Sequential Conditioning with Thiotepa in T Cell- Replete Hematopoietic Stem Cell Transplantation for the Treatment of Refractory Hematologic Malignancies: Comparison with Matched Related, Haplo-Mismatched, and Unrelated Donors.

The results of conventional allogeneic stem cell transplantation (SCT) in refractory hematologic malignancies are poor. Sequential strategies have shown promising results in refractory acute myelogenous leukemia (AML), but have not been validated in a haploidentical (Haplo) transplant setting. We have developed a new sequential approach combining chemotherapy with broad antitumor activity (thiotepa 10 mg/kg, etoposide 400 mg/m2, and cyclophosphamide 1600 mg/m2 from day -15 to day -10), followed after 3 days of rest by a reduced-intensity conditioning regimen (fludarabine 150 mg/m2, i.v. busulfan 6.4 mg/kg, and thymoglobulin 5 mg/kg from day -6 to day -2). High-dose post-transplantation cyclophosphamide was added in cases with Haplo donors. Seventy-two patients (median age, 54 years) with a refractory hematologic malignancy (44 with acute myelogenous leukemia, 7 with acute lymphoblastic leukemia, 15 with myelodysplastic syndrome/myeloproliferative neoplasms, and 6 with lymphomas) were included in this retrospective multicenter study. Donors were Haplo (n = 27), matched related (MRD; n = 16), and unrelated (UD; n = 29). With a median follow-up of 21 months, the 2-year overall survival (OS) and event-free survival (EFS) were 54.7% and 49.3%, respectively, in recipients of Haplo transplants, 49.2% and 43.8%, respectively, in recipients of MRD transplants, and 37.9% and 28%, respectively, in recipients of UD transplants. Compared with UD, the outcomes were improved in Haplo in terms of the incidences of acute grade II-IV graft-versus-host disease (GVHD) (11.1% versus 41.4%; P < .001) and GVHD-free, relapse-free survival (44.4 versus 10.3%; P = .022). These results support the safety and efficacy of a thiotepa-based sequential approach in allogeneic SCT with a Haplo donor with post-transplantation immune modulation. Thus, in patients with refractory hematologic malignancies, there seems to be no benefit in searching for a UD when a Haplo donor is readily available.

Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL.

Prognosis of Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL) in the elderly has improved during the imatinib era. We investigated dasatinib, another potent tyrosine kinase inhibitor, in combination with low-intensity chemotherapy. Patients older than age 55 years were included in the European Working Group on Adult ALL (EWALL) study number 01 for Ph(+) ALL (EWALL-PH-01 international study) and were treated with dasatinib 140 mg/day (100 mg/day over 70 years) with intrathecal chemotherapy, vincristine, and dexamethasone during induction. Patients in complete remission continued consolidation with dasatinib, sequentially with cytarabine, asparaginase, and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone reinductions for 18 months followed by dasatinib until relapse or death. Seventy-one patients with a median age of 69 years were enrolled; 77% had a high comorbidity score. Complete remission rate was 96% and 65% of patients achieved a 3-log reduction in BCR-ABL1 transcript levels during consolidation. Only 7 patients underwent allogeneic hematopoietic stem cell transplantation. At 5 years, overall survival was 36% and up to 45% taking into account deaths unrelated to disease or treatment as competitors. Thirty-six patients relapsed, 24 were tested for mutation by Sanger sequencing, and 75% were T315I-positive. BCR-ABL1(T315I) was tested by allele-specific oligonucleotide reverse transcription-quantitative polymerase chain reaction in 43 patients and detection was associated with short-term relapses. Ten patients (23%) were positive before any therapy and 8 relapsed, all with this mutation. In conclusion, dasatinib combined with low-intensity chemotherapy was well-tolerated and gave long-term survival in 36% of elderly patients with Ph(+) ALL. Monitoring of BCR-ABL1(T315I) from diagnosis identified patients with at high risk of early relapse and may help to personalize therapy.

A phase II study of the oral JAK1/JAK2 inhibitor ruxolitinib in advanced relapsed/refractory Hodgkin lymphoma.

