Does early disease progression predict survival after first line-treatment of Waldenström macroglobulinemia?

In symptomatic Waldenström macroglobulinemia (sWM) patients, prognosis is assessed with the international prognostic scoring system (IPSSWM). In follicular lymphoma and other B-cell and T-cell lymphomas, disease progression within 24 months (POD24) or (in patients without POD24) after 24 months has been proposed as the start date for stratifying subsequent survival. In the present report, we assessed in a large series of 472 sWM patients, the prognostic value of this new dynamic endpoint already reported in many other lymphomas subtypes. The 3 year subsequent survival for patients with POD24 was 75% and 93% for patients without POD24. In sWM patients, departure from the proportional hazards assumption complicated this analysis. In patients without POD24, the median subsequent progression-free survival time of 43 months accounted for favorable outcome, whereas survival after progression was not influenced by the time to progression. In addition, sensitivity analysis showed that the baseline IPSSWM score also influenced survival after POD24. In sWM patients, we conclude that the apparent difference in survival after POD24 or the 24 months time-point (in patients without POD24) is mainly explained by the prolonged subsequent progression free survival of latter patients. Indeed, the mortality after progression is not influenced by the time to this event.

First-line therapy for chronic lymphocytic leukemia in patients older than 79 years is feasible and achieves good results: A FILO retrospective study.

The mean age at diagnosis of chronic lymphocytic leukemia (CLL) is 72 years, with 22.8% of patients being older than 80 years. However, the elderly are underrepresented in clinical studies of CLL. We performed a retrospective study of CLL patients aged 80 years or older at the initiation of first-line therapy in hospitals affiliated with the French intergroup on CLL (French Innovative Leukemia Organization) between 2003 and 2013. Here, we describe the clinical and biological characteristics, treatment, and outcomes for 201 patients. The median age of the cohort was 83.2 years (80-92 years). The median Cumulative Index Rating Scale comorbidity score was 5 and the median creatinine clearance was 48 mL/min (Cockcroft-Gault formula). At treatment initiation, Binet stage was A (26.4%), B (27.9%), or C (40.3%). Therapy consisted mainly of chlorambucil (65.7%), bendamustine (10.5%), and rituximab (44.3%) as follows: chlorambucil alone (45.3%) or immunochemotherapy (48.3%) with rituximab + chlorambucil (22.7%), rituximab + bendamustine (10.4%), or rituximab + cyclophosphamide + dexamethasone (5.5%). The overall response rate was 66.2% with 31.8% clinical complete remission. The median overall and progression-free survival from treatment initiation was 53.7 and 18.3 months, respectively. These results suggest that treatment is feasible in this age group, even with immunochemotherapy. Thus, prospective trials should target this population and oncogeriatric evaluation and new targeted therapies should be part of such future trials.

Salvage outcomes in patients with first relapse after fludarabine, cyclophosphamide, and rituximab for chronic lymphocytic leukemia: the French intergroup experience.

The optimal management of patients with relapsed chronic lymphocytic leukemia (CLL) is dictated by the type of prior therapy, duration of prior response, presence of genomic aberrations, age, and comorbidities. The patterns of relapses and the clinical outcomes of second-line options after fludarabine-cyclophosphamide-rituximab (FCR) is given as a frontline treatment are currently unknown. In this retrospective and non-randomized study, we report the outcomes of 132 patients from databases of 14 French CLL study group centers who needed a second-line treatment after FCR frontline. Bendamustine + rituximab (BR) was the most frequently used second-line regimen, followed by alemtuzumab-based regimens, R-CHOP, and FCR. Median progression-free survival (PFS) was 18 months after BR with a median overall survival (OS) not reached. We also found that response durations of < 36 months and the presence of del(17p) are critical factors that contribute to poor overall survival. BR appears to be an effective salvage regimen in our series, both in terms of progression-free and overall survival. Patients who relapsed less than 36 months after FCR have a poor outcome, not significantly different in this study from patients with early relapses less than 12 or 24 months.

