The Case: A 45-year-old man with a known history of rheumatic fever and aortic valve replacement 15 years earlier presented with the chief complaint of a 1-month history of progressive, intense, nonmechanical lumbar pain. On physical examination, he was found to have splenomegaly (4 cm below the costal margin). An MRI demonstrated multiple osteolytic lesions of the thoracic spine, lumbar spine, pelvis, and both femoral heads.
Blood analyses showed an elevated white blood cell (WBC) count of 61.6 × 103/μL, a decreased hemoglobin level of 8.8 g/dL, and an increased platelet count of 475 × 103/μL. The differential leukocyte count revealed the following: neutrophils, 79%; lymphocytes, 5%; monocytes, 1%; eosinophils, 0%; basophils, 0%; bands, 2%; metamyelocytes, 10%; and myelocytes, 3%. His lactate dehydrogenase level was 623 U/L (normal range, 140–271 U/L). Examination of the bone marrow showed increased cellularity due to granulocytic proliferation, with 22% blasts, and with the morphology suggesting blast crisis (BC)-chronic myeloid leukemia. Immunophenotypic characterization of the bone marrow confirmed the presence of two distinct cell populations with leukemic features: a myeloid lineage, with blasts positive for CD34, human leukocyte antigen (HLA)-DR, CD13, CD117, and myeloperoxidase (MPO) expression; and a B-lymphoid lineage, with blasts positive for CD34, HLA-DR, CD10, CD19, CD22, and CD79a expression.
A core needle biopsy of the vertebrae was performed. The morphologic and immunophenotypic findings supported the diagnosis of chronic myeloid leukemia in biphenotypic BC with extramedullary infiltration (positive for paired box 5 [PAX5], CD79a, CD34, CD117, terminal deoxynucleotidyl transferase [TdT], MPO, CD10, and CD20; Figure 1).
On the cytogenetic analysis, the presence of a three-way translocation, with deletion of derivative chromosome 9—der(9)—was identified. The karyotype was interpreted as 46XY,t(1;9;22)(q21;q34;q11.2),der(9)del(9)(q34.1q34.3) on 20 metaphases (Figure 2). The fluorescence in situ hybridization dual color, dual fusion test for BCR-ABL was positive, showing loss of a fusion signal in 182 interphase nuclei, of the 200 analyzed. Reverse transcription-polymerase chain reaction testing for the t(9;22) BCR-ABL1 major (p210) fusion transcript was positive in 100% International Scale.
The patient was treated with the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen and imatinib, 800 mg daily. At the 3-month follow-up, his laboratory work demonstrated a complete cytogenetic response (CyR) and major molecular response. HLA typing was performed in his siblings, but no compatible donors were found. He relapsed 8 months later. His poor functional status precluded additional treatment and he died following disease progression.
Chronic myeloid leukemia is a clonal myeloproliferative disorder that usually runs a biphasic or triphasic course. BC is the transition of chronic myeloid leukemia in chronic phase (CP-CML) or accelerated phase (AP-CML) into an acute leukemia. A BC is characterized by ≥ 20% blasts among the WBCs of the peripheral blood or among the nucleated cells of the bone marrow, or by the presence of an extramedullary blast proliferation. Although BC superficially resembles an acute leukemia arising de novo, it is a distinct entity characterized by marked refractoriness to treatment and dismal outcomes. Even in the tyrosine kinase inhibitor (TKI) era, the median survival is 7 to 11 months from diagnosis.
Several pretreatment and posttreatment features have been associated with an unfavorable prognosis for BC. These include low performance status, elevated platelet count, > 50% blast cells, additional chromosomal abnormalities, myeloid blast morphology, and extramedullary disease. The most significant predictor of poor prognosis is an unsatisfactory response to initial therapy.[3,4]
Generally, BC is either myeloid or lymphoid. As in our patient, a mixed or biphenotypic lineage (both myeloblastic and lymphoblastic) can occur. Myeloid differentiation occurs in about 60% to 80% of cases, and lymphoid blasts are detected in about 20% to 30%; biphenotypic cases account for the remainder. Myeloid BC blasts characteristically stain positive for MPO, CD13, CD33, and CD117. The lymphoid blasts contain TdT and specifically express CD10, CD19, and CD22 when they are of a B-cell origin.[1,5,6]
Development of extramedullary disease, as in this case, occurs in 6% to 10% of patients. The lymph nodes, central nervous system (CNS), spleen, bone, and skin are the most common sites involved. Although evidence is scarce, the studies evaluating the clinical course and prognostic significance of extramedullary BC have shown that its presence is associated with poor outcomes. The overall rate of response to treatment is estimated to be 33%, and the reported median overall survival (OS) is 8 months.[7,8]
Most chronic myeloid leukemia patients harbor the classic Philadelphia chromosome (Ph), and 10% to 12% of patients have additional chromosomal abnormalities. These include variant translocations, lack of the Y chromosome, and additional chromosomal aberrations. Variant translocations involve 9q, 22q, and at least one additional genomic locus. This phenomenon was documented in our patient’s karyotype: t(1;9;22).[9,10] Some studies in the pre-imatinib era suggested that patients with a variant Ph translocation might have a worse outcome. However, the largest series reported, from the GIMEMA Working Party, found no significant impact of this feature on the CyR, molecular response, or patient outcomes, which suggests that, in the imatinib era, patients with variant translocations do not constitute a higher-risk category.
