Acute Lymphoblastic Leukemia at Birth with KMT2A Gene Rearrangement

Congenital leukemia (CL) is defined as leukemia that is diagnosed within 28 days of birth and the causative mutation develops in utero.1 Only 20% of CL are lymphoid in origin and usually are characterized by higher white blood cell count, high incidence of central nervous system (CNS) involvement, and strong association with KMT2A, a transcriptional coactivator, which is a positive global regulator of the gene transcription.2

A 34-year-old female delivered 2,680 g female baby at 38 weeks of gestation through normal vaginal delivery. Antenatal history of mother was not significant for any infection, drug, or radiation exposures. Child had a normal APGAR score at birth. Multiple blue, red, or purple firm nodules (blueberry lesions) over head, face, all limbs, and trunk were noted at birth (Fig. 1). There were no dysmorphic facies. Liver and spleen were palpable 3 and 4 cm below costal margin, respectively. Her complete blood cell (CBC) on day 1 of birth revealed hemoglobin of 9.9 g/dL, total leucocyte counts of 59,900/cu.mm with 66% blasts, and platelet count of 30,000/cu.mm. Bone marrow aspiration done on day 2 of birth revealed 80% blasts. Flow cytometry analysis confirmed precursor B cell acute lymphoblastic leukemia (ALL). Cerebrospinal fluid examination revealed leucocytosis (50 cells/µL) with 83% blast. Cytogenetics revealed t(11, 19) with KMT2A gene rearrangement. She was started on intravenous hydration along with tablet allopurinol. She was started on Interfant 99 protocol on day 7 of birth. She developed fever with tachypnea on day 17 of life during neutropenic phase and succumbed on day 19 of life due to pneumonia and septic shock. CBC and peripheral blood smear of the mother did not show any evidence of leukemia. Both parents' karyotypes performed to rule out germline mutations were normal.

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Fig. 1: Blueberry lesions of congential leukemia.

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CL is known to be associated with Down syndrome, Noonan syndrome, and other ill-defined constitutional syndromes.3 ALL at early neonatal age is frequently associated with high leucocyte count, CNS involvement, CD 10-negative B cell lineage, and organ infiltration with blast that may manifest in skin as blueberry muffin rash as in this case.

Thirty cases of neonatal leukemia were treated with hybrid regimen (Interfant-99 protocol) combining ALL treatment and element of acute myeloid leukemia regimen.3 Drug doses calculated on the basis of body surface area rather than body weight and reduced to two-third of older infant. Only 20% of congenital ALL patient survives for more than 2 years. In a randomized control study by Pieters et al in 482 infants treated with hybrid Interfant 99 protocol, 445 patients attained complete remission at the end of 5 weeks of induction therapy. At a median follow-up of 38 months, 58% were in completed remission with an event-free survival of 47% at 4 years.4 Consolidation with myeloid-style chemotherapy was not found to be superior to lymphoid-style chemotherapy.5 Management of CL is an unmet need and larger studies are required to improve knowledge about its etiology, pathogenesis, and treatment.