A phase 1 dose escalation study of idarubicin combined with methotrexate, vindesine, and prednisolone for untreated elderly patients with primary central nervous system lymphoma. The GOELAMS LCP 99 trial.

Treatment of primary central nervous system lymphoma (PCNSL) in elderly patients remains unsatisfactory. To develop a new high-dose methotrexate (HD-MTX)-based regimen including idarubicin, a phase 1 multicenter dose escalation study was conducted to determine the maximum-tolerated dose (MTD) of idarubicin. Thirty-five immunocompetent patients with PCNSL were enrolled. The median age was 65 years (range, 60-70 years). MTX and vindesine (VDS) were given at the fixed dose of 3 g/m(2) (6-hr intravenous [IV]) and 3 mg/m(2) IV on day 1, respectively. Prednisolone (PRED) was given at the fixed dose of 60 mg/m(2) (IV or orally) on days 1-5. Idarubicin was escalated in increments of 2 mg/m(2) with doses ranging from 12-18 mg/m(2) IV on day 1. Treatment was repeated three times every 3 weeks. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia for more than 7 days, thrombocytopenia grade 4 or nonhaematological toxicity more than grade 2. The MTD of idarubicin was reached at 16 mg/m(2) . At this level, the main haematological toxicities were thrombocytopenia grade 4: 5% and neutropenia grade 3 or 4 (52%); the main nonhaematological toxicities were grade 3 or 4 infectious disease (5%) and grade 2 renal failure (9%). For the study population, median overall and progression-free survival were 19 and 13 months, respectively. Our study suggests that the MTD of idarubicin in combination with HD-MTX, VDS, and PRED, should be 16 mg/m(2) . Further studies will be necessary to challenge a standard treatment in elderly patients with PCNSL.

Cytokine gene polymorphisms and progression-free survival in classical Hodgkin lymphoma by EBV status: results from two independent cohorts.

BACKGROUND: Cytokines are important immune mediators of classical Hodgkin lymphoma (CHL) pathogenesis, and circulating levels at diagnosis may help predict prognosis. Germline single nucleotide polymorphisms (SNPs) in immune genes have been correlated with cytokine production and function. METHODS: We investigated whether selected germline SNPs in IL10 (rs1800890, rs1800896, rs1800871, rs1800872), TNFA (rs1800629), IL6 (rs1800795), ILRN (rs419598), INFG (rs2430561) and CCL17 (rs223828) were associated with circulating levels of related cytokines at diagnosis and progression-free survival (PFS) in CHL. Patients were from France (GELA, N=464; median age=32years) and the United States (Iowa/Mayo Specialized Program Of Research Excellence [SPORE], N=239; median age=38years); 22% of 346 CHL cases with EBV tumor status were positive. RESULTS: There was no association with any of the SNPs with cytokine levels. Overall, there was no association of any of the SNPs with PFS. In exploratory analyses by EBV status, TNFA rs1800629 (HRAA/AG=2.41; 95%CI, 1.17-4.94) was associated with PFS in EBV-negative GELA patients, with similar trends in the SPORE patients (HRAA/AG=1.63; 95%CI, 0.61-4.40). In a meta-analysis of the two studies, TNFA (HRAA/AG=2.11; 95%CI, 1.18-3.77; P=0.01) was statistically significant, and further adjustment for the international prognostic system did not alter this result. CONCLUSIONS: This study showed that germline variation in TNFA was associated with CHL prognosis for EBV-negative patients, which will require confirmation. These results support broader studies on the differential impact of genetic variation in immune genes on EBV-positive vs. EBV-negative CHL pathogenesis.

Intrathecal liposomal cytarabine (lipoCIT) administration in patients with leukemic or lymphomatous meningitis: efficacy and long-term safety in a single institution.

