Efficacy of rabbit anti-thymocyte globulin in severe aplastic anemia

Background

A combination of horse anti-thymocyte globulin and cyclosporine produces responses in 60–70% of patients with severe aplastic anemia. We performed a phase II study of rabbit anti-thymocyte globulin and cyclosporine as first-line therapy for severe aplastic anemia.

Design and Methods

Twenty patients with severe aplastic anemia treated with rabbit anti-thymocyte globulin were compared to 67 historical control cases with matched clinical characteristics treated with horse anti-thymocyte globulin.

Results

Response rates at 3, 6 and 12 months were similar for patients treated with rabbit anti-thymocyte globulin or horse anti-thymocyte globulin: 40% versus 55% (P=0.43), 45% versus 58% (P=0.44) and 50% versus 58% (P=0.61), respectively. No differences in early mortality rates or overall survival were observed. We then performed multivariable analyses of response at 6 months and overall survival and identified the presence of a paroxysmal nocturnal hemoglobinuria clone (P=0.01) and a pretreatment absolute reticulocyte count greater than 30×10⁹/L (P=0.007) as independent predictors of response and younger age (P=0.003), higher pretreatment absolute neutrophil (P=0.02) and absolute lymphocyte counts (P=0.03) as independent predictors of overall survival. None of the immunogenetic polymorphisms studied was predictive of response to immunosupressive therapy.

Conclusions

Despite reports suggesting differences in biological activity of different anti-thymocyte globulin preparations, rabbit and horse anti-thymocyte globulin appear to have a similar efficacy for up-front treatment of severe aplastic anemia. Clinicaltrial.gov: {"type":"clinical-trial","attrs":{"text":"NCT01231841","term_id":"NCT01231841"}}NCT01231841)     

Universal antifungal therapy is not needed in persistent febrile neutropenia: a tailored diagnostic and therapeutic approach

Background

Giving antifungal therapy exclusively to selected patients with persistent febrile neutropenia may avoid over-treatment without increasing mortality. The aim of this study was to validate an innovative diagnostic and therapeutic approach based on assessing patients’ risk profile and clinical criteria in order to select those patients requiring antifungal therapy. The efficacy of this approach was compared to that of universal empirical antifungal therapy.

Design and Methods

This was a prospective study which included all consecutive adult hematology patients with neutropenia and fever refractory to 5 days of empirical antibacterial therapy admitted to a teaching hospital in Spain over a 2-year period. A diagnostic and therapeutic approach based on clinical criteria and risk profile was applied in order to select patients for antifungal therapy. The sensitivity, specificity and negative predictive value of this approach and also the overall success rate, according to the same criteria of efficacy described in classical clinical trials, were analyzed.

Results

Eighty-five episodes were included, 35 of them (41.2%) in patients at high risk of invasive fungal infections. Antifungal therapy was not indicated in 33 episodes (38.8%). The overall incidence of proven and probable invasive fungal infections was 14.1%, all of which occurred in patients who had received empirical antifungal therapy. The 30-day crude mortality rate was 15.3% and the invasive fungal infection-related mortality rate was 2.8% (2/72). The overall success rate following the diagnostic and therapeutic approach was 36.5% compared with 33.9% and 33.7% obtained in the trial by Walsh et al. The sensitivity, specificity and negative predictive value of the study approach were 100%, 52.4% and 100%, respectively.

Conclusions

Based on the high negative predictive value of this diagnostic and therapeutic approach in persistent febrile neutropenia patients with hematologic malignancies or patients who have received a hematopoietic stem cell transplant, the approach is useful for identifying patients who are not likely to develop invasive fungal infection and do not, therefore, require antifungal therapy. The effectiveness of the strategy is similar to that of universal empirical antifungal therapy reported in controlled trials.     

Reduced-toxicity conditioning with treosulfan and fludarabine in allogeneic hematopoietic stem cell transplantation for myelodysplastic syndromes: final results of an international prospective phase II trial

Background

An alternative reduced-toxicity conditioning regimen for allogeneic transplantation, based on treosulfan and fludarabine, has recently been identified. The rationale for this study was to investigate the efficacy and safety of this regimen prospectively in patients with a primary myelodysplastic syndrome.

