The most common BCR-ABL transcripts in chronic myeloid leukemia (CML) are e13a2(b2a2) and e14a2(b3a2). Other transcripts such as e1a2 are rare and their outcome with tyrosine kinase inhibitors (TKI) therapy is undefined. We analyzed 1292 CML patients and identified 14 with only e1a2 transcripts, 9 in chronic phase (CP), 1 in accelerated phase (AP), and 4 in blast phase (BP). Of the CP, 4 achieved complete hematologic response (CHR); 2, complete cytogenetic response (CCyR); 2, partial cytogenetic response (PCyR), and 1 did not respond to imatinib. Five patients progressed to myeloid BP (3), lymphoid BP (1), or AP (1). The AP patient received various TKIs sequentially and achieved only CHR. BP patients received hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, adriamycin, dexamethasone) plus imatinib/dasatinib or idarubicin plus cytarabine (Ara-C); 2 did not respond, 1 had CCyR, and 1 short-lasting complete molecular response (CMR). Overall, cytogenetic responses lasted 3 to 18 months; only 2 achieved major molecular response (MMR) on TKI. P190BCR-ABL CML is rare and is associated with an inferior outcome to therapy with TKI. These patients need to be identified as high-risk patients.
The Philadelphia chromosome (Ph), t(9;22)(q34;q11.2), in chronic myeloid leukemia (CML) is transcribed into a fusion gene, BCR-ABL. The breakpoint in BCR gene on chromosome 22 usually occurs in the major breakpoint cluster region (M-bcr) between exons e12-e16 (formerly named b1-b5), whereas breakpoints in ABL gene on chromosome 9 happen in exon a2, resulting in fusion transcripts e13a2(b2a2) and e14a2(b3a2).1 Rarely, the minor breakpoint cluster region (m-bcr) may be involved with a resultant fusion transcript e1a2.2–5 Other transcripts such as e19a2,2,6,7 e2a2,8 e1a3, e6a2, e13a3(b2a3), and e14a3(b3a3)9,10 occur less frequently. The e13a2(b2a2)/e14a2(b3a2) fusion transcripts encode for a 210-kDa protein (P210BCR-ABL), whereas the e1a2 encodes for a 190-kDa protein (P190BCR-ABL), and the e19a2 encodes for a 230-kDa protein (P230BCR-ABL).
In CML, the e1a2 transcripts may coexist with e13a2(b2a2)/e14a2(b3a2),11 but CML expressing only e1a2 transcripts (from here on referred to as P190BCR-ABL CML) is uncommon, and outcome of patients with this transcript alone in the era of tyrosine kinase inhibitors (TKIs) is not well known. Although there are anecdotal reports of patients with P190BCR-ABL CML treated with imatinib2 or other therapies,3–5,11–14 to our knowledge, there are no published series of data on efficacy of imatinib or other TKIs in CML with this transcript. We performed this study to investigate the frequency of P190BCR-ABL CML, the clinical characteristics of patients with this entity, and their outcome after treatment with TKI.
The records of all patients with CML treated with TKI at M. D. Anderson Cancer Center from January 2000 to November 2008 were reviewed to identify patients with only e1a2 BCR-ABL fusion transcripts consequent to breakpoints in minor bcr. Patients with e1a2 coexisting with e13a2(b2a2) and/or e14a2(b3a2) were excluded from this analysis. The criteria for chronic phase (CP), accelerated phase (AP), and blast phase (BP) were as previously described.15 All patients were enrolled in various studies approved by the institutional review board of M. D. Anderson Cancer Center and signed informed consents were in accordance with the Declaration of Helsinki.
Patients had complete blood counts and blood chemistry before the start of therapy and every month for the first 3 months, then every 3 months for 9 months, and then every 6 months. Cytogenetic response was assessed by G-banding assessed in the bone marrow with at least 20 metaphases counted. The BCR-ABL fusion transcripts were analyzed using reverse transcription quantitative polymerase chain reaction assay that detects e1a2, e13a2(b2a2), and e14a2(b3a2) transcripts in a single tube and is normalized to ABL1, with BCR-ABL transcript type determined by subsequent capillary electrophoretic separation of the fluorochrome-labeled products.16 Both cytogenetic and molecular response assessments were performed at baseline, every 3 months for the first 12 months, and then every 6 months. Response and relapse criteria were as previously reported.17,18
Event-free survival (EFS) was measured from the start of each therapy until loss of complete hematologic response (CHR) or major cytogenetic response, progression to the AP or BP, or death from any cause during treatment. Overall survival was defined from date of CML diagnosis to date of death or last follow-up.
