Abstract
Background: Lymphoid blast crisis, one of the two major forms of chronic myeloid leukemia (CML) blast crisis (BC), is comprised of lymphoblasts and occurs in about 30% of BC patients. These individuals often respond to the same treatment strategies used in Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Blinatumomab, a bispecific T engager, or BiTE, is an antibody with dual specificity against both CD3 and CD19, and is approved for use in relapsed/refractory ALL. We present the first known case of relapsed/refractory lymphoid blast phase CML, including treatment failure with blinatumomab, who achieved a complete response to inotuzumab ozogamicin.
Case report: In 2004, the patient was initially diagnosed with CML and received treatment with hydroxyurea followed by imatinib. He was intermittently compliant, later changed to nilotinib, and was ultimately lost to follow-up. Approximately 11 years after diagnosis, he returned with pancytopenia. Bone marrow aspiration and biopsy showed a hypercellular bone marrow with 10-15% lymphoid blasts that expressed CD34, CD19, cCD79a, HLA-Dr, CD10 and nTdt. Testing for the BCR-ABL translocation (at breakpoint P210) was positive confirming lymphoid blast phase CML. He received hyperCVAD + dasatinib, responded, and was referred for allogeneic hematopoietic cell transplantation (HCT) but deferred for social reasons. He was ultimately lost to follow-up.
The patient returned with relapsed disease in February 2017 and bone marrow aspiration and biopsy was consistent with CD19+ lymphoid blast phase CML with BCR-ABL major breakpoint p210 and new F317L mutation of ABL kinase domain. He received salvage therapy with vincristine/prednisone/bosutinib, however, repeat bone marrow testing confirmed persistent CD19+ lymphoid blasts (20%). He was treated with blinatumomab, entered a minimal residual disease (MRD)-positive morphologic remission with 1.9% abnormal B lymphoblasts by flow cytometry. A second cycle of blinatumomab was complicated by bone pain and repeat bone marrow testing showed progressive disease with 50-60% CD19+, CD22+ lymphoblasts. Salvage therapy with fludarabine, cytarabine, and idarubicin (FLAG-Ida) in September 2017 was unsuccessful and palliative treatment with vincristine, prednisone, and methotrexate was initiated. He developed new onset neurologic symptoms in March 2018 and lumbar puncture showed evidence of disease in his central nervous system (CNS) The patient received concurrent intrathecal methotrexate and inotuzumab ozogamicin which led to clearance of CNS disease and a morphologic remission in his marrow. He continues with MRD-positivity with 0.15% B lymphoblasts and is on ponatinib maintenance while allogeneic HCT evaluation is underway.
Discussion: This is the first reported patient with lymphoid blast phase CML, refractory to BiTE therapy, that was successfully salvaged with inotuzumab ozogamycin. Recent data from acute lymphoblastic leukemia (ALL) reported that the majority of BiTE failures remained CD19+ and the mechanisms of CD19 immunotherapy failure are poorly understood (Jabbour E, et al, AJH 2017). These patients may be successfully salvaged by CD19-directed chimeric antigen receptor (CAR) T cells or other directed therapies such as inotuzumab ozogamycin.
Conclusion: Patients with relapsed/refractory lymphoid blast phase CML should receive directed salvage therapies. This case report demonstrates that failure of one line of directed therapy does not predict for future failures.
Disclosures
No relevant conflicts of interest to declare.
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