Many somatic genetic abnormalities have been identified in T-cell acute lymphoblastic leukemia (T-ALL) but each individual abnormality accounts for a small proportion of cases; therapeutic ...stratification consequently still relies on classical clinical markers. NOTCH1 and/or FBXW7 mutations both lead to activation of the NOTCH1 pathway and are among the most frequent mutations in T-ALL. We screened 141 adult diagnostic T-ALL samples from patients treated on either the Lymphoblastic Acute Leukemia in Adults (LALA)-94 (n = 87) or the GRAALL-2003 (n = 54) trials. In 88 cases (62%) there were demonstrated NOTCH1 mutations (42% heterodimerization HD, 10% HD+proline glutamate serine threonine PEST, 6% PEST, 2% juxtamembrane mutations, 2% transactivation domain TAD) and 34 cases (24%) had FBXW7 mutations (21 cases had both NOTCH1 and FBXW7 mutations); 40 cases (28%) were wild type for both. There was no significant correlation between NOTCH1 and/or FBXW7 mutations and clinico-biologic features. Median event-free survival (EFS) and overall survival (OS) were 36 versus 17 months (P = .01) and not reached versus 32 months (P = .004) in patients with NOTCH1 and/or FBXW7 mutations versus other patients, respectively. Multivariate analysis showed that the presence of NOTCH1/FBXW7 mutations was an independent good prognostic factor for EFS and OS (P = .02 and P = .01, respectively). These data demonstrate that NOTCH1 pathway activation by either NOTCH1 or FBXW7 mutation identifies a large group of patients with a favorable outcome that could justify individual therapeutic stratification for T-ALL.
Allogeneic haematopoietic stem cell transplantation (HSCT) is a curative option for acute myeloid leukaemia (AML). A major improvement of conditioning regimen has been realized in the last two ...decades, offering the opportunity for older patients to undergo HSCT with an acceptable toxicity profile. Unfortunately, relapse remains the main cause of death, and only few studies analyzed the survival of patients presenting with post-HSCT AML relapse and their treatment options. The purpose of this study was to analyze the survival of patients with post-HSCT AML relapse, to describe the treatment options and to search for factors associated with poor prognosis at relapse. In this study, we collected the data of all the patients transplanted between January 2005 and December 2014 at Bordeaux university centre and showing AML relapse after HSCT.
Between 2005 and 2014, out of 312 HSCT for AML, one hundred patients relapsed at our center with a median time from transplant of 123.5 days (11-2726 days). Median age was 55 years old (range 17-65), 44 patients were male. Donors were matched related for 49 patients, unrelated for 35 patients, and cord blood units were used in 16 patients. Conditioning regimen was reduced for 70 patients and myeloablative for 30 patients. According to the Disease Risk Index, 4 patients were considered at low risk, 29 patients at intermediate risk, 43 patients at high risk and 11 patients at very high risk. Thirty one per cent of patients had refractory disease. Before relapse, 31 patients developed Acute Graft Versus Host Disease (GVHD) and 9 patients developed Chronic GVHD. At relapse, 62 patients were still on cyclosporine and 22 on steroids. Eighty four patients presented an isolated bone marrow relapse, while 5 patients showed isolated extramedullary relapse, and 11 mixed relapse.
With a median follow-up from relapse of 106 days (0-3619 days), the 1 and 2-year overall survival (OS) were 24% and 13%, respectively. At final follow-up 8 patients were still alive. For alive patients, median follow-up from relapse was 1524 days (980-3619 days). Median age was 39 years old (20-57 years old), DRI was considered at intermediate risk for 2 patients, at high risk for 5 patients and at very high risk for 1 patient. No patient was FLT3 mutation.
In univariate analysis, factors associated with better OS at relapse were age < 45 years old, male gender, performance status at relapse > 70%, and no initial FLT3 mutation. Male gender, performance status at relapse, early relapse and no initial FLT3 mutation were associated with a better OS in multivariate analysis.