BACKGROUND: There is limited information regarding the efficacy and long term safety of intrathecal injection of liposomal cytarabine in leukemic or lymphomatous meningitis. DESIGN AND METHODS: We studied 20 consecutive HIV-negative patients with leukemic or lymphomatous meningitis who were treated with intrathecal liposomal cytarabine between 2004 and 2007. We focused on efficacy and on any late effects of the drug. RESULTS: Twenty patients who received intrathecal liposomal cytarabine injection as part of their treatment; of these, 9 were alive and in complete remission at the end of the study. Median survival from the time of the first injection was 22.7 months (range, 0.5 to 64 months). Short-term toxicity related to intrathecal of liposomal cytarabine was observed in 2 cases; headache in 1 case and regressive facial palsy and diplopy in 1 case. Long-term toxicity was seen in 2 cases; clinical symptoms were urinary and fecal dysfunction with confusion in 1 case, and urinary dysfunction in 1 case. Both patients had been heavily pre-treated with neurotoxic drugs and neuraxis irradiation. CONCLUSION: In our experience, intrathecal liposomal cytarabine injections were convenient in the management of leukemic and lymphomatous meningitis, and can lead to long-term survival. Although neurotoxicity was rare, clinicians should exercise caution when retreatment is required in relapsing patients.

Vaccination coverage in hematological patients undergoing chemotherapy: Should we move towards personalized vaccination?

INTRODUCTION: Immunocompromised patients are at high-risk for severe influenza and invasive pneumococcal diseases (IPD). Despite the French Public Health Council (FPHC) and the 7th European Conference on Infections in Leukaemia (ECIL7) recommendations, vaccination coverage remains insufficient. This study aimed to estimate the coverage and determinants of influenza, pneumococcal and diphtheria-tetanus-poliomyelitis (dTP) vaccinations in hematological patients underlying chemotherapy. METHODS: A survey was distributed to all patients of the hematology day hospital assessing vaccine uptakes and general opinion about vaccination. Vaccine uptakes were collected from medical and vaccination records; knowledge of and attitudes towards vaccinations in immunocompromised patients were evaluated for each general practitioner (GP) by phone call. Adequacy between vaccine uptakes and indication or not to vaccinate according to ECIL7 guidelines was assessed. Factors associated with vaccine uptakes were assessed by multivariate logistic regression. RESULTS: Among 145 patients, 66 % were aged 65 years or older, 40 % were followed for lymphoma and 38 % for multiple myeloma, 39 % were treated with anti-CD20 antibodies. Vaccination coverage was suboptimal for influenza (45-56 %), dTP (44 %) and IPD (16-19 %) regardless of the guidelines followed, with a wide variation in rates by information source (19-76 %). Adequacy rate with ECIL7 recommendations were 63 % and 87 % for influenza and IPD respectively. Information of patients on specific vaccinations was positively associated with flu and IPD vaccinations, as well as favorable attitude toward vaccination and age ≥ 65 years for flu vaccination, and recommendation by hematologist for pneumococcal vaccination. CONCLUSION: Despite vaccination opportunities, the complexity of these specific recommendations and the lack of communication between the health actors could explain the suboptimal vaccination coverage in this high-risk population. A proactive attitude of all actors in the city and hospital, including better patient information and a personalized and evolving vaccination schedule to help GPs to coordinate vaccination would allow to improve vaccine coverage.

Assessing the impact of a quality improvement program on the quality and timeliness of discharge documents: A before and after study.

ABSTRACT: Whereas handover of pertinent information between hospital and primary care is necessary to ensure continuity of care and patient safety, both quality of content and timeliness of discharge summary need to be improved. This study aims to assess the impact of a quality improvement program on the quality and timeliness of the discharge summary/letter (DS/DL) in a University hospital with approximatively 40 clinical units using an Electronic medical record (EMR).A discharge documents (DD) quality improvement program including revision of the EMR, educational program, audit (using scoring of DD) and feedback with a ranking of clinical units, was conducted in our hospital between October 2016 and November 2018. Main outcome measures were the proportion of the DD given to the patient at discharge and the mean of the national score assessing the quality of the discharge documents (QDD score) with 95% confidence interval.Intermediate evaluation (2017) showed a significant improvement as the proportion of DD given to patients increased from 63% to 85% (P < .001) and mean QDD score rose from 41 (95%CI [36-46]) to 74/100 (95%CI [71-77]). In the final evaluation (2018), the proportion of DD given to the patient has reached 95% and the mean QDD score was 82/100 (95% CI [80-85]). The areas of the data for admission and discharge treatments remained the lowest level of compliance (44%).The involvement of doctors in the program and the challenge of participating units have fostered the improvement in the quality of the DD. However, the level of appropriation varied widely among clinical units and completeness of important information, such as discharge medications, remains in need of improvement.

