Chronic myeloid leukemia with p190^BCR-ABL: prevalence, morphology, tyrosine kinase inhibitor response, and kinase domain mutation analysis

To the editor:

The Ph1-positive chronic myeloproliferative neoplasm (MPN) with breakpoint in the minor breakpoint cluster region (m-BCR) and sole expression of the e1a2 BCR-ABL fusion transcript encoding for p190^BCR-ABL (ie, without concurrent expression of the e13a2/e14a2 transcript encoding for p210^BCR-ABL) is quite rare.^1,2  Many such patients have associated monocytosis with cytomorphologic characteristics that are intermediate between chronic myeloid leukemia (CML) and chronic myelomonocytic leukemia (CMML).³  Rarely, p190^BCR-ABL is acquired as a secondary event during the course of a MPN.⁴ 

The prognostic significance of p190^BCR-ABL in MPN remains obscure, particularly in the era of tyrosine kinase inhibitor (TKI) therapy. In this context, we read with interest the paper by Verma et al.⁵  In a cohort of 1292 CML patients treated with TKI, they identified 14 patients with p190^BCR-ABL (∼1%): of those in chronic phase or accelerated phase (CP-CML = 9; AP-CML = 1), 7 received TKI as frontline therapy, with 2 complete cytogenetic responses (CCyR), 1 partial cytogenetic response (PCyR), and 3 complete hematologic responses (CHR); 3 CP-CML patients received TKI as 2nd or more salvage therapy, with 1 PCyR and 1 CHR. Overall, the cytogenetic responses were short-lived (median, 5 months), and more than half of CP-CML patients progressed to AP-CML or BP-CML after a median of 48 months.

We examined our institutional experience with p190^BCR-ABL MPN/CML to further characterize this entity, and to examine why the response to TKI therapy is relatively shallow and short-lived. Specifically, we wondered whether resistance to TKI therapy results from acquisition of mutations in the ABL kinase domain (KD). Review of our molecular hematopathology database over a 2-year period identified 140 patients with p210^BCR-ABL; over the same period, only 3 patients (∼2%) were identified with sole expression of p190^BCR-ABL. BCR-ABL transcripts were analyzed by a reverse transcription–polymerase chain reaction (RT-PCR) assay with fluorescent bead array analysis that identifies all fusions containing the ABL a2 or a3 exons (including e1a2, e13a2, and e14a2). The aforementioned 2% incidence may be an overestimate because it does not account for CML cases identified by FISH alone, and, consequently, the true prevalence of p190^BCR-ABL CML is estimated at 1% to 2%. In our cohort, 2 patients had CP-CML and 1 AP-CML; follow-up since diagnosis ranged from 24 to 114 months (Table 1). All 3 patients had monocytosis at presentation, and one also had lymphocytosis from concurrent chronic lymphocytic leukemia. The CP-CML patients received imatinib as frontline therapy and achieved CHR that lasted 15 and 23 months; both received salvage TKI and achieved individual best responses with dasatinib (PCyR and CHR). Currently, both are in CHR (one each on nilotinib and dasatinib; Table 1). The AP-CML patient received imatinib (600-800 mg) after interferon intolerance, and achieved CCyR (Table 1). At last follow-up, p190^BCR-ABL transcript level in this patient was 1% of total ABL, and the bone marrow showed persistent panhyperplasia, dysgranulopoiesis, and monocytosis. All 3 patients were screened (2 retrospectively) for presence of common mutations in the ABL KD associated with clinical resistance to TKI; only one patient (78-year-old male) harbored a mutation (M244V in the P-loop). We conclude that monocytosis is a typical feature of p190^BCR-ABL MPN/CML; these patients are resistant to imatinib, and may not fare much better with secondary TKI therapy. Resistance to treatment is currently poorly understood and may be mediated by mechanism(s) independent of ABL KD mutations.