;9;22), repeat bone marrow examination, flow cytometry, and fluorescence in situ hybridization (FISH) consistently demonstrated persistent chronic-phase disease without evidence of accelerated- or blast-phase transformation. Similar variant Philadelphia chromosome translocations have been reported only rarely, and their long-term prognostic significance remains incompletely understood [8-10,12,13].

Summary

This case highlights several uncommon features of chronic myeloid leukemia, including diagnosis at 24 years of age, the presence of a rare three-way variant Philadelphia chromosome translocation t(6;9;22)(p21;q34;q11.2), and persistence of chronic-phase disease nearly nine years after diagnosis. Consistent with reports describing adolescents and young adults with CML, the patient exhibited a substantial disease burden characterized by marked leukocytosis and massive splenomegaly. However, unlike many cases in which such findings raise concern for disease progression, repeat bone marrow evaluation, peripheral blood flow cytometry, and cytogenetic studies demonstrated persistent chronic-phase disease without evidence of accelerated-phase or blast-phase transformation. Comparison with the existing literature suggests that although variant Philadelphia chromosome translocations are uncommon and their long-term clinical significance remains incompletely understood, durable chronic-phase disease can be maintained despite significant hematologic and morphologic abnormalities. This case underscores the importance of comprehensive molecular surveillance and long-term follow-up in young patients with CML. Although longitudinal quantitative BCR::ABL1 transcript data were unavailable in this case, repeat FISH, bone marrow morphology, and flow cytometric findings consistently demonstrated persistent chronic-phase disease without evidence of accelerated- or blast-phase transformation. Table 7 is a summary of the comparison between this case and the current literature.

Domain | Findings reported in the literature | Present case
Age at diagnosis | Median age at diagnosis is approximately 60–65 years; patients younger than 30 years represent a small minority of cases [1-7]. | Diagnosed at 24 years of age.
Initial presentation | Approximately 40–50% of patients are asymptomatic and diagnosed incidentally through routine laboratory testing [1-3]. | Leukocytosis was incidentally detected during blood donation.
Leukocyte count | Leukocytosis is common; younger patients often present with higher leukocyte counts than older adults [4,6,7]. | WBC 187.8 ×10³/µL at diagnosis and >500 ×10³/µL during hospitalization.
Splenomegaly | Common manifestation of CML; often more pronounced in younger patients [4,6,7]. | Massive splenomegaly measuring 31.9 cm with mass effect on adjacent organs.
Cytogenetics | Classic Philadelphia chromosome t(9;22)(q34;q11.2) is present in >90% of cases. Variant translocations occur in approximately 5-10% of patients [1,8–11]. | Rare three-way variant Philadelphia chromosome t(6;9;22)(p21;q34;q11.2).
Chromosome 6 involvement | Reported only in isolated case reports and small case series [10,12,13]. | Presence of rare t(6;9;22) translocation.
Bone marrow findings | Hypercellular marrow with granulocytic hyperplasia and left-shifted myelopoiesis [1-3]. | Markedly hypercellular marrow (95%) with myeloid predominance and MF-2 fibrosis.
Disease phase | Most patients present in chronic phase; progression to accelerated or blast phase may occur over time. [1–3] | Persistent chronic-phase disease despite a 9-year disease course.
Molecular findings | BCR::ABL1 positivity confirmed by FISH and/or molecular testing [1-3]. | BCR::ABL1 positivity confirmed at diagnosis and persisted on repeat FISH testing.
Treatment | TKI therapy is the standard of care; younger patients generally achieve outcomes comparable to older adults when adequately treated [1-3,6,7]. | Treated with hydroxyurea for cytoreduction followed by dasatinib 100 mg daily.
Outcome | Long-term survival is favorable with sustained molecular response [1-3]. | Clinical and hematologic improvement achieved; persistent chronic-phase disease without accelerated- or blast-phase transformation after nearly 9 years.
Unique feature | Rare reports describe variant Philadelphia chromosome translocations involving chromosome 6 [10,12,13]. | Combination of young age at diagnosis (24 years), rare t(6;9;22) translocation, massive splenomegaly, and persistent chronic-phase disease nearly 9 years after diagnosis.

What we learned from this case

This case illustrates several important lessons regarding the long-term management of chronic myeloid leukemia (CML) in young adults. First, although CML is predominantly diagnosed in older individuals, it can occur in patients in their twenties and may initially be detected incidentally. The diagnosis of CML in a 24-year-old patient highlights the importance of considering myeloproliferative neoplasms in the differential diagnosis of marked leukocytosis regardless of age.

Second, comprehensive cytogenetic and molecular characterization remains essential throughout the disease course. The identification of a rare three-way variant Philadelphia chromosome translocation, t(6;9;22)(p21;q34;q11.2), emphasizes the value of detailed cytogenetic analysis in defining uncommon disease subsets and guiding long-term surveillance.

Most importantly, this case demonstrates that a substantial disease burden does not necessarily indicate disease progression. Despite extreme leukocytosis, massive splenomegaly, persistent BCR::ABL1 positivity, and moderate marrow fibrosis, the patient remained in chronic phase nearly nine years after diagnosis without evidence of accelerated-phase or blast-phase transformation. This observation underscores the biologic heterogeneity of CML and reinforces the importance of disease-phase assessment using morphologic, immunophenotypic, cytogenetic, and molecular findings rather than relying solely on disease burden. Finally, continued molecular monitoring and adherence to tyrosine kinase inhibitor therapy remain critical for achieving durable long-term disease control in young patients with persistent CML.

Limitations

This report has several limitations inherent to retrospective single-patient case reports. Longitudinal quantitative BCR::ABL1 transcript measurements by real-time polymerase chain reaction (RT-qPCR) using the International Scale (IS) were unavailable for review, precluding documentation of standardized molecular response milestones such as major molecular response (MMR), MR4, and MR4.5 over the patient's nine-year disease course. Additionally, complete outpatient treatment records, including detailed timelines of tyrosine kinase inhibitor adherence, treatment interruptions, and serial molecular monitoring, were not consistently available. Nevertheless, the diagnosis and longitudinal assessment of disease persistence were supported by concordant clinical findings, serial hematologic parameters, repeat bone marrow morphology, peripheral blood flow cytometry, cytogenetic analysis, fluorescence in situ hybridization (FISH), and cross-sectional imaging. Despite these limitations, this case provides valuable long-term clinical insight into a young patient with chronic-phase CML harboring a rare three-way variant Philadelphia chromosome translocation, t(6;9;22)(p21;q34;q11.2).