Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial).

As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO-based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA-anthracycline for low-/intermediate-risk patients, or ATRA-ATO-anthracycline versus ATRA-anthracycline-cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of -5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI -0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan-Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA-chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).

Pregnancies in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitor.

We presented our experience in chronic myeloid leukemia (CML) patients who conceived children and/or became pregnant while receiving tyrosine kinase inhibitor (TKI). Among 7 male patients, 7 pregnancies resulted in the birth of 7 healthy babies. Among 18 female patients, 8 ended in elective abortion; 3 had spontaneous abortion, and 7 carried to term, resulting in the birth of 8 healthy babies. All children have normal growth and development. All patients remain in TKI therapy and in good response. It is suggested that female patients are advised to practice adequate contraception. No special precautions apply for male patients receiving TKI.

[Nilotinib treatment for imatinib resistant or intolerant chronic myelogenous leukemia.].

OBJECTIVE: To evaluate the safety and efficacy of nilotinib in chronic myelogenous leukemia (CML) patients with resistance or intolerance to imatinib. METHODS: Thirty-five CML patients after imatinib failure or intolerance received oral administration of 400 mg nilotinib twice daily. The overall survival, hematologic and cytogenetic responses, as well as adverse events were evaluated. RESULTS: The median duration of nilotinib therapy was 11 (1 - 23) months, with a median follow-up of 19 months. Nonhematologic adverse events were mostly of grade 1-2. The most common ones possibly related to nilotinib were increase of bilirubin (76%) and rash (46%). Grade 3-4 hematologic adverse events includes thrombocytopenia (37%), neutropenia (26%) and anemia (26%). Nilotinib was proved to be well-tolerated in this study. Grade 3-4 hematologic adverse events happened more frequently in advanced phase CML. The rate of major cytogenetic response in chronic phase (CP) CML was much higher than those in advanced CML (38.5% vs 22.2%). The median time to major cytogenetic response was 3 months. The estimated overall survival at 18 months was (93.5 +/- 1.0)%. CONCLUSION: Nilotinib is a more effective and safe treatment option for imatinib-resistant or -intolerant CML-CP patients.

[Efficacy and safety of imatinib in treatment of 151 chronic myeloid leukemia patients].

OBJECTIVE: To evaluate the safety and efficacy of imatinib in treatment of chronic myeloid leukemia (CML) patients. METHODS: From December 2003 to March 2007, 151 patients entered Glivec International Patient Assistance Program (GIPAP) in our center and received imatinib therapy. The overall and progression free survival, hematologic, cytogenetic and molecular response, and adverse events were evaluated. The factors associated with outcome of imatinib therapy were also analysed. RESULTS: One hundred and forty-two patients were evaluable with a median follow-up duration of 21.5 (6 -78) months. (1) The rate of cumulative complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR) and complete molecular response (CMoR) in chronic phase (CP) CML patients were 96.9%, 82.6%, 76.1% and 29.4%, respectively. These rates were significantly higher in patients with CP than in those with accelerated phase (AP) and blast crisis (BC) (P < 0.0001). (2) The overall survival (OS) rates at 1, 2 and 3 year were 100%, (97.3 +/- 1.9)% and (95.8 +/- 2.4)% for CP patients, they were (84.7 +/- 8.2)%, (77.0 +/- 10.4)% and (69.3 +/- 11.9)% for AP patients, and (62.9 +/- 8.9)%, (41.9 +/- 9.2)% and (28.5 +/- 9.1)% for BC patients, respectively (P < 0.0001). The progression-free survival (PFS) rates at 1, 2 and 3 year were (98.9 +/- 1.1)%, (93.9 +/- 2.7)%, (93.9 +/- 2.7)% for CP patients, (68.9 +/- 10.6)%, (61.3 +/- 11.9)%, (61.3 +/- 11.9)% for AP patients, (36.4 +/- 8.8)%, (25.4 +/- 8.1)%, (10.1 +/- 8.2)% (P < 0.0001) for BC patients respectively. (3) Among 92 CP patients, the rates of MCyR and CCyR in newly diagnosed patients were significantly higher than those in interferon therapy failure patients (P = 0.015, P = 0.010). Patients obtained CCyR at 12 months after the initiation of imatinib treatment were associated with longer PFS (P = 0.0099). According to the Sokal scoring system, the rates of MCyR and CCyR in low-risk patients were significantly higher than those in intermediate-risk and high-risk patients (P = 0.0013, P = 0.0024). Sokal score was also significantly associated with disease progression (P = 0.0467). (4) The adverse events of imatinib were moderate and tolerable. CONCLUSIONS: Treatment of CML patients in CP with imatinib can induce high hematologic, cytogenetic and molecular response and overall survival, but can not do satisfactorily for patients in AP and BC.

