Chronic Myeloid Leukemia (CML) Patients With Atypical e1a2 P190 BCR-ABL Translocation Show a Poor Response To Therapy With Tyrosine Kinase Inhibitors (TKI)

Abstract

Introduction P210 BCR-ABL translocation resulting from rearrangements within the major breakpoint cluster region (M-BCR), either e13a2 or e14a2, is the molecular hallmark of chronic myeloid leukemia (CML). However, some CML patients may harbor atypical BCR-ABL rearrangements such e1a2 P190 BCR-ABL which involves the minor breakpoint cluster region (m-BCR). Response to therapy with tyrosine kinase inhibitors (TKI) and outcome of such atypical patients is not well defined. Objective To evaluate response to TKI therapy of CML patients with the atypical e1a2 P190 BCR-ABL translocation. Patients and Methods Since 2009, 4 patients with CML in chronic phase and with atypical e1a2 P190 BCR-ABL rearrangement have been recruited in various institutions belonging to the Hematological Molecular Biology Group (GBMH) of the Spanish Society of Hematology (SEHH). Patient characteristics, treatments administered and response to therapy for the 4 patients is shown in Table 1. BCR-ABL transcripts were revealed at diagnosis by quantitative PCR followed by conventional agarose electrophoresis of PCR products. Molecular follow-up of BCR-ABL transcripts throughout treatment was performed by quantitative PCR following the guidelines of the European Leukemia Net. Results One patient received treatment (HU and INF+araC) prior to TKI (Pat. 1; Table 1). All 4 patients received Imatinib as initial TKI treatment. Two of the patients treated with Imatinib (Pat. 1,2) obtained a complete molecular response (CMR) and the other 2 (Pat. 3,4) only achieved a complete hematological response (CHR) as best response (Table 1). All patients had to switch to a second generation TKI (3 Nilotinib and 1 Dasatinib) due to intolerance to Imatinib (n=1; Pat. 1) or resistance (n=3; Pat. 2-4). The patient who received Dasatinib as second line TKI (Pat. 3) only achieved a partial hematologic response (PHR) and was changed to Nilotinib as third line TKI, achieving CHR after which the patient entered in blast crisis and died 36 months after diagnosis (Table 1). Overall, only 1 (Pat. 1) out of the 4 patients included in the present study achieved a sustained molecular response with Imatinib. At last follow-up, among the 4 patients included in the study, all 4 had needed a change of TKI, 1 had died due to disease progression (Pat. 3) and only 2 of them retained a molecular response (Pat. 1,2). Conclusion CML patients harboring atypical e1a2 P190 BCR-ABL transcripts show a poor response and short-lived responses to TKI therapy and therefore should be identified as high-risk patients at diagnosis. These patients must be closely monitored during therapy with TKI and should be treated upfront with a second generation TKI or even be considered for allogeneic SCT in the early phase of the disease. Paper presented on behalf of the Hematological Molecular Biology Group (GBMH) of the Spanish Society of Hematology (SEHH). AJ-V and IB contributed equally to this work. Disclosures: No relevant conflicts of interest to declare.

Coexistence of P190 BCR/ABL transcript and CALR 52-bp deletion in chronic myeloid leukemia blast crisis: a case report

“…Previous studies suggest no relationship between distinct clinical presentations of CML and type of BCR-ABL rearrangement 11 while many others put them in a high-risk category at diagnosis with an early transformation to blast phase similar to our patient. 12 , 13 …”

Eine klinische Perspektive auf die Behandlung von chronischer myeloischer Leukämie in der chronischen Phase

“…Da der Patient in dieser Fallstudie eine Hochrisiko-CML hat, wäre ein 2G-TKI am besten für die 1L-Behandlung geeignet. Unabhängig vom Risikoscore sollten auch jüngere Patienten [21] und solche mit seltenen Transkripten [22] als Hochrisikopatienten betrachtet werden, und ein 2G-TKI kann die bevorzugte Option sein. Patienten mit CML mit niedrigem Risiko können ebenfalls von einer Behandlung mit einem 1L-2G-TKI profitieren.…”

A clinician perspective on the treatment of chronic myeloid leukemia in the chronic phase

“…Because the patient in this case study has high-risk CML, a 2G TKI would be best suited for 1L treatment. Regardless of risk score, younger patients [ 21 ] and those with rare transcripts [ 22 ] should also be considered as high-risk, and a 2G TKI may be the preferred option. Patients with low-risk CML may also benefit from 1L 2G TKI treatment; in the 5-year report of the BFORE trial, the MR 4.5 rate for patients with a low Sokal risk score was 53.7% with bosutinib versus 42.5% with imatinib [ 19 ].…”