Submitting Author: Yang, Xuebin, MD, PhD
Institution: Penn State Hershey Medical Center
Additional authors:Michael G. Bayerl, M.D., Jeffrey Pu, M.D., Ph.D., Jozef Malysz, M.D., Jeremy Klapper, M.D.
Session: Therapy-related myeloid neoplasms

A 26 year old African-American female with sickle cell anemia, presents with severe abdominal pain leukocytosis 35.4 K/uL, anemia Hgb 6.9 g/dL, and thrombocytosis 405 K/dL. She has a medical history of frequent sickle cell crises, pulmonary fibrosis , asthma and avascular necrosis of bilateral hips. She received chronic RBC transfusion/exchange therapy since childhood and hydroxyurea (HU) for approximately 26 months, but discontinue it 6 months prior to presentation due to lack of clinical response.

After diagnosis of the current disease, patient failed 7+3 induction (complicated by stroke) and failed CLAG-M reinduction, then chose hospice care.

Peripheral blood smear: White blood cells comprise 25% myelobalsts, 5% promyelocytes, 24% neutrophilic myelocytes, 5% neutrophilic metamyelocytes, 14% bands and segmented neutrophils, 10% monocytes, and 17% lymphocytes. Neutrophils have nucleus-to-cytoplasmic dysynchrony, hypolobated nuclei, and hypogranular cytoplasm. Red blood cells have marked anisopoikilocytosis including rare sickle cells, microspherocytes, target cells, acanthocytes, hypochromic cells, Pappenheimer bodies and nucleated red blood cells. Platelets are medium to large with normal granularity.

Bone marrow aspirate and biopsy (AZF-fixation, RDO decalcified): Hypercellular, 100%. M:E ratio 8.3. Differential: 32% blasts, 13% promyelocytes, 17% neutrophilic myelocytes, 8% neutrophilic metamyelocytes, 7% band and segmented neutrophils, 2% eosinophils, 1% basophils, 1% monocytes, 10% erythroblasts, 9% lymphocytes. Megakaryocytes are increased with dysmegakaryopoiesis including hypolobated nuclei. Myeloid lineage is increased and markedly left-shifted with dysplastic features including nucleus-to-cytoplasmic dysynchrony, hypogranular cytoplasm and hypolobated nuclei. Erythroid lineage is decreased with dyserythropoiesis including megaloblastic change, cytoplasmic vacuoles, nuclear budding, nuclear irregularities and Pappenheimer bodies in mature forms.

Myeloblasts have SSC (low) and express: CD45 (dim), CD13, CD33 (dim), MPO (dim), CD117, CD34, HLA-DR, CD11c (dim) with aberrant expression of CD56 (heterogeneous).

Karyotype: 45-46, XX, del(5)(q13q35), der(7)t(7;12)(q32;q13), i(8)(q10)[16], +i(8)(q10)[2], -12, add(12)(p11.2), del(17)(p11.2), -18, der(19)t(11;19)(q13;p13.3), -20, add(21)(p11.2), add(21)(p11.2), add(22)(p11.2)x2[2], +add(22)(p11.2)[16], +0-1r, +0-2mar[cp18]/90-92, idemx2[2]/46,XX[1]

Interphase FISH:

Hyperdiploidy of chromosomes 5, 7, 11, 15, 16, 17 and 20; 5q deletion and trisomy 8.

Negative for PML/RARA, CBFb/MYH11, RUNX1/RUNX1T1, 11q23 translocations or rearrangement.

JAK2 V617F negative by allele-specific PCR.

1) Is this a “therapy-related” myeloid neoplasm due to HU vs. sporadic AML with myelodysplasia-related changes? We favor AML-MRC as only very rare cases of myeloid malignancy have been reported in patients taking HU for sickle cell anemia; whereas a long term, observational study of patients taking HU for sickle cell anemia, explicitly seeking adverse reactions, finds no increase in neoplasia and no reported case of myeloid malignancy (Steinberg, et al. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up. Am J Hematol. 85:403–408, 2010.)

2) AML is extremely rare in patients with sickle cell anemia.

3) The best Pappenheimer bodies I’ve ever seen

Acute myeloid leukemia with myelodysplasia-related changes.

Acute myeloid leukemia, possibly therapy-related following hydroxyurea

Case 87