Publications by authors named "Umberto Vitolo"

176 Publications

Genetic and Phenotypic Attributes of Splenic Marginal Zone Lymphoma.

Blood 2021 Oct 15. Epub 2021 Oct 15.

University of Milan & Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter, international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor meta-data and in genetically modified mouse models, and determined correlations with outcome data. We identified two prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcome, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated two basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2021012386DOI Listing
October 2021

Validation of POD24 As a Robust Early Clinical Endpoint of Poor Survival in FL from 5,225 Patients on 13 Clinical Trials.

Blood 2021 Oct 6. Epub 2021 Oct 6.

University of Texas MD Anderson Cancer Center, Houston, Texas, United States.

Observational studies and standalone trials indicate that patients with follicular lymphoma (FL) who experience disease progression within 24 months of front-line chemoimmunotherapy (POD24), have poor outcomes. We performed a pooled analysis of 13 randomized clinical trials of FL patients in the pre- and post-rituximab era to identify clinical factors predicting POD24. Logistic regression models evaluated the association between clinical factors and POD24. Cox regression evaluated the association between POD24 as a time-dependent factor and subsequent overall survival (OS). A landmark analysis evaluated the association of POD24 on OS for the subset of patients who were alive at 24 months post trial registration. Patients without progression at 24 months at baseline had favorable performance status (PS), limited stage (I/II) disease, low FLIPI risk score, normal baseline hemoglobin, and normal baseline beta 2 microglobulin (B2M). In a multivariable logistic regression model, male gender (odds ratio (OR) = 1.30), PS >= 2 (OR = 1.63), B2M (>= 3mg/L) (OR = 1.43), and high FLIPI risk score (3 - 5) (OR = 3.14) were associated with increased risk of progression before 24 months. In the time-dependent Cox model and the 24 month landmark analysis, POD24 was associated with poor subsequent OS (hazard ratio (HR) = 4.85 and HR = 3.06, respectively). This is the largest pooled analysis using clinical trials data validating POD24 as a robust indicator of poor FL survival and identified clinical predictors of early death and progression that can aid in building comprehensive prognostic models incorporating clinical and molecular predictors of POD24.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020010263DOI Listing
October 2021

Total metabolic tumor volume as a survival predictor for patients with diffuse large B-cell lymphoma in the GOYA study.

Haematologica 2021 Aug 19. Epub 2021 Aug 19.

First Department of Medicine, Charles University General Hospital, Prague, Czech Republic.

This retrospective analysis of the phase III GOYA study investigated the prognostic value of baseline metabolic tumor volume parameters and maximum standardized uptake values for overall and progression-free survival in treatment-naïve diffuse large B-cell lymphoma. Baseline total metabolic tumor volume (determined for tumors >1 mL using a threshold of 1.5 times the mean liver standardized uptake value +2 standard deviations), total lesion glycolysis, and maximum standardized uptake value positron emission tomography data were dichotomized based on receiver operating characteristic analysis and divided into quartiles by baseline population distribution. Of 1,418 enrolled patients, 1,305 had a baseline positron emission tomography scan with detectable lesions. Optimal cut-offs were 366 cm3 for total metabolic tumor volume and 3,004g for total lesion glycolysis. High total metabolic tumor volume and total lesion glycolysis predicted poorer progression-free survival, with associations retained after adjustment for baseline and disease characteristics (high total metabolic tumor volume hazard ratio: 1.71 [95% CI, 1.35-2.18]; total lesion glycolysis hazard ratio: 1.46 [95% CI, 1.15-1.86]). Total metabolic tumor volume was prognostic for progression-free survival in subgroups with International Prognostic Index scores 0-2 and 3-5, and those with different cell-of-origin subtypes. Maximum standardized uptake value had no prognostic value in this setting. High total metabolic tumor volume associated with high International Prognostic Index or non-germinal center B-cell classification identified the highest-risk cohort for unfavorable prognosis. In conclusion, baseline total metabolic tumor volume and total lesion glycolysis are independent predictors of progression-free survival in patients with diffuse large B-cell lymphoma after first-line immunochemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2021.278663DOI Listing
August 2021

Prognostic significance of FCGR2B expression for the response of DLBCL patients to rituximab or obinutuzumab treatment.

Blood Adv 2021 08;5(15):2945-2957

School of Cancer Sciences, University of Southampton, Southampton, United Kingdom.

Fc γ receptor IIB (FcγRIIB) is an inhibitory molecule capable of reducing antibody immunotherapy efficacy. We hypothesized its expression could confer resistance in patients with diffuse large B-cell lymphoma (DLBCL) treated with anti-CD20 monoclonal antibody (mAb) chemoimmunotherapy, with outcomes varying depending on mAb (rituximab [R]/obinutuzumab [G]) because of different mechanisms of action. We evaluated correlates between FCGR2B messenger RNA and/or FcγRIIB protein expression and outcomes in 3 de novo DLBCL discovery cohorts treated with R plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) reported by Arthur, Schmitz, and Reddy, and R-CHOP/G-CHOP-treated patients in the GOYA trial (NCT01287741). In the discovery cohorts, higher FCGR2B expression was associated with significantly shorter progression-free survival (PFS; Arthur: hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.01-1.19; P = .0360; Schmitz: HR, 1.13; 95% CI, 1.02-1.26; P = .0243). Similar results were observed in GOYA with R-CHOP (HR, 1.26; 95% CI, 1.00-1.58; P = .0455), but not G-CHOP (HR, 0.91; 95% CI, 0.69-1.20; P = .50). A nonsignificant trend that high FCGR2B expression favored G-CHOP over R-CHOP was observed (HR, 0.67; 95% CI, 0.44-1.02; P = .0622); however, low FCGR2B expression favored R-CHOP (HR, 1.58; 95% CI, 1.00-2.50; P = .0503). In Arthur and GOYA, FCGR2B expression was associated with tumor FcγRIIB expression; correlating with shorter PFS for R-CHOP (HR, 2.17; 95% CI, 1.04-4.50; P = .0378), but not G-CHOP (HR, 1.37; 95% CI, 0.66-2.87; P = .3997). This effect was independent of established prognostic biomarkers. High FcγRIIB/FCGR2B expression has prognostic value in R-treated patients with DLBCL and may confer differential responsiveness to R-CHOP/G-CHOP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361458PMC
August 2021

Single-nucleotide Fcγ receptor polymorphisms do not impact obinutuzumab/rituximab outcome in patients with lymphoma.

