Aurore Perrot

Dismal prognostic value of monosomal karyotype in elderly patients with acute myeloid leukemia: a GOELAMS study of 186 patients with unfavorable cytogenetic abnormalities

The prognosis of acute myeloid leukemia (AML) is very poor in elderly patients, especially in those classically defined as having unfavorable cytogenetics. The recent monosomal karyotype (MK) entity, defined as 2 or more autosomal monosomies or combination of 1 monosomy with structural abnormalities, has been reported to be associated with a worse outcome than the traditional complex karyotype (CK). In this retrospective study of 186 AML patients older than 60 years, the prognostic influence of MK was used to further stratify elderly patients with unfavorable cytogenetics. CK was observed in 129 patients (69%), and 110 exhibited abnormalities according to the definition of MK (59%). MK(+) patients had a complete response rate significantly lower than MK(-) patients: 37% vs 64% (P = .0008), and their 2-year overall survival was also decreased at 7% vs 22% (P < .0001). In multivariate analysis, MK appeared as the major independent prognostic factor related to complete remission achievement (odds ratio = 2.3; 95% confidence interval, 1-5.4, P = .05) and survival (hazard ratio = 1.7; 95% confidence interval, 1.1-2.5, P = .008). In the subgroup of 129 CK(+) patients, survival was dramatically decreased for MK(+) patients (8% vs 28% at P = .03). These results demonstrate that MK is a major independent factor of very poor prognosis in elderly AML.

The graft-versus-leukemia effect is mainly restricted to NIH-defined chronic graft-versus-host disease after reduced intensity conditioning before allogeneic stem cell transplantation.

Incidence on relapse and nonrelapse mortality (NRM) of chronic graft-versus-host disease (GVHD), per National Institutes of Health (NIH) criteria, is not well defined after reduced-intensity conditioning (RIC) regimens. We analyzed the association of chronic GVHD with the risk of relapse and NRM using Cox models in 177 consecutive patients who underwent transplantation for hematological malignancies after RIC. The cumulative incidence of chronic GVHD at 36 months was 74% when using Seattles criteria compared with 54% with NIH consensus. In Cox model, NRM was significantly higher in patients with late-onset, persistent and recurrent acute GVHD (hazard ratio (HR): 6, 25 and 11; P=0.014, P<0.0001, P<0.0001, respectively). The cumulative incidence of relapse was significantly decreased in patients with chronic GVHD compared with no GVHD group using either Seattles or NIH criteria (HR 0.43 and 0.38; P=0.022 and 0.016, respectively), whereas the presence of late-onset, persistent and recurrent acute GVHD was not associated with a decreased rate of relapse (HR: not significant, 0.70 and 0.71; P=not significant, P=0.73 and P=0.54, respectively). Chronic GVHD per NIH consensus definition is associated with the graft-versus-tumor effect, whereas all forms associated with acute features beyond day 100 are associated with NRM.

Core-binding factor acute myeloid leukemia in first relapse: a retrospective study from the French AML Intergroup.

Although core-binding factor-acute myeloid leukemia (CBF-AML) (t[8;21] or inv[16]/t[16;16]) represents a favorable cytogenetic AML subgroup, 30% to 40% of these patients relapse after standard intensive chemotherapy. The encouraging results of gemtuzumab ozogamicin (GO) in newly diagnosed AML, and particularly in CBF-AML, incited us to retrospectively investigate the impact of GO-based salvage in these patients. We retrospectively analyzed the outcome of 145 patients with CBF-AML (59 t[8;21], 86 inv[16]/t[16;16]) in first relapse. As salvage, 48 patients received GO-based chemotherapy and 97 patients received conventional chemotherapy. Median age was 43 years (range, 16-76). Median first complete remission duration was 12.1 months (range, 2.1-93.6). Overall, second complete remission (CR2) rate was 88%. With a median follow-up from relapse of 3.5 years, the estimated 5-year disease-free survival (DFS) was 50% and 5-year overall survival (OS) was 51%. Older age and shorter first complete remission duration was associated with a shorter OS. Patients treated with GO had similar CR2 rate but significantly higher 5-year DFS (68% vs 42%; P = .05) and OS (65% vs 44%; P = .02). In multivariate analysis, GO salvage was still associated with a significant benefit in DFS and OS. In the 78 patients who received allogeneic hematopoietic stem cell transplantation in CR2, GO before transplant significantly improved posttransplant DFS and OS without excess of treatment-related mortality.