JAK2 constitutive activation/overexpression is common in classical Hodgkin lymphoma, and several cytokines stimulate Hodgkin lymphoma cells by recognizing JAK1-/JAK2-bound receptors. JAK blockade may thus be therapeutically beneficial in Hodgkin lymphoma. In this phase II study we assessed the safety and efficacy of ruxolitinib, an oral JAK1/2 inhibitor, in patients with relapsed/refractory Hodgkin lymphoma. The primary objective was overall response rate according to the International Harmonization Project 2007 criteria. Thirty-three patients with advanced disease (median number of prior lines of treatment: 5; refractory: 82%) were included; nine (27.3%) received at least six cycles of ruxolitinib and six (18.2%) received more than six cycles. The overall response rate after six cycles was 9.4% (3/32 patients). All three responders had partial responses; another 11 patients had transient stable disease. Best overall response rate was 18.8% (6/32 patients). Rapid alleviation of B-symptoms was common. The median duration of response was 7.7 months, median progression-free survival 3.5 months (95% CI: 1.9-4.6), and the median overall survival 27.1 months (95% CI: 14.4-27.1). Forty adverse events were reported in 14/33 patients (42.4%). One event led to treatment discontinuation, while 87.5% of patients recovered without sequelae. Twenty-five adverse events were grade 3 or higher. These events were mostly anemia (n=11), all considered related to ruxolitinib. Other main causes of grade 3 or higher adverse events included lymphopenia and infections. Of note, no cases of grade 4 neutropenia or thrombocytopenia were observed. Ruxolitinib shows signs of activity, albeit short-lived, beyond a simple anti-inflammatory effect. Its limited toxicity suggests that it has the potential to be combined with other therapeutic modalities. ClinicalTrials.gov: NCT01877005.

Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia.

Because a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome-negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10(-3) (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678.

Sequential regimen of clofarabine, cytosine arabinoside and reduced-intensity conditioned transplantation for primary refractory acute myeloid leukemia.

The prognosis of patients with acute myeloid leukemia in whom primary treatment fails remains very poor. In order to improve such patients' outcome, we conducted a phase 2, prospective, multicenter trial to test the feasibility of a new sequential regimen, combining a short course of intensive chemotherapy and a reduced intensity-conditioning regimen, before allogeneic stem-cell transplantation. Twenty-four patients (median age, 47 years) with acute myeloid leukemia in primary treatment failure were included. Cytogenetic risk was poor in 15 patients (62%) and intermediate in nine (38%). The sequential regimen consisted of clofarabine (30 mg/m2/day) and cytosine arabinoside (1 g/m2/day) for 5 days, followed, after a 3-day rest, by reduced-intensity conditioning and allogeneic stem-cell transplantation combining cyclophosphamide (60 mg/kg), intravenous busulfan (3.2 mg/kg/day) for 2 days and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days. Patients in complete remission at day +120 received prophylactic donor lymphocyte infusion. Eighteen patients (75%) achieved complete remission. With a median follow-up of 24.6 months, the Kaplan-Meier estimate of overall survival was 54% (95% CI: 33-71) at 1 year and 38% (95% CI: 18-46) at 2 years. The Kaplan-Meier estimate of leukemia-free survival was 46% (95% CI: 26-64) at 1 year and 29% (95% CI: 13-48) at 2 years. The cumulative incidence of non-relapse mortality was 8% (95% CI: 1-24) at 1 year and 12% (95% CI: 3-19) at 2 years. Results from this phase 2 prospective multicenter trial endorsed the safety and efficacy of a clofarabine-based sequential reduced-toxicity conditioning regimen, which warrants further investigation. This study was registered at www.clinicaltrials.gov, identifier number: NCT01188174.

Blood transfusion in hematologic intensive care unit.