Blood Adv 2021 08;5(15):2935-2944

School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

Single-nucleotide polymorphisms (SNPs) have been shown to influence Fcγ receptor (FcγR) affinity and activity, but their effect on treatment response is unclear. We assessed their importance in the efficacy of obinutuzumab or rituximab combined with chemotherapy in untreated advanced follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) in the GALLIUM (www.clinicaltrials.gov #NCT01332968) and GOYA (#NCT01287741) trials, respectively. Genomic DNA was extracted from patients enrolled in GALLIUM (n = 1202) and GOYA (n = 1418). Key germline SNPs, FCGR2A R131H (rs1801274), FCGR3A F158V (rs396991), and FCGR2B I232T (rs1050501), were genotyped and assessed for their impact on investigator-assessed progression-free survival (PFS). In both cohorts there was no prognostic effect of FCGR2A or FCGR3A. In FL, FCGR2B was associated with favorable PFS in univariate and multivariate analyses comparing I232T with I232I, with a more modest association for rituximab-treated (univariate: hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.54-1.14; P = .21) vs obinutuzumab-treated patients (HR, 0.56; 95% CI, 0.34-0.91; P = .02). Comparing T232T with I232I, an association was found for obinutuzumab (univariate: HR, 2.76; 95% CI, 1.02-7.5; P = .0459). Neither observation retained significance after multiple-test adjustment. FCGR2B was associated with poorer PFS in multivariate analyses comparing T232T with I232I in rituximab- but not obinutuzumab-treated patients with DLBCL (HR, 4.40; 95% CI, 1.71-11.32; P = .002; multiple-test-adjusted P = .03); however, this genotype was rare (n = 13). This study shows that FcγR genotype is not associated with response to rituximab/obinutuzumab plus chemotherapy in treatment-naive patients with advanced FL or DLBCL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020003985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361457PMC
August 2021

Dual targeting of the DNA damage response pathway and BCL-2 in diffuse large B-cell lymphoma.

Leukemia 2021 Jul 24. Epub 2021 Jul 24.

Onco-Hematology Division, IEO European Institute of Oncology IRCCS, Milan, Italy.

Standard chemotherapies for diffuse large B-cell lymphoma (DLBCL), based on the induction of exogenous DNA damage and oxidative stress, are often less effective in the presence of increased MYC and BCL-2 levels, especially in the case of double hit (DH) lymphomas harboring rearrangements of the MYC and BCL-2 oncogenes, which enrich for a patient's population characterized by refractoriness to anthracycline-based chemotherapy. Here we hypothesized that adaptive mechanisms to MYC-induced replicative and oxidative stress, consisting in DNA damage response (DDR) activation and BCL-2 overexpression, could represent the biologic basis of the poor prognosis and chemoresistance observed in MYC/BCL-2-positive lymphoma. We first integrated targeted gene expression profiling (T-GEP), fluorescence in situ hybridization (FISH) analysis, and characterization of replicative and oxidative stress biomarkers in two independent DLBCL cohorts. The presence of oxidative DNA damage biomarkers identified a poor prognosis double expresser (DE)-DLBCL subset, characterized by relatively higher BCL-2 gene expression levels and enrichment for DH lymphomas. Based on these findings, we tested therapeutic strategies based on combined DDR and BCL-2 inhibition, confirming efficacy and synergistic interactions in in vitro and in vivo DH-DLBCL models. These data provide the rationale for precision-therapy strategies based on combined DDR and BCL-2 inhibition in DH or DE-DLBCL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-021-01347-6DOI Listing
July 2021

Outcomes and prognostic factors in angioimmunoblastic T-cell lymphoma: final report from the international T-cell Project.

Blood 2021 07;138(3):213-220

Department of Surgery, Medicine, Dentistry and Morphological Sciences with Transplant Surgery, Oncology and Regenerative Medicine Relevance (CHIMOMO), University of Modena and Reggio Emilia, Modena, Italy.

Angioimmunoblastic T-cell lymphoma (AITL) is a unique subtype of peripheral T-cell lymphoma (PTCL) with distinct clinicopathologic features and poor prognosis. We performed a subset analysis of 282 patients with AITL enrolled between 2006 and 2018 in the international prospective T-cell Project (NCT01142674). The primary and secondary end points were 5-year overall survival (OS) and progression-free survival (PFS), respectively. We analyzed the prognostic impact of clinical covariates and progression of disease within 24 months (POD24) and developed a novel prognostic score. The median age was 64 years, and 90% of patients had advanced-stage disease. Eighty-one percent received anthracycline-based regimens, and 13% underwent consolidative autologous stem cell transplant (ASCT) in first complete remission (CR1). Five-year OS and PFS estimates were 44% and 32%, respectively, with improved outcomes for patients who underwent ASCT in CR1. In multivariate analysis, age ≥60 years, Eastern Cooperative Oncology Group performance status >2, elevated C-reactive protein, and elevated β2 microglobulin were associated with inferior outcomes. A novel prognostic score (AITL score) combining these factors defined low-, intermediate-, and high-risk subgroups with 5-year OS estimates of 63%, 54%, and 21%, respectively, with greater discriminant power than established prognostic indices. Finally, POD24 was a powerful prognostic factor with 5-year OS of 63% for patients without POD24 compared with only 6% for patients with POD24 (P < .0001). These data will require validation in a prospective cohort of homogeneously treated patients. Optimal treatment of AITL continues to be an unmet need, and novel therapeutic approaches are required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020010387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493974PMC
July 2021

Antibody Therapies for Large B-Cell Lymphoma.