Design and Methods

A total of 45 patients with primary myelodysplastic syndromes were conditioned with 3×14 g/m² treosulfan and 5×30 mg/m² fludarabine followed by allogeneic hematopoietic stem cell transplantation. Subtypes of myelodysplastic syndromes were refractory anemia with excess blasts-2 (44%), refractory cytopenia with multilineage dysplasia (27%), refractory anemia (9%), refractory anemia with ringed sideroblasts (4%), refractory cytopenia with multilineage dysplasia and ringed sideroblasts (4%), refractory anemia with excess blasts-1 (2%), and myelodysplastic syndrome with isolated del (5q) (2%). The myelodysplastic syndrome was unclassified in 7% of the patients. Forty-seven percent of the patients had a favorable karyotype, 29% an unfavorable one, and 18% an intermediate karyotype. Patients were evaluated for engraftment, adverse events, graft-versus-host disease, non-relapse mortality, relapse incidence, overall survival and disease-free survival.

Results

All but one patient showed primary engraftment of neutrophils after a median of 17 days. Non-hematologic adverse events of grade III–IV in severity included mainly infections and gastrointestinal symptoms (80% and 22% of the patients, respectively). Acute graft-versus-host disease grade II–IV developed in 24%, and extensive chronic graft-versus-host disease in 28% of the patients. After a median follow-up of 780 days, the 2-year overall and disease-free survival estimates were 71% and 67%, respectively. The 2-year cumulative incidences of non-relapse mortality and relapse were 17% and 16%, respectively.

Conclusions

Our safety and efficacy data suggest that treosulfan-based conditioning therapy is a promising treatment option for patients with myelodysplastic syndromes. clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01062490","term_id":"NCT01062490"}}NCT01062490     

Cytopenia and leukocyte recovery shape cytokine fluctuations after myeloablative allogeneic hematopoietic stem cell transplantation

Background

Allogeneic hematopoietic stem cell transplantation is associated with profound changes in levels of various cytokines. Emphasis has been placed on conditioning-associated mucosal damage and neutropenia and associated bacterial translocation as the initiating conditions predisposing to acute graft-versus-host disease. The post-transplant period is, however, also associated with increases in certain homeostatic cytokines. It is unclear how much the homeostatic drive to lymphocyte recovery and the production of cytokines from the engrafting donor immune system determine cytokine fluctuations in the peri- and immediate post-transplant period. The aim of this study was to examine the contributions of the conditioning regimen, donor engraftment, infections, and graft-versus-host disease to fluctuations in cytokines involved in homeostasis and inflammation.

Design and Methods

We examined the levels of 33 cytokines in relation to peri- and post-transplant events such as conditioning regimen, chimerism, and acute graft-versus-host disease in myeloablative, non-T cell-replete HLA-identical sibling donor stem cell transplantation for hematologic malignancies.

Results

We identified two cytokine storms. The first occurred following conditioning and reached peak levels when all the leukocytes were at their lowest concentrations. The second cytokine storm occurred concurrently with hematopoietic reconstitution and subsided with the achievement of full donor lymphocyte chimerism.

Conclusions

Our results indicate that both recipient-related and donor-related factors contribute to the changes in cytokine levels in the recipient following allogeneic hematopoietic stem cell transplantation. The study reported here was performed using plasma samples drawn from patients enrolled in the ClinicalTrials.gov-registered trials {"type":"clinical-trial","attrs":{"text":"NCT00467961","term_id":"NCT00467961"}}NCT00467961 and {"type":"clinical-trial","attrs":{"text":"NCT00378534","term_id":"NCT00378534"}}NCT00378534     

Thalidomide versus dexamethasone for the treatment of relapsed and/or refractory multiple myeloma: results from OPTIMUM, a randomized trial

Background

Thalidomide has potent antimyeloma activity, but no prospective, randomized controlled trial has evaluated thalidomide monotherapy in patients with relapsed/refractory multiple myeloma.

Design and Methods

We conducted an international, randomized, open-label, four-arm, phase III trial to compare three different doses of thalidomide (100, 200, or 400 mg/day) with standard dexamethasone in patients who had received one to three prior therapies. The primary end-point was time to progression.