[Prognostic factors analysis for R-CHOP regimen therapy in diffuse large B cell lymphoma].

OBJECTIVE: To reassess the prognostic factors of diffuse large B cell lymphoma (DLBCL) treated with R-CHOP therapy. METHODS: One hundred and twenty five patients were enrolled in this study from Feb. 2000 to Sep. 2006. They received 6 courses of R-CHOP regimen consisting of rituximab 375 mg/ m2, intravenously, d 1; cyclophosphamide 750 mg/m2, bolus intravenously, d 2; doxorubicin 50 mg/m2, bolus intravenously, d 2; vincristine 1.4 mg/m2, bolus intravenously, d 2 and prednisone 60 mg, orally, d 2 - 6. All the patients were evaluated and followed up after the treatment. RESULTS: Eighty six patients (68.8%) achieved complete response (CR), 16 (12.8%) partial response (PR), 11 (12.8%) stable disease (SD) and 12 (9.6%) progressive disease (PD). In univariate analysis, performance status (PS), clinical stage, LDH level, extranodal disease, international prognostic index (IPI) and bulky disease were statistically significantly correlated with the induction of CR; however, only PS, clinical stage and bulky disease remained significant in multi-variate analysis (P = 0.0098, 0.000 and 0.004, respectively). Twenty four month for time to treatment failure (TTF) rate, overall survival (OS) rate, and disease free survival (DFS) rate was (59.7 +/- 5. 3)%, (67.1 +/- 5.6)% and (77.6 +/- 5.8)%, respectively. In univariate analysis, LDH, clinical stage and PS exerted significant effect on TTF and OS rate, but not on DFS rate; age and extranodal disease was not related with TTF, OS and DFS rate. In multi-variate analysis, achieved CR was the only prognostic factor for TTF (P =0.001) and bulky disease had influence on DFS rate. LDH level, PS, and achieved CR was correlated with the OS rate in multi-variate setting (P = 0.002, 0.009 and 0.001 respectively). CONCLUSION: IPI score has its limitation in predicting the prognosis in the R-CHOP era in DLBCL. Other two relevant prognostic factors are bulky disease and achieved CR after 6 courses of treatment.

AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec.

To explore the genetic abnormalities that cooperate with AML1-ETO (AE) fusion gene to cause acute myeloid leukemia (AML) with t(8;21), we screened a number of candidate genes and identified 11 types of mutations in C-KIT gene (mC-KIT), including 6 previously undescribed ones among 26 of 54 (48.1%) cases with t(8;21). To address a possible chronological order between AE and mC-KIT, we showed that, among patients with AE and mC-KIT, most leukemic cells at disease presentation harbored both genetic alteration, whereas in three such cases investigated during complete remission, only AE, but not mC-KIT, could be detected by allele-specific PCR. Therefore, mC-KIT should be a subsequent event on the basis of t(8;21). Furthermore, induced expression of AE in U937-A/E cells significantly up-regulated mRNA and protein levels of C-KIT. This may lead to an alternative way of C-KIT activation and may explain the significantly higher C-KIT expression in 81.3% of patients with t(8;21) than in patients with other leukemias. These data strongly suggest that t(8;21) AML follows a stepwise model in leukemogenesis, i.e., AE represents the first, fundamental genetic hit to initiate the disease, whereas activation of the C-KIT pathway may be a second but also crucial hit for the development of a full-blown leukemia. Additionally, Gleevec suppressed the C-KIT activity and induced proliferation inhibition and apoptosis in cells bearing C-KIT N822K mutation or overexpression, but not in cells with D816 mC-KIT. Gleevec also exerted a synergic effect in apoptosis induction with cytarabine, thus providing a potential therapeutic for t(8;21) leukemia.