Biologics 2021 18;15:153-174. Epub 2021 May 18.

Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Torino, Italy.

Large B-cell lymphomas (LBCLs) constitute a subgroup of aggressive but highly curable lymphoproliferative diseases. Treatment of relapsed/refractory (R/R) patients still represents an unmet clinical need, and novel drugs and combinations are in continuous development. The pan-B cell panel of surface antigens that characterizes LBCL leads to a large umbrella of druggable targets. Monoclonal antibodies (mAbs) express their activity against lymphoma by targeting multiple tumor-specific antigens. This category consists of a number of molecules with different mechanisms of action, including naked mAbs, radioimmunoconjugates, antibody-drug conjugates, checkpoint inhibitors, and bispecific antibodies. In the last decade, apart from the well-known role of the anti-CD20 mAb rituximab, novel mAbs have led to remarkable steps forward in the treatment of R/R LBCL in monotherapy and combined with chemotherapy. Multiple studies are in development trying to bring these novel compounds into the frontline setting to empower the RCHOP effect or as alternative chemotherapy-free options for elderly/unfit patients. This review provides insight into antilymphoma mAbs, focused on the efficacy and safety of the main molecules approved or in development for LBCL andperspectives on the treatment of this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/BTT.S281618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141264PMC
May 2021

Outcomes of older patients with follicular lymphoma using individual data from 5922 patients in 18 randomized controlled trials.

Blood Adv 2021 03;5(6):1737-1745

University of Texas MD Anderson Cancer Center, Houston, TX.

Limited data exist to describe the clinical features and outcomes for elderly patients with follicular lymphoma (FL). The Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) group performed a prospectively planned pooled analysis of individual patient data from first-line randomized controlled trials (RCTs) and examined associations between age (≤70 vs >70 years), clinical characteristics, and FL outcomes. We identified 18 multicenter clinical RCTs in the FLASH database that enrolled elderly patients (>70 years). Primary end points were early disease outcomes, CR24 and CR30, and progression-free survival (PFS) at 24 months (PFS24). Secondary end points were PFS and overall survival (OS). We identified 5922 previously untreated FL patients from 18 RCTs. Patients age >70 years (vs ≤70 years) more commonly had elevated lactate dehydrogenase, hemoglobin <12 g/dL, ECOG PS ≥2, and elevated β2-microglobulin. Median follow-up was 5.6 years. Patients >70 years did not differ from patients ≤70 years in rates of CR24, CR30, or PFS24. With a median OS of 14.6 years for all patients, median OS was 7.4 and 15.7 years for patients >70 and ≤70 years of age, respectively (hazard ratio = 2.35; 95% confidence interval = 2.03-2.73; P < .001). Age >70 years was a significant predictor of OS and PFS due to higher rates of death without progression, but not PFS24, CR24, or CR30. FL patients >70 years treated on trials have similar early disease outcomes to younger patients. There is no disease-specific outcome difference between age groups. Age alone should not disqualify patients from standard treatments or RCTs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020002724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993094PMC
March 2021

Targeted locus amplification to detect molecular markers in mantle cell and follicular lymphoma.

Hematol Oncol 2021 Aug 31;39(3):293-303. Epub 2021 Mar 31.

Department of Molecular Biotechnology and Health Sciences, Division of Hematology, University of Torino, Torino, Italy.

Minimal residual disease (MRD) monitoring by PCR methods is a strong and standardized predictor of clinical outcome in mantle cell lymphoma (MCL) and follicular lymphoma (FL). However, about 20% of MCL and 40% of FL patients lack a reliable molecular marker, being thus not eligible for MRD studies. Recently, targeted locus amplification (TLA), a next-generation sequencing (NGS) method based on the physical proximity of DNA sequences for target selection, identified novel gene rearrangements in leukemia. The aim of this study was to test TLA in MCL and FL diagnostic samples lacking a classical, PCR-detectable, t(11; 14) MTC (BCL1/IGH), or t(14; 18) major breakpoint region and minor cluster region (BCL2/IGH) rearrangements. Overall, TLA was performed on 20 MCL bone marrow (BM) or peripheral blood (PB) primary samples and on 20 FL BM, identifying a novel BCL1 or BCL2/IGH breakpoint in 16 MCL and 8 FL patients (80% and 40%, respectively). These new breakpoints (named BCL1-TLA and BCL2-TLA) were validated by ASO primers design and compared as MRD markers to classical IGH rearrangements in eight MCL: overall, MRD results by BCL1-TLA were superimposable (R Pearson = 0.76) to the standardized IGH-based approach. Moreover, MRD by BCL2-TLA reached good sensitivity levels also in FL and was predictive of a primary refractory case. In conclusion, this study offers the proof of principle that TLA is a promising and reliable NGS-based technology for the identification of novel molecular markers, suitable for further MRD analysis in previously not traceable MCL and FL patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hon.2864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451873PMC
August 2021

End-of-treatment PET/CT predicts PFS and OS in DLBCL after first-line treatment: results from GOYA.

Blood Adv 2021 03;5(5):1283-1290

1st Department of Medicine, 1st Faculty of Medicine, Charles University General Hospital, Prague, Czech Republic.

GOYA was a randomized phase 3 study comparing obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) vs standard-of-care rituximab plus CHOP in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). This retrospective analysis of GOYA aimed to assess the association between progression-free survival (PFS) and overall survival (OS) with positron emission tomography (PET)-based complete response (CR) status. Overall, 1418 patients were randomly assigned to receive 8 21-day cycles of obinutuzumab (n = 706) or rituximab (n = 712) plus 6 or 8 cycles of CHOP. Patients received a mandatory fluoro-2-deoxy-d-glucose-PET/computed tomography scan at baseline and end of treatment. After a median follow-up of 29 months, the numbers of independent review committee-assessed PFS and OS events in the entire cohort were 416 (29.3%) and 252 (17.8%), respectively. End-of-treatment PET CR was highly prognostic for PFS and OS according to Lugano 2014 criteria (PFS: hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.19-0.38; P < .0001; OS: HR, 0.12; 95% CI, 0.08-0.17; P < .0001), irrespective of international prognostic index score and cell of origin. In conclusion, the results from this prospectively acquired large cohort corroborated previously published data from smaller sample sizes showing that end-of-treatment PET CR is an independent predictor of PFS and OS and a promising prognostic marker in DLBCL. Long-term survival analysis confirmed the robustness of these data over time. Additional meta-analyses including other prospective studies are necessary to support the substitution of PET CR for PFS as an effective and practical surrogate end point. This trial was registered at www.clinicaltrials.gov as #NCT01287741.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020002690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948296PMC
March 2021

ROBUST: A Phase III Study of Lenalidomide Plus R-CHOP Versus Placebo Plus R-CHOP in Previously Untreated Patients With ABC-Type Diffuse Large B-Cell Lymphoma.

