Current survival measures reliably reflect modern sequential treatment in CML: correlation with prognostic stratifications.

Using the data of 723 chronic myeloid leukemia (CML) patients in the chronic phase, we analyzed the prognostic value of the Sokal, Euro, and EUTOS scores as well as the level of BCR-ABL1 and the achievement of complete cytogenetic response (CCgR) at 3 months of imatinib therapy in relation to the so-called current survival measures: the current cumulative incidence (CCI) reflecting the probability of being alive and in CCgR after starting imatinib therapy; the current leukemia-free survival (CLFS) reflecting the probability of being alive and in CCgR after achieving the first CCgR; and the overall survival. The greatest difference between the CCI curves at 5 years after initiating imatinib therapy was observed for the BCR-ABL1 transcripts at 3 months. The 5-year CCI was 94.3% in patients with BCR-ABL1 transcripts ≤ 10% and 57.1% in patients with BCR-ABL1 transcripts > 10% (P = 0.005). Therefore, the examination of BCR-ABL1 transcripts at 3 months may help in early identification of patients who are likely to perform poorly with imatinib. On the other hand, CLFS was not significantly affected by the considered stratifications. In conclusion, our results indicate that once the CCgR is achieved, the prognosis is good irrespective of the starting prognostic risks.

Evaluation of 5-year imatinib treatment of 458 patients with CP-CML in routine clinical practice and prognostic impact of different BCR-ABL cutoff levels.

We evaluated responses to the treatment and long-term outcomes of chronic myeloid leukemia patients treated with imatinib as first-line treatment in routine clinical setting from two countries with centralized tyrosine kinase inhibitors (TKIs) treatment. We assessed prognostic significance of European LeukemiaNet (ELN) 2006- and 2009-defined responses and the prognostic value of molecular responses at defined time points on 5-year survivals. Among the cumulative rates of incidence of hematologic, cytogenetic, and molecular responses and all important survival parameters, we evaluated the prognostic significance of different BCR-ABL transcript-level ratios (≤1%; >1%-≤10%; >10%) at 3, 6, 12, and 18 months (n = 199). The ELN optimal response criteria and their predictive role were significantly beneficial for event-free survival at all given time points. We found significant improvement in survivals of patients with BCR-ABL lower than 10% in the 6th and 12th months. Significantly better outcome was found in patients who achieved major molecular response (MMR) in the 12th month. The cumulative incidences of complete cytogenetic response (CCyR) and MMR were significantly associated with the molecular response in the 3rd month. The ELN response criteria and their predictive role were helpful at given time points; however, the 2009 definition did not significantly alter the prognostic accuracy compared with that of the 2006 definition. The significant value was observed for cytogenetic responses at the 6th and 12th month. Moreover, progression-free and event-free survivals were improved with MMR at the 12th month.

Micafungin as empirical antifungal therapy in hematological patients: a retrospective, multicenter study in the Czech and Slovak Republics.

The objective of this retrospective, multicenter study was to evaluate the efficacy and safety of micafungin as empirical antifungal therapy during febrile neutropenia (FN) in 73 hematological patients from six centers in two countries. All patients received 100 mg of micafungin/day. The overall favorable response rate (RR) was 64.8% when the resolution of fever during neutropenia was included in the response criteria and 84.5% when excluded. A significantly lower favorable RR in patients with persistent fever and non-specific pulmonary infiltrates compared to patients with persistent fever only (82.8 vs. 52.4%, respectively; p = 0.011) was not found when resolution of fever was not included in the composite endpoint criteria (93.1 vs. 78.6%, respectively; p = 0.180). Breakthrough fungal disease developed in 2.7% of patients. Treatment was discontinued in 16.4% of cases. Only one patient (1.4%) discontinued therapy due to an adverse event. Posaconazole prophylaxis improved favorable RR when defervescence was included as composite endpoint criterion (p = 0.047), but not when it was excluded (p = 0.485). However, neutrophil recovery did not influence favorable RR (p = 0.803 and p = 0.112, respectively). These data suggest that micafungin is safe and effective as an empirical therapy in patients with FN.

Invasive aspergillosis in patients with hematological malignancies in the Czech and Slovak republics: Fungal InfectioN Database (FIND) analysis, 2005-2009.

OBJECTIVES: To evaluate risk factors, diagnostic procedures, and treatment outcomes of invasive aspergillosis (IA) in patients with hematological malignancies. METHODS: A retrospective analysis of data from proven/probable IA cases that occurred from 2005 to 2009 at 10 hematology centers was performed. RESULTS: We identified 176 IA cases that mainly occurred in patients with acute leukemias (58.5%), mostly those on induction/re-induction treatments (39.8%). Prolonged neutropenia was the most frequent risk factor for IA (61.4%). The lungs were the most frequently affected site (93.8%) and computed tomography detected abnormalities in all episodes; however, only 53.7% of patients had findings suggestive of IA. Galactomannan (GM) detection in serum or bronchoalveolar lavage fluid (positive in 79.1% and 78.8% of episodes, respectively) played a crucial role in IA diagnosis. Neutrophil count and antifungal prophylaxis did not influence the GM positivity rate, but empirical therapy decreased this rate (in serum). Of the IA cases, 53.2% responded to initial antifungal therapy. The combination of voriconazole and echinocandin, even as initial or salvage therapy, did not perform better than voriconazole monotherapy (p=0.924 for initial therapy and p=0.205 for salvage therapy). Neutrophil recovery had a significant role in the response to initial (but not salvage) antifungal therapy. CONCLUSIONS: Our retrospective analysis identified key diagnostic and treatment characteristics, and this understanding could improve the management of hematological malignancy patients with IA.