Seven patients responded to immunosuppression tapering and 19 patients to first line treatment containing local radiotherapy, chemotherapy and/or Donor Lymphocyte Infusion (DLI). Developing GVHD after immunosuppression tapering or DLI was associated to disease response: Seven patients responded after immunosuppression only of whom 4 after developing GVHD (p=0.0013). Twelve patients responded after DLI of whom 7 after developing GVHD (p=0.05). Patients receiving an association of chemotherapy and DLI showed a better response and a better survival compared to chemotherapy only (p= 0.03). Patients with FLT3 mutation did not respond to any treatment.
This study confirms the severity of AML relapse after HSCT with a poor long term OS. The particularly poor impact of FL3 mutation suggests the use of targeted therapy in a prophylactic setting. Immunomodulatory approaches resulted in disease response in some patients and should be evaluated prospectively to identify clinical and biological factors predictive of the response.
No relevant conflicts of interest to declare.
We analyzed 526 consecutive acute myeloid leukemia patients refractory to or relapsing after chemotherapy. 270 patients received intensive salvage chemotherapy (IC), 97 azacitidine (AZA) and 159 best ...supportive care (BSC). Complete response was obtained in 37/19/0% (p = .0008). Allogeneic stem-cell transplantation (alloSCT) was performed in 39.3/10.3/0%. Median overall survival (OS) and 5-year OS were 8.2/9.6/2.2 months and 16/6/2% (p < .0001). Predictive factors of worse OS were post-myelodysplastic/chronic myelomonocytic leukemia, bone marrow blasts ≥20%, adverse cytogenetics, AZA cycle ≥2 and no alloSCT at R/R for AZA and age, performance status, white blood cell count and myelodysplasia-related changes for IC. The impact of treatment was time-dependent: adjusted hazard ratio for OS was in favor of AZA up to 1 month, was not different between 1 and 7 months, then was in favor of IC after 7 months. While AZA represents a therapeutic option for the oldest patients, it does not lead to long-term survivors.
Whereas the prognosis of adult patients with Philadelphia-negative acute lymphoblastic leukemia (ALL) has greatly improved since the advent of pediatric-inspired regimens, the impact of initial ...central nervous system (CNS) involvement has not been formerly reevaluated. We report herein the outcome of patients with initial CNS involvement included in the pediatric-inspired prospective randomized GRAALL-2005 study. Between 2006 and 2014, 784 adult patients (18-59 years old) with newly diagnosed Philadelphia-negative ALL were included of whom 55 (7%) had CNS involvement. In CNS-positive patients, overall survival was shorter (median 1.9 years vs. not reached, HR=1.8 1.3-2.6, P.
Abstract
Clofarabine, a second-generation purine analog displaying potent inhibition of DNA synthesis and favorable pharmacologic profile, is approved for the treatment of acute lymphoblastic ...leukemia (ALL) after failure of at least two previous regimens in patients up to 21 years of age at diagnosis. Good neurologic tolerance, synergy with alkylating agents, management guidelines defined through pediatric ALL and adult acute myeloid leukemia, have also prompted its administration in more than 100 adults with Philadelphia chromosome-positive and negative B lineage and T lineage ALL, as single agent (40 mg/m2/ day for 5 days), or in combination. In a Group for Research on Adult Acute Lympho- blastic Leukemia (GRAALL) retrospective study of two regimens (clofarabine ± cyclophosphamide + / − etoposide (ENDEVOL) ± mitoxantrone ± asparaginase ± dexamethasone (VANDEVOL)), remission was achieved in 50% of 55 relapsed/refractory patients, and 17-35% could proceed to allogeneic stem cell. Clofarabine warrants further exploration in advanced ALL treatment and bridge-to-transplant.