J Clin Oncol 2021 04 23;39(12):1317-1328. Epub 2021 Feb 23.

Division of Hematology, A.O.U. Città della Salute e della Scienza Hospital and University, Torino, Italy.

Purpose: Patients with the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) historically showed inferior survival with standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Phase II studies demonstrated that adding the immunomodulatory agent lenalidomide to R-CHOP improved outcomes in ABC-type DLBCL. The goal of the global, phase III ROBUST study was to compare lenalidomide plus R-CHOP (R2-CHOP) with placebo/R-CHOP in previously untreated, ABC-type DLBCL.

Methods: Histology and cell-of-origin type were prospectively analyzed by central pathology prior to random assignment and study treatment. Patients with ABC-DLBCL received lenalidomide oral 15 mg/d, days 1-14/21 plus standard R-CHOP21 versus placebo/R-CHOP21 for six cycles. The primary end point was progression-free survival (PFS) per independent central radiology review.

Results: A total of 570 patients with ABC-DLBCL (n = 285 per arm) were stratified by International Prognostic Index score, age, and bulky disease, and randomly assigned to R2-CHOP or placebo/R-CHOP. Baseline demographics were similar between arms. Most patients completed six cycles of treatment: 74% R2-CHOP and 84% placebo/R-CHOP. The most common grade 3/4 adverse events for R2-CHOP versus placebo/R-CHOP were neutropenia (60% 48%), anemia (22% 14%), thrombocytopenia (17% 11%), and leukopenia (14% 15%). The primary end point of PFS was not met, with a hazard ratio of 0.85 (95% CI, 0.63 to 1.14) and = .29; median PFS has not been reached for either arm. PFS trends favoring R2-CHOP over placebo/R-CHOP were seen in patients with higher-risk disease.

Conclusion: ROBUST is the first DLBCL phase III study to integrate biomarker-driven identification of eligible ABC patients. Although the ROBUST trial did not meet the primary end point of PFS in all patients, the safety profile of R2-CHOP was consistent with individual treatments with no new safety signals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.01366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078325PMC
April 2021

Bcl-2 inhibition in DLBCL: "the times they are a-changing"?

Blood 2021 02;137(5):577-579

Candiolo Cancer Institute, FPO-IRCCS.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020008924DOI Listing
February 2021

A brief rituximab, bendamustine, mitoxantrone (R-BM) induction followed by rituximab consolidation in elderly patients with advanced follicular lymphoma: a phase II study by the Fondazione Italiana Linfomi (FIL).

Br J Haematol 2021 04 21;193(2):280-289. Epub 2021 Jan 21.

SC Ematologia AOU Città della Salute e della Scienza di Torino, Torino, Italy.

Treatment for follicular lymphoma (FL) in the elderly is not well standardized. A phase II, multicentre, single arm trial was conducted in this setting with a brief chemoimmunotherapy regimen. Treatment consisted in four monthly courses of rituximab, bendamustine and mitoxantrone (R-BM) followed by 4 weekly rituximab as consolidation; rituximab maintenance was not applied because the drug was not licensed at the time of enrolment. The primary endpoint was the complete remission rate (CR). Seventy-six treatment-naive FL patients (aged 65-80 and a "FIT" score, according to the Comprehensive Geriatric Assessment) were enrolled. CR was documented in 59/76 patients (78%), partial remission in 12 (16%) and stable/progressive disease in five (6%) with an overall response rate in 71/76 (94%). Median follow-up was 44 months with 3-year progression-free-survival (PFS) and overall-survival of 67% and 92% respectively. Nine deaths occurred, three of progressive disease. The regimen was well tolerated and the most frequent severe toxicity was neutropenia (18% of the cycles). Bcl-2/IGH rearrangement was found in 40/75 (53%) of evaluated patients. R-BM was highly effective in clearing polymerase chain reaction-detectable disease: 29/31 (96%) evaluated patients converted to bcl-2/IGH negativity at the end of treatment. A brief R-BM regimen plus rituximab consolidation is effective and safe in "FIT" elderly, treatment-naïve, FL patients, inducing high CR and molecular remission rates with prolonged PFS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.17283DOI Listing
April 2021

Lenalidomide maintenance after autologous haematopoietic stem-cell transplantation in mantle cell lymphoma: results of a Fondazione Italiana Linfomi (FIL) multicentre, randomised, phase 3 trial.

Lancet Haematol 2021 Jan 22;8(1):e34-e44. Epub 2020 Dec 22.

Department of Translational and Precision Medicine, Sapienza University of Rome, Roma, Italy.

Background: Fit patients with mantle cell lymphoma aged 18-65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population.