Treatment of consecutive patients with chronic myeloid leukaemia in the cooperating centres from the Czech Republic and the whole of Slovakia after 2000--a report from the population-based CAMELIA Registry.

BACKGROUND: Most results on the treatment of chronic myeloid leukaemia (CML) with imatinib were obtained from clinical trials that may differ from the routine practice. We report the results of treatment of consecutive patients with CML at ten major centres during 2000-2008. PATIENTS AND METHODS: Data reporting was retrospective in 2000-2004 and prospective from 2005 on. A total of 661 patients [301 women and 360 men; median age 51 (range, 15-83)] with Ph+CML were registered. The median follow-up was 46.1 months (0-122.2). RESULTS: Most patients were treated with first- (379; 57.3%) or second-line (193; 29.2%) imatinib; some of the patients underwent allogeneic hematopoietic stem cell transplantation (AHSCT) (83; 12.6%), but 6.1% were treated with other modalities [40 patients; median age 66 (range, 32-83)]. The probability of overall survival (OS) at 5 years, according to Kaplan and Meier, was 88.9%, 77.5% and 68.7% for chronic-phase patients treated with first-line imatinib, second-line imatinib and first-line AHSCT, respectively, but only 25.2% for patients receiving other modalities. The OS was dependent on the disease phase and Sokal, Hasford and European group for blood and marrow transplantation (EBMT) risk scores (P<0.001; each). Only 46.2% of deaths in patients treated with other modalities were attributable to CML. Elderly patients over 65 years achieved similar response rates and progression-free survival to the younger ones. There was a trend for inferior results of AHSCT performed after the failure of imatinib (P=0.075), probably as a result of differences in EBMT risk scores (P<0.001). CONCLUSIONS: The ability to achieve results comparable to those of previous clinical studies in our CML cohort was influenced by centralised care. Decisions not to initiate imatinib or to delay AHSCT may have a negative impact on OS, but comorbidities may limit the treatment potential of imatinib in the elderly.

Light chain-induced acute renal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multiple myeloma: results of a phase II study.

PURPOSE: To assess the efficacy of bortezomib-doxorubicin-dexamethasone (BDD) therapy in patients with multiple myeloma with light chain-induced acute renal failure. PATIENTS AND METHODS: Sixty-eight patients with light chain-induced acute renal failure and glomerular filtration rate (GFR) less than 50 mL/min received bortezomib (1.0 mg/m(2) on days 1, 4, 8, and 11), doxorubicin (9 mg/m(2) on days 1 and 4), and dexamethasone (40 mg on days 1, 4, 8, and 11); if well tolerated after two cycles, bortezomib could be increased to 1.3 mg/m(2) and doxorubicin administered on days 1, 4, 8, and 11. RESULTS: By intent-to-treat analysis a myeloma response was obtained in 72% of 18 previously and 50 not previously treated patients (complete response [CR]/near CR [nCR], 38%; very good partial response [VGPR], 15%; partial response [PR], 13%; minor response [MR], 6%). Renal response was achieved in 62% of patients (renal CR, 31%; renal PR, 7%; renal MR, 24%). Median GFR increased from 20.5 to 48.4 mL/min. GFR improvement correlated with tumor response; the greatest increase to 59.6 mL/min was seen in the group of patients with CR/nCR/VGPR. Median progression-free survival was 12.1 months. One- and 2-year survival rates were 72% and 58%, respectively. Survival did not differ between patients with and without renal response but was inferior in previously treated patients (P < .001). In multivariate analysis, baseline GFR and tumor response correlated with renal response, and pretreatment status, lactate dehydrogenase, and myeloma response correlated with survival. The most common grade 3 or 4 toxicities were infection (19.1%), thrombocytopenia (14.7%), neutropenia (14.7%), fatigue/weakness (10.3%), and polyneuropathy (8.8%). CONCLUSION: BDD induced a high rate of myeloma and renal responses, and treatment was well tolerated.

Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma.