Results

In the intent-to-treat population (N=499), the median time to progression was 6.1, 7.0, 7.6, and 9.1 months in patients treated with dexamethasone, and thalidomide 100, 200, and 400 mg/day, respectively; the difference between treatment groups was not statistically significant. In the per-protocol population (n=465), the median time to progression was 6.0, 7.0, 8.0, and 9.1 months, respectively. In patients who had received two or three prior therapies, thalidomide significantly prolonged the time to progression at all dose levels compared to the result achieved with dexamethasone. Response rates and median survival were similar in all treatment groups, but the median duration of response was significantly longer in all thalidomide groups than in the dexamethasone group. Adverse events reported in the thalidomide groups, such as fatigue, constipation and neuropathy, confirmed the known safety profile of thalidomide.

Conclusions

Although thalidomide was not superior to dexamethasone in this randomized trial, thalidomide monotherapy may be considered an effective salvage therapy option for patients with relapsed/refractory multiple myeloma, particularly those with a good prognosis and those who have received two or three prior therapies. The recommended starting dose of thalidomide monotherapy is 400 mg/day, which can be rapidly reduced for patients who do not tolerate this treatment. (Clinical trial registration number: {"type":"clinical-trial","attrs":{"text":"NCT00452569","term_id":"NCT00452569"}}NCT00452569)     

High-dose imatinib improves cytogenetic and molecular remissions in patients with pretreated Philadelphia-positive, BCR-ABL-positive chronic phase chronic myeloid leukemia: first results from the randomized CELSG phase III CML 11 ��ISTAHIT�� study

Background

Imatinib 400 mg/day is the standard treatment for patients with chronic phase chronic myeloid leukemia. Recent reports suggested higher and more rapid cytogenetic and molecular responses with higher doses of imatinib.

Design and Methods

In this prospective international, multicenter phase III study, 227 patients with pre-treated Philadelphia chromosome-positive, BCR-ABL-positive chronic myeloid leukemia were randomized to a standard-dose imatinib arm (400 mg/day) or a high-dose imatinib arm (800 mg/day for 6 months followed by 400 mg/day as maintenance therapy). In this planned interim analysis hematologic, cytogenetic and molecular responses as well as toxicity were evaluated.

Results

Compared to the standard-dose, high-dose imatinib led to higher rates of major and complete cytogenetic responses at both 3 months (major: 21% versus 37%, P=0.01; complete: 6% versus 25%, P<0.001) and 6 months (major: 34% versus 54%, P=0.009; complete: 20% versus 44%, P<0.001). This was paralleled by a significantly higher major molecular response rate at 6 months in the high-dose imatinib arm (11.8% versus 30.4%; P=0.003). At 12 months, the rates of major cytogenetic response (the primary end-point) were comparable between the two arms (57% versus 59%). In contrast to non-hematologic toxicities, grade 3/4 hematologic toxicities were more common in the high-dose arm. Cumulative complete cytogenetic response rates were higher in patients without dose reduction in the high-dose arm (61%) than in the patients with no dose reduction in the standard-dose arm (36%) (P=0.014).

Conclusions

This is the first randomized phase III trial in patients with pre-treated chronic phase chronic myeloid leukemia demonstrating improvements in major cytogenetic response, complete cytogentic response and major molecular response rates with high-dose imatinib therapy (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00327262","term_id":"NCT00327262"}}NCT00327262).     

Leukemia-free survival as a surrogate end point for overall survival in the evaluation of maintenance therapy for patients with acute myeloid leukemia in complete remission

Background

In trials designed to evaluate new therapies for hematologic malignancies, end points such as leukemia-free survival are often used as surrogates for overall survival in acute leukemia. We aimed to assess whether leukemia-free survival is an acceptable statistical surrogate for overall survival when applied to remission maintenance therapy for acute myeloid leukemia.

Design and Methods

Data were analyzed from a randomized Phase III trial of remission maintenance immunotherapy with histamine dihydrochloride plus low-dose interleukin-2 versus no treatment in adults with acute myeloid leukemia. A two-stage surrogate validation model was applied in which correlations between Kaplan-Meier estimates of leukemia-free survival and overall survival, and between log hazard ratios reflecting treatment effects were analyzed. Country of patient enrollment was the unit of analysis.

Results

Kaplan-Meier estimates of overall survival at 36, 48, and 60 months and leukemia-free survival at 24 months were reasonably correlated (R² ranging from 0.44 to 0.84) both for the overall (n=320) and first complete remission (n=261) populations. The effects of histamine dihydrochloride/interleukin-2 on log hazard ratios for leukemia-free survival and overall survival were well correlated (R²=0.88–0.93).