Methods: This open-label, randomised, multicentre, phase 3 trial was done at 49 haematology and oncology units in Italy and Portugal. Eligible patients had Ann Arbor stage III or IV treatment-naive mantle cell lymphoma (or stage II plus bulky disease [≥5 cm] or B symptoms), and had evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32). Patients were aged 18-59 years with Eastern Cooperative Oncology Group (ECOG) performance status 0-3, or aged 60-65 years with ECOG 0-2. After an optional prephase with vincristine and steroids (intravenous vincristine 1·4 mg/m on day 1, oral prednisone 100 mg [total dose] on days 1-5), patients were given three courses of R-CHOP (21-day cycle, intravenous rituximab 375 mg/m on day 1; intravenous doxorubicin 50 mg/m, vincristine 1·4 mg/m, and cyclophosphamide 750 mg/m on day 2; oral prednisone 100 mg/m on day 2-6). Patients then received one cycle of high-dose CTX (intravenous cyclophosphamide 4 g/m on day 1, intravenous rituximab 375 mg/m on day 4). After restaging, patients received two cycles of R-HD-cytarabine (high-dose intravenous cytarabine 2 g/m every 12 h on days 1-3, intravenous rituximab 375 mg/m on days 4 and 10). Patients with complete remission or partial remission proceeded to autologous HSCT and responding patients (complete remission or partial remission) with haematological recovery were randomly assigned (1:1) to receive 24 courses of oral lenalidomide maintenance (15 mg per day for patients with platelets >100 × 10 cells per L or 10 mg per day for platelets 60-100 × 10 cells per L, days 1-21 every 28 days) for 24 months, or observation. The primary endpoint was progression-free survival, measured in the randomised population. This study is registered with EudraCT (2009-012807-25) and ClinicalTrials.gov (NCT02354313).

Findings: Between May 4, 2010, and Aug 24, 2015, 303 patients were screened for inclusion and 300 patients were enrolled (median age 57 years, IQR 51-62; 235 [78%] male). 95 patients were excluded before randomisation, mostly due to disease progression, adverse events, and inadequate recovery. 104 patients were randomly assigned to the lenalidomide maintenance group and 101 patients to the observation group. 11 (11%) of 104 patients assigned to lenalidomide did not start treatment (3 withdrew, 6 adverse events or protocol breach, 2 lost to follow-up). At a median follow-up of 38 months after randomisation (IQR 24-50), 3-year progression-free survival was 80% (95% CI 70-87) in the lenalidomide group versus 64% (53-73) in the observation group (log-rank test p=0·012; hazard ratio 0·51, 95% CI 0·30-0·87). 41 (39%) of 104 patients discontinued lenalidomide for reasons including death or progression. Treatment-related deaths were recorded in two (2%) of 93 patients in the lenalidomide group (1 pneumonia, 1 thrombotic thrombocytopenic purpura), and one (1%) of 101 in the observation group (pneumonia). 59 (63%) of 93 patients in the lenalidomide group had grade 3-4 haematological adverse events versus 12 (12%) of 101 patients in the observation group (p<0·0001). 29 (31%) of 93 patients in the lenalidomide group and eight (8%) of 101 patients in the observation group had grade 3-4 non-haematological adverse events (p<0·0001), of which infections were the most common.Serious adverse events were reported in 22 (24%) of 93 patients in the lenalidomide group and five (5%) of 101 patients in the observation group. Pneumonia and other infections were the most common serious adverse events.

Interpretation: Despite non-negligibile toxicity, lenalidomide after autologous HSCT improved progression-free survival in patients with mantle cell lymphoma, highlighting the role of maintenance in mantle cell lymphoma.

Funding: Fondazione Italiana Linfomi and Celgene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-3026(20)30358-6DOI Listing
January 2021

BCL2 Expression in First-Line Diffuse Large B-Cell Lymphoma Identifies a Patient Population With Poor Prognosis.

Clin Lymphoma Myeloma Leuk 2021 04 10;21(4):267-278.e10. Epub 2020 Nov 10.

Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.

Introduction: The prognostic value of B-cell lymphoma 2 (BCL2) expression in de novo diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy is of interest to define a target patient population for clinical development of BCL2 inhibitors. We aimed to develop a reproducible immunohistochemistry algorithm and assay to determine BCL2 protein expression and assess the prognostic value of BCL2 in newly diagnosed DLBCL cohorts.

Patients And Methods: The prospectively defined algorithm incorporated BCL2 staining intensity and percentage of BCL2-positive cells. Functionally relevant cutoffs were based on the sensitivity of lymphoma cell lines to venetoclax. This assay was highly reproducible across laboratories. The prognostic impact of BCL2 expression was assessed in DLBCL patients from the phase 3 MAIN (n = 230) and GOYA (n = 366) trials, and a population-based registry (n = 310).

Results: Approximately 50% of tumors were BCL2 positive, with a higher frequency in high International Prognostic Index (IPI) and activated B-cell-like DLBCL subgroups. BCL2 expression was associated with poorer progression-free survival in the MAIN study (hazard ratio [HR], 1.66; 95% confidence interval [CI], 0.81-3.40; multivariate Cox regression adjusted for IPI and cell of origin). This trend was confirmed in the GOYA and registry cohorts in adjusted multivariate analyses (GOYA: HR, 1.72; 95% CI, 1.05-2.82; registry: HR, 1.89; 95% CI, 1.29-2.78). Patients with BCL2 immunohistochemistry-positive and IPI-high disease had the poorest prognosis: 3-year progression-free survival rates were 51% (GOYA) and 37% (registry).

Conclusion: Findings support use of our BCL2 immunohistochemistry scoring system and assay to select patients with BCL2-positive tumors for future studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2020.11.004DOI Listing
April 2021

Partial responses to ibrutinib in Waldenström macroglobulinaemia - good enough?

Br J Haematol 2021 02 18;192(3):423-424. Epub 2020 Nov 18.

Multidisciplinary Outpatient Oncology Clinic, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (Torino), Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.17228DOI Listing
February 2021

Prognostic impact of somatic mutations in diffuse large B-cell lymphoma and relationship to cell-of-origin: data from the phase III GOYA study.

Haematologica 2020 09 1;105(9):2298-2307. Epub 2020 Sep 1.