BACKGROUND: Thalidomide maintenance therapy after stem cell transplantation resulted in increased progression-free survival and overall survival in a few trials, but its role in non-transplant eligible patients with multiple myeloma remains unclear. This study assessed the impact of thalidomide-interferon in comparison to interferon maintenance therapy in elderly patients with multiple myeloma. DESIGN AND METHODS: Of 289 elderly patients with multiple myeloma who were randomized to thalidomide-dexamethasone or melphalan-prednisolone induction therapy, 137 finally completed 9 cycles of induction therapy with stable disease or better and thereby qualified for maintenance treatment. Of these, 128 have been randomized to either thalidomide-interferon or interferon alone. Primary study endpoints were progression-free survival and response rates; secondary endpoints were overall survival, toxicity and quality of life. RESULTS: Thalidomide-interferon maintenance therapy led to a significantly longer progression-free survival compared to interferon (27.7 vs. 13.2 months, P=0.0068), but overall survival was similar in both groups (52.6 vs. 51.4 months, P=0.81) and did not differ between patients aged 75 years or older, or younger patients (P=0.39). Survival after disease progression tended to be shorter in patients on thalidomide-interferon maintenance therapy (P=0.056). Progression-free survival and overall survival tended to be shorter in patients with adverse cytogenetic (FISH) findings compared to the standard risk group but differences were not significant (P=0.084 and P=0.082, respectively). Patients on thalidomide-interferon presented with more neuropathy (P=0.0015), constipation (P=0.0004), skin toxicity (P=0.0041) and elevated creatinine (P=0.026). CONCLUSIONS: Thalidomide plus interferon maintenance therapy increased progression-free survival but not overall survival and was associated with slightly more toxicity than maintenance with interferon alone. (ClinicalTrials.gov Identifier: NCT00205751).

Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study.

PURPOSE: To evaluate the safety and efficacy of initial treatment with imatinib mesylate 800 mg/d (400 mg twice daily) versus 400 mg/d in patients with newly diagnosed chronic myeloid leukemia in chronic phase. PATIENTS AND METHODS: A total of 476 patients were randomly assigned 2:1 to imatinib 800 mg (n = 319) or 400 mg (n = 157) daily. The primary end point was the major molecular response (MMR) rate at 12 months. RESULTS: At 12 months, differences in MMR and complete cytogenetic response (CCyR) rates were not statistically significant (MMR, 46% v 40%; P = .2035; CCyR, 70% v 66%; P = .3470). However, MMR occurred faster among patients randomly assigned to imatinib 800 mg/d, who had higher rates of MMR at 3 and 6 months compared with those in the imatinib 400-mg/d arm (P = .0035 by log-rank test). CCyR also occurred faster in the 800-mg/d arm (CCyR at 6 months, 57% v 45%; P = .0146). The most common adverse events were edema, gastrointestinal problems, and rash, and all were more common in patients in the 800-mg/d arm. Grades 3 to 4 hematologic toxicity also occurred more frequently in patients receiving imatinib 800 mg/d. CONCLUSION: MMR rates at 1 year were similar with imatinib 800 mg/d and 400 mg/d, but MMR and CCyR occurred earlier in patients treated with 800 mg/d. Continued follow-up is needed to determine the clinical significance of earlier responses on high-dose imatinib.

A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older.

This phase 3, multicenter, open-label study evaluated the efficacy and safety of tipifarnib compared with best supportive care (BSC), including hydroxyurea, as first-line therapy in elderly patients (>or=70 years) with newly diagnosed, de novo, or secondary acute myeloid leukemia. A total of 457 patients were enrolled with 24% 80 years of age or older. Tipifarnib 600 mg orally twice a day was administered for the first 21 consecutive days, in 28-day cycles. The primary endpoint was overall survival. The median survival was 107 days for the tipifarnib arm and 109 days for the BSC arm. The hazard ratio (tipifarnib vs BSC) for overall survival was 1.02 (P value by stratified log-rank test, .843). The complete response rate for tipifarnib in this study (8%) was lower than that observed previously, but with a similar median duration of 8 months. The most frequent grade 3 or 4 adverse events were cytopenias in both arms, slightly more infections (39% vs 33%), and febrile neutropenia (16% vs 10%) seen in the tipifarnib arm. The results of this randomized study showed that tipifarnib treatment did not result in an increased survival compared with BSC, including hydroxyurea. This trial was registered at www.clinicaltrials.gov as #NCT00093990.

Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma.

We compared thalidomide-dexamethasone (TD) with melphalan-prednisolone (MP) in 289 elderly patients with multiple myeloma (MM). Patients received either thalidomide 200 mg plus dexamethasone 40 mg, days 1 to 4 and 15 to 18 on even cycles and days 1 to 4 on odd cycles, during a 28-day cycle or to melphalan 0.25 mg/kg and prednisolone 2 mg/kg orally on days 1 to 4 during a 28- to 42-day cycle. Patients achieving stable disease or better were randomly assigned to maintenance therapy with either thalidomide 100 mg daily and 3 MU interferon alpha-2b thrice weekly or to 3 MU interferon alpha-2b thrice weekly only. TD resulted in a higher proportion of complete and very good remissions (26% vs 13%; P= .006) and overall responses (68% vs 50%; P= .002) compared with MP. Time to progression (21.2 vs 29.1 months; P= .2), and progression-free survival was similar (16.7 vs 20.7 months; P= .1), but overall survival was significantly shorter in the TD group (41.5 vs 49.4 months; P= .024). Toxicity was higher with TD, particularly in patients older than 75 years with poor performance status. The study was registered at ClinicalTrials.gov as NCT00205751.