Bortezomib consolidation following autologous transplant in younger and older patients with newly diagnosed multiple myeloma in two phase III trials.

OBJECTIVE: A post hoc analysis of two phase III trials was carried out to explore the influence of age and treatment factors on the effect of bortezomib consolidation on progression-free survival (PFS) post autologous stem cell transplantation (ASCT). METHODS: Patients with newly diagnosed multiple myeloma were assigned to one of two trials (ClinicalTrials.gov IDs: NCT00416273, NCT00416208), which were conducted in parallel, based on age (18-60 or 61-75 years, respectively). Following induction and ASCT, patients were randomized 1:1 to four 35-day cycles of bortezomib consolidation (1.6 mg/m2 IV on days 1, 8, 15, 22) or observation only. RESULTS: Median PFS with bortezomib consolidation vs observation was 33.6 vs 29.0 months (P = 0.3599) in patients aged 18-60 years (n = 202), and 33.4 vs 26.4 months (P = 0.0073) in patients aged 61-75 years (n = 155), respectively. Bortezomib consolidation post-ASCT appeared to equalize outcomes between older and younger patients who received prior treatment of differing intensity. This suggests that the effect of consolidation may be relative and may depend on the composition and intensity of induction and high-dose therapy. CONCLUSION: Older patients receiving less intensive prior treatment could experience a larger PFS benefit from bortezomib consolidation.

Autologous Stem Cell Transplantation for Patients with Early Progression of Follicular Lymphoma: A Follow-Up Study of 2 Randomized Trials from the German Low Grade Lymphoma Study Group.

Patients with follicular lymphoma (FL) and progression of disease (POD) within 24 months after frontline treatment (POD24) have poor overall survival (OS). The optimal salvage treatment for these patients is unknown. We assessed the role of high-dose therapy and autologous stem cell transplantation (ASCT) in transplant-eligible patients. We analyzed 162 patients with advanced-stage FL who had received frontline treatment within the GLSG1996 or GLSG2000 trials. All patients had POD at age ≤ 65 years and had not received a prior transplant. Second-line treatment was not specified by study protocols. Survival was calculated from time of second-line treatment. Eighteen patients (11%) progressed (n = 16) or died (n = 2) during cytoreductive second-line treatment (considered "cytoreduction failure"); none received ASCT, and their median second-line OS was <1 year. A total of 113 patients had POD24 (70%), whereas 49 had POD after 24 months (30%). Sixty-three patients without cytoreduction failure received ASCT (39%), and 81 received no transplant (50%). In patients with POD24, a significant survival benefit was associated with ASCT with a 5-year second-line progression-free survival for ASCT versus no transplant of 51% versus 19% (hazard ratio, .38; 95% confidence interval, .24 to .62; P < .0001) and a 5-year second-line OS of 77% versus 59% (hazard ratio, .54, 95% confidence interval, .30 to .95; P= .031). Thus, ASCT is an effective treatment option for transplant-eligible patients with high-risk FL as identified by POD24 and should be evaluated in prospective clinical trials.

Autotransplant with and without induction chemotherapy in older multiple myeloma patients: long-term outcome of a randomized trial.

Autologous transplantation is controversial for older patients with multiple myeloma. The role of age-adjusted high-dose melphalan and the impact of induction chemotherapy cycles is still unclear. A total of 434 patients aged 60-70 years were randomly assigned to 4 cycles of standard anthracycline-based induction chemotherapy or no induction. For all patients, double autologous transplantation after melphalan 140 mg/m2 (MEL140) was planned. The primary end point was progression-free survival. Of 420 eligible patients, 85% received a first transplant and 69% completed double transplantation. Treatment duration was short with a median of 7.7 months with induction chemotherapy cycles and 4.6 months without induction. On an intention-to-treat basis, median progression-free survival with induction chemotherapy cycles (207 patients) was 21.4 months versus 20.0 months with no induction cycles (213 patients) (hazard ratio 1.04, 95% confidence interval 0.84-1.28; P=0.36). Per protocol, progression-free survival was 23.7 months versus 23.0 months (P=0.28). Patients aged 65 years or over (55%) did not have an inferior outcome. Patients with low-risk cytogenetics [absence of del17p13, t(4;14) and 1q21 gains] showed a favorable overall survival and included the patients with sustained first remission. MEL140 was associated with a low rate of severe mucositis (10%) and treatment-related deaths (1%). Based on hazard ratio, the short treatment arm consisting of mobilization chemotherapy and tandem MEL140 achieved 96% of the progression-free survival, demonstrating its value as an independent component of therapy in older patients with multiple myeloma who are considered fit for autologous transplantation. (clinicaltrials.gov identifier: 02288741).

