Case Report

A woman aged 39 years was transferred to a tertiary care center after a bone marrow biopsy revealed 80% to 90% blasts. She had been well until 1 month before admission, when she noted fatigue, a 25-pound weight loss with concurrent otitis media, and sinus infections lasting 4 weeks. She was evaluated by her primary care physician and found to have new-onset anemia and thrombocytopenia. She was referred to a local hospital where a CBC confirmed a WBC count of 7.9 × 10³/mcL, hemoglobin level of 6.7 g/dL, platelet count of 111 × 10³/mcL, and 45% circulating blasts. A bone marrow aspiration and biopsy performed at the local hospital revealed 80% to 90% blasts. The patient was transferred to our hospital for further evaluation and management of acute leukemia. She denied night sweats, rash, ecchymosis, epistaxis, or menorrhagia. She also denied a personal history of cancer and exposure to chemotherapy, ionizing radiation therapy, or petrochemicals. Her family history was significant for liver cancer (father) and melanoma (brother). The patient had a 30 pack-year history of smoking but did not drink alcohol or use illicit drugs. There was no evidence of lymphadenopathy or organomegaly on physical examination.

Admission laboratories are shown in Table 1. Bone marrow aspirate slides from the outside hospital showed 82% blasts, 0% promyelocytes, 0% myelocytes, 1% metamyelocytes, 3% bands/neutrophils, 6% lymphocytes, 1% monocytes, 0% eosinophils, 0% basophils, 7% erythroids, and 0% plasma cells. Blasts were small to medium in size with a high nucleus/cytoplasm ratio, fine chromatin, and variably prominent nucleoli; no Auer rods were observed (Figure 1). Flow cytometric analysis of the marrow aspirate showed 82% blasts that were positive for CD45, CD34, CD38, CD117, HLA-DR, and TdT, and negative for myeloperoxidase (MPO), cytoplasmic CD3, cytoplasmic CD79a (9%), CD19, cytoplasmic CD22, CD13 (7%), CD20 (7%), CD25 (8%), CD33, CD11b, CD11c, CD14, CD10, CD2, CD5, CD7, CD41, CD56, CD64, and glycophorin (Figure 2). Cytogenetic analysis revealed a normal female karyotype. Fluorescence in situ hybridization was negative for RUNX1T1/RUNX1 (8q22/21q22), KMT2A (11q23), PML/RARA (15q24/17q21), CBFB (16q22), and TP53 (17p13.1).

Table 1.

Laboratory Findings During Treatment

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Blast morphology (Wright-Giemsa, original magnification ×100).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 1; 10.6004/jnccn.2019.7368

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Flow cytometric analysis showed that blasts were positive for (A) CD34 and HLA-DR and (B) CD117 and TdT, and negative for (C) MPO and cCD22, (D) CD5 and CD19, and (E) cCD3 and cCD79a.

Abbreviations: cCD22, cytoplasmic CD22; cCD3, cytoplasmic CD3; cCD79a, cytoplasmic CD79a; MPO, myeloperoxidase; R, residue; TdT, terminal deoxynucleotidyl transferase.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 1; 10.6004/jnccn.2019.7368

The patient was diagnosed with AUL based on the WHO classification, which includes leukemic cells that are not positive for any lineage-specific markers (myeloid lineage: MPO [flow cytometry]; B-cell lineage: CD19, CD79a, cytoplasmic CD22 or CD10; T-cell lineage: cytoplasmic CD3 or surface CD3).⁴ A targeted sequencing panel revealed mutations in IDH1 R132G (variant allele frequency [VAF], 0.30), BCOR G1520V (VAF, 0.28), BCOR G1520C (VAF, 0.27), and a variant of unknown significance of RUNX1 G135D (VAF, 0.53).

