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Introduction/background: Leveraging the Follicular Lymphoma Analysis of Surrogacy Hypothesis database of individual patient data from first-line clinical trials, we studied the clinical course of follicular lymphoma (FL) and investigated clinical factors associated with FL outcomes., Patients and Methods: We examined 2428 patients from 8 randomized trials using multistate survival models with 4 states: induction treatment, progression, death from FL, and death from other causes. We utilized Aalen-Johansen estimator and Cox models to assess the likelihood of FL outcomes and quantify predictors' effects., Results: Two-year progression, FL-related death, and death from other causes estimates were 26.5%, 3.4% and 1.4%, respectively. FL-associated deaths were the primary cause of mortality within 10 years of follow-up. Male sex (hazard ratio: 1.25; 95% confidence interval: 1.05-1.47), > 4 involved nodal areas (1.51; 1.23-1.86), elevated LDH (1.20; 1.01-1.43), low hemoglobin (1.44; 1.15-1.81), and elevated β-2 levels (1.23; 1.02-1.47) increased risk of progression. CD20-targeting agents reduced risks for progression (0.29; 0.22-0.39), death from FL (0.05; 0.01-0.20), and death from other causes without progression (0.13; 0.05-0.33) and following progression (0.52; 0.30-0.92). Estimated 2-year progression rates were 22.3% and 43.5% with or without CD20-targeting agents, respectively. Two-year FL-associated mortality rate was 8.3% among patients without CD20-targeting agents, 5.4% with B-symptoms, 4.9% with elevated LDH, and 9.1% with low hemoglobin., Conclusion: This study identified independent contributions of baseline clinical factors to distinct outcomes for patients with FL following first-line therapy on a clinical trial. Similar analytical approaches are needed to increase understanding of factors that influence FL outcomes in other settings., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Rituximab monotherapy is widely used for follicular lymphoma. However, there are no established predictors for response or response duration. We analyzed the long-term prognostic relevance of pre-treatment absolute blood counts of lymphocytes with subsets and monocytes in 265 follicular lymphoma patients, uniformly treated with rituximab without chemotherapy, in two Nordic Lymphoma Group trials. There were 265 previously untreated, stage II-IV follicular lymphoma patients with a median follow-up of over 10 years. Absolute B cell counts ≥ median (0.09 × 10 9 /L) were an independent predictor for shorter time to next treatment or death (multivariable analysis P = 0.010). In univariate analysis, absolute monocyte counts ≥ median (0.5 × 10 9 /L) did not correlate with time to next treatment or death, but with inferior overall survival (P = 0.034). Absolute T cell or T cell subset counts were not predictive for outcome. High absolute B cell counts, possibly reflecting circulating lymphoma cells, have an unfavorable impact on time to next treatment or death in patients treated with rituximab without chemotherapy.

In chronic lymphocytic leukaemia (CLL) patients, treatment with the Bruton tyrosine kinase inhibitor ibrutinib induces a rapid shift of tumour cells from lymph nodes (LN) to peripheral blood (PB). Here, we characterized in depth the dynamics of ibrutinib-induced inflammatory, transcriptional and cellular changes in different compartments immediately after treatment initiation in seven relapsed/refractory CLL patients. Serial PB and LN samples were taken before start and during the first 29 days of treatment. Changes in plasma inflammation-related biomarkers, CLL cell RNA expression, B-cell activation and migration markers expression, and PB mononuclear cell populations were assessed. A significant reduction of 10 plasma inflammation markers, the majority of which were chemokines and not CLL-derived, was observed within hours, and was paralleled by very early increase of CD19 + circulating cells. At the RNA level, significant and continuous changes in transcription factors and signalling molecules linked to B-cell receptor signalling and CLL biology was observed in both PB and LN CLL cells already after 2 days of treatment. In conclusion, ibrutinib seems to instantly shut off an ongoing inflammatory response and interfere with diverse sensitive pathways in the LN., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

