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 .).
Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing and whole-genome ...analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of 2 genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n = 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph− B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n = 17/723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (male/female ratio, 0.2, P = .002). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% vs 3%, P = .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10−4, 93% vs 46%, P < .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P = .004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3 fusion, representing a high-risk disease in young adults.
•CDX2 cis-deregulation and UBTF::ATXN7L3 fusion driven by focal deletions define a novel subtype of B-ALL.•CDX2/UBTF::ATXN7L3 is a high-risk B-ALL subtype in young adults, which warrants improved therapeutic strategies.
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Allogeneic hematopoietic cell transplant (allo‐HCT) provides the only potential route to long‐term remission in patients diagnosed with blast phase transformation of myeloproliferative neoplasm ...(BP‐MPN). We report on a large, retrospective European Society for Blood and Marrow Transplantation registry‐based study of BP‐MPN patients undergoing allo‐HCT. BP‐MPN patients undergoing first allo‐HCT between 2005 and 2019 were included. A total of 663 patients were included. With a median follow‐up of 62 months, the estimated 3‐year overall survival (OS) was 36% (95% confidence interval CI, 32–36). Factors associated with lower OS were Karnofsky Performance Score (KPS) <90 (hazard ratio HR 1.65, p < .001) and active disease at allo‐HCT (HR 1.45, p < .001), whereas patients undergoing allo‐HCT more recently associated with a higher OS (HR 0.96, p = .008). In a selected patient's population, the 3‐year OS of patients undergoing allo‐HCT in complete response (CR) and with a KPS ≥90 was 60%. KPS < 90 (HR 1.4, p = .001) and active disease (HR 1.44, p = .0004) were associated with a lower progression‐free survival (PFS). Conversely, most recent allo‐HCT associated with a higher PFS (HR 0.96, p = .008). Active disease at allo‐HCT (HR 1.34, p = .03) was associated with a higher cumulative incidence of relapse (RI) and allo‐HCT in earlier calendar years (HR 0.96, p = .02) associated with a lower RI. Last, KPS < 90 (HR 1.91, p < .001), active disease (HR 1.74, p = .003) and allo‐HCT from mismatched related donors were associated with a higher non‐relapse mortality (HR 2.66, p = .003). In this large series of BP‐MPN patients, about one third were alive at 3 years after transplantation. Patients undergoing allo‐HCT in the more recent era, with a KPS ≥90 and in CR at transplant had a better prognosis.
Although CMML since long has been separated from MDS, many studies continue to evaluate the outcomes of both diseases after hematopoietic cell transplantation (allo‐HCT) together. Data evaluating ...outcomes of a large CMML cohort after allo‐HCT compared to MDS are limited. We aim to compare outcomes of CMML to MDS patients who underwent allo‐HCT between 2010 and 2018. Patients ≥18 years with CMML and MDS undergoing allo‐HCT reported to the EBMT registry were analyzed. Progression to AML before allo‐HCT was an exclusion criterion. Overall survival (OS), progression/relapse‐free survival (PFS), relapse incidence (including progression) (REL), and non‐relapse mortality (NRM) were evaluated in univariable and multivariable (MVA) Cox proportional hazard models including interaction terms between disease and confounders. In total, 10832 patients who underwent allo‐HCT were included in the study, there were a total of 1466 CMML, and 9366 MDS. The median age at time of allo‐HCT in CMML (median 60.5, IQR 54.3–65.2 years) was significantly higher than in the MDS cohort (median 58.8, IQR 50.2–64.5 years; p < .001). A significantly higher percentage of CMML patients were male (69.4%) compared to MDS (61.2%; p < .001). There were no clinically meaningful differences in the distribution of Karnofsky score, Sorror HCT‐CI score at allo‐HCT, and donor type, between the CMML and MDS patients. RIC platforms were utilized in 63.9% of CMML allo‐HCT, and in 61.4% of MDS patients (p = .08). In univariable analyses, we found that OS, PFS, and REL were significantly worse in CMML when compared with MDS (all p < .0001), whereas no significant difference was observed in NRM (p = .77). In multivariable analyses, the HR comparing MDS versus CMML for OS was 0.81 (95% CI, 0.74–0.88, p < .001), PFS 0.76 (95% CI 0.70–0.82, p < .001), relapse 0.66 (95% CI 0.59–0.74, p < .001), and NRM 0.87 (95% CI 0.78–0.98, p = .02), respectively. The association between baseline variables and outcome was found to be similar in MDS and CMML (all interaction p > .05) except for a decreasing trend over time of the risk of relapse in CMML (HR allo‐HCT per year later 0.94, 95% CI 0.90–0.98), whereas no such trend was observed in MDS (HR 1.00, 95% CI 0.98–1.02). The poor outcome observed for CMML could be related to variables not measured in this study or to factors inherent to the disease itself. This study demonstrates that outcomes of CMML patients after allo‐HCT are significantly worse compared to MDS. The results of this study may contribute to future recommendations for allo‐HCT in CMML patients.