Allogeneic stem-cell transplantation in patients with NPM1-mutated acute myeloid leukemia: results from a prospective donor versus no-donor analysis of patients after upfront HLA typing within the SAL-AML 2003 trial.

PURPOSE: The presence of a mutated nucleophosmin-1 gene (NPM1(mut)) in acute myeloid leukemia (AML) is associated with a favorable prognosis. To assess the predictive value with regard to allogeneic stem-cell transplantation (SCT), we compared the clinical course of patients with NPM1(mut) AML eligible for allogeneic SCT in a donor versus no-donor analysis. PATIENTS AND METHODS: Of 1,179 patients with AML (age 18 to 60 years) treated in the Study Alliance Leukemia AML 2003 trial, we identified all NPM1(mut) patients with an intermediate-risk karyotype. According to the trial protocol, patients were intended to receive an allogeneic SCT if an HLA-identical sibling donor was available. Patients with no available donor received consolidation or autologous SCT. We compared relapse-free survival (RFS) and overall survival (OS) depending on the availability of a suitable donor. RESULTS: Of 304 eligible patients, 77 patients had a sibling donor and 227 had no available matched family donor. The 3-year RFS rates in the donor and no-donor groups were 71% and 47%, respectively (P = .005); OS rates were 70% and 60%, respectively (P = .114). In patients with normal karyotype and no FLT3 internal tandem duplication (n = 148), the 3-year RFS rates in the donor and no-donor groups were 83% and 53%, respectively (P = .004); and the 3-year OS rates were 81% and 75%, respectively (P = .300). CONCLUSION: Allogeneic SCT led to a significantly prolonged RFS in patients with NPM1(mut) AML. The absence of a statistically significant difference in OS is most likely a result of the fact that NPM1(mut) patients who experienced relapse responded well to salvage treatment. Allogeneic SCT in first remission has potent antileukemic efficacy and is a valuable treatment option in patients with NPM1(mut) AML with a sibling donor.

Granulocyte-colony stimulating factor response is superior to neutropenia duration in predicting the risk of infection after high-dose chemotherapy for myeloma and lymphoma.

The patient granulocyte-colony stimulating factor (G-CSF) response is represented by the leukocyte peak in the blood induced by a single dose of G-CSF after chemotherapy, and is correlated with subsequent neutropenic infection risk. General patterns for a meaningful risk group stratification, have not yet been determined. Two independent data sets including a total of 306 cases with myeloma or lymphoma and autologous blood stem cell transplant were available. An infection susceptibility curve plotted according to ranked G-CSF responses from a multicenter study reproduced and validated a curve from the previous single center. Two trend changes were seen within these curves at around 11,000 and 22,000 leukocytes/µL, which separated three groups with a high, medium and low risk of infection. While G-CSF response is related to the consecutive duration of neutropenia, it retains additional independent predictive information for infection risk (p<0.0001) and, more important, is a tool available before the onset of the critical period.

Platelet transfusion in hematology, oncology and surgery.