We report the largest retrospective, phase IV non-interventional, observational study of ofatumumab therapy in heavily pre-treated patients with poor-prognosis chronic lymphocytic leukemia. Total number of patients was 103; median age was 65 years (range 39-85). Median number of prior lines of therapy was 4 (range 1-13), including, in most cases, rituximab-, fludarabine- and alemtuzumab-based regimens; 13 patients had been allografted. Of 113 adverse events, 28 (29%) were considered to be directly related to ofatumumab. Grade 3-4 toxicities included neutropenia (10%), thrombocytopenia (5%), anemia (3%), pneumonia (17%), and fever (3%). Two heavily pre-treated patients developed progressive multifocal leukoencephalopathy. On an intention-to-treat analysis, the overall response rate was 22% (3 complete response, 1 incomplete complete response). Median progression-free and overall survival times were 5 and 11 months, respectively. This study confirms in a daily-life setting the feasibility and acceptable toxicity of ofatumumab treatment in advanced chronic lymphocytic leukemia. The complete response rate, however, was low. Therefore, treatment with ofatumumab should be moved to earlier phases of the disease. Ideally, this should be done in combination with other agents, as recently approved for ofatumumab plus chlorambucil as front-line treatment for patients unfit for fludarabine. This study is registered at clinicaltrials.gov identifier:01453062., (Copyright© Ferrata Storti Foundation.)

The randomized Haemato Oncology Foundation for Adults in The Netherlands 68 phase 3 trial compared front-line chemotherapy with chemotherapy plus the CD52 monoclonal antibody alemtuzumab for high-risk chronic lymphocytic leukemia, defined as at least 1 of the following: unmutated immunoglobulin heavy chain genes, deletion 17p or 11q, or trisomy 12. Fit patients were randomized to receive either 6 28-day cycles of oral FC chemotherapy (days 1 through 3: fludarabine 40 mg/m(2) per day and cyclophosphamide 250 mg/m(2) per day: n = 139) or FC plus subcutaneous alemtuzumab 30 mg day 1 (FCA, n = 133). FCA prolonged the primary end point, progression-free survival (3-year progression-free survival 53 vs 37%, P = .01), but not the secondary end point, overall survival (OS). However, a post hoc analysis showed that FCA increased OS in patients younger than 65 years (3-year OS 85% vs 76%, P = .035). FCA also increased the overall response rate (88 vs 78%, P = .036), and the bone marrow minimal residual disease-negative complete remission rate (64% vs 43%, P = .016). Opportunistic infections were more frequent following FCA, but without an increase in treatment related mortality (FCA: 3.8%, FC: 4.3%). FCA improves progression-free survival in high-risk chronic lymphocytic leukemia. As anticipated, FCA is more immunosuppressive than FC, but with due vigilance, does not lead to a higher treatment-related mortality. This study was registered at www.trialregister.nl as trial no. NTR529., (© 2014 by The American Society of Hematology.)

Purpose: The objective of this randomized trial was to assess the efficacy and safety of rituximab as in vivo purging before transplantation and as maintenance treatment immediately after high-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT) in patients with relapsed follicular lymphoma (FL)., Patients and Methods: Patients with relapsed FL who achieved either complete or very good partial remission with salvage chemotherapy were randomly assigned using a factorial design to rituximab purging (P+; 375 mg/m(2) once per week for 4 weeks) or observation (NP) before HDC-ASCT and to maintenance rituximab (M+; 375 mg/m(2) once every 2 months for four infusions) or observation (NM)., Results: From October 1999 to April 2006, 280 patients were enrolled. The median age was 51 years (range, 26 to 70 years), and baseline characteristics were well balanced between groups. On average, patients were 44 months (range, 3 to 464 months) from diagnosis, with 79% having received two lines and 15% three lines of prior therapy. Median follow-up was 8.3 years. In contrast to purging, 10-year progression-free survival (PFS) was 48% for P+ and 42% for NP groups (hazard ratio [HR], 0.80; 95% CI, 0.58 to 1.11; P = .18); maintenance had a significant effect on PFS (10-year PFS, 54% for M+ and 37% for NM; HR, 0.66; 95% CI, 0.47 to 0.91; P = .012). Overall survival (OS) was not improved by either rituximab purging or maintenance., Conclusion: Rituximab maintenance after HDC-ASCT is safe and significantly prolongs PFS but not OS in patients undergoing transplantation for relapsed FL. Pretransplantation rituximab in vivo purging, even in rituximab-naive patients, failed to improve PFS or OS.

