ClinVar

A patient with a 10-year history of elevated and increasing platelet counts had a bone marrow biopsy in the absence of symptoms. The biopsy revealed thrombocythemia, with normal cytogenetics and without mutation of JAK2. CALR was not tested at that time. Approximately 2 ½ years later, a second BM biopsy was performed when the patient began having symptoms and counts were worsening. The biopsy had hypercellular marrow with 5-9% blasts and normal karyotype, but revealed this CALR exon 9 mutation at 11% allele frequency. She was started on 5-azyctadine; however, five months later, a BM biopsy showed 37% blasts positive for CD33, CD34, CD117, and HLA-DR, consistent with acute myeloid leukemia, and the karyotype included a novel translocation, t(4;7)(q12;q21.2), in 17 of 20 metaphase spreads examined. After induction chemotherapy with cytarabine and daunorubicin, a day-14 biopsy showed response to therapy, with a hypercellular marrow (80%) that displayed panmyelosis (trilineage hyperplasia), granulocytic hyperplasia, and megakaryocytic atypia without an increase in blasts, consistent with residual/persistent myeloid disease. A PB specimen revealed normocytic normochromatic anemia, leukocytosis, and thrombocytosis. Chromosome microarray analysis and NGS of DNA from a BM sample revealed no detectable genomic imbalances, the CALR deletion at 3.2% allele frequency, and no other pathogenic variants. After eight months in remission, the AML relapsed with blood DNA showing oncogenic somatic mutations at around 50% allele frequency, but no evidence of the CALR deletion.