Background: Approximately 30% of adult acute lymphoblastic leukemia (ALL) occurs after the age of 60. The improvements observed in the past decade in adults with pediatric-inspired regimen do not ...translate in this population with increase treatment related toxicity and early deaths. The European Working Group for Adult ALL (EWALL) backbone, adapted for elderly patients, reported a poor 3 year overall survival (3y-OS) of about 24% due to high relapse rates. Our center report the outcome of a regimen designed to improve the outcome of the EWALL backbone taking advantage of the favorable results of pediatric-inspired protocols in younger adults and retrospectively compared it to an historical cohort.
Methods: Since 2012, patients > 60 y-old with Ph-neg ALL were treated in our center according to the EWALL first induction backbone. Patients achieving complete response (CR) were eligible to receive a pediatric-inspired consolidation phase designed for younger patients. After two consolidations courses, patients received late intensification phase followed by a third consolidation course. Monthly maintenance course was then started for CR patients. CNS prophylaxis included intrathecal injections and cranial irradiation. Consolidations included 9 cycles alternating cytarabine (8000mg/m2) intermediate-dose methotrexate (1500mg/m2) and cyclophosphamide (1000mg/m2) plus VP-16 (150mg/m2). Patients aged more than 70 years received reduced doses of chemotherapy during consolidation. Treatments are detailed in the table. We retrospectively compared the outcomes with those observed in patients > 60 y-old treated according to the EWALL induction and consolidation backbone (Goekbuget et al. 2008) in our center between 2007 and 2011.
Results: Twenty-four patients were included in the study. Median age was 67 IQR: 64-71. Nineteen patients (79%) had B-phenotype ALL. Four (13%) patients had adverse cytogenetics, three (13%) had hyperleukocytosis, none had CNS involvement. Twenty nine percent of patients had a Charlson Comorbidity Index > 1. Twenty-one patients were included in the historical cohort treated according to the EWALL backbone from 2007 to 2011. Main baseline characteristics were well balanced between the two study cohorts. Complete remission (CR) rate was 81% in the experimental cohort versus 79% in the historical cohort. The induction deaths were 4% in the experimental cohort versus 14% in the historical cohort. All patients in CR (19) in the experimental group were eligible to intensive consolidations and late intensification. Two of these patients were unable to reach maintenance phase (1 deterioration of general status and 1 relapse) and 1 patients omitted late intensification because of renal failure. During late intensification, the median duration with neutrophils < 0.5 X 109/L was 8 days IQR: 4-14. Six patients (32%) developed an infection during consolidation courses and 3 patients during late intensification course. Major toxicities during pediatric-inspired consolidation courses included infections (9 patients, including three with bacteremia, two with pyelonephritis and one with pneumonia), grade 3-4 liver toxicity (6), acute kidney failure (3) and hyperglycemia requiring insulin (1). Eighty-one percent of patients eligible to late intensification received over 80% of the scheduled dose of L-ASP. No death was observed during consolidations or late intensification. The median follow up times were 2,6 years and 8,2 years for the experimental cohort and the historical cohort, respectively. The experimental regimen translated into a significantly longer two years disease-free survival (57% IC95% 31-76 vs 29% IC95% 11-51 p=0.007 by log-rank test) and a longer two years overall survival than the historical cohort (54% CI95% 30-73 vs 24% CI95% 12-47 p=0.01 by log-rank test). The OS and DFS of the experimental and historical cohorts are show in the figure.
Conclusion: Results presented here strongly suggest that an intensified pediatric-inspired protocol after an age-adapted induction course might yield significantly better results than former protocols in older adults with Ph-negative ALL. The intensity of this consolidation treatment was tolerable, and the low rate of relapse is promising in this population with an unmet medical need.
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Forcade:Neovii: Other: Travel grant.
