Background
The combination of chemotherapy with a tyrosine kinase inhibitor (TKI) is effective in the treatment of Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Ponatinib is a more potent BCR-ABL1 inhibitor and selectively suppresses the resistant T315I clones. We examined the efficacy and safety of combining chemotherapy with ponatinib for patients with Ph+ ALL in this ongoing Phase II prospective trial.
Methods
Adult patients with newly diagnosed Ph+ ALL and good performance and organ status received 8 cycles of hyper-CVAD alternating with high dose methotrexate/cytarabine every 21 days. Ponatinib was given at 45 mg daily for the first 14 days of cycle 1 then continuously for the subsequent cycles. Patients in complete remission (CR) received maintenance with ponatinib 45 mg daily with vincristine/prednisone monthly for 2 years followed by ponatinib indefinitely. The primary endpoint for this study was the improvement of median event-free survival from 24 to 36 months. The trial was registered on clinicaltrials.gov with the identifier NCT01424982.
Results
Thirty-seven patients with a median age of 51 years were treated. The overall complete cytogenetic response, major molecular response, and complete molecular response rates were 32/32 (100%), 35/37 (95%), and 29/37 (78%), respectively. By multiparameter flow cytometry, 35 patients (95%) had no detectable minimal residual disease after a median of 3 weeks of therapy. Grade ≥ 3 toxicity included infections during induction (20 patients), increased liver functional tests (14 patients), thrombotic events (3 patients), myocardial infarction (3 patients), hypertension (6 patients), skin rash (8 patients), and pancreatitis (6 patients). Two potentially related deaths from myocardial infarction were observed. Nine patients underwent allogeneic stem cell transplantation. With a median follow up of 26 months, 29 patients (78%) remain alive and in CR. The 2-year event-free and overall survival rates are 81% and 80%, respectively.
Conclusion
The first results of this ongoing trial indicate that the combination of chemotherapy with ponatinib is highly effective in achieving early sustained remissions in patients with newly diagnosed Ph+ ALL. New strategies, including dosing titration of ponatinib and optimized control of vascular risk factors may further improve outcomes. ARIAD Pharmaceuticals Inc. provided free drug and financial support from the ARIAD Investigator Sponsored Trial program.
BackgroundPlasmablastic lymphoma (PBL) is a rare aggressive neoplasm with lymphoid and plasmacytic differentiation that is commonly associated with immunodeficiency and an unfavorable prognosis. Clinicopathologic features have been largely derived from cases reports and small series with limited outcome analyses.Patients and methodsThe demographic, clinicopathologic features, and clinical outcomes of a cohort of 61 patients with PBL were reviewed and analyzed.ResultsPatients had a median age of 49 years (range 21–83 years) and most (49/61; 80 %) were men. Human immunodeficiency virus (HIV) status was available for 50 patients: 20 were HIV-positive and 30 HIV-negative. Twenty-three patients were immunocompetent. Abdominal/gastrointestinal complaints were the most common presenting symptoms, reported in 14 of 47 (30 %) of patients. At presentation, 24 of 43 (56 %) patients had stage III or IV disease. Epstein-Barr virus (EBV) was detected in 40 of 57 (70 %) cases. MYC rearrangement was identified in 10/15 (67 %) cases assessed, and MYC overexpression was seen in all cases assessed regardless of MYC rearrangement status. HIV-positive patients were significantly younger than those who were HIV-negative (median 42 vs. 58 years; p = 0.006). HIV-positive patients were also significantly more likely to have EBV-positive disease compared with HIV-negative patients (19/19, 100 % vs. 15/29, 52 %; p = 0.002). Patients who received CHOP chemotherapy tended to have better overall survival (OS) compared with those who received hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) (p = 0.078). HIV status had no impact on OS. Patients with EBV-positive PBL had a better event-free survival (EFS) (p = 0.047) but not OS (p = 0.306). Notably, OS was adversely impacted by age ≥50 years (p = 0.013), stage III or IV disease (p = <0.001), and lymph node involvement (p = 0.008).ConclusionsThe most significant prognostic parameters in patients with PBL are age, stage, and, to a lesser extent, EBV status. In this study, two-thirds of PBL cases assessed were associated with MYC rearrangement and all showed MYC overexpression.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0163-z) contains supplementary material, which is available to authorized users.
R-EPOCH therapy does not seem to impact the known poorer prognosis of patients with de novo CD5+ DLBCL, and CD5 expression was still an independent prognostic factor in R-EPOCH-treated patients with DLBCL.
Isolated isochromosome 17q, i(17q), accounts for less than 1% of myeloid neoplasms that are commonly classified as myelodysplastic/myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN). We have shown previously that these cases have distinctive clinicopathologic features, a poor prognosis and absence of TP53 mutations. However, their molecular mutation profile has not been studied. Here, we explored the mutation profile of 32 cases of myeloid neoplasm with isolated i(17q) that included AML, MDS/MPN, MDS and MPN. In addition to the common i(17q), these neoplasms had frequent mutations in SRSF2 (55%), SETBP1 (59%), ASXL1 (55%), and NRAS (31%); TET2 and TP53 mutations were rare. Eight of 28 patients (29%) showed concurrent mutations in ASXL1, SRSF2, SETBP1 and RAS. There was a significant association between mutations in SETBP1 and RAS (p = 0.003). The mutation pattern was independent of the morphologic diagnosis. Sequential analysis of 5 cases showed evolution from a diploid karyotype to i(17q) and that SRSF2 and ASXL1 mutations precede the detection of i(17q) whereas SETBP1 mutations are associated with i(17q).
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