A genome-wide association study identifies susceptibility loci for primary central nervous system lymphoma at 6p25.3 and 3p22.1: a LOC Network study.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. PCNSL is a distinct subtype of non-Hodgkin lymphoma, with over 95% of tumors belonging to the diffuse large B-cell lymphoma (DLBCL) group. We have conducted a genome-wide association study (GWAS) on immunocompetent patients to address the possibility that common genetic variants influence the risk of developing PCNSL. METHODS: We performed a meta-analysis of 2 new GWASs of PCNSL totaling 475 cases and 1134 controls of European ancestry. To increase genomic resolution, we imputed >10 million single nucleotide polymorphisms using the 1000 Genomes Project combined with UK10K as reference. In addition we performed a transcription factor binding disruption analysis and investigated the patterns of local chromatin by Capture Hi-C data. RESULTS: We identified independent risk loci at 3p22.1 (rs41289586, ANO10, P = 2.17 × 10-8) and 6p25.3 near EXOC2 (rs116446171, P = 1.95 x 10-13). In contrast, the lack of an association between rs41289586 and DLBCL suggests distinct germline predisposition to PCNSL and DLBCL. We found looping chromatin interactions between noncoding regions at 6p25.3 (rs11646171) with the IRF4 promoter and at 8q24.21 (rs13254990) with the MYC promoter, both genes with strong relevance to B-cell tumorigenesis. CONCLUSION: To our knowledge this is the first study providing insight into the genetic predisposition to PCNSL. Our findings represent an important step in defining the contribution of common genetic variation to the risk of developing PCNSL.

Primary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC network.

BACKGROUND: Treatment of relapsed/refractory (R/R) primary CNS lymphoma (PCNSL) is poorly defined, because randomized trials and large studies are lacking. The aim of this study was to analyze the characteristics, management, and outcome of R/R PCNSL patients after first-line therapy in a nationwide cohort. METHODS: We analyzed R/R PCNSL patients following first-line treatment who had been prospectively registered in the database of the French network for oculocerebral lymphoma (LOC) between 2011 and 2014. RESULTS: Among 563 PCNSL patients treated with first-line therapy, we identified 256 with relapsed (n = 93, 16.5%) or refractory (n = 163, 29.0%) disease. Patients who were asymptomatic at relapse/progression (25.5%), mostly diagnosed on routine follow-up neuroimaging, tended to have a better outcome. Patients who received salvage therapy followed by consolidation (mostly intensive chemotherapy plus autologous hematopoietic stem cell transplantation [ICT + AHSCT]) experienced prolonged survival compared with those who did not receive salvage or consolidation therapy. Independent prognostic factors at first relapse/progression were: KPS ≥ 70 vs KPS < 70), sensitivity to first-line therapy (relapsed vs refractory disease), duration of first remission (progression-free survival [PFS] ≥1 y vs <1 y), and management at relapse/progression (palliative care vs salvage therapy). Patients who relapsed early after first-line therapy (ie, PFS < 1 y) had a poor outcome, comparable to that of refractory patients. Conversely, patients experiencing late relapses (PFS ≥ 1 y) and/or undergoing consolidation with ICT + AHSCT experienced prolonged survival. CONCLUSIONS: About a third of PCNSL patients are primary refractory to first line treatment. We identified several independent prognostic factors that can guide the management of R/R PCNSL patients.