Deletion adjacent to the Ph translocation breakpoint on der(9) occurred in our patient and is reported in more than 30% of chronic myeloid leukemia patients with a variant Ph translocation. The der(9) deletion mainly occurs in the setting of disease progression and is a powerful indicator of a poor prognosis.
The aim of treatment for a chronic myeloid leukemia BC (BC-CML) is to return the patient to an earlier phase of the disease. The best survival rates are seen in those who return to CP-CML and undergo successful transplantation. There is no standard therapy for BC-CML. Several approaches can be considered based on the patient’s previous therapy and type of leukemia (myeloid, lymphoid, or biphenotypic). Currently, treatment recommendations for AP-CML and BC-CML are based mainly on results of retrospective and prospective single-arm studies, as well as on expert opinion panels.[13-17] According to the European LeukemiaNet 2013 guidelines, a TKI (imatinib, 800 mg daily, or dasatinib, 140 mg daily) along with chemotherapy to control disease burden, plus stem cell donor search, is the recommended initial approach.
Retrospective studies have been reported of patients with lymphoid BC treated with regimens for Ph-positive acute lymphoblastic leukemia. Of the patients treated with hyper-CVAD plus imatinib or dasatinib, 90% experienced a complete hematologic response (CHR), 58% experienced a complete CyR, and 25% experienced a complete molecular response. The median duration of remission was 14 months, and the median OS was 17 months. OS was better among stem cell transplantation (SCT) recipients, at 93 months.
However, the outcome of myeloid BC treated with cytarabine-based regimens for acute myeloid leukemia is known to be worse. Prospective evidence suggests an overall response rate of 28%, a median duration of remission of 29 weeks, and a median OS of 22 weeks. Outcomes of phase I/II trials in which the treatment regimen features the addition of a TKI have not demonstrated better results, with a median OS of 6.4 months.
In patients with biphenotypic BC, the decision of whether to prescribe a lymphoid or myeloid induction regimen remains a quandary. Because biphenotypic BC is uncommon, with evidence restricted to case series or small cohorts, most therapeutic decisions are based on the management of biphenotypic acute leukemia (BAL).
Retrospective studies have compared outcomes among BAL and unilineage acute leukemias. One study analyzed 452 adult acute leukemia patients, of which 21 (4.6%) had BAL. There was no statistical difference in complete remission (CR) rate after induction. However, the BAL patients showed a significantly higher incidence of relapse, lower rates of CR after relapse, and decreased survival. Patients with BAL were treated with either an acute lymphoblastic leukemia or an acute myeloid leukemia induction regimen. Of those allocated to receive an acute lymphoblastic leukemia–based induction regimen, 87% experienced a CR, while only 20% of patients treated with an acute myeloid leukemia–based regimen achieved a CR. Based on these data, we started our patient on the hyper-CVAD regimen.
The use of TKIs during a BC has resulted in a survival benefit.[24,25] Data on which TKI should be the upfront treatment are scarce. Recommendations are mainly based on extrapolation from data from randomized trials in patients with CP-CML.
The benefit of imatinib use in BC-CML patients, with and without previous TKI treatment, has been demonstrated by multiple trials. In patients with lymphoid and myeloid BC, the CHR was 50% to 70%, the CyR was 12% to 17%, the 1-year survival was 22% to 36%, and the median OS was 6.5 to 10 months.[24-27] A second-generation TKI should be considered at diagnosis in patients with mutations due to TKI resistance, extramedullary disease (particularly with CNS involvement), or high-risk cytogenetics, as well as in patients in whom BC evolves during imatinib use. Given that our patient had more than one of these high-risk features, dasatinib therapy was considered; however, his insurance policy only covered first-generation TKI treatment.
Dasatinib has been approved by the US Food and Drug Administration (FDA) and international government agencies for the treatment of BC-CML at a dose of 140 mg daily. The studies related to the efficacy of this drug showed a CHR of 26%; a complete CyR of 27% and 43% for myeloid and lymphoid BC, respectively; and a median OS of 8 to 11 months.[15,28,29] In addition, dasatinib has been linked to better responses in the setting of extramedullary disease, particularly in patients with CNS involvement, given that the drug crosses the blood-brain barrier.[8,30] Nilotinib has been approved by the FDA for the treatment of CP-CML and AP-CML, but not for BC-CML. However, its efficacy was evaluated in this setting in a prospective study with a 24-month follow-up; results of this study included a CHR of 60%, a complete CyR of 30%, a 1-year OS of 44%, and a 2-year OS of 32%. The use of nilotinib should also be considered in the presence of V299L, T315A, or F317L/V/I/C mutations.
When return to CP-CML or a CR has been achieved with an induction regimen, proceeding to allogeneic SCT offers the best opportunity for long-term remission or cure in BC-CML. A recent TKI-era study from the German CML Study Group evaluated the outcomes of 84 chronic myeloid leukemia patients who underwent transplantation, reporting a 3-year survival (following transplantation) of 59% for 28 patients with AP-CML. Our patient showed complete response to induction treatment with hyper-CVAD and imatinib[32,33]; unfortunately, he could not receive treatment with SCT due to the lack of an HLA-compatible donor.
Acknowledgements: The authors would like to thank the Aramont Foundation for their support in research activities and Dr. Oswaldo Mutchinick and the Department of Genetics for providing the cytogenetic analysis images of this case.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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