BACKGROUND: The standard recommendation to date has been that acute hypoproliferative thrombocytopenia should be treated with a prophylactic platelet transfusion if the morning platelet count is less than 10 000/µL, or less than 20 000/µL if there are additional risk factors. For chronic thrombocytopenia, transfusion has been recommended if the platelet count is less than 5000/µL. In Germany, half a million platelet transfusions are now being given every year, and the number is rising. New studies indicate, however, that a more restrictive transfusion strategy is justified. METHODS: A selective literature search was carried out in PubMed, with additional attention to recommendations from Germany and abroad, and to the guidelines of medical specialty societies. RESULTS: Prophylactic platelet transfusions should be given when clinically indicated in consideration of the individual hemorrhagic risk. To prevent severe hemorrhage, it is more important to respond to the first signs of bleeding than to pay exclusive attention to morning platelet counts below 10 000/µL. This threshold value remains standard for patients with acute leukemia. According to recent studies, however, clinically stable patients who are at low risk for bleeding-e.g., patients who have undergone autologous hematopoietic stem-cell transplantation-may be well served by a therapeutic, rather than prophylactic, platelet transfusion strategy, in which platelets are transfused only when evidence of bleeding has been observed. For cancer patients, intensive-care patients, and patients with other risk factors, a clinically oriented transfusion strategy is recommended, in addition to close attention to threshold platelet values. CONCLUSION: The number of platelet transfusions could be safely lowered by a more restrictive transfusion strategy that takes account of the risk of bleeding, as recommended in the hemotherapy guidelines.

Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial.

PURPOSE: The prognosis of elderly patients with acute myeloid leukemia (AML) is still dismal even with intensive chemotherapy. In this trial, we compared the antileukemic activity of standard induction and consolidation therapy with or without the addition of the kinase inhibitor sorafenib in elderly patients with AML. PATIENTS AND METHODS: All patients received standard cytarabine and daunorubicin induction (7+3 regimen) and up to two cycles of intermediate-dose cytarabine consolidation. Two hundred one patients were equally randomly assigned to receive either sorafenib or placebo between the chemotherapy cycles and subsequently for up to 1 year after the beginning of therapy. The primary objective was to test for an improvement in event-free survival (EFS). Overall survival (OS), complete remission (CR) rate, tolerability, and several predefined subgroup analyses were among the secondary objectives. RESULTS: Age, sex, CR and early death (ED) probability, and prognostic factors were balanced between both study arms. Treatment in the sorafenib arm did not result in significant improvement in EFS or OS. This was also true for subgroup analyses, including the subgroup positive for FLT3 internal tandem duplications. Results of induction therapy were worse in the sorafenib arm, with higher treatment-related mortality and lower CR rates. More adverse effects occurred during induction therapy in the sorafenib arm, and patients in this arm received less consolidation chemotherapy as a result of higher induction toxicity. CONCLUSION: In conclusion, combination of standard induction and consolidation therapy with sorafenib in the schedule investigated in our trial is not beneficial for elderly patients with AML.

Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with haematological malignancies: an open-label, multicentre, randomised study.

BACKGROUND: Routine prophylactic platelet transfusion is the standard of care for patients with severe thrombocytopenia. We assessed the effect of a new strategy of therapeutic platelet transfusion on the number of transfusions and safety in patients with hypoproliferative thrombocytopenia. METHODS: We did a multicentre, open-label, randomised parallel-group trial at eight haematology centres in Germany. Patients aged 16-80 years, who were undergoing intensive chemotherapy for acute myeloid leukaemia or autologous haemopoietic stem-cell transplantation for haematological cancers, were randomly assigned via a computer-generated randomisation sequence to receive either platelet transfusion when bleeding occurred (therapeutic strategy) or when morning platelet counts were 10×10(9) per L or lower (prophylactic strategy). Investigators undertaking interventions were not masked to group assignment. The primary endpoint was the number of platelet transfusions. Analysis was by intention to treat. This trial is registered, NCT00521664. FINDINGS: 197 patients were assigned the prophylactic strategy and 199 the therapeutic strategy. Of 391 patients analysed, the therapeutic strategy reduced the mean number of platelet transfusions by 33·5% (95% CI 22·2-43·1; p<0·0001) in all patients (2·44 [2·22-2·67] in prophylactic group vs 1·63 [1·42-1·83] in therapeutic group), 31·6% (18·6-42·6; p<0·0001) in those with acute myeloid leukaemia (2·68 [2·35-3·01] vs 1·83 [1·58-2·10]), and 34·2% (6·6-53·7; p=0·0193) in those who had had autologous transplantation (1·80 [1·45-2·15] vs 1·18 [0·82-1·55]. We noted no increased risk of major haemorrhage in patients who had undergone autologous transplantation. In those with acute myeloid leukaemia, risk of non-fatal grade 4 (mostly CNS) bleeding was increased. We recorded 15 cases of non-fatal haemorrhage: four retinal in each transfusion group, and one vaginal and six cerebral in the therapeutic group. 12 patients died in the study: two from fatal cerebral haemorrhages in the therapeutic group, and ten (five in each treatment group) unrelated to major bleeding. INTERPRETATION: The therapeutic strategy could become a new standard of care after autologous stem-cell transplantation; however, prophylactic platelet transfusion should remain the standard for patients with acute myeloid leukaemia. The new strategy should be used by some haematology centres only if the staff are well educated and experienced in the new approach and can react in a timely way to first signs of CNS bleeding. FUNDING: Deutsche Krebshilfe eV (German Cancer Aid).

