Etoposide, intermediate-dose cytarabine and carboplatin (VAC): A combination therapy for the blastic phase of chronic myelogenous leukemia

Background: Carboplatin is a second-generation platinum compound that in combination with etoposide and intermediate doses of cytarabine, in early clinical trials has demonstrated high efficacy in refractory acute myelogenous leukemia and the blastic phase of CML. Patients and methods: Starting in April 1992, 17 consecutive patients with the blastic phase (BP) of chronic myelogenous leukemia (CML) and a median age of 33 years (range 10 to 45) received a new treatment regimen consisting of etoposide (100 mg/m(2)/d i.v. over one hour), intermediate-dose cytarabine (500 mg/m(2)/d i.v. over one hour, q12 hours) and carboplatin (150 mg/m(2)/d continuous infusion) on days 1-3 and 8-10 (VAC regimen). The BP phenotype was myeloid in 16 patients and hybrid in one. At the time of their BP diagnoses, two patients showed extramedullary involvement, in eight patients the BP was preceded by an accelerated phase. Results: Overall, 11 of 17 patients (65%) achieved complete remission and 7 of 11 responding patients (64%) manifested a cytogenetic conversion ranging from 38% to 100% Ph-negative metaphases; one patient died in CR of hemothorax, three died of sepsis during induction therapy and three patients (17.5%) had resistant disease. As of April 1996, four patients are alive, three of them in first remission at +7, +10, +16 months after CR, and one in BP at +38 months after the start of VAC therapy. Profound myelosuppression was observed in all patients; extrahematologic toxicity, especially involved the gastrointestinal tract, with grade >2 mucositis in five patients (29.5%) and liver dysfunction in five (29.5%). No renal toxicity or ototoxicity was observed. Conclusions: Despite the brief relapse-free duration, the high remission rate and tolerable toxicity indicate that the VAC combination chemotherapy has a high antileukemic efficacy, and warrants further evaluation for the treatment of CML in acute phase, provided a post-remission BMT strategy is feasible

Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and Idarubicin (AIDA) therapy

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High incidence of post-transplant cytomegalovirus reactivations in myeloma patients undergoing autologous stem cell transplantation after treatment with bortezomib-based regimens: a survey from the Rome transplant network.

The incidence of cytomegalovirus (CMV) reactivations in patients with multiple myeloma (MM) receiving autologous stem cell transplantation (ASCT) is relatively low. However, the recent increased use of novel agents, such as bortezomib and/or immunomodulators, before transplant, has led to an increasing incidence of Herpesviridae family virus infections. The aim of the study was to establish the incidence of post-engraftment symptomatic CMV reactivations in MM patients receiving ASCT, and to compare this incidence with that of patients treated with novel agents or with conventional chemotherapy before transplant. The study was a survey of 80 consecutive patients who underwent ASCT after treatment with novel agents (Group A). These patients were compared with a cohort of 89 patients treated with VAD regimen (vincristine, doxorubicin, and dexamethasone) before ASCT (Group B). Overall, 7 patients (4.1%) received an antiviral treatment for a symptomatic CMV reactivation and 1 died. The incidence of CMV reactivations was significantly higher in Group A than in Group B (7.5% vs. 1.1%; P = 0.048). When compared with Group B, the CMV reactivations observed in Group A were significantly more frequent in patients who received bortezomib, whether or not associated with immunomodulators (9.4% vs. 1.1%; P = 0.019), but not in those treated with immunomodulators only (3.7% vs. 1.1%; P = 0.396). These results suggest that MM patients treated with bortezomib-based regimens are at higher risk of developing a symptomatic CMV reactivation after ASCT

Treatment of elderly patients (≥60 years) with newly diagnosed acute promyelocytic leukemia. Results of the Italian multicenter group GIMEMA with ATRA and idarubicin (AIDA) protocols

In all, 134 elderly patients (median age 66 years, range 60-75 years) with newly diagnosed acute promyelocytic leukemia (APL) were enrolled in two successive protocols of the Italian multicenter group GIMEMA. All patients received an identical induction with all-trans retinoic acid and idarubicin; 116 (86%) entered complete remission (CR), two (2%) were resistant and 16 (12%) died during induction. After CR, 106 patients received further therapy whereas 10 did not, because of refusal (n=5) or toxicity (n = 5). Consolidation consisted of three chemotherapy courses in the AIDA protocol (AIDA, 67 patients) or, since 1997, of an amended protocol including only the first cycle (amended AIDA, aAIDA, 39 patients). In the AIDA group, 43 patients (64%) completed consolidation, while seven (11%) and 17 (25%) patients were withdrawn after first and second courses, respectively; nine patients (13%) died in CR and 12 (18%) relapsed. In the aAIDA group, all patients received the assigned treatment; two patients (5%) died in CR and six (15%) relapsed. In the AIDA and aAIDA series, the 3-year overall and discase-free survival rates were 81 and 83% (P= NS), 73 and 72% (P=NS), respectively. We highlight here the frequency and severity of complications linked to intensive chemotherapy in this clinical setting and suggest that, in APL of the elderly, less intensive postremission therapy allows significant reduction of severe treatment-related toxicity and may be equally effective

Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study

Background: The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study. Methods: In this randomised, open-label, phase 3 study, patients aged 18\u201365 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1\u20132, 4\u20135, 8\u20139, and 11\u201312 in the VTD regimen, and 40 mg on days 1\u20134 and 9\u201312 in the TD regimen), either alone (TD group) or with bortezomib (1\ub73 mg/m2 intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484. Findings: Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124\ub71 months (IQR 117\ub72\u2013131\ub77). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28\u201341) compared with 17% (13\u201323) for the TD group (hazard ratio [HR] 0\ub762 [95% CI 0\ub750\u20130\ub777]; p<0\ub70001). 60% (95% CI 54\u201367) of patients in the VTD group were alive at 10 years versus 46% (40\u201354) of patients in the TD group (HR 0\ub768 [95% CI 0\ub751\u20130\ub790]; p=0\ub70068). VTD was an independent predictor of improved progression-free survival (HR 0\ub760 [95% CI 0\ub748\u20130\ub776]; p<0\ub70001) and overall survival (HR 0\ub768 [0\ub750\u20130\ub791]; p=0\ub7010). The incidence of second primary malignancies per 100 person-years was 0\ub787 (95% CI 0\ub749\u20131\ub744) in the VTD group compared with 1\ub741 (0\ub788\u20132\ub713) in the TD group. Interpretation: Incorporation of VTD into double autologous HSCT resulted in clinically meaningful improvements in long-term progression-free survival and overall survival, confirming that a regimen including bortezomib and an immunomodulatory drug is the gold standard treatment for patients with newly diagnosed myeloma who are fit for high-dose chemotherapy. Funding: Ser\ue0gnoli Institute of Haematology, University of Bologna, and BolognAIL