Conclusions

The significant correlations between overall survival and the surrogate end point (leukemia-free survival) and between the effect of histamine dihydrochloride/interleukin-2 on leukemia-free survival and overall survival satisfy the two-stage surrogate validation model. (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00003991","term_id":"NCT00003991"}}NCT00003991)     

Early intervention during imatinib therapy in patients with newly diagnosed chronic-phase chronic myeloid leukemia: a study of the Spanish PETHEMA group

Background

Despite the favorable results of imatinib front line in chronic-phase chronic myeloid leukemia there is room for improvement.

Design and Methods

Early intervention during imatinib therapy was undertaken in 210 adults with chronic-phase chronic myeloid leukemia less than three months from diagnosis (Sokal high risk: 16%). Patients received imatinib 400 mg/day. At three months, dose was increased if complete hematologic response was not achieved. At six months, patients in complete cytogenetic response were kept on 400 mg and the remainder randomized to higher imatinib dose or 400 mg plus interferon-alfa. At 18 months, randomized patients were switched to a 2^nd generation tyrosine kinase inhibitor if not in complete cytogenetic response and imatinib dose increased in non-randomized patients not in major molecular response.

Results

Seventy-two percent of patients started imatinib within one month from diagnosis. Median follow-up is 50.5 (range: 1.2–78) months. At three months 4 patients did not have complete hematologic response; at six months 73.8% were in complete cytogenetic response; among the remainder, 9 could not be randomized (toxicity or consent withdrawal), 17 were assigned to high imatinib dose, and 15 to 400 mg + interferon-alpha. The low number of randomized patients precluded comparison between the two arms. Cumulative response at three years was: complete hematologic response 98.6%, complete cytogenetic response 90% and major molecular response 82%. On an intention-to-treat basis, complete cytogenetic response was 78.8% at 18 months. At five years, survival was 97.5%, survival free from accelerated/blastic phase 94.3%, failure free survival 82.5%, and event free survival (including permanent imatinib discontinuation) 71.5%.

Conclusions

These results indicate the benefit of early intervention during imatinib therapy (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00390897","term_id":"NCT00390897"}}NCT00390897).     

Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

Background

Patients with chromosome 5 abnormalities and high-risk myelodysplastic syndromes or acute myeloid leukemia have a poor outcome. We hypothesized that increasing doses of lenalidomide may benefit this group of patients by inhibiting the tumor clone, as assessed by fluorescence in situ hybridization for del(5q31).

Design and Methods

Twenty-eight patients at diagnosis or with relapsed disease and not eligible for standard therapy (16 with acute myeloid leukemia, 12 with intermediate-risk 2 or high-risk myelodysplastic syndrome) were enrolled in this prospective phase II multicenter trial and treated with lenalidomide up to 30 mg daily for 16 weeks. Three patients had isolated del(5q), six had del(5q) plus one additional aberration, 14 had del(5q) and a complex karyotype, four had monosomy 5, and one had del(5q) identified by fluorescence in situ hybridization only.

Results

Major and minor cytogenetic responses, assessed by fluorescence in situ hybridization, were achieved in 5/26 (19%) and 2/26 (8%) patients, respectively, who received one or more dose of lenalidomide, while two patients achieved only a bone marrow response. Nine of all 26 patients (35%) and nine of the ten who completed the 16 weeks of trial responded to treatment. Using the International Working Group criteria for acute myeloid leukemia and myelodysplastic syndrome the overall response rate in treated patients with acute myeloid leukemia was 20% (3/15), while that for patients with myelodysplastic syndrome was 36% (4/11). Seven patients stopped therapy due to progressive disease and nine because of complications, most of which were disease-related. Response rates were similar in patients with isolated del(5q) and in those with additional aberrations. Interestingly, patients with TP53 mutations responded less well than those without mutations (2/13 versus 5/9, respectively; P=0.047). No responses were observed among 11 cases with deleterious TP53 mutations.

Conclusions

Our data support a role for higher doses of lenalidomide in poor prognosis patients with myelodysplastic syndrome and acute myeloid leukemia with deletion 5q. (Clinicaltrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00761449","term_id":"NCT00761449"}}NCT00761449).     