Oncology Biomarker Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Diffuse large B-cell lymphoma represents a biologically and clinically heterogeneous diagnostic category with well-defined cell-of-origin subtypes. Using data from the GOYA study (NCT01287741), we characterized the mutational profile of diffuse large B-cell lymphoma and evaluated the prognostic impact of somatic mutations in relation to cell-of-origin. Targeted DNA next-generation sequencing was performed in 499 formalin-fixed paraffin-embedded tissue biopsies from previously untreated patients. Prevalence of genetic alterations/mutations was examined. Multivariate Cox regression was used to evaluate the prognostic effect of individual genomic alterations. Of 465 genes analyzed, 59 were identified with mutations occurring in at least 10 of 499 patients (≥2% prevalence); 334 additional genes had mutations occurring in ≥1 patient. Single nucleotide variants were the most common mutation type. On multivariate analysis, BCL2 alterations were most strongly associated with shorter progression-free survival (multivariate hazard ratio: 2.6; 95% confidence interval: 1.6 to 4.2). BCL2 alterations were detected in 102 of 499 patients; 92 had BCL2 translocations, 90% of whom had germinal center B-cell-like diffuse large B-cell lymphoma. BCL2 alterations were also significantly correlated with BCL2 gene and protein expression levels. Validation of published mutational subsets revealed consistent patterns of co-occurrence, but no consistent prognostic differences between subsets. Our data confirm the molecular heterogeneity of diffuse large B-cell lymphoma, with potential treatment targets occurring in distinct cell-of-origin subtypes. clinicaltrials.gov identifier: NCT01287741.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2019.227892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556630PMC
September 2020

A three-gene signature based on , and improves risk stratification in diffuse large B-cell lymphoma.

Haematologica 2021 09 1;106(9):2405-2416. Epub 2021 Sep 1.

Division of Diagnostic Haematopathology, European Institute of Oncology IRCCS, Milan, Italy.

Recent randomized trials focused on gene expression-based determination of the cell of origin in diffuse large B-cell lymphoma could not show significant improvements by adding novel agents to standard chemoimmunotherapy. The aim of this study was the identification of a gene signature able to refine current prognostication algorithms and applicable to clinical practice. Here we used a targeted gene expression profiling panel combining the Lymph2Cx signature for cell of origin classification with additional targets including MYC, BCL-2 and NFKBIA, in 186 patients from 2 randomized trials (discovery cohort) (NCT00355199 and NCT00499018). Data were validated in 3 independent series (2 large public datasets and a real-life cohort). By integrating the cell of origin, MYC/BCL-2 double expressor status and NFKBIA expression, we defined a 3-gene signature combining MYC, BCL-2 and NFKBIA (MBN-signature), which outperformed the MYC/BCL-2 double expressor status in multivariate analysis, and allowed further risk stratification within the germinal center B-cell/unclassified subset. The high-risk (MBN Sig-high) subgroup identified the vast majority of double hit cases and a significant fraction of Activated B-Cell-derived diffuse large B-cell lymphomas. These results were validated in 3 independent series including a cohort from the REMoDL-B trial, where, in an exploratory ad hoc analysis, the addition of bortezomib in the MBN Sig-high subgroup provided a progression free survival advantage compared with standard chemoimmunotherapy. These data indicate that a simple 3-gene signature based on MYC, BCL-2 and NFKBIA could refine the prognostic stratification in diffuse large B-cell lymphoma, and might be the basis for future precision-therapy approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2019.236455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409021PMC
September 2021

Outcomes in first relapsed-refractory younger patients with mantle cell lymphoma: results from the MANTLE-FIRST study.

Leukemia 2021 03 11;35(3):787-795. Epub 2020 Aug 11.

Haematology, University of Plymouth and Derriford Hospital, Plymouth, United Kingdom.

Patients with mantle cell lymphoma (MCL) that fail induction treatment represent a difficult-to-treat population, where no standard therapy exists. We evaluated outcomes in patients with first relapsed-refractory (r/r) MCL after upfront high dose cytarabine including standard regimens. Overall survival (OS-2) and progression-free survival (PFS-2) were estimated from the time of salvage therapy. The previously described threshold of 24 months was used to define patients as early- or late-progressors (POD). Overall, 261 r/r MCL patients were included. Second-line regimens consisted of rituximab-bendamustine (R-B, 21%), R-B and cytarabine (R-BAC, 29%), ibrutinib (19%), and others (31%). The four groups were balanced in terms of clinicopathological features. Adjusting for age and early/late-POD, patients treated with R-BAC had significantly higher complete remission (63%) than comparators. Overall, Ibrutinib and R-BAC were associated with improved median PFS-2 [24 and 25 months, respectively], compared to R-B (13) or others (7). In patients with early-POD (n = 127), ibrutinib was associated with inferior risk of death than comparators (HR 2.41 for R-B, 2.17 for others, 2.78 for R-BAC). In patients with late-POD (n = 134), no significant differences were observed between ibrutinib and bendamustine-based treatments. Ibrutinib was associated with improved outcome in early-POD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-020-01013-3DOI Listing
March 2021

Avadomide plus obinutuzumab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (CC-122-NHL-001): a multicentre, dose escalation and expansion phase 1 study.

Lancet Haematol 2020 Sep 3;7(9):e649-e659. Epub 2020 Aug 3.

Institut Gustave Roussy, Villejuif, France.

Background: Avadomide (CC-122) is a novel oral cereblon-modulating agent with promising activity in non-Hodgkin lymphoma. We aimed to examine the safety and preliminary activity of avadomide plus obinutuzumab in patients with relapsed or refractory non-Hodgkin lymphoma.

Methods: CC-122-NHL-001 was a phase 1b dose escalation and expansion study at eight sites in France, Italy, and the Netherlands. Eligible patients (aged ≥18 years) had histologically confirmed CD20-positive relapsed or refractory non-Hodgkin lymphoma, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had received previous treatment. In the dose expansion phase, only patients with previously treated relapsed or refractory follicular lymphoma (grade 1, 2, or 3a) were included. Avadomide was administered in escalating doses and two formulations: active pharmaceutical ingredient in capsule in 1·0 mg, 2·0 mg, 3·0 mg, and 4·0 mg doses and as formulated capsules in 3·0 mg and 4·0 mg doses orally once daily on days 1-5 followed by 2 days off (5-7-day schedule) every week of each 28-day cycle. Obinutuzumab 1000 mg was administered intravenously on days 2, 8, and 15 of cycle 1 and day 1 of cycles 2-8. Primary objectives were to determine the safety and tolerability, the non-tolerated dose, maximum tolerated dose, and recommended phase 2 dose (RP2D). All patients who received treatment were included in the safety analyses. Efficacy-evaluable patients completed at least one cycle of treatment and had baseline and at least one post-baseline assessment. The study is registered with ClinicalTrials.gov, NCT02417285 and EudraCT 2014-003333-26, and is ongoing.

