Novel Calr Mutation in Acute Lymphoblastic Leukemia

ABSTRACT

Introduction: Acute lymphoblastic leukemia in adults represent amajor therapeutic challenge even in modern era. Constantly evolvinggenomics has led to a better risk stratification and prognostication.Aims &Objectives: Here we present a novel mutation in calreticulingene in a patient with Precursor B lineage Acute lymphoblasticleukemia.Materials &Methods: A 19 year old boy presented with fever,jaundice and pancytopenia. Initial investigation revealed a hemoglobin of 5.8 g/dl with a total leukocyte count of 700 cells/mm3 andplatelet count of 11,000/mm3. Differential count showed 95% lymphocytes and 5% neutrophils and no blasts with mildanisopoikilocytosis on PBF. Bone marrow biopsy demonstartedreduction granulocytic and erythroid lineage with adequatemegakaryocytes and occasional collections of immature appearingcells, whose charcter was not able to be definitely ascertained. PETCT showed FDG avid lymph nodes on both sides of diaphragm, withPET guided biopsy was suggestive of non specific lymphocyticinflammatory infiltrate. A diagnosis of hemophagocytic lymphohistiocytosis (HLH) was made according to HLH 2004 criteria (Fever,cytopenias, hypertriglyceridemia, splenomegaly and elevated serumferritin levels). However workup for primary HLH and primaryimmune deficiencies were negative.Clinical exome sequencing forprim was postive for mvk transcript (c.808G >A). He was treatedwith IVIG and short course steroids. Repeat bone marrow was normocellular with mild erythroid prominence and adequaterepresentation of granulocytic and megakaryocytic lineage elements.He was under regular follow up thereafter.Result: He developed mild Covid illness a month after discharge. Amonth after recovery from illness, he presented with easy fatiguabilityand pancytopenia (Hb 7.1 g/dl, TLC 900 cells/mm3 and Plateletcount 1.46 lakhs) with presence of occasional blast in PBF. Repeatbone marrow was markedly hypercellular with 76% blast.Megakaryocytes were relatively preserved. On flow cytometry, blastswere positive for CD 10, CD 19, CD 20, cyto CD 79a, CytoCD22, CD34, CD 45, HLA DR and TDT and negative for MPO CD 2 CD 3 CD13 aand CD 33 consistent with Precursor B Lineage acute lymphoblastic leukemia. Multiplex RT-PCR for recurrent geneticabnormalities (ALL) were negative. A never reported CALR (TYPE1) mutation was found in this patient. CALR plays an important rolein cell proliferation, apoptosis and immune responses. Patient wastreated with modified BFM regimen and Rituximab, attained CR postinduction and currently in consolidation phase of therapy.Conclusions: CALR mutation has never been reported before in acase of acute lymphoblastic leukemia. Long term follow up of patient is required to conclude whether the novel mutation has prognostic andtherapeutic implications.