High rates of durable response are achieved with imatinib after treatment with interferon α plus cytarabine: results from the International Randomized Study of Interferon and STI571 (IRIS) trial

Background

Imatinib is the standard of care for newly diagnosed chronic-phase chronic myeloid leukemia. The largest randomized clinical trial of imatinib was the multinational IRIS trial in which 1106 patients were randomized to receive either imatinib 400 mg/day or a standard regimen of interferon-α plus cytarabine.

Design and Methods

Patients were allowed to cross over to the opposite treatment for intolerance, lack of response, disease progression, and, following release of the initial efficacy data, reluctance to remain on therapy with interferon-α plus cytarabine. The safety and efficacy of imatinib in patients who crossed over from interferon-α plus cytarabine to imatinib is reported here.

Results

Of 553 patients originally assigned to interferon-α plus cytarabine, 65% crossed over to imatinib, of whom 67% continue to receive treatment. After a median of 54 months of imatinib treatment on study, 93% achieved complete hematologic remission, 86% achieved major cytogenetic remission, and 81% achieved a complete cytogenetic remission as the best observed response. Estimated rates of freedom from progression to accelerated or blast phase and overall survival were 91% and 89%, respectively, at 48 months after starting imatinib.

Conclusions

This is the largest analysis to date describing the efficacy of imatinib in patients who have received prior therapies for chronic myeloid leukemia and it demonstrates excellent responses to this treatment. (ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00006343","term_id":"NCT00006343"}}NCT00006343)     

Subcutaneous injections of low-dose veltuzumab (humanized anti-CD20 antibody) are safe and active in patients with indolent non-Hodgkin's lymphoma

Background

Subcutaneous injections of anti-CD20 antibodies may offer benefits to both patients and the healthcare system for treatment of B-cell malignancies.

Design and Methods

A pilot study was undertaken to evaluate the potential for subcutaneous dosing with 2^nd generation anti-CD20 antibody veltuzumab in patients with CD20⁺ indolent non-Hodgkin’s lymphoma. Patients with previously untreated or relapsed disease received 4 doses of 80, 160, or 320 mg veltuzumab injected subcutaneously every two weeks. Responses were assessed by computed tomography scans, with other evaluations including adverse events, safety laboratories, B-cell blood levels, serum veltuzumab levels, and human anti-veltuzumab antibody (HAHA) titers.

Results

Seventeen patients (14 follicular lymphoma; 13 stage III or IV disease; 5 treatment-naive) completed treatment with only occasional, mild-moderate, transient injection reactions and no other safety issues. Subcutaneous veltuzumab demonstrated a slow release pattern over several days, achieving a mean Cmax of 19, 25 and 63 μg/mL at 80, 160, and 320 mg doses for a total of 4 administrations, respectively. Depletion of circulating B cells occurred after the first injection. The objective response rate (partial responses plus complete responses plus complete responses unconfirmed) was 47% (8/17) with a complete response/complete response unconfirmed rate of 24% (4/17); 4 of 8 objective responses continued for 60 weeks or more. All serum samples evaluated for human anti-veltuzumab antibody were negative.

Conclusions

Subcutaneous injections of low-dose veltuzumab are convenient, well tolerated, and capable of achieving sustained serum levels, B-cell depletion, and durable objective responses in indolent non-Hodgkin’s lymphoma. (Clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00546793","term_id":"NCT00546793"}}NCT00546793)     

Impact of post-remission therapy in patients aged 65-70 years with de novo acute myeloid leukemia: a comparison of two concomitant randomized ALFA trials with overlapping age inclusion criteria

Background

There is no standard post-remission therapy in older patients with acute myeloid leukemia.

Design and Methods

From 1999 to 2006, the Acute Leukemia French Association group ran two concurrent randomized trials with overlapping inclusion criteria for patients aged 65 to 70 with acute myeloid leukemia, with different post-remission strategies: two intensive courses in the 9801 trial, one intensive course or six outpatient courses in the 9803 trial. We analyzed the outcome of these patients per protocol and per post-remission therapy.