Long-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the European LeukemiaNet recommendations: evaluation of the proposed reporting system.

PURPOSE: The current European LeukemiaNet (ELN) recommendations for acute myeloid leukemia (AML) propose a new risk reporting system, integrating molecular and cytogenetic factors and subdividing the large heterogenous group of intermediate-risk patients into intermediate-I (IR-I) and intermediate-II (IR-II). We assessed the prognostic value of the new risk classification in a large cohort of patients. PATIENTS AND METHODS: Complete data for classification were available for 1,557 of 1,862 patients treated in the AML96 trial. Patients were assigned to the proposed genetic groups from the ELN recommendations, and survival analyses were performed using the Kaplan-Meier method and log-rank test for significance testing. RESULTS: The median age of all patients was 67 years. With a median follow-up of 8.3 years, significant differences between all risk categories were observed in patients age ≤ 60 years regarding the time to relapse, relapse-free survival, and overall survival (OS). Patients in the IR-II group had a better prognosis than patients in the IR-I group. The median OS times in young patients with favorable risk (FR), IR-I, IR-II, and adverse risk (AR) were 5.3, 1.1, 1.6, and 0.5 years, respectively. Separate analyses in the age group older than 60 years revealed significant differences between FR, AR, and IR as a whole, but not between IR-I and IR-II. CONCLUSION: In younger patients with AML, the ELN classification seems to be the best available framework for prognostic estimations to date. Caution is advised concerning its use for prospective treatment allocation before it has been prospectively validated. In elderly patients, alternative prognostic factors are desirable for further risk stratification of IR.

Cytarabine dose of 36 g/m² compared with 12 g/m² within first consolidation in acute myeloid leukemia: results of patients enrolled onto the prospective randomized AML96 study.

PURPOSE: To assess the optimal cumulative dose of cytarabine for treatment of young adults with acute myeloid leukemia (AML) within a prospective multicenter treatment trial. PATIENTS AND METHODS: Between 1996 and 2003, 933 patients (median age, 47 years; range 15 to 60 years) with untreated AML were randomly assigned at diagnosis to receive cytarabine within the first consolidation therapy at either a intermediate-dose of 12 g/m² (I-MAC) or a high-dose of 36 g/m² (H-MAC) combined with mitoxantrone. Autologous hematopoietic stem-cell transplantation or intermediate-dose cytarabine (10 g/m²) were offered as second consolidation. Patients with a matched donor could receive an allogeneic transplantation in a risk-adapted manner. RESULTS: After double induction therapy including intermediate-dose cytarabine (10 g/m²), mitoxantrone, etoposide, and amsacrine, complete remission was achieved in 66% of patients. In the primary efficacy analysis population, a consolidation with either I-MAC or H-MAC did not result in significant differences in the 5-year overall (30% v 33%; P = .77) or disease-free survival (37% v 38%; P = .86) according to the intention-to-treat analysis. Besides a prolongation of neutropenia and higher transfusion demands in the H-MAC arm, rates of serious adverse events were comparable in the two groups. CONCLUSION: In young adults with AML receiving intermediate-dose cytarabine induction, intensification of the cytarabine dose beyond 12 g/m² within first consolidation did not improve treatment outcome.