BACKGROUND: There is increasing evidence that excessive blood transfusion may be associated with impaired survival or cardiovascular events. One way to reduce the number of red blood cells (RBCs) is to transfuse 1 unit (1RBC) instead of 2 units of RBCs (2RBC). STUDY DESIGN AND METHODS: Patients requiring blood transfusions in hematologic intensive care unit were included in a prospective study using a single RBC unit per transfusion and were compared with an historical cohort who received 2 RBC units per transfusion. RESULTS: A total of 1323 units were transfused to 126 patients between 2013 and 2014. The 186 patients in the comparative cohort received a total of 1824 RBC units in a 2-RBC-unit policy between 2010 and 2012. The mean number of units was 7.35 (SD, 5.9 units; 95% confidence interval [CI], 6.5-8.2 units) in the 1RBC group and 8.14 units (SD, 6.2 units; 95% CI, 7.3-8.9 units) in the 2RBC group. The absolute mean difference was -0.79 (95% CI, -1.98 to 0.40; p = 0.09). In the 1RBC allogeneic hematopoietic stem cell transplantation (allo-HSCT) subgroup, a significant reduction in the number of RBC units transfused was observed in comparison with the historical 2RBC allo-HSCT group (5 units vs. 7.7 units; p = 0.01). No anemia-related side effects were reported. Overall survival did not differ between the two groups. CONCLUSION: The 1RBC transfusion policy made is feasible in patients with transient hematologic toxicity after chemotherapy. The number of units transfused between the two groups was not different. However, in the allo-HSCT group, the use of a single RBC unit reduced significantly RBC consumption. A randomized trial comparing the two strategies is planned with a medicoeconomic evaluation.

Flow cytometry minimal residual disease after allogeneic transplant for chronic lymphocytic leukemia.

OBJECTIVES: This study investigates whether achieving complete remission (CR) with undetectable minimal residual disease (MRD) after allogeneic stem cell transplantation (allo-SCT) for chronic lymphocytic leukemia (CLL) affects outcome. METHODS: We retrospectively studied 46 patients transplanted for CLL and evaluated for post-transplant MRD by flow cytometry. RESULTS: At transplant time, 43% of the patients were in CR, including one with undetectable MRD, 46% were in partial response, and 11% had refractory disease. After transplant, 61% of the patients achieved CR with undetectable MRD status. By multivariate analysis, reaching CR with undetectable MRD 12 months after transplant was the only factor associated with better progression-free survival (P = 0.02) and attaining undetectable MRD, independently of the time of negativity, was the only factor that correlated with better overall survival (P = 0.04). CONCLUSION: Thus, achieving undetectable MRD status after allo-SCT for CLL is a major goal to improve post-transplant outcome.

Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy.

Treatment outcomes for older patients with acute myeloid leukemia (AML) have remained dismal. This randomized, phase 2 trial in AML patients not considered suitable for intensive induction therapy compared low-dose cytarabine (LDAC) with or without volasertib, a highly potent and selective inhibitor of polo-like kinases. Eighty-seven patients (median age 75 years) received LDAC 20 mg twice daily subcutaneously days 1-10 or LDAC + volasertib 350 mg IV days 1 + 15 every 4 weeks. Response rate (complete remission and complete remission with incomplete blood count recovery) was higher for LDAC + volasertib vs LDAC (31.0% vs 13.3%; odds ratio, 2.91; P = .052). Responses in the LDAC + volasertib arm were observed across all genetic groups, including 5 of 14 patients with adverse cytogenetics. Median event-free survival was significantly prolonged by LDAC + volasertib compared with LDAC (5.6 vs 2.3 months; hazard ratio, 0.57; 95% confidence interval, 0.35-0.92; P = .021); median overall survival was 8.0 vs 5.2 months, respectively (hazard ratio, 0.63; 95% confidence interval, 0.40-1.00; P = .047). LDAC + volasertib led to an increased frequency of adverse events that was most pronounced for neutropenic fever/infections and gastrointestinal events; there was no increase in the death rate at days 60 + 90. This study was registered at www.clinicaltrials.gov as #NCT00804856.

Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia.

With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by immunoglobulin/T-cell receptor minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as the primary end point. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with postinduction MRD level ≥10(-4) and unfavorable genetic characteristics (ie, MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-cell ALL). These 2 factors allowed definition of a new risk classification that is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and GRAALL-2005 trials. Both trials were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.

The prognostic value of hematogones in patients with acute myeloid leukemia.