Results

Two hundred and eleven patients aged 65 to 70 years with de novo acute myeloid leukemia were enrolled in trial 9801 (n=76) or 9803 (n=135). The patients in the two trials had comparable white blood cell counts (P=0.3), cytogenetics (P=0.49), and complete remission rates (70% and 57%, respectively; P=0.17). Overall survival was identical in both trials (32% and 34% at 2 years, respectively; P=0.71). Overall survival after complete remission was identical in the 103 of 130 patients who received the planned post-remission courses (n=44 with two intensive courses, n=28 with one intensive course, n=31 with six outpatient courses; 41%, 55%, and 58% at 2 years, respectively; P=0.34). Even in patients with favorable or normal karyotype (n=97), overall survival from complete remission was not improved by more intensive post-remission therapy.

Conclusions

In patients aged 65 to 70 years with de novo acute myeloid leukemia in complete remission after standard intensive induction chemotherapy, there is no apparent benefit from intensive post-remission therapy. (ClinicalTrials.gov Identifiers: {"type":"clinical-trial","attrs":{"text":"NCT00931138","term_id":"NCT00931138"}}NCT00931138 and {"type":"clinical-trial","attrs":{"text":"NCT00363025","term_id":"NCT00363025"}}NCT00363025)     

Posaconazole prophylaxis during front-line chemotherapy of acute myeloid leukemia: a single-center, real-life experience

Background

Posaconazole is effective as primary antifungal prophylaxis of invasive fungal diseases in patients with acute myeloid leukemia.

Design and Methods

The impact of primary antifungal prophylaxis administered during front-line chemotherapy for acute myeloid leukemia was evaluated by comparing 58 patients who received oral amphotericin B (control group) to 99 patients who received oral posaconazole (posaconazole group). The primary endpoint was the incidence of proven/probable invasive fungal diseases. Secondary endpoints included incidence of invasive aspergillosis, survival at 4 and 12 months after the diagnosis of acute myeloid leukemia and costs.

Results

Proven/probable invasive fungal diseases were documented in 51.7% of patients in the control group and in 23.2% in the posaconazole group (P=0.0002). Invasive aspergillosis was documented in 43% of patients in the control group and in 15% in the posaconazole group (P=0.002). No survival difference was observed in patients aged over 60 years. In patients aged 60 years or less, a statistically significant survival advantage was observed at 4 months, but no longer at 12 months, in the posaconazole group (P=0.03). It was calculated that in the posaconazole group there was a mean 50% cost reduction for the antifungal drugs.

Conclusions

Primary antifungal prophylaxis with posaconazole during front-line chemotherapy was effective in preventing invasive fungal diseases in a “real-life” scenario of patients with acute myeloid leukemia, resulted in an early but transitory survival advantage in younger patients and was economically advantageous.     

FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with normal karyotype

Background

Several genetic aberrations with prognostic impact in first-line therapy have been described in patients with acute myeloid leukemia and normal karyotype. However, little is known about the influence of these aberrations on outcome after relapse. This study aimed to identify clinical and molecular risk factors for patients with relapsed acute myeloid leukemia with normal karyotype.

Design and Methods

We analyzed 94 patients with acute myeloid leukemia and normal karyotype after first relapse for clinical and molecular risk factors for survival. All patients had received first-line treatment and follow-up within two prospective, multicenter trials. Leukemic blasts were analyzed at diagnosis for genetic aberrations in the FLT3, NPM1, CEBPA, WT1, IDH1 and IDH2 genes by polymerase chain reaction and/or direct sequencing.

Results

A second complete remission was achieved in 52% of patients who received re-induction therapy. The presence of an FLT3-internal tandem duplication, duration of first complete remission less than 6 months and age above the median of 47 years were associated with a significantly lower rate of second complete remission. The median survival after relapse was 11 months and the 6-year survival rate was 28%. In multivariate analysis, FLT3-internal tandem duplication and age above the median were the only independent negative prognostic factors for survival. The 6-year survival rate of patients with none of these factors was 56%, whereas it was significantly inferior in patients with one or both of these factors (15% and 6%, respectively). This was also true for patients who underwent allogeneic stem cell transplantation after relapse.

Conclusions

FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with a normal karyotype. Patients with at least one of these risk factors have a dismal outcome and might be considered for investigational treatment approaches after relapse. (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00209833","term_id":"NCT00209833"}}NCT00209833)     

Telomere length is associated with disease severity and declines with age in dyskeratosis congenita

Background

Dyskeratosis congenita is a cancer-prone bone marrow failure syndrome caused by aberrations in telomere biology.