The patient was initially treated with 7+3 (cytarabine, 100 mg/m² 24-hour continuous intravenous infusion on days 1–7 and daunorubicin, 60 mg/m²/d intravenously on days 1–3) because of the presence of the IDH1 mutation, which is present in 7% to 14% of patients with acute myeloid leukemia (AML).⁵ On day 8 of 7+3 treatment, she developed hemoptysis and blurry vision due to bilateral preretinal hemorrhages. She subsequently experienced various bleeding complications, including right-sided cerebellar hemorrhage, epistaxis, severe oral mucosal bleeding, and conjunctival hemorrhage. Her platelet counts were trending down and then became undetectable during this time (Figure 3). She received intravenous aminocaproic acid and HLA-matched platelets but experienced no improvement in platelet count; she was found to have transfusion-refractory thrombocytopenia due to severe HLA alloimmunization (panel-reactive antibody, 100%).

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Timeline of platelet counts during treatment course.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 1; 10.6004/jnccn.2019.7368

Published incidence of platelet transfusion refractoriness in patients with AML is approximately 5% and is more frequently observed in parous women, increasing the risk of overall deaths from bleeding events.⁶ This patient had 2 children but had never received packed RBCs or platelet transfusions before her leukemia diagnosis. A bone marrow biopsy on day 14 of 7+3 treatment confirmed persistent AUL in a fibrotic hypocellular bone marrow (25%), with 15% blasts (Figure 4). The blasts expressed HLA-DR and CD34, with subpopulations expressing CD19 and CD11b. The targeted sequencing panel after completion of 7+3 therapy was not obtained because of paucicellular and hemodiluted bone marrow aspirate and a clot section that only showed blood without bone marrow elements.

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Bone marrow biopsy performed on day 14 of 7+3 treatment showed that blasts were (A) increased (hematoxylin-eosin, original magnification ×40) and (B) positive for CD34 (immunohistochemical, original magnification ×40).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 1; 10.6004/jnccn.2019.7368

Because of the patient’s persistent disease and the presence of an IDH1 mutation at diagnosis, on day 17 of 7+3 she was started on ivosidenib, 500 mg/d rather than a 5+2 reinduction due to her significant life-threatening bleeding complications and platelet-refractory thrombocytopenia. On day 19 of 7+3 therapy she declined further, with an increase in the work of breathing, and developed hypoxemia, requiring mechanical ventilator support. Bronchoscopy with bronchoalveolar lavage and cytology were significant for diffuse alveolar hemorrhage, and the patient was treated with methylprednisolone, 1 g/d aggressive transfusion support, and a furosemide drip for significant volume overload secondary to multiple blood transfusions. Due to her decline, she was transitioned to Do-Not-Resuscitate Comfort Care-Arrest status as per family wishes. The patient received continuous ivosidenib through a nasogastric tube during this period of critical illness and her blood cell counts began to recover (Figure 3, Table 1) after 14 days of ivosidenib; hemorrhagic complications resolved and she recovered without neurologic sequelae.

On discharge from the hospital, the patient had experienced improvement in her vision and was on room air. Improvement in preretinal hemorrhages in both eyes was also observed during an outpatient ophthalmology examination. On day 31 of ivosidenib, her platelet count was 189 10³/mcL, and on day 34, a bone marrow biopsy confirmed a complete remission (CR) with hematologic recovery with 0% blasts, and the targeted sequencing panel did not detect IDH1 R132G, BCOR G1520V, BCOR G1520C, or RUNX1 G135D mutations.

