Outcome of patients with diffuse large B-cell lymphoma and testicular involvement - real world data.

Patients with testicular lymphoma are at an increased risk of central nervous system (CNS) disease. Optimal strategy for CNS relapse prevention is unknown. We analyzed treatment strategies, cumulative incidence of CNS relapse and prognosis in 229 patients with diffuse large B-cell lymphoma (DLBCL) and testicular involvement: 157 primary testicular lymphomas (PTL) in clinical stages IE/IIE and 72 patients in advanced stages (T-DLBCL) IIIE/IV. Treatments for PTL vs. T-DLBCL included: rituximab-based chemotherapy (80.9% vs. 90.3%), orchiectomy (94.3% vs. 65.3%) and contralateral testicular irradiation (59.8% vs. 44.4%). Majority (84.3%) received CNS prophylaxis with similar rates of prophylactic methotrexate (intravenous 19.1% vs. 16.6%, intrathecal 40.8% vs. 40.4%, or both 24.2% vs. 27.8%) between PTL and T-DLBCL (p = 0.89). Median follow-up was 51.8 months. CNS relapses occurred in 14 (6.1%) of 63 relapsing patients. The 5-year cumulative incidence of CNS relapse in PTL was 4.5% and in T-DLBCL 12.1%. Median time to CNS relapse was 21.9 months. In univariate analyses, orchiectomy was the single significant factor associated with lower risk of CNS relapse in PTL (HR = 0.11 [95% CI, 0-0.124], p = 0.001). Rituximab significantly reduced CNS relapse risk in T-DLBCL (HR = 0.1002, p = 0.0005). Median progression-free survival (PFS) and overall survival (OS) following CNS relapse was dismal in T-DLBCL compared to PTL (PFS 1.6 vs. 37.8 months, p = 0.04 and OS 2.3 vs. 37.8 months, p = 0.05). This study confirmed a favorable impact of rituximab in prevention of CNS relapse in T-DLBCL. Methotrexate prophylaxis did not alter CNS relapse risk. Prognosis of CNS relapse is particularly poor in T-DLBCL.

Effectiveness of autologous haematopoietic stem cell transplantation versus natalizumab in progressive multiple sclerosis.

BACKGROUND: Natalizumab was not shown to modify disability in progressive multiple sclerosis (MS). This matched observational study compared the effectiveness of autologous haematopoietic stem cell transplantation (AHSCT) with natalizumab in progressive MS. METHODS: Patients with primary/secondary progressive MS from seven AHSCT MS centres and the MSBase registry, treated with AHSCT or natalizumab, were matched on a propensity score derived from sex, age, Expanded Disability Status Scale (EDSS), number of relapses 12/24 months before baseline, time from MS onset, the most effective prior therapy and country. The pairwise-censored groups were compared on hazards of 6-month confirmed EDSS worsening and improvement, relapses and annualised relapse rates (ARRs), using Andersen-Gill proportional hazards models and conditional negative binomial model. RESULTS: 39 patients treated with AHSCT (37 with secondary progressive MS, mean age 37 years, EDSS 5.7, 28% with recent disability progression, ARR 0.54 during the preceding year) were matched with 65 patients treated with natalizumab. The study found no evidence for difference in hazards of confirmed EDSS worsening (HR 1.49, 95% CI 0.70 to 3.14) and improvement (HR 1.50, 95% CI 0.22 to 10.29) between AHSCT and natalizumab over up to 4 years. The relapse activity was also similar while treated with AHSCT and natalizumab (ARR: mean±SD 0.08±0.28 vs 0.08±0.25; HR 1.05, 95% CI 0.39 to 2.82). In the AHSCT group, 3 patients experienced febrile neutropenia during mobilisation, 9 patients experienced serum sickness, 6 patients required intensive care unit admission and 36 patients experienced complications after discharge. No treatment-related deaths were reported. CONCLUSION: This study does not support the use of AHSCT to control disability in progressive MS with advanced disability and low relapse activity.

Pretreatment Cancer-Related Cognitive Impairment in Hodgkin Lymphoma Patients.

