Rituximab in B-Lineage Adult Acute Lymphoblastic Leukemia Maury, Sébastien; Chevret, Sylvie; Thomas, Xavier ...
New England journal of medicine/The New England journal of medicine,
09/2016, Volume:
375, Issue:
11
Journal Article
Peer reviewed
Open access
Treatment with rituximab has improved the outcome for patients with non-Hodgkin's lymphoma. Patients with B-lineage acute lymphoblastic leukemia (ALL) may also have the CD20 antigen, which is ...targeted by rituximab. Although single-group studies suggest that adding rituximab to chemotherapy could improve the outcome in such patients, this hypothesis has not been tested in a randomized trial.
We randomly assigned adults (18 to 59 years of age) with CD20-positive, Philadelphia chromosome (Ph)-negative ALL to receive chemotherapy with or without rituximab, with event-free survival as the primary end point. Rituximab was given during all treatment phases, for a total of 16 to 18 infusions.
From May 2006 through April 2014, a total of 209 patients were enrolled: 105 in the rituximab group and 104 in the control group. After a median follow-up of 30 months, event-free survival was longer in the rituximab group than in the control group (hazard ratio, 0.66; 95% confidence interval CI, 0.45 to 0.98; P=0.04); the estimated 2-year event-free survival rates were 65% (95% CI, 56 to 75) and 52% (95% CI, 43 to 63), respectively. Treatment with rituximab remained associated with longer event-free survival in a multivariate analysis. The overall incidence rate of severe adverse events did not differ significantly between the two groups, but fewer allergic reactions to asparaginase were observed in the rituximab group.
Adding rituximab to the ALL chemotherapy protocol improved the outcome for younger adults with CD20-positive, Ph-negative ALL. (Funded by the Regional Clinical Research Office, Paris, and others; ClinicalTrials.gov number, NCT00327678 .).
Bone marrow failure (BMF) syndromes are severe complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this paper, we distinguish two different entities, the graft failure ...(GF) and the poor graft function (PGF), and we review the current understanding of the interactions between the immune and hematopoietic compartments in these conditions. We first discuss how GF occurs as the result of classical alloreactive immune responses mediated by residual host cellular and humoral immunity persisting after conditioning and prevented by host and donor regulatory T cells. We next summarize the current knowledge about the contribution of inflammatory mediators to the development of PGF. In situations of chronic inflammation complicating allo-HSCT, such as graft-versus-host disease or infections, PGF seems to be essentially the result of a sustained impairment of hematopoietic stem cells (HSC) self-renewal and proliferation caused by inflammatory mediators, such as interferon-γ (IFN-γ) and tumor necrosis factor-α, and of induction of apoptosis through the Fas/Fas ligand pathway. Interestingly, the production of inflammatory molecules leads to a non-MHC restricted, bystander inhibition of hematopoiesis, therefore, representing a promising target for immunological interventions. Finally, we discuss immune-mediated impairment of bone marrow microenvironment as a potential mechanism hampering hematopoietic recovery. Better understanding of immunological mechanisms responsible for BMF syndromes after allo-HSCT may lead to the development of more efficient immunotherapeutic interventions.
Advances in understanding the pathogenesis and molecular landscape of myelofibrosis have occurred over the last decade. Treating physicians now have access to an ever-evolving armamentarium of novel ...agents to treat patients, although allogeneic hematopoietic stem cell transplantation remains the only curative approach. Improvements in donor selection, conditioning regimens, disease monitoring and supportive care have led to augmented survival after transplantation. Nowadays, there are comprehensive guidelines concerning allogeneic hematopoietic stem cell transplantation for patients with myelofibrosis. However, it commonly remains difficult for both physicians and patients alike to weigh up the risk-benefit ratio of transplantation given the inherent heterogeneity regarding both clinical course and therapeutic response. In this timely review, we provide an up-to-date synopsis of current transplantation recommendations, discuss usage of JAK inhibitors before and after transplantation, examine donor selection and compare conditioning platforms. Moreover, we discuss emerging data concerning the impact of the myelofibrosis mutational landscape on transplantation outcome, peritransplant management of splenomegaly, poor graft function and prevention/management of relapse.
The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 ...(N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse.
In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion).
N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio HR, 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001).
These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.
Acute graft-versus-host disease (aGvHD) remains a major threat to successful outcome following allogeneic hematopoietic cell transplantation though advances in prophylaxis and supportive care have ...been made. The aim of this study is to test whether the incidence and mortality of aGvHD have decreased over time. 102,557 patients with a median age of 47.6 years and with malignancies after first allogeneic sibling or unrelated donor (URD) transplant were studied in the following periods: 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2011-2015. Findings: 100-day incidences of aGvHD grades II-IV decreased from 40% to 38%, 32%, 29% and 28%, respectively, over calendar time (P<0.001). In multivariate analysis URD, not in complete remission (CR) at transplant or untreated, and female donor for male recipient were factors associated with increased risk whereas the use of ATG/alemtuzumab decreased aGvHD incidence. Median follow-up was 214, 169, 127, 81 and 30 months, respectively, for the periods analyzed. Three-year-survival after aGvHD grades II-IV increased significantly from 38% to 40%, 43%, 44%, and 45%, respectively. In multivariate analysis URD, not in CR at transplant, peripheral blood as stem cell source, female donor for male recipient, and the use of ATG/alemtuzumab were associated with increased mortality whereas reduced-intensity conditioning was linked to lower mortality. Mortality increased with increasing patient age but decreased in the recent cohorts. Our analysis demonstrates that aGvHD has decreased over recent decades and also that the survival rates of patients affected with aGvHD has improved.
Retrospective comparisons have suggested that adolescents or teenagers with acute lymphoblastic leukemia (ALL) benefit from pediatric rather than adult chemotherapy regimens. Thus, the aim of the ...present phase II study was to test a pediatric-inspired treatment, including intensified doses of nonmyelotoxic drugs, such as prednisone, vincristine, or L-asparaginase, in adult patients with ALL up to the age of 60 years.
Between 2003 and 2005, 225 adult patients (median age, 31 years; range, 15 to 60 years) with Philadelphia chromosome-negative ALL were enrolled onto the Group for Research on Adult Acute Lymphoblastic Leukemia 2003 protocol, which included several pediatric options. Some adult options, such as allogeneic stem-cell transplantation for patients with high-risk ALL, were nevertheless retained.
were retrospectively compared with the historical France-Belgium Group for Lymphoblastic Acute Leukemia in Adults 94 (LALA-94) trial experience in 712 patients age 15 to 55 years. Results Complete remission rate was 93.5%. At 42 months, event-free survival (EFS) and overall survival (OS) rates were 55% (95% CI, 48% to 52%) and 60% (95% CI, 53% to 66%), respectively. Age remained an important bad prognostic factor, with 45 years of age as best cutoff. In older versus younger patients, there was a higher cumulative incidence of chemotherapy-related deaths (23% v 5%, respectively; P < .001) and deaths in first CR (22% v 5%, respectively; P < .001), whereas the incidence of relapse remained stable (30% v 32%, respectively). Complete remission rate (P = .02), EFS (P < .001), and OS (P < .001) compared favorably with the previous LALA-94 experience.
These results suggest that pediatric-inspired therapy markedly improves the outcome of adult patients with ALL, at least until the age of 45 years.
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