Rituximab (R) is a monoclonal antibody with high therapeutic efficacy in low-grade CD20+ lymphoma. The combination of R with chemotherapy is the most common treatment option for patients with follicular lymphoma (FL). The efficacy of R has also been shown to be augmented, when used in combinations with biologicals such as interferon-alpha-2a (IFN), bortezomib, or lenalidomide. The best combination of these drugs are not well defined and a better understanding of pharmacokinetics and timing of drugs relative to the rituximab infusion is crucial. Other new targeted agents, such as inhibitors of BTK and PI3Kdelta, have also been promising in FL. Translational research questions should be added to clinical trial protocols to increase the knowledge on how the tumor microenvironment and the host immune system affect the response to the different drugs and combinations with the aim of a more individualized therapy.

This phase II study (n = 20) aimed to evaluate type, severity and duration of side-effects and efficacy following subcutaneous (SC) alemtuzumab, without dose-escalation, in advanced-stage relapsed chronic lymphocytic leukaemia (CLL) patients. Alemtuzumab 30 and 3 mg was administered SC simultaneously day 1, followed by 30 mg three times per week. Injection-site-reactions were recorded every 6-24 h until resolved using National Cancer Institute criteria and a new skin toxicity subscale. The first doses of 30 mg and 3 mg produced injection-site-reactions (all but one were grade 1/2) in 13/20 and 9/20 patients, respectively. The second dose (on day 3) resulted in skin-reactions in 10/20 patients and the third, fourth, fifth and sixth injections produced reactions in 6/20, 1/20, 2/20 and 0/20 patients, respectively. Mild "flu-like" symptoms occurred during week 1 in 10/20 patients. All side-effects had subsided by the sixth dose. 15/20 patients (75%) responded (12 partial responses, three complete responses) with a median time-to-treatment-failure of 20 months. Symptomatic cytomegalovirus-reactivation occurred in 6/20 patients. Two deaths occurred: one bacterial pneumonia and one adenovirus-infection. The present study showed how to assess cutaneous-toxicity in detail and that 30 mg alemtuzumab SC administered upfront was well tolerated. Optimized alemtuzumab therapy in properly selected patients may result in high efficacy even in advanced CLL. Our results need to be confirmed in extended studies.

R-etodolac is a novel pro-apoptotic agent with potential antitumor activity against B-cell chronic lymphocytic leukemia (B-CLL). This phase I clinical trial was conducted to determine the tolerability, safety, and maximum tolerated dose (MTD) of R-etodolac, administered orally twice a day (BID), in patients with B-CLL. Secondary objectives included evaluating clinical response, pharmacodynamic activity (reduction of lymphocytes), and pharmacokinetic (PK) profile. Forty-three patients were enrolled in the study. The most frequently reported adverse events were diarrhea, rash, pruritus, and headache. Increases in alanine aminotransferase (ALT) were also observed. Adverse events were generally mild and self-limiting, although in an apparent dose-response relationship, grade 2 and 3 gastrointestinal toxicities and grade 3 skin toxicities were reported with the highest dose regimens (1,800 and 2,400 mg BID). Hematologic toxicity was rare. The MTD was determined to be 1,200 mg BID. PK results indicated that oral absorption of R-etodolac was rapid (time to maximum concentration ranged from 2 to 4 h), and the half-life ranged from 5 to 7 h. The increase in maximum concentration, however, was not proportional to the increase in dose. R-etodolac significantly reduced absolute lymphocyte count (ALC) in B-CLL patients in a dose-dependent manner up to 1,800 mg BID and caused partial responses in 2 patients. Further study of R-etodolac as a possible new maintenance therapy or as a part of combination therapy of B-CLL appears warranted.