Lenalidomide Maintenance Compared With Placebo in Responding Elderly Patients With Diffuse Large B-Cell Lymphoma Treated With First-Line Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone

Purpose The standard treatment of patients with diffuse large B-cell lymphoma (DLBCL) is rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Lenalidomide, an immunomodulatory agent, has shown activity in DLBCL. This randomized phase III trial compared lenalidomide as maintenance therapy with placebo in elderly patients with DLBCL who achieved a complete response (CR) or partial response (PR) to R-CHOP induction. Methods Patients with previously untreated DLBCL or other aggressive B-cell lymphoma were 60 to 80 years old, had CR or PR after six or eight cycles of R-CHOP, and were randomly assigned to lenalidomide maintenance 25 mg/d or placebo for 21 days of every 28-day cycle for 24 months. The primary end point was progression-free survival (PFS). Results A total of 650 patients were randomly assigned. At the time of the primary analysis (December 2015), with a median follow-up of 39 months from random assignment, median PFS was not reached for lenalidomide maintenance versus 58.9 months for placebo (hazard ratio, 0.708; 95% CI, 0.537 to 0.933; P = .01). The result was consistent among analyzed subgroups (eg, male v female, age-adjusted International Prognostic Index 0 or 1 v 2 or 3, age younger than 70 v ≥ 70 years), response (PR v CR) after R-CHOP, and positron emission tomography status at assignment (negative v positive). With longer median follow-up of 52 months (October 2016), overall survival was similar between arms (hazard ratio, 1.218; 95% CI, 0.861 to 1.721; P = .26). Most common grade 3 or 4 adverse events associated with lenalidomide versus placebo maintenance were neutropenia (56% v 22%) and cutaneous reactions (5% v 1%), respectively. Conclusion Lenalidomide maintenance for 24 months after obtaining a CR or PR to R-CHOP significantly prolonged PFS in elderly patients with DLBCL.

A unique proteomic profile on surface IgM ligation in unmutated chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course with 2 extreme subsets: indolent, ZAP70(-) and mutated immunoglobulin heavy chain gene (M-CLL); and aggressive, ZAP70(+) and unmutated immunoglobulin heavy chain (UM-CLL). Given the long-term suspicion of antigenic stimulation as a primum movens in the disease, the role of the B-cell receptor has been extensively studied in various experimental settings; albeit scarcely in a comparative dynamic proteomic approach. Here we use a quantitative 2-dimensional fluorescence difference gel electrophoresis technology to compare 48 proteomic profiles of the 2 CLL subsets before and after anti-IgM ligation. Differentially expressed proteins were subsequently identified by mass spectrometry. We show that unstimulated M- and UM-CLL cells display distinct proteomic profiles. Furthermore, anti-IgM stimulation induces a specific proteomic response, more pronounced in the more aggressive CLL. Statistical analyses demonstrate several significant protein variations according to stimulation conditions. Finally, we identify an intermediate form of M-CLL cells, with an indolent profile (ZAP70(-)) but sharing aggressive proteomic profiles alike UM-CLL cells. Collectively, this first quantitative and dynamic proteome analysis of CLL further dissects the complex molecular pathway after B-cell receptor stimulation and depicts distinct proteomic profiles, which could lead to novel molecular stratification of the disease.

Efficacy and safety profile of long-term exposure to lenalidomide in patients with recurrent multiple myeloma.

Lenalidomide in combination with dexamethasone (Len/Dex) is indicated for patients with recurrent/refractory multiple myeloma (RRMM) who were treated with 1 prior therapy until evidence of disease progression. The objective of the current study was to determine the efficacy and safety profile of long‐term exposure to Len/Dex.

Serum free light chains, not urine specimens, should be used to evaluate response in light-chain multiple myeloma.

