Treatment of CD19‐positive mixed phenotype acute leukemia with blinatumomab
Authors: Firas El Chaer, Omer M. Ali, Edward A. Sausville, Jennie Y. Law, Seung Tae Lee, Vu H. Duong, Maria R. Baer, Rima Koka, Zeba N. Singh, Jerry Wong, Jean A. Yared, Elizabeth A. Griffiths, Ashkan Emadi
Journal: American Journal of Hematology (2018)

Mixed-phenotype acute leukemia (MPAL) represents 1.5%-2.5% of all acute leukemias.1 MPAL is characterized by lineage promiscuity or infidelity. MPAL blasts express more than one specific marker from each hematopoietic lineage: myeloperoxidase (MPO) for myeloid lineage in addition to either the cytoplasmic or surface CD3 antigen for T-cell lineage, or the CD19 antigen for B-cell lineage.2 MPAL is associated with poor prognosis. Treatment has been guided by heterogenous case reports or small case series using cytotoxic chemotherapy. Based on the current literature, treating patients with newly diagnosed MPAL with an acute lymphoblastic leukemia (ALL) regimen, rather than an acute myeloid leukemia (AML) regimen, has better efficacy in inducing complete remission (CR), albeit with only ~20% 5-year overall survival (OS).3 Moreover, the prognosis of refractory or relapsed (R/R) MPAL is grim, with a median survival of <3-6 months.4 Blinatumomab, a bispecific CD19-directed CD3 T-Cell engager antibody, is approved by the United States Food and Drug Administration (US FDA) for treatment of R/R B-cell precursor ALL (B-ALL) and B-ALL in first or second CR with measurable (minimal) residual diease (MRD). The TOWER study, demonstrated improved OS in R/R B-ALL with blinatumomab treatment, compared to chemotherapy, and in the BLAST study 80% of patients with ALL who had hematologic CR with MRD ≥0.1% achieved undetectable MRD. Here, we report two patients with CD19+ MPAL (B/myeloid) who were successfully treated with blinatumomab. We hypothesized that due to CD19 expression on MPAL blasts, blinatumomab therapy would result in CR and eradication of MRD, if present. A previously healthy 39-year-old man presented with abdominal pain. He had splenomegaly. White blood cell (WBC) count was 133 000 per microliter (mcL), with 85% blasts, hemoglobin 11.2 g per deciliter (g/dL) and platelet count 165 000/mcL. Bone marrow aspirate and biopsy (BMBx) were hypercellular for his age. Blasts accounted for 80% of the bone marrow cellularity, with immunohistochemical staining for MPO, CD19 (99%), CD20, CD22, CD33, and CD123, confirming the diagnosis of MPAL (B/Myeloid). Cytogenetic analysis showed a complex karyotype with t(9;22). The patient received induction chemotherapy with cytarabine and daunorubicin and daily dasatinib without interruption. Cerebrospinal fluid (CSF) evaluation showed involvement with leukemia, which was treated with intrathecal cytarabine injections. Day 14 (D + 14) BMBx showed <5% cellularity and 20% blasts. D + 31 BMBx, at the time of count recovery, showed 30% cellularity with progressive trilineage hematopoiesis, 3% blasts and a normal male karyotype. Fluorescence in situ hybridization identified t(9;22). MRD was detected by flow cytometry at 0.13% and by polymerase chain reaction (PCR) for BCR-ABL p190 transcript at 0.02824%. Based on presence of MRD, treatment was switched to blinatumomab at standard dose, with dasatinib. No cytokine release syndrome (CRS) or neurological toxicity was observed. BMBx after 1 cycle of blinatumomab showed mild hypercellularity with maturing hematopoiesis and 2% regenerating blasts. MRD was not detected by flow cytometry or by PCR. Based on superior outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Ph(+) ALL and since MRD was detected after induction chemotherapy, he proceeded to allo-HSCT following 1 cycle of blinatumomab and is currently D + 60. His leukemia remains in CR 6 months after diagnosis. A 55-year-old woman with insulin-dependent diabetes mellites, hypertension, obesity, and hypothyroidism presented with new-onset dyspnea on exertion, multiple ecchymoses, 20 lb weight loss, and menorraghia. WBC was 1800/mcL (12% blasts), hemoglobin 7.9 g/dL, and platelet count 88 000/mcL. BMBx showed hypercellularity for age, with blasts accounting for 34% of bone marrow cells, and immunohistochemical staining for MPO, CD19 (66%), CD20, CD22, and CD33 establishing the diagnosis of B/myeloid MPAL. Cytogenetic analysis showed a 46,XX, inv(16)(p13;q24) karyotype, different from the more common inv(16)(p13;q22), without CBFB/MYH11 rearrangement. The patient received induction therapy with hyperCVAD. CSF evaluation showed no involvement with leukemia. D + 27 BMBx, at the time of full count recovery, showed hypercellularity with full-spectrum trilineage hematopoiesis and no blasts. Cytogenetic analysis showed a 46,XX karyotype. MRD was not detected by flow cytometry. Her induction therapy was complicated by mitral valve endocarditis with acute ischemic infarcts, pneumonia and skin and soft tissue infection. Her performance status significantly declined and she was not a candidate for further cytotoxic therpay. Therefore, due to the expression of CD19 on MPAL cells, treatment was switched to blinatumomab. She received three courses of blinatumomab, without development of CRS or neurologic symptoms, with sustained MRD-free morphologic and cytogenetic remission. Her performance status improved and since allo-HSCT in CR1 has been associated with superior outcomes compared with consolidation chemotherapy in patients with MPAL,5 she underwent an allo-HSCT. She remains in CR with negative MRD 14 months after diagnosis. Here we report successful treatment of CD19+ MPAL with blinatumomab, specifically targeting the CD19 antigen present on these leukemia cells. Although the therapeutic success of blinatumomab has been shown in CD19+ ALL, to the best of our knowledge the present report is the first to describe the use of blinatumomab in the treatment of CD19+ MPAL and to establish its efficacy in controlling this rare type of acute leukemia. Although the survival of patients with MPAL has improved in recent years, primarly due to incorporation of allo-HSCT into treatment, the overall prognosis remains poor. The risk of death from MPAL is 59% and 26% higher than for ALL and AML, respectively.6 In the absence of prospective clinical trials, MPAL treatment is guided by retrospective studies and is based on ALL regimens. Given high relapse rates with chemotherapy, targeted approaches may improve outcomes. B/myeloid MPAL blasts express CD19. In this report, we aimed to study the efficacy of blinatumomab in the treatment of two patients with CD19+ MPAL. The clinical hypothesis was that treatment of these patients with CD19+ MPAL with blinatumomab, along with a tyrosine kinase inhibitor for Ph(+) disease in the first patient, would result in the achievement of sustained MRD-negative CR and maintenance of MRD-negative CR in the first and second patient, respectively. Our patients had short periods of myelosuppression and few adverse events, which led to overall improved functional status after therapy. Both patients were able to proceed to allo-HSCT, thus far resulting in sustained MRD-negative clinical remissions. The poor outcomes of R/R MPAL with chemotherapy underscore the need for a prospective clinical study of targeted therapy in this patient population. We suggest that blinatumomab is an excellent candidate for this purpose. A.E. is a Global Oncology Advisory Board Member for Amgen and has served as a consultant to Amgen.