Late-onset neutropenia, i.e. an absolute neutrophil count of <1.5 x 10(9)/l, may follow 4 weeks or more after therapy with rituximab for lymphoma. However, incidence, predisposing factors, and pathogenic mechanisms are still poorly defined. In a retrospective study of 113 consecutive lymphoma patients treated with rituximab, with or without chemotherapy, we found eight patients (7%) with late-onset neutropenia (LON). Median time to onset was 88 days (range, 1-9 months) after last rituximab dose. Median duration of LON was 54 days (range, 1-17 weeks). Four of the eight patients underwent stem cell transplantation. Three patients developed febrile neutropenia and two required treatment with granulocyte colony-stimulating factor. In four subsequently identified patients with severe LON, a maturation arrest at the (pro)myelocyte stage was observed in the bone marrow, similar to that found in severe congenital neutropenia or Kostmann disease. However, none carried mutations in HAX1, thus ruling out such mutations in the development of the maturation arrest in these patients. Nevertheless, our data suggest that rituximab-related LON and congenital neutropenia might share similar neutropenia-causing mechanisms resulting in maturation arrest.

Introduction: Rituximab has significantly improved the prognosis for patients with both indolent and aggressive non-Hodgkin's lymphoma. An economic evaluation was carried out to assess the cost-effectiveness in Sweden of rituximab as maintenance therapy for patients with follicular lymphoma in remission after second line therapy., Materials and Methods: The incremental cost and effectiveness of rituximab maintenance therapy versus observation were evaluated in a health-state transition model. Primary effect measures were quality-adjusted life-years (QALY) and life-years gained (LYG). Model state transitions were calculated based on progression-free and overall survival data from the EORTC20981 trial. The analysis was made from the perspective of the healthcare provider, including direct medical costs presented in euro, 2007 value. Effects and costs were discounted at a 3% annual rate. The stability of the base case results were tested in one-way and probabilistic sensitivity analyses., Results: The evaluation assessed rituximab maintenance therapy to be associated with an incremental cost per QALY gained of euro 12,600 and an incremental cost per LYG of euro 11,200. The average discounted life expectancy for patients on rituximab maintenance was 1.0 year longer than for patients on observation (5.96 vs. 4.94 years). Rituximab maintenance was associated with an additional 0.9 QALY, and total costs per patient were euro 11,500 higher in the treatment arm, compared to observation., Discussion: The results indicate that rituximab maintenance treatment after successful induction therapy for patients with relapsed/refractory follicular lymphoma in Sweden is cost-effective compared to observation.

B-cell chronic lymphocytic leukemia has traditionally been treated with alkylating agents and purine analogues. The introduction of alemtuzumab, a CD52 monoclonal antibody with significant clinical activity in chemotherapy refractory B-cell chronic lymphocytic leukemia, is accompanied by a side effect profile different from that resulting from chemotherapy. The intravenous administration of alemtuzumab is usually accompanied by transient infusion-related side effects manifesting primarily as flu-like symptoms. These reactions can be reduced by use of corticosteroid prophylaxis, and will subside gradually during continued treatment. Alternatively, administration of alemtuzumab subcutaneously may markedly reduce the occurrence of general side effects but results in limited transient local skin reactions in most patients. Neutropenia (grade 4) may occur in approximately 20% of patients, but is usually transient and/or responds promptly to colony stimulating factor therapy; episodes of febrile neutropenia are infrequent. The major side effect of alemtuzumab is T-cell depletion, leading to an increased risk of infection, in particular reactivation of cytomegalovirus. This event typically occurs 3 to 8 weeks after initiation of therapy, coinciding with the T-cell nadir. With vigilance and early detection, these infections are usually manageable and do not cause organ failure. Preliminary data indicate that other infections following alemtuzumab therapy do not seem to occur at a frequency that is higher than expected, probably because of the general prophylactic use of cotrimoxazole (trimethoprim and sulfamethoxazole) and valacyclovir in combination with clinical tumor regressions. The overall safety profile of alemtuzumab appears to be beneficial in relation to disease severity and prognosis in patients with fludarabine-refractory B-cell chronic lymphocytic leukemia.