Guidelines for monitoring multiple myeloma (MM) patients expressing light chains only (light-chain MM [LCMM]) rely on measurements of monoclonal protein in urine. Alternatively, serum free light chain (sFLC) measurements have better sensitivity over urine methods, however, demonstration that improved sensitivity provides any clinical benefit is lacking. Here, we compared performance of serum and urine measurements in 113 (72κ, 41λ) newly diagnosed LCMM patients enrolled in the Intergroupe Francophone du Myélome (IFM) 2009 trial. All diagnostic samples (100%) had an abnormal κ:λ sFLC ratio, and involved (monoclonal) FLC (iFLC) expressed at levels deemed measurable for monitoring (≥100 mg/L). By contrast, only 64% patients had measurable levels of monoclonal protein (≥200 mg per 24 hours) in urine protein electrophoresis (UPEP). After 1 and 3 treatment cycles, iFLC remained elevated in 71% and 46% of patients, respectively, whereas UPEP reported a positive result in 37% and 18%; all of the patients with positive UPEP at cycle 3 also had elevated iFLC levels. Importantly, elevated iFLC or an abnormal κ:λ sFLC ratio after 3 treatment cycles associated with poorer progression-free survival (P = .006 and P < .0001, respectively), whereas positive UPEP or urine immunofixation electrophoresis (uIFE) did not. In addition, patients with an abnormal κ:λ sFLC ratio had poorer overall survival (P = .022). Finally, early normalization of κ:λ sFLC ratio but not negative uIFE predicted achieving negative minimal residual disease, as determined by flow cytometry, after consolidation therapy (100% positive predictive value). We conclude that improved sensitivity and prognostic value of serum over urine measurements provide a strong basis for recommending the former for monitoring LCMM patients.

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

This study investigates whether achieving complete remission (CR) with undetectable minimal residual disease (MRD) after allogeneic stem cell transplantation (allo‐SCT) for chronic lymphocytic leukemia (CLL) affects outcome.

Transformed Waldenström macroglobulinaemia: clinical presentation and outcome. A multi-institutional retrospective study of 77 cases from the French Innovative Leukemia Organization (FILO)

Histological transformation (HT) to diffuse large B‐cell lymphoma (DLBCL) is a rare and poorly reported complication of Waldenström macroglobulinaemia (WM). We performed a retrospective study of 77 WM patients with biopsy‐proven transformation to DLBCL. The median time from WM diagnosis to HT was 4·6 years and 16 patients (21%) had never been treated for WM. At HT, extranodal sites were observed in 91% of patients with a rather high incidence of central nervous system, cutaneous or testicular involvement. Fluorodeoxyglucose‐positron emission tomography was performed in half of the patients and the median maximum standardized uptake value was 15 for transformed disease. More than 80% of cases with available data for assessment by the Hans’ algorithm harboured a non‐germinal centre B‐cell phenotype. First‐line treatment for transformation consisted of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)‐like regimen in 85% of patients. The overall response rate after first‐line treatment was 61% and the median overall survival was only 16 months for the entire cohort. Time to transformation above 5 years (P = 0·0004) and elevated LDH (P = 0·02) were associated with worse outcome. Based on these findings, HT should be considered and lead to a biopsy in WM patients presenting with extranodal involvement, elevated LDH and constitutional symptoms. The optimal therapeutic approaches remain to be defined.

A susceptibility locus for classical Hodgkin lymphoma at 8q24 near MYC/PVT1 predicts patient outcome in two independent cohorts