Testing G-CSF responsiveness predicts the individual susceptibility to infection and consecutive treatment in recipients of high-dose chemotherapy.

The individual risk of infection and requirements for medical treatment after high-dose chemotherapy have been unpredictable. In this prospective, multicenter, open-label study we investigated the potential of granulocyte colony-stimulating factor (G-CSF) responsiveness as a predictor. A total of 168 patients with multiple myeloma or lymphoma received a single dose of subcutaneous G-CSF (lenograstim, 263 µg) after high-dose chemotherapy. Highly variable leukocyte peaks were measured and grouped as low (quartile 1; leukocytes 100-10 100/µL), medium (quartile 2; leukocytes > 10 100-18 300/µL), and high (quartiles 3/4; leukocytes > 18 300-44 800/µL). G-CSF responsiveness (low vs medium vs high) was inversely correlated with febrile neutropenia (77% vs 60% vs 48%; P = .0037); the rate of infection, including fever of unknown origin (91% vs 67% vs 54%; P < .0001); days with intravenous antibiotics (9 vs 6 vs 5; P < .0001); and antifungal therapy (P = .042). In multivariate analysis, G-CSF responsiveness remained the only factor significantly associated with infection (P = .016). In addition, G-CSF responsiveness was inversely correlated with grade 3/4 oral mucositis (67% vs 33% vs 23%; P < .0001). G-CSF responsiveness appears as a signature of the myeloid marrow reserve predicting defense against neutropenic infection after intensive chemotherapy. This study is registered at http://www.clinicaltrials.gov as NCT01085058.

Allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies after dose-escalated treosulfan/fludarabine conditioning.

PURPOSE: Treosulfan was introduced recently as a conditioning agent for allogeneic blood stem-cell transplantation. The favorable nonhematologic toxicity profile at 3 x 10 g/m(2) was the basis for dose escalation in this prospective, multicenter trial. PATIENTS AND METHODS: Fifty-six patients with various hematologic malignancies who were not eligible for standard conditioning were treated with one of three doses: 10 g/m(2), 12 g/m(2), or 14 g/m(2) of intravenous treosulfan, which was administered on days -6 to -4 combined with fludarabine 30 mg/m(2) on days -6 to -2. Patients in complete remission (CR; 42%) or non-CR (58%) received grafts from matched related (47%) or matched unrelated (51%) donors; one patient had a mismatched related donor (2%). RESULTS: No engraftment failure occurred. Overall, extramedullary toxicity and the nonrelapse mortality rate at 2 years (20%) were low and did not increase with dose. Cumulative incidence of relapse/progression reached 31%. The overall survival and progression-free survival rates were 64% and 49%, respectively, in the total study population. An inverse dose dependency of relapse incidence was indicated in the subgroup receiving transplantations from matched related donors (P = .0568). CONCLUSION: Treosulfan-based conditioning was feasible at all three doses. The 3 x 14 g/m(2) dose was selected for additional studies, because it combines desired characteristics of low toxicity and a low relapse rate.

A novel prognostic model in elderly patients with acute myeloid leukemia: results of 909 patients entered into the prospective AML96 trial.

We present an analysis of prognostic factors derived from a trial in patients with acute myeloid leukemia older than 60 years. The AML96 trial included 909 patients with a median age of 67 years (range, 61-87 years). Treatment included cytarabine-based induction therapy followed by 1 consolidation. The median follow-up time for all patients is 68 months (5.7 years). A total of 454 of all 909 patients reached a complete remission (50%). Five-year overall survival (OS) and disease-free survival were 9.7% and 14%, respectively. Multivariate analyses revealed that karyotype, age, NPM1 mutation status, white blood cell count, lactate dehydrogenase, and CD34 expression were of independent prognostic significance for OS. On the basis of the multivariate Cox model, an additive risk score was developed that allowed the subdivision of the largest group of patients with an intermediate-risk karyotype into 2 groups. We are, therefore, able to distinguish 4 prognostic groups: favorable risk, good intermediate risk, adverse intermediate risk, and high risk. The corresponding 3-year OS rates were 39.5%, 30%, 10.6%, and 3.3%, respectively. The risk model allows further stratification of patients with intermediate-risk karyotype into 2 prognostic groups with implications for the therapeutic strategy.

