Double Hit Ph-Negative B-ALL Patients with MYC and BCL2 Rearrangements and CDKN2A Genetic Abnormalities Have Poor Clinical Outcomes: Report of Two Cases
CONTEXT: While much research has focused on the poorer prognosis of double/triple hit diffuse large B cell lymphoma patients, much less is known about the impact of concomitant MYC and BCL2 rearrangements on the outcomes of B-acute lymphoblastic leukemia (B-ALL) patients.
DESIGN: Two rare cases of MYC+/BCL2+ double hit B-ALL were identified: one de novo and one likely dedifferentiated from a follicular lymphoma (FL). Clinical characteristics, lab findings, and outcomes were analyzed along with tissue evaluation and cytogenetic studies. Bone marrows were subjected to next-generation sequencing to identify gene mutations which may modify prognosis in these double hit acute leukemia patients.
RESULTS: Patient 1 presented with high grade FL in a lymph node and bone marrow involvement by B-ALL and FL. Patient 2 was initially diagnosed with B-ALL in the bone marrow and a perirenal mass. Both were Philadelphia chromosome negative. Patient 1 initial FISH showed MYC+/BCL2+ double hit in the bone marrow while the lymph node only had t(14;18). Patient 2 had t(2;8) and homozygous t(14;18) in his marrow at relapse. Patient 2 achieved short-lived remission while patient 1 had a negative post-induction marrow but imaging consistent with extensive residual disease. Both had CDKN2A missense mutations at different exon 2 loci. Patient 1 also had CDKN2A deletion and KIT, ATRX, and STAG2 missense mutations post-induction and expired nine months post-diagnosis. Patient 2 expired at 6 months post-diagnosis.
CONCLUSIONS: Double hit B-ALL is rare and may occur de novo or may dedifferentiate from a clonally related follicular lymphoma. Characterization of distinct features and outcomes of these patients is limited because fluorescence in situ hybridization (FISH) for MYC, BCL2, and/or BCL6 translocations are not generally performed for acute leukemia. Both patients were either refractory to or only experienced a short-lived remission with HyperCVAD induction. Both also were found to have CDKN2A copy number alterations which have been associated with adverse prognosis in B-ALL, independent of age, and passed away prior to 1 year from their initial diagnosis. Larger studies of double hit B-ALL patients are necessary to confirm the poorer prognosis of these patients and their need for more aggressive induction regimens than HyperCVAD.