Minimally-Myelosuppressive Asparaginase-Containing Induction Regimen for Treatment of a Jehovah's Witness with mutant IDH1/NPM1/NRAS Acute Myeloid Leukemia

Ashkan Emadi, Najeebah A Bade, Brandi Stevenson, Zeba Singh, Ashkan Emadi, Najeebah A Bade, Brandi Stevenson, Zeba Singh

Abstract

Treatment of patients with acute myeloid leukemia (AML) who do not wish to accept blood product transfusion, including Jehovah's Witnesses, is extremely challenging. The use of conventional chemotherapy for induction of complete remission (CR) results in profound anemia and thrombocytopenia requiring frequent transfusions of blood products, without which such treatment will be life-threatening. Finding a well tolerable, minimally myelosuppressive induction regimen for such patients with AML is a clear example of area of unmet medical need. Here, we report a successful treatment of a 52-year-old Jehovah's Witness with newly diagnosed AML with peg-asparaginase, vincristine and methylprednisolone. The AML was characterized with normal karyotype, and mutations in isocitrate dehydrogenase 1 (IDH1-Arg132Ser), nucleophosmin 1 (NPM1-Trp289Cysfs*12) and neuroblastoma RAS viral oncogene homolog (NRAS-G1y12Va1). After one 28-day cycle of treatment, the patient achieved complete remission with incomplete count recovery (CRi) and after the second cycle, he achieved CR with full blood count recovery. The patient has never received any blood products. Notwithstanding that myeloperoxidase-induced oxidative degradation of vincristine results in its lack of activity as monotherapy in AML, its combination with corticosteroid and asparaginase has resulted in a robust remission in this patient. Diminished steroid clearance by asparaginase activity as well as reduction in serum glutamine level induced by glutaminase enzymatic activity of asparaginase may have contributed to effective killing of the myeloblasts that carry IDH1/NPM1/NRAS mutations. In conclusion, asparaginase-containing regimens, which are approved for treatment of acute lymphoblastic leukemia (ALL) but not AML, can be used to treat patients with AML who do not accept blood transfusion.

Keywords: acute myeloid leukemia (AML); asparaginase; isocitrate dehydrogenase (IDH).

Figures

Figure 1
Figure 1
Bone marrow aspirate, biopsy and clot section smears. (A) Clot section at diagnosis (Hematoxylin and Eosin [H&E] stain ×20) showing large hypercellular marrow fragments (cellularity >90%) with predominantly blasts (70%) admixed with maturing erythroid precursors and lymphocytes. Megakaryocytes are identified, but decreased in proportion to the cellularity. Maturing granulopoiesis is markedly reduced; (B) Bone marrow aspirate at diagnosis (Wright stain ×40) showing myeloid:erythroid (M:E) ratio of 3:1, markedly reduced and left-shifted granulopoiesis, blasts comprising 52% of the cellularity; (C) Bone marrow core biopsy on day 28 (H&E stain ×20) showing maturing erythroid precursors as the majority of the cells, lymphocytes, and a few megakaryocytes with decreased granulopoiesis and no overt increase in blasts; (D) Bone marrow aspirate on day 28 (Wright stain ×40) showing decreased M:E ratio (0.5:1), most of the cells being of erythroid lineage and lymphocytes with a few maturing granulocytes and mildly dysplastic megakaryocytes related to chemotherapy and no increase in blast cells; (E) Bone marrow core biopsy on day 81 (H&E stain ×20) showing normocellular (50%–60%) marrow for the age of the patient, maturing granulopoiesis and erythropoiesis with an erythroid predominance, adequate megakaryocytes focally clustered with occasional small forms, no lymphoid aggregates, and no myeloblasts; (F) Bone marrow aspirate on day 81 (Wright stain x40) showing M:E ratio of 0.8:1, full spectrum maturation in the granulocytic and erythroid series, megakaryocytes with normal morphology, no increase in lymphocytes, plasma cells, or presence of any other abnormal cell population including no increase in blasts.
Figure 2
Figure 2
White blood cell, hemoglobin, and platelet counts from diagnosis throughout two cycles of chemotherapy regimens; Arrows indicate the days of bone marrow biopsy (B), receiving vincristine (V), or pegasparaginase (P).

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