The role of the human leucocyte antigen (HLA) system in Hodgkin lymphoma (HL) susceptibility has been known for many years. Large genome-wide association studies also identified genetic variants outside of the HLA region, including 2p16.1 (near REL, rs1432295), 8q24.21 (near MYC/PVT1, rs2608053 and rs2019960), 10p14 (near GATA3, rs501764 and rs485411) and 19p13.3 (intron 2 of TCF3, rs1860661) (Enciso-Mora et al, 2010; Cozen et al, 2014). REL, encodes REL (also termed c-rel), a member of the NFkB pathway is activated in classical HL (cHL) and GATA3 is aberrantly expressed in cHL. PVT1, which is downstream of the MYC locus, encodes five non-coding microRNAs (miR-1204, 1205, 1206, 1207, 1208), with suspected oncogenic properties (Barsotti et al, 2012). TCF3, a crucial gene for lymphoid progenitor commitment in B-cell and T-cell lineages, is disturbed in cHL (Renne et al, 2006). We investigated whether single nucleotide polymorphisms (SNPs) at 6p21 (HLA-DRA), 2p16 (REL), 8q24 (MYC/PVT1), 10p14 (GATA3) and 19p13.3 (TCF3), associated with HL susceptibility, were also associated with outcome in two independent prospective cohorts. The first cohort consisted of 342 cHL patients enrolled in a prospective biological study of the Lymphoma Study Association (LYSA) and the second cohort consisted of 239 cHL patients prospectively enrolled in the University of Iowa/ Mayo Clinic Specialized Program of Research Excellence (SPORE) Molecular Epidemiology Resource (Casasnovas et al, 2007; Thompson et al, 2011). The clinical characteristics of these patients are presented in Table SI. Patients were mainly treated with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) (LYSA, 85%; SPORE, 90%). After a median follow-up of 5 years (range 0 04–9 75), the 5-year progression-free survival (PFS) and overall survival (OS) were 83% and 92% for the LYSA patients, respectively. After a median follow-up of 7 8 years (range 0 45–11 03), the PFS and OS for the SPORE cohort were 76% and 86%, respectively. A peripheral blood sample for DNA analysis was collected from all patients. Details of DNA extraction and genotyping are presented in the Supporting Information. The seven SNPs genotyped from 2p16 (REL, rs1432295), 6p21 (HLADRA, rs6903608), 8q24 (MYC/PVT1, rs2608053 and rs2019960), 10p14 (GATA3, rs501764 and rs485411) and 19p13.3 (TCF3, rs1860661) had a similar minor allele frequency (MAF) between the two study cohorts (Table SII) and frequencies were consistent with prior studies (EncisoMora et al, 2010; Cozen et al, 2014). No significant correlation between the seven SNPs and the International Prognostic Score (IPS) was shown (Tables SIII and SIV). Correlation between the seven SNPs and outcome is presented in Table I. In the LYSA cohort, GATA3 (rs501767) was associated with PFS [hazard ratio (HR) = 1 86; 95% confidence interval (CI), 1 11–3 12; P = 0 02]. There were suggestive associations for MYC/PVT1 (rs2608053) (HR = 1 76; 95% CI, 0 95–3 26; P = 0 07) and REL (rs1432295) (HR = 0 63; 95% CI 0 37–1 06; P = 0 08). In SPORE patietns, only MYC/PVT1 (rs2608053) was associated with PFS (HR = 2 22; 95% CI, 1 09–4 54; P = 0 03). In a meta-analysis of the two studies, MYC/PVT1 (rs2608053) was significantly associated with PFS (HR = 1 94; 95% CI, 1 22– 3 10; P = 0 01), and adjustment for IPS did not alter the results (HR = 1 83; 95% CI, 1 13–2 96; P = 0 03). In SPORE, MYC/PVT1 (rs2608053) was also associated with OS (HR = 2 52; 95% CI, 1 06–6 00; P = 0 04), while in LYSA the HR was attenuated (HR = 1 38; 95% CI, 0 65–2 96; P = 0 40). The number of deaths was lower in the LYSA cohort, limiting the power to detect a statistically significant difference for OS. In the meta-analysis, the pooled OS estimate for MYC/PVT1 (rs2608053) was statistically significant in univariate analysis (HR = 1 80; 95% CI, 1 01–3 18; P = 0 04) in the two studies, but not after IPS adjustment (HR = 1 60; 95% CI, 0 89–2 85; P = 0 11). Survival curves comparing patients with MYC/PVT1 (rs2608053) GG versus AG + AA genotypes are presented in Fig 1. The second SNP in the MYC/PVT1 locus (rs2019960) was associated with OS in only the SPORE cohort (HR = 0 49; 95% CI, 0 26–0 93; P = 0 03). In an exploratory analysis, associations of MYC/ PVT1 (rs2608053) with PFS were stronger for older age (≥45 years), male sex, nodular sclerosis subtype and stage I-II disease (Table SV). We conducted exploratory analyses to assess these SNPs with PFS stratified by Epstein–Barr virus (EBV) status (Table SVI). The only significant association was observed for the HLA-DRA SNP (rs6903608) with PFS in EBV-negative cHL from the SPORE cohort (HR = 0 35; 95% CI, 0 13– 0 94; P = 0 04); a much weaker association was observed in the LYSA cohort (HR = 0 67; 95% CI, 0 30–1 51) (P = 0 33). These suggestive results could parallel the findings of risk studies in which the HLA class II SNP rs6903608 correspondence