BACKGROUND: Cancer-related cognitive impairment (CRCI) is one of the most serious side effects of cancer that negatively impacts the quality of life of cancer patients and survivors. There is evidence of CRCI in Hodgkin lymphoma patients (HL); however, there is a lack of studies examining the presence of cognitive deficits before starting any treatment in HL patients. METHODS: Forty adult patients (N = 40) newly diagnosed with HL (with no previous cancer diagnoses) and 40 healthy controls (N = 40) matched for age, sex, education, and premorbid intellect completed the neuropsychological battery and subjective and objective measures of affective distress and quality of life. RESULTS: The results showed impairment in three out of six cognitive domains: verbal memory and learning, speed of processing/psychomotor speed, and abstraction/executive functions in the HL patients before the initiation of any treatment. The speed of processing/psychomotor speed domain is negatively correlated with depression. CONCLUSION: Cognitive deterioration in verbal memory and learning and abstraction/executive functions domains in HL patients seems to occur before the initiation of treatment independently of anxiety, depression, or physical symptoms. This suggests that HL itself may cause cognitive deficits in these cognitive domains. However, the underlying causes of CRCI still remain unclear.

Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis.

Importance: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). Objective: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. Design, Setting, and Participants: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. Exposure: AHSCT vs fingolimod, natalizumab, or ocrelizumab. Main outcomes: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. Results: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). Conclusion: In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.

Cognitive impairment associated with Hodgkin's lymphoma and chemotherapy.

Chemotherapy-related cognitive impairment (CRCI) is a well-documented side effect of cancer treatment in various types of tumors including Hodgkin's lymphoma (HL). However, a longitudinal study evaluating the cognitive performance of HL patients has been completely lacking. The aim of the study was to determine the presence of CRCI in HL patients before, promptly after, and 6 months after treatment. Thirty-six patients newly diagnosed with HL and 45 healthy controls (HC) completed the neuropsychological battery and psychological measures of affective distress and quality of life. The results indicate that HL patients have impaired performance compared to HC which cannot be explained by emotional factors. Cognitive impairments prior to treatment were found in 3 of 6 cognitive domains, i.e., verbal memory and learning, speed of processing/psychomotor speed, and abstraction/executive function. Promptly after the chemotherapy, deficits were found in the domains of memory and learning, verbal memory, speed of processing/psychomotor speed, and abstraction/executive function. Weaker cognitive performance persist even 6 months after the end of chemotherapy, specifically in domains of verbal memory and learning, and abstraction/executive function. Our results indicate the presence of cognitive impairment in HL patients already prior to treatment and increased damages caused by chemotherapy, while some of them may last for up to 6 months after the treatment.

Circulating tumor DNA in Hodgkin lymphoma.

Somatic mutations of genes involved in NF-κB, PI3K/AKT, NOTCH, and JAK/STAT signaling pathways play an important role in the pathogenesis of Hodgkin lymphoma (HL). HL tumor cells form only about 5% of the tumor mass; however, it was shown that HL tumor-derived DNA could be detected in the bloodstream. This circulating tumor DNA (ctDNA) reflects the genetic profile of HL tumor cells and can be used for qualitative and quantitative analysis of tumor-specific somatic DNA mutations within the concept of liquid biopsy. Overall, the most frequently mutated gene in HL is STAT6; however, the exact spectrum of mutations differs between individual HL histological subtypes. Importantly, reduction of ctDNA plasma levels after initial treatment is highly correlated with prognosis. Therefore, ctDNA shows great promise as a novel tool for non-invasive tumor genome analysis for biomarker driven therapy as well as for superior minimal residual disease monitoring and treatment resistance detection. Here, we summarize the recent advancements of ctDNA analysis in HL with focus on ctDNA detection methodologies, genetic profiling of HL and its clonal evolution, and the emerging prognostic value of ctDNA.

Effectiveness and Safety of Romiplostim Among Patients with Newly Diagnosed, Persistent and Chronic Immune Thrombocytopenia in European Clinical Practice.

