BCR-ABL1+ AML De Novo and CBF-Leukemia at Relapse: Game of Clones
Authors: Kulemina Olga , Siordia Nadia , Bogdanov Konstantin , Alexeeva Julia , Girshova Larisa , Lomaia Elza , Zaritskey Andrey 
Published: November 2019

BCR-ABL1-positive acute myeloid leukemia (AML) is a rare subtype of acute leukemia and can co-occur with different aberrations such as CBFβ-MYH11, RUNX1-RUNX1T1, PML-RARα, and NPM1. Based on leukemogenesis model, BCR-ABL belongs to the class I mutations, providing a proliferative advantage to the affected cells, where inv(16) is a characteristic class II event, conferring inhibition of differentiation and apoptosis.

We observed BCR-ABL1-positive AML de novo without any other molecular/cytogenetic features and CBF-AML (inv(16) at relapse. There are no definite clinical management of BCR-ABL+ AML and it is still a debate whether BCR-ABL1-positive AML patients should be treated with TKI ± chemotherapy as the first-line therapy.

A 61-year-old man was diagnosed as having AML in May 2018. Laboratory findings showed: 51.1x 109/L WBC with 58% of blast cells; 38.8% and 4% of blasts in bone marrow and in cerebrospinal fluid (CSF) respectively; but 50% t(9;22) positive cells by fluorescence in situ hybridization (FISH) and conventional cytogenetic analysis (CyG). Both qualitative and quantitative polymerase chain reaction (PCR) tests confirmed the presence of BCR-ABL1p190 (10.2%) without any ABL1 kinase domain mutations. No other molecular abnormalities including mutations FLT3/ITD, NPM1, MLL, JAK2/V617F, DNMT3A, IDH1/IDH2, ASXL1, EZH2 or fusion genes PML-RARα, CBFβ-MYH11, RUNX1-RUNX1T1, BCR-ABL1p210/p230 were found. Also, 5q-, 7q- or 20q deletions were not detected by FISH. Flow cytometry analysis demonstrated single population of leukemic cells with CD34+CD117+CD13+CD33+CD11c+/-CD4+/-MPO+immunophenotype. No organomegaly was revealed. There was no history of antecedent hematological disorder.

The patient was diagnosed as BCR-ABL1+ AML with CNS disease. Undetectable MRD was achieved after 1st cycle of FLAG regimen with dasatinib and intrathecal chemotherapy (IC), which was stopped after 1 month because of severe liquor hypotension. There were no matched related/unrelated donor. Due to severe complications during induction chemotherapy (hemorrhoidal bleeding, paroxysmal atrial fibrillation, febrile neutropenia) he continued dasatinib monotherapy for the subsequent 4 months with stable uMRD. Therapy was interrupted for 1 month due to adverse events (grade 3 diarrhea, grade 3 peripheral edema).

The relapse occurred in Nov 2018 (after 5 months of uMRD) with 20%, 11% and 3% of blasts in peripheral blood, in bone marrow and in CSF, respectively. Laboratory showed no BCR-ABL1 or t(9;22) by quantitative PCR (qPCR), FISH or CyG, but new transcript CBFβ-MYH11A was detected (100.2%) by qPCR. Cytogenetic analysis showed inv(16)(p13;q22) in 80% cells with absence of additional abnormalities. No mutations of FLT3/ITD,IKZF, TP53 were found.

Noteworthy, the patient was refractory to induction chemotherapy "High dose cytarabine (Ara-C) + gemtuzumab ozogamicin (GO)" despite CBF-leukemia. CSF complete response was achieved after triple IC.

Hematological remission was achieved after 2 cycles of "Ara-C with 5-azacitidine" in combination with tyrosine kinase inhibitors (TKI) - imatinib 800mg QD. Triple IC was continued once a month as a prophylaxis of CNS disease. After 6 cycles of therapy CBFβ-MYH11A demonstrated 2log reduction, BCR-ABL1 transcript remains undetectable. The patient is in stable hematological and CSF remission. The clone dynamic and treatment see in table 1.

BCR-ABL1 positive AML remains a provisional entity inside a huge part of AML with unclear pathogenesis and clinical management.

We presented the first description of BCR-ABL1+ AML de novo leukemia followed by CBF-leukemia at relapse, and a clearance of blast cells in preceding BCR-ABL1 positive cells.

Despite the absence of leukemic BCR-ABL1 burden, probably its the subliminal expression is able to maintain the mutational background. While TKI treatment may allow to maintain BCR-ABL1+ AML uMRD, it did not prevent the relapse of AML. High dose combination chemotherapy with BCR-ABL inhibitors is advantageous in these leukemia types in patients ineligible for allogeneic hematopoietic stem cell transplantation.

Disclosures

Lomaia: Novartis: Other: Travel Grant;Lecture fee; Pfizer: Other: Travel Grant.

OffLabel Disclosure:

Tyrosine kinase inhibitors of BCR-ABL (Dasatinib, Imatinib) were used in case of BCR-ABL positive AML in combination with chemotherapy