Background: The prognosis of Philadelphia-negative Acute Lymphoblastic Leukemia (Ph-neg ALL) in patients over 55 years of age is dismal. The European Working Group for Adult ALL (EWALL) backbone, ...adapted for elderly patients, reported a poor 3 year overall survival (3y-OS) of about 24% due to high relapse rates. Many attempts to improve this outcome have failed due to increased toxicity. In a report, the French Group for Research on Adult ALL (GRAALL) considered that adjunction of L-Asparaginase (L-Asp) seemed too toxic to be recommended during induction chemotherapy in older patients. The GRAALL-SA2 study recently showed no advantage to the adjunction of erythrocytes encapsulated L-Asp to the EWALL backbone. The question of whether L-Asp could be included in a more intensive consolidation regimen has not been addressed so far.
Methods: Since 2012, patients > 60-years-old with Ph-neg ALL were treated in our center according to the EWALL first induction backbone. Patients achieving complete response (CR) were eligible to receive a pediatric-inspired consolidation phase designed for younger patients. After two consolidations courses, patients received late intensification phase (with 6 intravenous infusions of native L-Asparaginase 6000 UI/m2 at Days 8, 10, 12, 20, 22 and 24) according to the GRAALL-2005 (previously published, Huguet et al. 2009). Antithrombin (AT) and fibrinogen levels were monitored prospectively on alternate days. No other coagulation factor was systematically evaluated. Fresh frozen plasma was recommended if fibrinogen levels were below 0.5 g/L, platelet transfusion support was recommended for platelets levels below 20 x 109/L and AT concentrate substitution therapy (Aclotine 25 U/kg) was recommended to maintain AT levels above 60%. AT levels were re-evaluated the days following AT infusion. L-ASP was administrated after correcting the acquired deficiency in AT. Unfractionated heparin at 100 UI/kg/day in continuous infusion or low molecular weight heparin at prophylactic doses in subcutaneous injection was also used. Broad-spectrum antibiotics were administered in case of fever and prophylactic antifungal prophylaxis using micafungin was provided with a daily dose of 50 mg, from the start to the end of neutropenic period (ANC ≤ 0.5×109/L). Toxicity and outcomes were retrospectively analyzed.
Results: Twenty-four patients were included in this study between 2012 and 2016 in our single center. Median age was 67 IQR: 64-71. Nineteen patients (79%) had B-phenotype ALL. Four (13%) patients had adverse cytogenetics, three (13%) had hyperleukocytosis, none had CNS involvement. Twenty nine percent of patients had a Charlson Comorbidity Index > 1. Nineteen (79%) patients were in CR and all received a pediatric-inspired consolidation. One patient (4%) died during induction and 4 (17%) were alive with primary refractory disease. After two consolidation courses, 16/19 of CR patients were eligible for late intensification (two relapses and one renal failure). During late intensification, the median duration with neutrophils < 0.5 X 109/L was 8 days IQR: 4-14. A platelet unit transfusion was necessary on 3/16 patients. Infection was diagnosed in 3/16 patients. Eighty-one percent of patients eligible to late intensification received over 80% of the scheduled dose of L-ASP. A patient was switched to Erwinia chrysanthemi L-Asp (Erwiniase 12,000 UI/m2/IV) due to suspected allergic reaction and 2 patients stopped because of grade 4 elevated bilirubin. The rates of grade 3-4 cytolysis, cholestasis and elevated bilirubin were respectively 38%, 25% and 13%. No elevation of amylase or lipase was noticed. No thrombo-embolic event and no grade 3-4 renal, cardiac or neurological event was reported. The median AT nadir was 46% IQR 42-53. The median dose of AT substitution for the patients who underwent late intensification was 166 UI/kg IQR: 135-243. No patient needed insulin therapy. No death was observed during late intensification. With a median follow up of 2.6 years, the 2y-EFS and 2y-OS were 54% and 55% respectively, highlighting a marked improvement compared to historical controls.
Summary/conclusion: Late intensification with high dose of L-ASP according to GRAALL-2005 pediatric-inspired protocol for ALL in the elderly is feasible and well tolerated in this population with an unmet medical need.
Forcade:Neovii: Other: Travel grant.
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