Long-term follow-up of an intensified myeloablative conditioning regimen with in vivo T cell depletion followed by allografting in patients with advanced multiple myeloma.

We report long-term results after a median follow-up of 105 months in 18 patients with multiple myeloma who received an intensified myeloablative conditioning regimen regimen consisting of modified total body irradiation, busulfan, cyclophosphamide, and antithymocyte globulin, followed by allogeneic stem cell transplantation (SCT). Grade II-IV acute graft-versus-host disease occurred in 7 patients (44%), and treatment-related mortality was 17%. Complete remission (CR) with negative immunofixation after allogeneic SCT occurred in 53% of the patients. For all patients, the estimated overall survival at 12 years was 50% (95% confidence interval [CI], 26%-74%), and the estimated event-free survival (EFS) was 35% (95% CI, 23%-57%). Those patients who achieved CR after SCT had a 12-year estimated PFS of 60%, whereas none of the patients without CR remained progression-free. Our data indicate that an intensified myeloablative conditioning regimen followed by allogeneic SCT can produce long-term survival and freedom from disease in patients with multiple myeloma who achieve CR.

Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

From 2002 to 2007, 103 patients with primary myelofibrosis or postessential thrombocythemia and polycythemia vera myelofibrosis and a median age of 55 years (range, 32-68 years) were included in a prospective multicenter phase 2 trial to determine efficacy of a busulfan (10 mg/kg)/fludarabine (180 mg/m(2))-based reduced-intensity conditioning regimen followed by allogeneic stem cell transplantation from related (n = 33) or unrelated donors (n = 70). All but 2 patients (2%) showed leukocyte and platelet engraftment after a median of 18 and 22 days, respectively. Acute graft-versus-host disease grade 2 to 4 occurred in 27% and chronic graft-versus-host disease in 43% of the patients. Cumulative incidence of nonrelapse mortality at 1 year was 16% (95% confidence interval, 9%-23%) and significantly lower for patients with a completely matched donor (12% vs 38%; P = .003). The cumulative incidence of relapse at 3 years was 22% (95% confidence interval, 13%-31%) and was influenced by Lille risk profile (low, 14%; intermediate, 22%; and high, 34%; P = .02). The estimated 5-year event-free and overall survival was 51% and 67%, respectively. In a multivariate analysis, age older than 55 years (hazard ratio = 2.70; P = .02) and human leukocyte antigen-mismatched donor (hazard ratio = 3.04; P = .006) remained significant factors for survival. The study was registered at www.clinicaltrials.gov as #NCT 00599547.

MLD according to the WHO classification in AML has no correlation with age and no independent prognostic relevance as analyzed in 1766 patients.

Between February 1996 and December 2004, the German Leukemia Study Initiative registered 1766 consecutive patients for the acute myeloid leukemia (AML) 96 study, all of whom were diagnosed by central cytomorphology according to the French-American-British (FAB) and the new World Health Organization (WHO) classification. We focused our analysis on the prognostic impact of multilineage dysplasia (MLD) as a new parameter of the WHO classification for AML. We could not confirm the WHO statement that MLD occurs most frequently in older individuals, but we confirmed that MLD is often associated with an unfavorable cytogenetic profile (P < .001). In 1332 individuals receiving intensive AML therapy presence of MLD was negatively correlated with complete remission (P = .001) in univariate, but not in multivariate, analysis. Multivariate analysis of either event-free or overall survival again failed to show an independent prognostic significance of MLD besides age, cytogenetics, and, in part, NPM1/FLT3-ITD mutations. Our data support a reassessment of the WHO classification in the light of a more biologic understanding of AML. This study is registered at www.ClinicalTrials.gov as #NCT00180115.