Findings: Between June 24, 2015, and Dec 5, 2018, 73 patients were enrolled and treated; 19 had diffuse large B-cell lymphoma, 53 follicular lymphoma, and one marginal zone lymphoma. Median follow-up was 253 days (IQR 127-448). The median number of previous anticancer regimens was three (IQR 2-4). The maximum tolerated dose and non-tolerated dose were not reached in the dose escalation phase. On the basis of safety and pharmacokinetic-pharmacodynamic data, the avadomide RP2D was established as 3·0 mg as formulated capsules on a 5-7-day schedule in combination with 1000 mg of obinutuzumab. Patients enrolled in the expansion cohort received the established RP2D of avadomide. Across all doses, three patients had dose-limiting toxicities; one patient treated at the RP2D had dose-limiting toxicity (grade 3 sepsis). The most common adverse events of grade 3 and above were neutropenia (41 [56%] of 73) and thrombocytopenia (17 [23%] of 73). 34 (47%) patients had serious adverse events, which were considered to be avadomide-related in 23 (32%) of 73 patients and obinutuzumab-related in 20 (27%) of 73 patients. Two treatment-related deaths occurred, one owing to tumour flare and one from acute myeloid leukaemia after study discontinuation.

Interpretation: Avadomide plus obinutuzumab has a manageable toxicity, being a tolerable treatment option for most patients. Although the prespecified threshold for activity was not met in the trial, we believe that the preliminary antitumour activity of cereblon modulators plus next-generation anti-CD20 antibodies in heavily pretreated relapsed or refractory non-Hodgkin lymphoma warrants further investigation as a chemotherapy-free option in this setting.

Funding: Celgene Corporation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-3026(20)30208-8DOI Listing
September 2020

Chemotherapy combinations for B-cell lymphoma and chemo-free approach in elderly patients: an update on best practice.

Expert Rev Hematol 2020 08 1;13(8):851-869. Epub 2020 Aug 1.

Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS , Candiolo, Italy.

Introduction: Elderly patients represent a consistent portion of new diagnoses of B cell Non-Hodgkin Lymphoma (B-NHL). The treatment approach in this setting can be challenging for clinicians due to treatment toxicities and patients' comorbidities to deal with. Immunochemotherapy still represents the main option in the front-line setting for diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL), with different options to choose depending on patient characteristics. In the last decade, a number of new drugs and combinations have been investigated, demonstrating efficacy and safety even in the older population and extending the spectrum of treatment choices for this setting.

Areas Covered: This article reviews the majority data in literature on immunochemotherapy regimens and chemo-free approaches available for DLBCL, FL, and MCL in the elderly, both in front-line and relapse/refractory setting, the incoming drugs and how to identify the best option for each patient.

Expert Opinion: The therapeutic approach for elderly B-NHL is challenging and a tailored approach guided by a geriatric assessment is mandatory, in order to optimize efficacy and minimize treatment-related toxicities. The more extended use of biological drugs may potentially lead to prolonged survival with reduction of toxicities and improved quality of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17474086.2020.1796623DOI Listing
August 2020

Nonpeghylated liposomal doxorubicin combination regimen (R-COMP) for the treatment of lymphoma patients with advanced age or cardiac comorbidity.

Hematol Oncol 2020 Oct 9;38(4):478-486. Epub 2020 Jul 9.

Ematologia e Trapianto Midollo Osseo, Ospedale Santa Maria della Misericordia, Azienda Ospedaliera Perugia, Perugia, Italy.

Doxorubicin is the most effective single agent in the treatment of non-Hodgkin's lymphoma (NHL). Its use is limited because of the cardiac toxicity primarily in elderly patients (pts) and in pts with history of cardiac disease. Liposomal doxorubicin has been proven to reduce cardiotoxicity. The aim of this retrospective study was the use of nonpeghylated liposomal doxorubicin (NPLD) in term of efficacy, response rate and incidence of cardiac events. We retrospectively collected the experience of 33 Hematological Italian Centers in using NPLD. Nine hundred and forty-six consecutive pts treated with R-COMP (doxorubicin was substituted with NPLD, Myocet) were collected. Median age was 74 years, the reasons for use of NPLD were: age (466 pts), cardiac disease (298 pts), uncontrolled hypertension (126 pts), other reasons (56 pts). According to clinicians' evaluation, 49.9% of pts would not have used standard doxorubicin for different situations (age, cardiomyopathy, previous use of doxorubicin, and uncontrolled hypertension). Overall 687 pts (72.6%) obtained a complete remission (CR). About 5% (n = 51) of subjects developed major cardiotoxic events including heart failure (N = 31), ischemic heart disease (N = 16), acute heart attack (N = 3), and acute pulmonary oedema (N = 1). After a median follow-up of 32 months, 651 pts were alive and the overall survival (OS) was 72%. After a median observation period of 23 months disease free survival (DFS) was 58%. Either in univariate or in multivariate analysis OS and DFS were not significantly affected by age or cardiac disease. Our findings strongly support that including R-COMP is effective and safe when the population is at high risk of cardiac events and negatively selected. Moreover, the use of this NPLD permitted that about half of our population had the opportunity to receive the best available treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hon.2764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689940PMC
October 2020

A randomized, open-label, Phase III study of obinutuzumab or rituximab plus CHOP in patients with previously untreated diffuse large B-Cell lymphoma: final analysis of GOYA.