The prognostic implications of
genotype in T-cell acute lymphoblastic leukemia are incompletely understood. We performed comprehensive genetic and clinico-biological analyses of T-cell acute ...lymphoblastic leukemia patients with
mutations treated during the GRAALL-2003 and -2005 studies. Eighteen of 198 cases (9.1%) had
alterations. Two patients also had
mutations in non-leukemic cell DNA, providing the first potential evidence of age-related clonal hematopoiesis in T-cell acute lymphoblastic leukemia.
mutation was associated with older age (median 43.9 years
29.4 years,
<0.001), immature T-cell receptor genotype (53.3%
24.4%,
=0.016) and lower remission rates (72.2% mutated
94.4% non-mutated,
=0.006).
alterations were significantly associated with worse clinical outcome, with higher cumulative incidence of relapse (HR 2.33, 95% CI: 1.05-5.16,
=0.037) and markedly poorer event-free survival (HR 3.22, 95% CI: 1.81-5.72,
<0.001) and overall survival (HR 2.91, 95% CI: 1.56-5.43,
=0.001). Adjusting for age as a covariate, or restricting the analysis to patients over 40 years, who account for almost 90% of
-mutated cases, did not modify these observations. In multivariate analysis using the risk factors that were used to stratify treatment during the GRAALL studies,
mutation was significantly associated with shorter event-free survival (HR 2.33, 95% CI: 1.06 - 4.04,
=0.02). Altogether, these results identify
genotype as a predictor of aggressive T-cell acute lymphoblastic leukemia biology. The GRAALL-2003 and -2005 studies were registered at
as
and
, respectively.
Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) ...with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as SAMD9 and SAMD9L (N = 16 of the 86 patients, 18.6%), MECOM/EVI1 (N = 6, 7.0%), and ERCC6L2 (N = 7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, whereas MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.
•Next-generation sequencing broadens the spectrum of germ line mutations in a cohort of patients with likely-inherited BMF.•Salient clinical features and distinct natural histories are consistently found in SAMD9L and SAMD9, MECOM/EVI1, and ERCC6L2 disorders.
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Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). We characterize 58 primary human RS ...samples by genome-wide DNA methylation and whole-transcriptome profiling. Our comprehensive approach determines RS DNA methylation profile and unravels a CLL epigenetic imprint, allowing CLL-RS clonal relationship assessment without the need of the initial CLL tumor DNA. DNA methylation- and transcriptomic-based classifiers were developed, and testing on landmark DLBCL datasets identifies a poor-prognosis, activated B-cell-like DLBCL subset in 111/1772 samples. The classification robustly identifies phenotypes very similar to RS with a specific genomic profile, accounting for 4.3-8.3% of de novo DLBCLs. In this work, RS multi-omics characterization determines oncogenic mechanisms, establishes a surrogate marker for CLL-RS clonal relationship, and provides a clinically relevant classifier for a subset of primary "RS-type DLBCL" with unfavorable prognosis.
Internal tandem duplications in the FLT3 gene, termed FLT3-ITDs, are useful molecular markers in acute myeloid leukemia (AML) for patient risk stratification and follow-up. FLT3-ITDs are increasingly ...screened through high-throughput sequencing (HTS) raising the need for robust and efficient algorithms. We developed a new algorithm, which performs no alignment and uses little resources, to identify and quantify FLT3-ITDs in HTS data.
Our algorithm (FiLT3r) focuses on the k-mers from reads covering FLT3 exons 14 and 15. We show that those k-mers bring enough information to accurately detect, determine the length and quantify FLT3-ITD duplications. We compare the performances of FiLT3r to state-of-the-art alternatives and to fragment analysis, the gold standard method, on a cohort of 185 AML patients sequenced with capture-based HTS. On this dataset FiLT3r is more precise (no false positive nor false negative) than the other software evaluated. We also assess the software on public RNA-Seq data, which confirms the previous results and shows that FiLT3r requires little resources compared to other software.
FiLT3r is a free software available at https://gitlab.univ-lille.fr/filt3r/filt3r . The repository also contains a Snakefile to reproduce our experiments. We show that FiLT3r detects FLT3-ITDs better than other software while using less memory and time.
Summary
In myeloproliferative neoplasms (MPN), JAK2V617F allele burden measurement has an impact on prognosis that helps in patient monitoring. Less is known about its usefulness in CALR‐mutated ...cases. Additional mutations found by next‐generation sequencing have also shown an impact on prognosis that may drive therapeutic choices, especially in myelofibrosis, but few studies focused on CALR‐mutated patients. We performed a molecular evaluation combining next‐generation sequencing with a myeloid panel and CALR allele burden measurement at diagnosis and during follow‐up in a cohort of 45 patients with CALR‐mutated essential thrombocythaemia. The bone marrow histology was also blindly reviewed in order to apply the WHO2016 classification. The most frequently mutated gene was TET2 (11/21 mutations). CALR type 1‐like patients appear to have a more complex molecular landscape. We found an association between disease progression and CALR allele burden increase during follow‐up, independently of additional mutations and WHO2016‐reviewed diagnosis. Patients with disease progression at the time of follow‐up showed a significant increase in CALR allele burden (+16·7%, P = 0·005) whereas patients without disease progression had a stable allele burden (+3·7%, P = 0·194). This result argues for clinical interest in CALR allele burden monitoring.
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