In acute myeloid leukemia (AML), new prognostic tools are needed to assess the risk of relapse. Hematogones (HGs) are normal B-lymphocyte precursors that increase in hematological diseases and may influence remission duration in AML. HG detection was prospectively investigated in 262 AML patients to determine its prognostic value. Flow cytometric HG detection was performed in bone marrow aspiration after intensive chemotherapy at the time of hematological recovery. Patients with HGs in bone marrow samples had a significantly better relapse-free survival (RFS) and overall survival (OS) than patients without HGs (P = 0.0021, and P = 0.0016). Detectable HGs independently predicted RFS (HR = 0.61, 95%CI: 0.42 - 0.89, P = 0.012) and OS (HR = 0.59, 95%CI: 0.38 - 0.92, 0.019) controlling for age, ELN classification, the number of chemotherapy cycles to achieve CR, performance status, secondary AML and flow cytometric minimal residual disease (MRD). In intensively treated AML, individual determination of HGs could be useful to stratify the optimal risk-adapted therapeutic strategy after induction chemotherapy. Am. J. Hematol. 91:566-570, 2016. © 2016 Wiley Periodicals, Inc.

Budesonide/Formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation.

RATIONALE: Systemic steroids are the standard treatment for bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) despite their poor efficacy and disabling side effects. OBJECTIVES: To evaluate the effectiveness and tolerance of budesonide/formoterol as an alternative treatment for BOS after HSCT. METHODS: In this randomized, double-blind, placebo-controlled study, we randomly assigned 32 HSCT recipients with mild/severe BOS to receive budesonide/formoterol or placebo for 6 months. The primary outcome was the change in the FEV1 after 1 month of treatment (M1) compared with the baseline value. Patients were unblinded at M1 if there was no improvement in the FEV1. Those who had initially received placebo were switched to budesonide/formoterol. Intention-to-treat analysis was performed to assess the primary outcome. Additional analyses took scheduled treatment contamination into account. MEASUREMENTS AND MAIN RESULTS: At M1, the median FEV1 increased by 260 ml in the budesonide/formoterol arm compared with 5 ml in the placebo arm (P = 0.012). The median increases in the FEV1 at M1 relative to the baseline value for the treated and placebo groups were 13 and 0%, respectively (P = 0.019). Twenty-five patients received budesonide/formoterol during the study. The median difference in the FEV1 between the baseline and after 1 month of treatment for these patients was +240 ml (P = 0.0001). The effect of budesonide/formoterol on the FEV1 was maintained in the 13 patients who completed 6 months of treatment. CONCLUSIONS: Budesonide/formoterol administration led to a significant improvement in the FEV1 in patients with mild/severe BOS after allogeneic HSCT. Clinical trial registered with www.clinicaltrials.gov (NCT00624754).

Cerebral venous thrombosis in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma during induction chemotherapy with l-asparaginase: The GRAALL experience.

Central nervous system (CNS) thrombotic events are a well-known complication of acute lymphoblastic leukemia (ALL) induction therapy, especially with treatments including l-asparaginase (l-ASP). Data on risk factors and clinical evolution is still lacking in adult patients. We report on the clinical evolution of 22 CNS venous thrombosis cases occurring in 708 adults treated for ALL or lymphoblastic lymphoma (LL) with the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-induction protocol, which included eight L-ASP (6,000 IU/m(2) ) infusions. The prevalence of CNS thrombosis was 3.1%. CNS thrombosis occurred after a median of 18 days (range: 11-31) when patients had received a median of three l-ASP injections (range: 2-7). Patients with CNS thrombosis exhibited a median antithrombin (AT) nadir of 47.5% (range: 36-67%) at Day 17 (range: D3-D28), and 95% of them exhibited AT levels lower than 60%. There were no evident increase in hereditary thrombotic risk factors prevalence, and thrombosis occurred despite heparin prophylaxis which was performed in 90% of patients. Acquired AT deficiency was frequently detected in patients with l-ASP-based therapy, and patients with CNS thrombosis received AT prophylaxis (45%) less frequently than patients without CNS thrombosis (83%), P = 0.0002). CNS thrombosis was lethal in 5% of patients, while 20% had persistent sequelae. One patient received all planned l-ASP infusions without recurrence of CNS thrombotic whereas l-ASP injections were discontinued in 20 patients during the management of thrombosis without a significant impact on overall survival (P = 0.4).

A Phase 2 study of L-asparaginase encapsulated in erythrocytes in elderly patients with Philadelphia chromosome negative acute lymphoblastic leukemia: The GRASPALL/GRAALL-SA2-2008 study.