Design and Methods

We studied 65 patients with dyskeratosis congenita and 127 unaffected relatives. Telomere length was measured by automated multicolor flow fluorescence in situ hybridization in peripheral blood leukocyte subsets. We age-adjusted telomere length using Z-scores (standard deviations from the mean for age).

Results

We confirmed that telomere lengths below the first percentile for age are very sensitive and specific for the diagnosis of dyskeratosis congenita. We provide evidence that lymphocytes alone and not granulocytes may suffice for clinical screening, while lymphocyte subsets may be required for challenging cases, including identification of silent carriers. We show for the first time using flow fluorescence in situ hybridization that the shortest telomeres are associated with severe variants (Hoyeraal-Hreidarsson and Revesz syndromes), mutations in DKC1, TINF2, or unknown genes, and moderate or severe aplastic anemia. In the first longitudinal follow up of dyskeratosis congenita patients, we demonstrate that telomere lengths decline with age, in contrast to the apparent stable telomere length observed in cross-sectional data.

Conclusions

Telomere length by flow fluorescence in situ hybridization is an important diagnostic test for dyskeratosis congenita; age-adjusted values provide a quantitative measure of disease severity (clinical subset, mutated gene, and degree of bone marrow failure). Patients with dyskeratosis congenita have accelerated telomere shortening. This study is registered at www.clinicaltrials.gov (identifier: {"type":"clinical-trial","attrs":{"text":"NCT00027274","term_id":"NCT00027274"}}NCT00027274).     

Detection of minimal residual disease following induction immunochemotherapy predicts progression free survival in mantle cell lymphoma: final results of CALGB 59909

Background

In the present study, the prognostic impact of minimal residual disease during treatment on time to progression and overall survival was analyzed prospectively in patients with mantle cell lymphoma treated on the Cancer and Leukemia Group B 59909 clinical trial.

Design and Methods

Peripheral blood and bone marrow samples were collected during different phases of the Cancer and Leukemia Group B 59909 study for minimal residual disease analysis. Minimal residual disease status was determined by quantitative polymerase chain reaction of IgH and/or BCL-1/JH gene rearrangement. Correlation of minimal residual disease status with time to progression and overall survival was determined. In multivariable analysis, minimal residual disease, and other risk factors were correlated with time to progression.

Results

Thirty-nine patients had evaluable, sequential peripheral blood and bone marrow samples for minimal residual disease analysis. Using peripheral blood monitoring, 18 of 39 (46%) achieved molecular remission following induction therapy. The molecular remission rate increased from 46 to 74% after one course of intensification therapy. Twelve of 21 minimal residual disease positive patients (57%) progressed within three years of follow up compared to 4 of 18 (22%) molecular remission patients (P=0.049). Detection of minimal residual disease following induction therapy predicted disease progression with a hazard ratio of 3.7 (P=0.016). The 3-year probability of time to progression among those who were in molecular remission after induction chemotherapy was 82% compared to 48% in patients with detectable minimal residual disease. The prediction of time to progression by post-induction minimal residual disease was independent of other prognostic factors in multivariable analysis.

Conclusions

Detection of minimal residual disease following induction immunochemotherapy was an independent predictor of time to progression following immunochemotherapy and autologous stem cell transplantation for mantle cell lymphoma. The clinical trial was registered at ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT00020943","term_id":"NCT00020943"}}NCT00020943.     

High-dose imatinib induction followed by standard-dose maintenance in pre-treated chronic phase chronic myeloid leukemia patients �C final analysis of a randomized, multicenter, phase III trial

Background

Previous data suggest that the response of chronic myeloid leukemia cells to imatinib is dose-dependent. The potential benefit of initial dose intensification of imatinib in pre-treated patients with chronic phase chronic myeloid leukemia remains unknown.

Design and Methods

Two hundred and twenty-seven pre-treated patients with chronic myeloid leukemia in chronic phase were randomly assigned to continuous treatment with a standard dose of imatinib (400 mg/day; n=113) or to 6 months of high-dose induction with imatinib (800 mg/day) followed by a standard dose of imatinib as maintenance therapy (n=114).