INTRODUCTION: Romiplostim has been approved in Europe since 2009 to treat patients with chronic primary immune thrombocytopenia (ITP). Using real-world data from seven European countries, we measured the effectiveness and safety outcomes within 24 weeks following romiplostim initiation by duration of ITP: less than 3 months ("newly diagnosed"), 3-12 months ("persistent"), and more than 12 months ("chronic"). METHODS: Adults with ITP and ≥ 1 romiplostim administration between 2009 and 2012 were included. Endpoints included durable platelet response, median platelet count, rescue therapy, bleeding and adverse events. We used inverse probability of censoring weighted estimators to estimate cumulative risk of each outcome. There were 64 newly diagnosed, 50 persistent, and 226 chronic ITP patients at romiplostim initiation. RESULTS: Durable platelet response at 24 weeks ranged from 32% [confidence interval (CI): 18-46%] in newly diagnosed patients to 53% (CI 37-68%) in persistent patients. Median platelet count during follow-up ranged from 88 (CI 80-96) × 109/L in chronic patients to 131 (CI 102-160) × 109/L in newly diagnosed patients. CONCLUSION: Regardless of ITP duration, over half of patients discontinued concomitant ITP medications. Few adverse events were observed. Although only approved for chronic patients, estimates of the romiplostim treatment effect were similar across patients being managed in European clinical practice, regardless of ITP duration at romiplostim initiation.

Autologous stem cell transplantation for post-transplant lymphoproliferative disorders after solid organ transplantation: a retrospective analysis from the Lymphoma Working Party of the EBMT.

Published data describing the efficacy and safety of autologous stem-cell transplantation (autoSCT) in post-transplant lymphoproliferative disorders (PTLD) is limited to case reports. This is a retrospective analysis of 21 patients reported to the EBMT registry who received an autoSCT for PTLD post solid organ transplant (SOT). Median age at autoSCT was 47 (range: 22-71) years. The commonest SOTs were kidney (48%) and liver (24%). Commonest histologies included DLBCL-type PTLD (14/21) and plasmacytoma-like PTLD (3/21). Patients received a median of two lines of therapy (range: 1-4) pre-autoSCT. ECOG performance status pre-autoSCT was 0 in 14% and 1 in 86%. Remission status pre-autoSCT was CR 47% and PR 38%. BEAM conditioning was used in 57% and high-dose melphalan in 10%. The median follow-up post-autoSCT was 64 months for alive patients. 3-year PFS was 62% [95% confidence interval (CI) 44-87%] and 3-year OS was 61% [95% CI:43-86]. There were 12 deaths, including four related to autoSCT. 100-day non-relapse-mortality (NRM) was 14% and 1-year NRM was 24%. This study suggests that autoSCT, although feasible and with potential therapeutic activity, is associated with a high NRM, primarily driven by infectious toxicity. A multi-disciplinary approach, expert microbiological input and stringent patient selection are required to optimise outcomes.

Low-dose fludarabine and cyclophosphamide combined with rituximab in the first-line treatment of elderly/comorbid patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL): long-term results of project Q-lite by the Czech CLL Study Group.

Therapeutic options used to be very limited for treatment-naïve elderly/comorbid patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) before the introduction of chemo-immunotherapy. Because dose-reduced fludarabine-based regimens yielded promising results, the Czech CLL Study Group initiated a prospective observational study to assess safety and efficacy of low-dose fludarabine and cyclophosphamide combined with rituximab (FCR) in elderly/comorbid patients. Between March 2009 and July 2012, we enrolled 107 patients considered ineligible for full-dose FCR (median age, 70 years; median Cumulative Illness Rating Scale score, 5; median creatinine clearance, 69 ml/min). Notably, 77% patients had unfavourable biological prognosis [unmutated immunoglobulin heavy-chain variable-region gene (IGHV), 74%; deletion 17p, 9%). Fludarabine was reduced to 12 mg/m2 intravenously (iv) or 20 mg/m2 orally on days 1-3 and cyclophosphamide to 150 mg/m2 iv/orally on days 1-3. Grade 3-4 neutropenia occurred in 56% of the patients, but there were serious infections in only 15%. The median progression-free survival was 29 months, but was markedly longer in patients with mutated IGHV (median 53 months), especially in absence of del 11q or 17p (median 74 months). Low-dose FCR is a well-tolerated and effective first-line regimen for selected elderly/comorbid patients with CLL/SLL with favourable biology. The study was registered at clinicaltrials.gov (NCT02156726).

ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia.

PURPOSE: Acalabrutinib, a highly selective, potent, Bruton tyrosine kinase inhibitor, was evaluated in this global, multicenter, randomized, open-label, phase III study in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). METHODS: Eligible patients, aged ≥ 18 years with R/R CLL, were randomly assigned 1:1 centrally and stratified by del(17p) status, Eastern Cooperative Oncology Group performance status score, and number of prior lines of therapy. Patients received acalabrutinib monotherapy or investigator's choice (idelalisib plus rituximab [I-R] or bendamustine plus rituximab [B-R]). The primary end point was progression-free survival (PFS) assessed by an independent review committee (IRC) in the intent-to-treat population. Key secondary end points included IRC-assessed overall response rate, overall survival, and safety. RESULTS: From February 21, 2017, to January 17, 2018, a total of 398 patients were assessed for eligibility; 310 patients were randomly assigned to acalabrutinib monotherapy (n = 155) or investigator's choice (n = 155; I-R, n = 119; B-R, n = 36). Patients had received a median of two prior therapies (range, 1-10). After a median follow-up of 16.1 months (range, 0.03-22.4 months), median PFS was significantly longer with acalabrutinib monotherapy (PFS not reached) compared with investigator's choice (16.5 months [95% CI, 14.0 to 17.1 months]; hazard ratio, 0.31 [95% CI, 0.20 to 0.49]; P < .0001). Estimated 12-month PFS was 88% (95% CI, 81% to 92%) for acalabrutinib and 68% (95% CI, 59% to 75%) for investigator's choice. Serious adverse events occurred in 29% of patients (n = 44 of 154) treated with acalabrutinib monotherapy, 56% (n = 66 of 118) with I-R, and 26% (n = 9 of 35) with B-R. Deaths occurred in 10% (n = 15 of 154), 11% (n = 13 of 118), and 14% (n = 5 of 35) of patients receiving acalabrutinib monotherapy, I-R, and B-R, respectively. CONCLUSION: Acalabrutinib significantly improved PFS compared with I-R or B-R and has an acceptable safety profile in patients with R/R CLL.

Durable Response to Brentuximab Vedotin-Based Chemotherapy in Refractory Hodgkin Lymphoma with Central Nervous System (CNS) Involvement.

BACKGROUND CNS involvement in Hodgkin lymphoma is rare. Despite various treatment options, median overall survival is only 13 months after diagnosis of CNS involvement in relapsed/refractory HL. CASE REPORT A 29-year-old woman with classical HL (mixed cellularity) in clinical stage IIB was treated with multilineage chemotherapy and radiotherapy without achieving a sustained complete remission. Systemic and CNS progression of HL occurred at the age of 32 years and the patient received 2 cycles of brentuximab vedotin with bendamustine alternating with 2 cycles of high-dose methotrexate-based treatment and achieved partial remission. She then underwent autologous stem cell transplantation followed by brentuximab vedotin consolidation. The disease progressed and the patient died 6 months after the last dose of brentuximab vedotin. CONCLUSIONS We demonstrated a durable response to brentuximab vedotin-based chemotherapy in a patient with refractory Hodgkin lymphoma with CNS involvement. Prognosis of these patients is poor and new treatment options are needed.

Rituximab maintenance overcomes the negative prognostic factor of obesity in CLL: Subgroup analysis of the international randomized AGMT CLL-8a mabtenance trial.