PURPOSE: The GRASPALL/GRAALL-SA2-2008 Phase II trial evaluated the safety and efficacy of L-asparaginase encapsulated within erythrocytes (GRASPA®) in patients ≥ 55 years with Philadelphia chromosome-negative acute lymphoblastic leukemia. FINDINGS: Thirty patients received escalating doses of GRASPA® on Day 3 and 6 of induction Phases 1 and 2. The primary efficacy endpoint was asparagine depletion < 2 µmol/L for at least 7 days. This was reached in 85 and 71% of patients with 100 and 150 IU/kg respectively but not with 50 IU/kg. Grade 3/4 infection, hypertransaminasemia, hyperbilirubinemia and deep vein thrombosis occurred in 77, 20, 7, and 7% of patients, respectively. No allergic reaction or clinical pancreatitis was observed despite 17% of Grade 3/4 lipase elevation. Anti-asparaginase antibodies were detected in 50% of patients and related to a reduction in the duration of asparagine depletion during induction Phase 2 without decrease of encapsulated L-asparaginase activity. Complete remission rate was 70%. With a median follow-up of 42 months, median overall survival was 15.8 and 9.7 months, in the 100 and 150 IU/kg cohorts respectively. CONCLUSIONS: The addition of GRASPA®, especially at the 100 IU/kg dose level, is feasible in elderly patients without excessive toxicity and associated with durable asparagine depletion. (clinicaltrials.gov identifier NCT01523782).

Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study.

BACKGROUND: The results of the addition of gemtuzumab ozogamicin, an anti-CD33 antibody conjugate, to the standard treatment for patients with acute myeloid leukaemia in phase 3 trials were contradictory. We investigated whether the addition of low fractionated-dose gemtuzumab ozogamicin to standard front-line chemotherapy would improve the outcome of patients with this leukaemia without causing excessive toxicity. METHODS: In a phase 3, open-label study, undertaken in 26 haematology centres in France, patients aged 50-70 years with previously untreated de novo acute myeloid leukaemia were randomly assigned with a computer-generated sequence in a 1:1 ratio with block sizes of four to standard treatment (control group) with or without five doses of intravenous gemtuzumab ozogamicin (3 mg/m(2) on days 1, 4, and 7 during induction and day 1 of each of the two consolidation chemotherapy courses). The primary endpoint was event-free survival (EFS). Secondary endpoints were relapse-free (RFS), overall survival (OS), and safety. Analysis was by intention to treat. This study is registered with EudraCT, number 2007-002933-36. FINDINGS: 280 patients were randomly assigned to the control (n=140) and gemtuzumab ozogamicin groups (n=140), and 139 patients were analysed in each group. Complete response with or without incomplete platelet recovery to induction was 104 (75%) in the control group and 113 (81%) in the gemtuzumab ozogamicin group (odds ratio 1·46, 95% CI 0·20-2·59; p=0·25). At 2 years, EFS was estimated as 17·1% (10·8-27·1) in the control group versus 40·8% (32·8-50·8) in the gemtuzumab ozogamicin group (hazard ratio 0·58, 0·43-0·78; p=0·0003), OS 41·9% (33·1-53·1) versus 53·2% (44·6-63·5), respectively (0·69, 0·49-0·98; p=0·0368), and RFS 22·7% (14·5-35·7) versus 50·3% (41·0-61·6), respectively (0·52, 0·36-0·75; p=0·0003). Haematological toxicity, particularly persistent thrombocytopenia, was more common in the gemtuzumab ozogamicin group than in the control group (22 [16%] vs 4 [3%]; p<0·0001), without an increase in the risk of death from toxicity. INTERPRETATION: The use of fractionated lower doses of gemtuzumab ozogamicin allows the safe delivery of higher cumulative doses and substantially improves outcomes in patients with acute myeloid leukaemia. The findings warrant reassessment of gemtuzumab ozogamicin as front-line therapy for acute myeloid leukaemia. FUNDING: Wyeth (Pfizer).

Hematogones: a new prognostic factor for acute myeloblastic leukemia.