J Hematol Oncol 2020 06 6;13(1):71. Epub 2020 Jun 6.

Candiolo Cancer Institute, FPO-IRCCS, (Turin), Candiolo, Italy.

Background: Rituximab (R) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is the current standard therapy for diffuse large B cell lymphoma (DLBCL). Obinutuzumab (G), a glycoengineered, type II anti-CD20 monoclonal antibody, has shown activity and an acceptable safety profile when combined with CHOP (G-CHOP) in patients with advanced DLBCL. We present the final analysis results of the Phase III GOYA study (NCT01287741), which compared the efficacy and safety of G-CHOP versus R-CHOP in patients with previously untreated DLBCL.

Methods: Patients aged ≥ 18 years with previously untreated advanced DLBCL were randomly assigned to receive eight 21-day cycles of R or G, plus six or eight cycles of CHOP. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival, other time-to-event endpoints, and safety; investigator-assessed PFS by cell of origin subgroup was an exploratory endpoint.

Results: A total of 1418 patients were randomized, with 1414 included in this final analysis (G-CHOP, N = 704; R-CHOP, N = 710). Five-year PFS rates were 63.8% and 62.6% for G-CHOP and R-CHOP, respectively (stratified hazard ratio 0.94, 95% CI 0.78-1.12; p = 0.48). The results of the secondary efficacy endpoints did not show a benefit of G-CHOP over R-CHOP. In the exploratory analysis, a trend towards benefit with G-CHOP over R-CHOP was apparent in the patients with germinal center B cell DLBCL. The safety profile of G-CHOP was as expected, and no new safety signals were observed. More grade 3-5 (75.1% vs 65.8%), serious (44.4% vs 38.4%), and fatal (6.1% vs 4.4%) adverse events (AEs) were observed in the G-CHOP arm compared with the R-CHOP arm, respectively, with the most common fatal AEs being infections. A higher incidence of late-onset neutropenia occurred in the G-CHOP arm (8.7%) versus the R-CHOP arm (4.9%).

Conclusions: The final analysis, similar to the primary analysis, did not show a PFS benefit of G-CHOP over R-CHOP in previously untreated patients with DLBCL. The results of the secondary endpoints were consistent with the primary endpoint. Further exploratory analyses and investigation of biomarkers are ongoing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13045-020-00900-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276080PMC
June 2020

Impact of bone marrow biopsy on response assessment in immunochemotherapy-treated lymphoma patients in GALLIUM and GOYA.

Blood Adv 2020 04;4(8):1589-1593

Department of Medicine, Weill Cornell Medicine, New York, NY.

The utility of posttreatment bone marrow biopsy (BMB) histology to confirm complete response (CR) in lymphoma clinical trials is in question. We retrospectively evaluated the impact of BMB on response assessment in immunochemotherapy-treated patients with previously untreated follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) in the phase 3 Study of Obinutuzumab (RO5072759) Plus Chemotherapy in Comparison With Rituximab Plus Chemotherapy Followed by Obinutuzumab or Rituximab Maintenance in Patients With Untreated Advanced Indolent Non-Hodgkin's Lymphoma (GALLIUM; NCT01332968) and A Study of Obinutuzumab in Combination With CHOP Chemotherapy Versus Rituximab With CHOP in Participants With CD20-Positive Diffuse Large B-Cell Lymphoma (GOYA; NCT01287741) trials, respectively. Baseline BMB was performed in all patients, with repeat BMBs in patients with a CR by computed tomography (CT) at end of induction (EOI) and a positive BMB at baseline, to confirm response. Positron emission tomography imaging was also used in some patients to assess EOI response (Lugano 2014 criteria). Among patients with an EOI CR by CT in GALLIUM and GOYA, 2.8% and 4.1%, respectively, had a BMB-altered response. These results suggest that postinduction BMB histology has minimal impact on radiographically (CT)-defined responses in both FL and DLBCL patients. In GALLIUM and GOYA, respectively, 4.7% of FL patients and 7.1% of DLBCL patients had a repeat BMB result that altered response assessment when applying Lugano 2014 criteria, indicating that bone marrow evaluation appears to add little value to response assessment in FL; however, its evaluation may still have merit in DLBCL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019001261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189300PMC
April 2020

Impact of the type of anthracycline and of stem cell transplantation in younger patients with acute myeloid leukaemia: Long-term follow up of a phase III study.

Am J Hematol 2020 07 17;95(7):749-758. Epub 2020 Apr 17.

EORTC Headquarters, Brussels, Belgium.

We provide a long-term evaluation of patients enrolled in the EORTC/GIMEMA AML-10 trial which included a total of 2157 patients, 15-60 years old, randomized to receive either daunorubicin (DNR, 50 mg/m ), mitoxantrone (MXR, 12 mg/m ), or idarubicin (IDA, 10 mg/m ) in addition to standard-dose cytarabine and etoposide for induction chemotherapy and intermediate dose cytarabine for consolidation. Younger patients who reached complete remission with complete (CR) or incomplete (CRi) recovery were then scheduled to receive an allogeneic hematopoietic stem cell transplantation (HSCT). That was if they had a HLA-identical sibling donor; in all other cases, an autologous HSCT had to be administered. At an 11-year median follow-up, the 5-year, 10-year and 15-year overall survival (OS) rates were 33.2%, 30.1% and 28.0%, respectively. No significant difference between the three randomized groups regarding OS was observed (P = .38). In young patients, 15-45 years old, no treatment difference (P = .89) regarding OS was observed, while in patients 46-60 years old, MXR and IDA groups had a trend for a longer OS as compared to the DNR group (P = .029). Among younger patients without a favorable MRC cytogenetic risk subgroup who achieved a CR/CRi after induction chemotherapy, those with a HLA-identical sibling donor had higher 10-year and 15-year OS rates than those without. In older patients who reached CR/CRi, the long-term outcomes of those with or without a donor was similar. In conclusion, long-term outcomes of the study confirmed similar OS in the three randomized groups in the whole cohort of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.25795DOI Listing
July 2020
-->