Results and discussion
Fourteen (1%) of the 1292 CML patients treated with TKI, during the study period had P190BCR-ABL CML. At the time of diagnosis, 9 patients were in CP, 4 in BP (1 myeloid [MyBP], 3 lymphoid [LyBP]), and 1 in AP (based on clonal evolution–double Philadelphia and t(9;17)(q32;q12), +8, +10, +19, +21). Patient characteristics are shown in Table 1. The median age at the time of diagnosis was 60 years (range, 28-86 years). The median follow-up since the diagnosis of CML is 40 months (range, 3-109 months).
Ten patients (6 CP, 1 AP, 3 BP) received TKI alone or in combination as their initial therapy (9 imatinib, 1 nilotinib; Table 2). Among patients in CP, 5 received imatinib as frontline therapy and 3 after IFN failure, and after a median follow-up of 37 months (range, 12-72 months), 1 patient (frontline) had no response to imatinib, and the best response for the others was CHR in 4, complete cytogenetic response (CCyR) in 1, and partial cytogenetic response (PCyR) in 2. Notably, only 1 of 5 patients receiving imatinib as frontline therapy achieved CCyR. The patient treated with nilotinib frontline has achieved CCyR after 3 months. None of these patients achieved a major molecular response (MMR), except one who received HCVAD (hyperfractionated cyclophosphamide, vincristine, adriamycin, dexamethasone) with dasatinib after progression to LyBP, achieved CCyR, underwent allogeneic stem cell transplantation (SCT), and has been in complete molecular response (CMR) for 9 months on dasatinib after transplantation. Cytogenetic responses were short lived, lasting a median of 5 months (range, 3-18 months). Five (56%) of the 9 patients in CP (3 receiving frontline TKI therapy) progressed to AP (n = 1) or BP (myeloid n = 3, lymphoid n = 1) after a median of 48 months (range, 4-92 months) and only 1 is alive (after SCT).
The sole patient in AP at diagnosis received imatinib, dasatinib, and bosutinib sequentially, achieving only CHR with each of them. Of the 4 patients with BP at diagnosis, 3 had transient CCyR with HCVAD plus TKI or with clofarabine, but eventually all relapsed and died.
Overall, 6 patients (5 CP, 1 AP) were alive at a median of 39 months (range, 3-85 months) after diagnosis: 3 with CHR (2 on imatinib, 1 bosutinib), 1 with PCyR on imatinib, 1 with CCyR on nilotinib, and 1 with CMR after allogeneic SCT. Median survival was 56 months for patients in CP at the start of therapy, and 13 months for those in BP; the patient in AP has been alive for 55 months.
The e1a2 transcripts may coexist with e13a2(b2a2)/e14a2(b3a2),11 but their expression as the only transcript in CML is rare. P190BCR-ABL is present in 60% to 75% of patients with Ph+ acute lymphoblastic leukemia,19,20 and it can induce rapid transformation of lymphoid progenitor cells.21–23 P190BCR-ABL CML has been reported to have increased monocytosis, with a peripheral blood morphology resembling chronic myelomonocytic leukemia.13 In our study, 4 patients (2 CP, 1 AP, 1 BP) had splenomegaly and 5 (3 CP, 2 BP) had monocytosis. The 3 with CP and monocytosis at presentation continue to be in CP with imatinib treatment, whereas the 2 in BP did not respond to treatment.
Anecdotal reports suggest a poor outcome of patients with P190BCR-ABL CML treated with imatinib2 or other therapies.3–5,11–14 Our analysis demonstrates the poor outcome of these patients despite therapy with TKI. Of the 6 CP patients treated with TKI as initial therapy, 3 transformed to AP or BP and 2 of them died shortly thereafter, whereas the one patient treated with nilotinib as initial therapy has achieved CCyR after 3 months of therapy. In addition, none of the 14 patients reported on our analysis achieved MMR with TKI therapy.
We conclude that although P190BCR-ABL CML represents only 1% of patients with CML, it is associated with an inferior outcome to therapy with TKI, with few, usually short-lived responses. These patients need to be identified as high-risk patients, monitored closely for efficacy during therapy with TKI, and offered SCT early if eligible for this procedure.
Contribution: D.V. wrote the paper, analyzed data, and approved the paper; J.C. designed the study, managed the patients, analyzed data, and reviewed and approved the paper; and H.M.K., D.J., R.L., G.B., S.V., and M.B.R. approved the paper and managed the patients.
Conflict-of-interest disclosure: H.M.K. and J.C. have research grants from Novartis and BMS. The remaining authors declare no competing financial interests.
Correspondence: Jorge Cortes, Professor of Medicine, Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX 77030; e-mail:.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
- Submitted February 10, 2009.
- Accepted June 7, 2009.
- © 2009 by The American Society of Hematology