Acute myeloid leukemia (AML) patient outcomes remain heterogeneous, and new prognostic tools are needed to assess the risk of relapse. Hematogones (HGs) are normal B-lymphocyte precursors, which increase in number in hematologic diseases. The prognostic impact of the presence of detectable HGs on the leukemia-free survival (LFS) and overall survival of 120 consecutive patients with AML in first complete remission was investigated by flow cytometry. Patients who had HG levels more than 0.01% had a significantly better median LFS (29.2 vs 11.7 months; P = .001) and overall survival (not reached vs 23.5 months; P = .011). According to Cox analysis, an HG level more than 0.01% was an independent predictor of LFS (hazard ratio = 0.5; 95% confidence interval, 0.28-0.90, P < .03) when age, leukocytosis, the number of chemotherapy cycles, and the standardized cytogenetic and molecular risk subgroups were controlled for. These results indicate that HG analysis may help to define the risk of relapse in AML patients.

Comparison of high-dose cytarabine and timed-sequential chemotherapy as consolidation for younger adults with AML in first remission: the ALFA-9802 study.

To assess the value of administering timed-sequential chemotherapy (TSC; 2 therapeutic sequences separated by a 4-day interval-free chemotherapy) or high-dose cytarabine (HDAraC) cycles in consolidation therapy for acute myeloid leukemia (AML), 459 patients 15 to 50 years of age were enrolled in the prospective randomized Acute Leukemia French Association-9802 trial. Complete remission was achieved in 89%. A total of 237 patients were then randomized to either TSC consolidation (120 patients) or HDAraC consolidation cycles (117 patients). Overall, there was no significant difference between the 2 consolidation arms (5-year event-free survival [EFS]: 41% for HDAraC vs 35% for TSC), or cumulative incidence of relapse, or treatment-related mortality. Cytogenetically normal AML NPM1(+) or CEBPA(+) and FLT3-ITD(-) had the same outcome as those with favorable cytogenetics. When considering favorable and unfavorable risk groups, the trend was in favor of HDAraC. However, the difference became significant when considering intermediate cytogenetics (5-year EFS: 49% vs 29%; P = .02), especially cytogenetically normal AML (5-year EFS: 48% vs 31%; P = .04), which was related to lower relapse rate and less toxicity. This study demonstrates that TSC did not produce any benefit when used as consolidation therapy in younger adults compared with HDAraC. This trial was registered at www.clinicaltrials.gov as #NCT00880243.

Pediatric-inspired intensified therapy of adult T-ALL reveals the favorable outcome of NOTCH1/FBXW7 mutations, but not of low ERG/BAALC expression: a GRAALL study.

Despite recent progress in the understanding of acute lymphoblastic leukemia (T-ALL) oncogenesis, few markers are sufficiently frequent in large subgroups to allow their use in therapeutic stratification. Low ERG and BAALC expression (E/B(low)) and NOTCH1/FBXW7 (N/F) mutations have been proposed as powerful prognostic markers in large cohorts of adult T-ALL. We therefore compared the predictive prognostic value of N/F mutations versus E/B(low) in 232 adult T-ALLs enrolled in the LALA-94 and Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocols. The outcome of T-ALLs treated in the pediatric-inspired GRAALL trials was significantly superior to the LALA-94 trial. Overall, 43% and 69% of adult T-ALL patients were classified as E/B(low) and N/F mutated, respectively. Strikingly, the good prognosis of N/F mutated patients was stronger in more intensively treated, pediatric-inspired GRAALL patients. The E/B expression level did not influence the prognosis in any subgroup. N/F mutation status and the GRAALL trial were the only 2 independent factors that correlated with longer overall survival by multivariate analysis. This study demonstrates that the N/F mutational status and treatment protocol are major outcome determinants for adults with T-ALL, the benefit of pediatric inspired protocols being essentially restricted to the N/F mutated subgroup.

Classical Hodgkin's lymphoma: the Lymphoma Study Association guidelines for relapsed and refractory adult patients eligible for transplant.

