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.

Background Impact of FLT3 mutations and mutation burden in cytogenetic subgroups of acute myeloid leukemia (AML) other than normal karyotype (NK-AML) is unclear. Methods Patients with newly diagnosed AML were divided among three cytogenetic subgroups: Core-Binding Factor (CBF) AML, NK-AML, Poor Risk AML. Results A total of 481 patients were included (CBF-AML – 13%, NK-AML – 57%, poor risk – 30%). FLT3 mutations (any) frequency was 20%, 32% and 7.6% in respective cytogenetic subgroups. FLT3 mutation did not impact event free survival (EFS) in patients with CBF (P=0.84) and poor-risk AML (P=0.37). In NK-AML, EFS was worse in the FLT3-internal tandem duplication (ITD) group (20 vs. 41 weeks, P<0.00001) but not in FLT3 tyrosine kinase domain (TKD) point mutation group (61 vs. 41 weeks, P=0.15). Patients with NK-AML and higher FLT3-ITD burden had worse EFS and overall survival (OS), but not so with FLT3-TKD mutation. In multivariate analysis, FLT3-ITD mutation was prognostic for EFS in NK-AML patients (hazard ratio 3.1, P=0.03). Conclusion FLT3 mutations did not have a prognostic impact in AML patients with good and poor-risk karyotype. In patients with NK-AML, FLT3-ITD mutations led to worse survival, more so in patients with high mutation burden.

Success of tyrosine kinase inhibitors

Most patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with tyrosine kinase inhibitors (TKI) achieve complete cytogenetic response (CCyR). An increasing number of patients also achieve deep molecular responses (MR). We determined the frequency and significance of deep MR after TKI therapy for CML in CP. MR included: major molecular response (MMR), MR4, MR4.5, and undetectable transcripts (UND), ie BCR-ABL/ABL of ≤0.1%, ≤0.01%, ≤0.0032%, and undetectable transcripts, respectively. 483 patients received imatinib 400mg/day (IM400, 71, July 2000-April 2001), imatinib 800mg/day (IM800, 204, June 2001-July 2005), nilotinib (NILO, 106, July 2005 to date), or dasatinib (DASA, 102, November 2005 to date). UND rates at 36 months were 18.1%, 30.6%, 29.2%, and 28.6%, respectively. Patients achieving UND have superior transformation-free survival (TFS) and overall survival (OS) versus those obtaining ≤MMR, but not other MR levels. At the 18- and 24-month landmark analysis patients achieving UND have no advantage in TFS and OS compared to those achieving a lesser degree of MR. Among patients achieving MR4.5, those who maintain it for ≥2 years (susMR4·5) have no additional benefit in TFS or OS. Most patients with early CP CML receiving TKI achieve MMR. BCR-ABL transcripts become undetectable in a significant fraction of them. Deeper MR at 18 or 24 months are not associated with a benefit in TFS or OS. Furthermore, achieving susMR4·5 does not appear to further reduce the risk of transformation or death.

Relapse after 5 years of complete remission (CR) is uncommon in acute myeloid leukemia (AML). Among 2347 patients seen between 1980 and 2008, 1366 achieved CR; 942 relapsed. Eleven (1.16% of all relapses) relapsed after a CR of >5 years. The median age was 66 years (range, 37–79). Initial therapy was cytarabine plus anthracycline in six, amsacrine-based in three, and other in two. The median CR1 duration was 81 months (range, 60–137). At relapse, the karyotype was different from the initial finding in five of eight (63%) patients with available data. Treatment for relapse included cytarabine with anthracycline in eight, and other in three patients, with a second CR (CR2) achieved in four (36%). The median CR2 duration was 1 month (range, 0–37), and median survival after relapse was 6.4 months (range, 1–39). Late relapses in AML are infrequent, with poor response to therapy. Karyotype at relapse is frequently different, raising the question of second AML versus relapse with the original clone.