Results

The rates of major and complete cytogenetic responses were significantly higher in the high-dose arm than in the standard-dose arm at both 3 and 6 months (major cytogenetic responses: 36.8% versus 21.2%, P=0.01 and 50.0% versus 34.5%, P=0.018; complete cytogenetic responses: 22.8% versus 6.2%, P<0.001 and 40.4% versus 16.8%, P<0.001) on the basis of an intention-to-treat analysis. At 12 months, the difference between treatment arms remained statistically significant for complete cytogenetic responses (40.4% versus 24.8%, P=0.012) but not for major cytogenetic responses (49.1% versus 44.2%, P=0.462). The rate of major molecular responses was also significantly better at 3 and 6 months in the high-dose arm (month 3: 14.9% versus 3.5%, P=0.003; month 6: 32.5% versus 8.8%, P<0.001). Overall and progression-free survival rates were comparable between arms, but event-free survival was significantly worse in the high-dose arm (P=0.014).

Conclusions

Standard-dose imatinib remains the standard of care for pre-treated patients with chronic phase chronic myeloid leukemia (Clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00327262","term_id":"NCT00327262"}}NCT00327262).Key words: CML, chronic phase, pre-treated, imatinib, high-dose, phase III study     

Efficacy of escalated imatinib combined with cytarabine in newly diagnosed patients with chronic myeloid leukemia

Background

In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with chronic myeloid leukemia in the HOVON-51 study.

Design and Methods

Having reported feasibility previously, we hereby report the efficacy of escalated imatinib (200 mg, 400 mg, 600 mg or 800 mg) in combination with two cycles of intravenous cytarabine (200 mg/m² or 1000 mg/m² days 1 to 7) in 162 patients with chronic myeloid leukemia.

Results

With a median follow-up of 55 months, the 5-year cumulative incidences of complete cytogenetic response, major molecular response, and complete molecular response were 89%, 71%, and 53%, respectively. A higher Sokal risk score was inversely associated with complete cytogenetic response (hazard ratio of 0.63; 95% confidence interval, 0.50–0.79, P<0.001). A higher dose of imatinib and a higher dose of cytarabine were associated with increased complete molecular response with hazard ratios of 1.60 (95% confidence interval, 0.96–2.68, P=0.07) and 1.66 (95% confidence interval, 1.02–2.72, P=0.04), respectively. Progression-free survival and overall survival rates at 5 years were 92% and 96%, respectively. Achieving a major molecular response at 1 year was associated with complete absence of progression and a probability of achieving a complete molecular response of 89%.

Conclusions

The addition of intravenous cytarabine to imatinib as upfront therapy for patients with chronic myeloid leukemia is associated with a high rate of complete molecular responses (Clinicaltrials.Gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00028847","term_id":"NCT00028847"}}NCT00028847).     

Gene mutations and response to treatment with all-trans retinoic acid in elderly patients with acute myeloid leukemia. Results from the AMLSG Trial AML HD98B

Background

In a previous randomized trial, AML HD98B, we showed that administration of all-trans retinoic acid in addition to intensive chemotherapy improved the outcome of older patients with acute myeloid leukemia. The objectives of this study were to evaluate the prognostic impact of gene mutations and to identify predictive genetic factors for the all-trans retinoic acid treatment effect.

Design and Methods

Data from mutation analyses of the NPM1, CEBPA, FLT3, and MLL genes were correlated with outcome in patients 61 years and older treated within the AML HD98B trial.

Results

The frequencies of mutations were: NPM1, 23%; CEBPA, 8.5% (analysis restricted to patients with a normal karyotype); FLT3 internal tandem duplications (ITD), 17%; FLT3 tyrosine kinase domain mutations, 5%; and MLL partial tandem duplications, 4.5%. The genotype mutant NPM1 was positively and adverse cytogenetics as well as higher white blood cell count negatively correlated with achievement of complete remission. In Cox regression analysis, a significant interaction between the genotype mutant NPM1 without FLT3-ITD and treatment with all-trans retinoic acid was identified, in that the beneficial effect of all-trans retinoic acid on relapse-free and overall survival was restricted to this subgroup of patients. Other significant factors for survival were age, adverse cytogenetics, and logarithm of white cell count.

Conclusions

In elderly patients with acute myeloid leukemia, NPM1 mutations are associated with achievement of complete remission, and the genotype ‘mutant NPM1 without FLT3-ITD’ appears to be a predictive marker for response to all-trans retinoic acid given as an adjunct to intensive chemotherapy (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00151242","term_id":"NCT00151242"}}NCT00151242).