Bortezomib, Doxorubicin, Cyclophosphamide, Dexamethasone Induction Followed by Stem Cell Transplantation for Primary Plasma Cell Leukemia: A Prospective Phase II Study of the Intergroupe Francophone du Myélome.

PURPOSE: Primary plasma cell leukemia (pPCL) is a rare and aggressive malignancy with a poor prognosis. With conventional chemotherapy, patients typically die within 1 year. In all but one of the retrospective studies reported to date, bortezomib and lenalidomide seem to improve survival. We conducted a prospective phase II trial in patients with pPCL to assess the efficacy of an alternate regimen that combines standard chemotherapy, a proteasome inhibitor, and high-dose melphalan and autologous stem cell transplantation (HDM/ASCT) followed by either allogeneic transplantation or bortezomib/lenalidomide maintenance. PATIENTS AND METHODS: Patients 70 years old and younger with newly diagnosed pPCL received four alternating cycles of bortezomib, dexamethasone plus doxorubicin or cyclophosphamide. Peripheral blood stem cells were collected from responding patients with < 1% of circulating plasma cells before HDM/ASCT. As consolidation, young patients received a reduced-intensity conditioning allograft, whereas the remaining patients underwent a second HDM/ASCT followed by 1 year of bortezomib, lenalidomide, dexamethasone. The primary end point was progression-free survival (PFS). RESULTS: Forty patients (median age, 57 years; range, 27 to 71 years) were enrolled. The median follow-up was 28.7 months. In the intention-to-treat analysis, the median PFS and overall survival were 15.1 (95% CI, 8.4; -) and 36.3 (95% CI, 25.6; -) months, respectively. The overall response rate to induction was 69%. One patient underwent a syngeneic allograft and 25 HDM/ASCT (16 of whom subsequently received a reduced-intensity conditioning allograft and seven a second ASCT followed by maintenance). CONCLUSION: In this prospective trial in patients with pPCL, we show that bortezomib, dexamethasone plus doxorubicin or cyclophosphamide induction followed by transplantation induces high response rates and appears to significantly improve PFS.

Cost Effectiveness of Cardioprotective Strategies in Patients with Aggressive Non-Hodgkin's Lymphoma.

OBJECTIVE: The cardiotoxicity of anthracyclines remains a key problem in patients with aggressive non-Hodgkin's lymphoma (NHL). With regard to the actual long-term prognosis of aggressive NHL, the development of cardioprotective strategies is mandatory for these patients. A cost-effectiveness analysis was carried out to determine the potential economic profile of dexrazoxane or liposome-encapsulated doxorubicin in patients with aggressive NHL treated with a CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) as first-line therapy. METHODS: A decision-analysis model described clinical events and economic consequences for theoretical patients who were to receive eight consecutive cycles of a CHOP regimen containing 50 mg/m(2) of doxorubicin as first-line chemotherapy. The timeframe of the model was the patient's lifetime. The probabilities were related to the cumulative dose of doxorubicin and age. The study was carried out from the perspective of the French healthcare system. Patients entered the model at 'choose' node: no cardioprotection versus cardioprotection with dexrazoxane or liposome-encapsulated doxorubicin. The model was based on a retrospective epidemiological study and on published data. The clinical end-point was life expectancy. Direct medical costs related to the cardioprotection and the treatment of congestive heart failure were considered. Monetary values for French prices in the year 2002 were used. Several univariate sensitivity analyses were carried out with varying clinical and economic parameters. RESULTS: Per 100 patients, the two cardioprotective strategies provided similar benefits that were estimated as 24.5 and 13.4 life-years in 60- and 40-year-old patients, respectively. The cost per life-year saved with dexrazoxane was estimated as euro6931 and euro15 599 in 60- and 40-year-old patients, respectively, and euro22 940 and euro44 982, respectively, with liposome-encapsulated doxorubicin. Several sensitivity analyses showed the robustness of the model. CONCLUSION: The results suggest the potential clinical and economic usefulness of cardioprotective therapies in patients with aggressive NHL. Prospective studies are needed to confirm these findings.