Discussion

ALAL is a rare subset of acute leukemia that cannot be classified as having either myeloid or lymphoid lineage despite comprehensive immunophenotyping. ALAL represents a heterogeneous group of rare leukemias, and according to the 2016 update of the WHO classification it is categorized into 5 entities: AUL; mixed-phenotype acute leukemia (MPAL) with t(9;22)(q34.1;q11.2) (Philadelphia chromosome/BCR-ABL); MPAL with t(v;11q23.3) (KMT2A/MLL rearrangement); MPAL, B/myeloid, not otherwise specified (NOS); and MPAL, T/myeloid, NOS.¹ Overall, patients with ALAL have relatively inferior outcomes compared with those with AML or acute lymphoblastic leukemia (ALL).⁷ In one study, patients with AUL were characterized by frequent expression of CD34, TdT, and HLA-DR, supporting the stem cell–like characteristics of this leukemia subtype¹ and consistent with our patient’s presentation. Lao et al⁷ reported that patients with AUL frequently harbor myelodysplastic syndromes–related chromosomal alterations, such as del5/5q, del7/7q, and del17/17p, and mutations in DNMT3A, spliceosome (ZRSR2, F236Vfs*6), RUNX1 (frameshift-deletion, T214Pfs*23), cohesin complex (STAG2 and RAD21), and TP53. A high incidence of chromosomal abnormalities, including del(20q), tetrasomy 8 and 7, 5q deletion, trisomy 13, and trisomy 12q,^8–10 has also been reported in AUL. Our patient was found to have a normal karyotype in both blood and bone marrow aspiration samples.

Standard treatment approaches for patients with AUL have yet to be established. Most published reports have analyzed the treatment of AUL together with that of MPAL despite different clinical characteristics that support an ALL-like regimen for induction therapy for patients with MPAL.^1,11,12 However, Heesch et al¹ reported that 25% of patients with AUL achieved CR using ALL-like therapy, whereas 40% achieved CR using AML-like therapy. We chose to treat our patient using an AML regimen because of the presence of the IDH1 mutation at diagnosis. Point mutations in IDH1 and IDH2 are found in multiple cancer types, including glioma, cholangiocarcinoma, chondrosarcoma, and AML.¹³ IDH2 mutations are more frequent in AML, affecting 8% to 19% of patients, compared with 7% to 14% for IDH1 mutations.⁵ Mutations in IDH1 induce amino acid changes, most commonly involving a cysteine or histidine substitution for arginine at residue 132 (R132C and R132H, respectively),¹⁴ resulting in production of 2-hydroxyglutarate (R-2-HG) instead of alpha-ketoglutarate with neomorphic enzymatic activity. This oncometabolite, R-2-HG, modifies DNA and histone methylation and DNA hypermethylation by inhibiting TET2,¹⁵ resulting in impaired hematopoietic cell differentiation, proliferation, and DNA damage.

IDH1 mutations have been classified as driver mutations and are acquired early in leukemogenesis, suggesting that inhibition of the mutation may more effectively target the leukemic clone.¹⁶ Ivosidenib is a small molecule inhibitor of mutant IDH1 that suppresses 2-HG production, thereby releasing the differentiation block in dysfunctional mutant IDH blast cells and allowing them to continue differentiation into normal functional cells.¹³ DiNardo et al¹⁶ reported that in patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at 500 mg/d was associated with CR or CR with a partial hematologic recovery rate of 30.4% (95% CI, 22.5–39.3), an overall response rate of 41.6% (95% CI, 32.9–50.8), and a median CR duration of 9.3 months (95% CI, 5.6–18.3). On July 20, 2018, the FDA approved ivosidenib for the treatment of patients with relapsed or refractory AML with a susceptible IDH1 mutation,¹⁷ and more recently on May 2, 2019, for patients with newly diagnosed AML with IDH1 mutation who are aged ≥75 years or have comorbidities that preclude the use of intensive induction chemotherapy,¹⁸ based on an open-label, single-arm, multicenter clinical trial (AG120-C-001; ClinicalTrials.gov identifier: NCT02074839).

For our patient, we chose ivosidenib for reinduction therapy rather than a 5+2 regimen due to the dominant VAF IDH1 mutation and life-threatening bleeding episodes from platelet transfusion–refractory thrombocytopenia. The patient responded exceptionally well to ivosidenib, with recovery of blood counts, including platelets (Figure 3, Table 1), and complete morphologic and molecular responses noted on bone marrow biopsy and the targeted sequencing panel, respectively. Given the morphologic and molecular remission achieved with ivosidenib in this patient, it may be reasonable to consider targeted therapy with ivosidenib for patients with AUL and dominant mutations of IDH1. However, a prospective study is needed to further investigate the role of ivosidenib in patients with AUL and IDH1 mutations.