The Hodgkin's Lymphoma Committee of the Lymphoma Study Association (LYSA) gathered in 2012 to prepare guidelines on the management of transplant-eligible patients with relapsing or refractory Hodgkin's lymphoma. The working group is made up of a multidisciplinary panel of experts with a significant background in Hodgkin's lymphoma. Each member of the panel of experts provided an interpretation of the evidence and a systematic approach to obtain consensus was used. Grades of recommendation were not required since levels of evidence are mainly based on phase II trials or standard practice. Data arising from randomized trials are emphasized. The final version was endorsed by the scientific council of the LYSA. The expert panel recommends a risk-adapted strategy (conventional treatment, or single/double transplantation and/or radiotherapy) based on three risk factors at progression (primary refractory disease, remission duration < 1 year, stage III/IV), and an early evaluation of salvage chemosensitivity, including (18)fluorodeoxy glucose-positron emission tomography interpreted according to the Deauville scoring system. Most relapsed or refractory Hodgkin's lymphoma patients chemosensitive to salvage should receive high-dose therapy and autologous stem-cell transplantation as standard. Efforts should be made to increase the proportion of chemosensitive patients by alternating non-cross-resistant chemotherapy lines or exploring the role of novel drugs.

The prognosis of CALM-AF10-positive adult T-cell acute lymphoblastic leukemias depends on the stage of maturation arrest.

CALM-AF10 (also known as PICALM-MLLT10) is the commonest fusion protein in T-cell acute lymphoblastic leukemia, but its prognostic impact remains unclear. Molecular screening at diagnosis identified CALM-AF10 in 30/431 (7%) patients with T-cell acute lymphoblastic leukemia aged 16 years and over and in 15/234 (6%) of those aged up to 15 years. Adult CALM-AF10-positive patients were predominantly (72%) negative for surface (s)CD3/T-cell receptor, whereas children were predominantly (67%) positive for T-cell receptor. Among 22 adult CALM-AF10-positive patients treated according to the LALA94/GRAALL03-05 protocols, the poor prognosis for event-free survival (P=0.0017) and overall survival (P=0.0014) was restricted to the 15 T-cell receptor-negative cases. Among CALM-AF10-positive, T-cell receptor-negative patients, 82% had an early T-cell precursor phenotype, reported to be of poor prognosis in pediatric T-cell acute lymphoblastic leukemia. Early T-cell precursor acute lymphoblastic leukemia corresponded to 22% of adult LALA94/GRAALL03-05 T-cell acute lymphoblastic leukemias, but had no prognostic impact per se. CALM-AF10 fusion within early T-cell precursor acute lymphoblastic leukemia (21%) did, however, identify a group with a poor prognosis with regards to event-free survival (P=0.04). CALM-AF10 therefore identifies a poor prognostic group within sCD3/T-cell receptor negative adult T-cell acute lymphoblastic leukemias and is over-represented within early T-cell precursor acute lymphoblastic leukemias, in which it identifies patients in whom treatment is likely to fail. Its prognosis and overlap with early T-cell precursor acute lymphoblastic leukemia in pediatric T-cell acute lymphoblastic leukemia merits analysis. The clinical trial GRAALL was registered at Clinical Trials.gov number NCT00327678.

Fractionated doses of gemtuzumab ozogamicin with escalated doses of daunorubicin and cytarabine as first acute myeloid leukemia salvage in patients aged 50-70-year old: a phase 1/2 study of the acute leukemia French association.

This Phase 1/2 study aimed to determine optimal doses of daunorubicin (DNR; mg/m(2)) and cytarabine (mg/m(2)) to be combined with fractionated doses of gemtuzumab ozogamicin (GO, Mylotarg(®); 3 mg/m(2) on day 1, 4, and 7) satisfying safety requirements. Three dose levels of DNR/AraC were investigated namely (45, 100), (60, 100), and (60, 200). Patients included were acute myeloid leukemia in first relapse, aged 50-70 years. Hematological recovery was 31 days for neutrophil and 32 days for platelet counts. A documented infectious episode > Grade 2 occurred in 11/20 patients (55%). None of the 20 patients had signs of veno-occlusive disease. Overall, eleven patients reached complete remission (CR), two CR with incomplete platelets recovery. The results showed that combination of fractionated GO doses with DNR at 60 mg/m(2)/d for 3 days and cytarabine at 200 mg/m(2)/d for 7 days is tolerable and could be further investigated in the front-line therapy.