No data are available regarding obesity and outcome in Chronic Lymphocytic Leukemia (CLL). We analyzed 263 patients from the AGMT CLL-8a Mabtenance trial for the impact of obesity. The trial included patients after rituximab-containing induction treatment in first or second line that had achieved at least a PR. A randomization to rituximab maintenance treatment (375 mg/m2 q3 months for 2 years) vs observation was performed. In this cohort 22% of the patients (58/263) were classified as obese. The baseline response to induction treatment was inferior in obese patients with a lower CR rate (43.1% vs 60.5% in obese vs non-obese, P = 0.018) and with a lower rate of patients achieving MRD negativity after chemoimmunotherapy induction treatment (19.6% vs 35.8%, P = 0.02). The PFS outcome of obese patients was significantly worse in the observation group of the trial (24 vs 39 months median PFS, P = 0.03). However, in the rituximab maintenance group the outcome for obese vs non-obese was not different (P = 0.4). In summary, obesity was overall associated with a worse outcome of chemoimmunotherapy induction. However, rituximab maintenance treatment seems to be able to overcome this negative effect.

Secondary central nervous system lymphoma: spectrum of morphological MRI appearances.

BACKGROUND: Secondary central nervous system lymphoma (SCNSL) is a rare and aggressive disease, which is defined as secondary central nervous system (CNS) involvement in patients with systemic lymphoma. According to previous reports, SCNSL presents mostly with leptomeningeal spread; however, our experience differs. In the present study, we demonstrate the diversity of magnetic resonance imaging (MRI) patterns in SCNSL. PATIENTS AND METHODS: Initial morphological MRI findings in 21 patients (10 women and 11 men with mean age 62.3±16.2 years) with SCNSL were retrospectively evaluated. All patients suffered from neurological symptoms and underwent MRI, and all cases were histologically verified. Twelve patients were treated by corticosteroids at the time of the initial MRI. RESULTS: Parenchymal lesions were present in 18 of 21 cases (85.7%), solitary meningeal infiltration was present in 1 patient (4.8%), leptomeningeal infiltration in combination with hypophyseal involvement in 1 patient (4.8%), and solitary involvement of the sixth cranial nerve (CN) was found in 1 patient (4.8%). Multiple lesions were present in 11 of 21 cases (52.4%). Diffusion restriction in all or part of the lesion was detected in 14 of 18 cases (77.8%). All parenchymal lesions had an infiltrative appearance and most enhanced homogenously (11 of 17 cases; 64.7%). A combination of parenchymal and meningeal involvement was found in 10 of 21 cases (47.6%). Infiltration of the CNs, basal ganglia, corpus callosum, and ependyma was present in 8 of 21 cases (38.1%) for each of the abovementioned structures; hypothalamic-hypophyseal axis was affected in 7 of 21 cases (33.3%). CONCLUSION: In contrast to previous reports, SCNSL presented as parenchymal disease. MRI is not sufficient for differentiation between primary and secondary CNS lymphoma.

Clinical case: idelalisib-induced immunoglobulin flare.

IgM flare is a transient, treatment-induced, increase of monoclonal IgM levels in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) patients. Until recently this phenomenon was observed in patients treated with Cladribine and Rituximab. Here we report a case of a heavily pretreated chronic lymphocytic leukemia patient with an atypically high immunoglobulin production who developed clinically significant immunoglobulin flare following Idelalisib treatment.

Soluble CD52 is an indicator of disease activity in chronic lymphocytic leukemia.

CD52 is a glycoprotein expressed on normal as well as leukemic immune cells and shed as soluble CD52 (sCD52). We studied sCD52 levels in three CLL cohorts: the 'early', the 'high-risk', and the 'ibrutinib-treated'. The 'high-risk' patients had significantly higher sCD52 levels than the 'early' patients. For the 'early' patients, high sCD52 levels were associated with a significantly shorter time to first treatment. Regarding prognostic factors, no clear correlations with stage, IGHV, or beta-2-microglobulin were found; in a cox multivariate analysis of the 'early' patients, sCD52 and IGHV both had independent prognostic value. Following chemo-immunotherapy, sCD52 decreased in parallel with leukocytes while during ibrutinib treatment and ibrutinib-induced ymphocytosis, sCD52 decreased along with lymph node reductions. In vitro IgM stimulation of CLL cells led to increased sCD52 levels in the medium. Our findings indicate that sCD52 reflects disease activity and potentially treatment efficacy in CLL.

Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis.

IMPORTANCE: Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies. OBJECTIVE: To evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort. DESIGN, SETTING, AND PARTICIPANTS: Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015. EXPOSURES: Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen. MAIN OUTCOMES AND MEASURES: The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models. RESULTS: Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95). CONCLUSIONS AND RELEVANCE: In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.

The HOVON68 CLL trial revisited: performance status and comorbidity affect survival in elderly patients with chronic lymphocytic leukemia.

In the HOVON68 CLL trial, patients 65 to 75 years of age had no survival benefit from the addition of low-dose alemtuzumab to fludarabine and cyclophosphamide (FC) in contrast to younger patients. The reasons are explored in this 5-year trial update using both survival analysis and competing risk analysis on non-CLL-related mortality. Elderly FCA patients died more frequently from causes not related to CLL, and more often related to comorbidity (mostly cardiovascular) than to infection. In a Cox multivariate analysis, del(17p), performance status >0, and comorbidity were associated with a higher non-CLL-related mortality in the elderly independent of the treatment modality. Thus, while the 'fit' elderly with no comorbidity or performance status of 0 might potentially benefit from chemo-immunotherapy with FC, caution is warranted, when considering alemtuzumab treatment in elderly patients with cardiovascular comorbidity.

A large observational study of patients with primary immune thrombocytopenia receiving romiplostim in European clinical practice.

OBJECTIVE: Romiplostim has maintained long-term platelet counts in patients with immune thrombocytopenia (ITP) for up to 5 yr in clinical studies. This prospective observational study aimed to describe romiplostim utilisation and outcomes in European clinical practice. METHODS: Adults with primary ITP who received romiplostim in routine care were eligible. RESULTS: Three-hundred and forty patients were eligible for analysis, of whom 299 (88%) completed the 2-yr observation period. The median age was 62 yr, with 43% of patients aged ≥65 yr, and two-thirds of patients initiated romiplostim before splenectomy. The median average weekly dose of romiplostim was 2.8 µg/kg. The median baseline platelet count was 20 × 109 /L, which increased after 2 wk of romiplostim treatment and remained >50 × 109 /L thereafter. After romiplostim initiation, there was a decrease in rates of grade ≥3 bleeding events (from 12 to 2 per 100 patient-years) and ITP-related hospitalisations (from 87 to 33 per 100 patient-years). The rate of thrombotic events was 2 per 100 patient-years, and bone marrow fibrosis occurred in two patients. CONCLUSIONS: Romiplostim dosing, effectiveness and safety in an unselected real-world ITP population seemed comparable with that observed in clinical studies.

Frontline intensive chemotherapy improves outcome in young, high-risk patients with follicular lymphoma: pair-matched analysis from the Czech Lymphoma Study Group Database.

Optimal frontline treatment in younger high tumor-burden risk follicular lymphoma patients remains a challenge given the reduced efficacy of standard immunochemotherapy (R-CHOP) in widespread disease and unclear role of intensive induction. The retrospective non-randomized pair-matched (1:3) analysis compared 48 intermediate/high Follicular Lymphoma International Prognostic Index (FLIPI) patients receiving intensive rituximab sequential chemotherapy (R-SQ) with 144 random controls (R-CHOP) matched for age, FLIPI score, and maintenance delivery. Complete response rates were 91.7% and 74.1%, respectively (p = .038). After a median follow-up of 8.8 (R-SQ) and 6.5 years (R-CHOP), 5-year time to treatment failure, progression-free survival, and overall survival were 80.9%, 83.2%, and 100% and 57.5%, 60.3%, and 92.1% (p = .0044; p = .0047; p = .22), respectively. Intensive treatment was accompanied by higher acute hematologic toxicity and infections, comparable non-hematologic toxicity, and incidence of secondary malignancies. Intensive induction demonstrates superior long-term disease control compared to R-CHOP, with higher acute hematologic toxicity, but without acute treatment-related mortality. Further studies are needed to define ultra-high-risk FL patients benefiting most from treatment intensity.