Rituximab, a human/mouse chimeric anti-CD20 antibody, has become part of standard therapy for patients with CD20-expressing B-cell lymphoma, and is currently under investigation for other indications including autoimmune diseases, in particular rheumatoid arthritis (RA). Its characteristic tolerability profile was established soon after clinical testing began and compares favourably with chemotherapy. The majority of patients experience mild to moderate infusion-related reactions (IRRs) during the first administration of rituximab, but the incidence decreases markedly with subsequent infusions. Current data suggest that the type of adverse events in patients with RA are similar to those in lymphoma, but that adverse events related to the rituximab infusions are less severe and less frequent. Rituximab induces a rapid depletion of normal CD20-expressing B-cells in the peripheral blood, and levels remain low or undetectable for 2-6 months before returning to pretreatment levels, generally within 12 months. Serum immunoglobulin levels remain largely stable, although a reduction in IgM has been described. T-cells are unaffected by rituximab and consequently opportunistic infections rarely occur in association with rituximab therapy. When used in combination with a variety of chemotherapeutic regimens, rituximab does not add to the toxicity of chemotherapy, with the exception of a higher rate of neutropenia. However, this does not translate into a higher infection rate. Over 540,000 patients worldwide have now received rituximab and serious adverse reactions have occurred in a small minority of patients, but for the great majority of patients, rituximab is safe and well tolerated.

Purpose: Rituximab is an important therapeutic for Waldenstrom's macroglobulinemia (WM). Polymorphisms in FcgammaRIIIA (CD16) receptor expression modulate human immunoglobulin G1 binding and antibody-dependent cell-mediated cytotoxicity, and may therefore influence responses to rituximab., Patients and Methods: Sequence analysis of the entire coding region of FcgammaRIIIA was undertaken in 58 patients with WM whose outcomes after rituximab were known., Results: Variations in five codons of FcgammaRIIIA were identified. Two were commonly observed (FcgammaRIIIA-48 and FcgammaRIIIA-158) and predicted for amino acid polymorphisms at FcgammaRIIIA-48: leucine/leucine (L/L), leucine/arginine (L/R), and leucine/histidine (L/H). Polymorphisms at FcgammaRIIIA-158 were phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V), and valine/valine (V/V). A clear linkage between these polymorphisms was detected and all patients with FcgammaRIIIA-158F/F were always FcgammaRIIIA-48L/L, and patients with either FcgammaRIIIA-L/R or -L/H always expressed at least one valine at FcgammaRIIIA-158 (P < or = .001). The response trend was higher for patients with FcgammaRIIIA-48L/H (38.5%) versus -48L/R (25.0%) and LL (22.0%), and was significantly higher for patients with FcgammaRIIIA-158V/V (40.0%) and -V/F (35%) versus -158F/F (9.0%; P = .030). Responses for patients with FcgammaRIIIA-48L/L were higher when at least one valine was present at FcgammaRIIIA-158 (P = .057), thereby supporting a primary role for FcgammaRIIIA-158 polymorphisms in predicting rituximab responses. With a median follow-up of 13 months, no significant differences in the median time to progression and progression-free survival were observed when patients were grouped according to their FcgammaRIIIA-48 and -158 polymorphisms., Conclusion: The results of these studies therefore support a predictive role for FcgammaRIIIA-158 polymorphisms and responses to rituximab in WM.

The optimal treatment of non-Hodgkin's lymphoma (NHL) during pregnancy is currently undefined. The potential teratogenic effects of conventional chemotherapy preclude its use during the first trimester of pregnancy. We report the case of a pregnant woman with relapsed indolent follicular NHL who was treated with rituximab (unintentionally) during the first trimester. The treatment stabilised the disease. Following an uncomplicated pregnancy, a healthy child was born at full term and careful haematological and immunological monitoring has revealed no adverse effects resulting from exposure to rituximab. Data of using rituximab during pregnancy are scarce, but the present case shows that rituximab may be one option for treatment of NHL in early pregnancy.

Indolent non-Hodgkin's lymphomas (NHLs) are essentially incurable with current treatments. Rituximab is a specific anti-CD20 chimeric monoclonal antibody against the CD20 antigen, which is stably expressed on most B-cells (from the pre-B-cell stage). Compared with chemotherapy, rituximab has an excellent tolerability profile, making it a good therapeutic option for patients with indolent NHL. In the pivotal study for rituximab, patients with relapsed or refractory indolent or follicular lymphoma (FL) had an overall response rate of 50%. There is evidence that first-line rituximab therapy may be associated with better response rates; in previously untreated FL with a low tumor burden, rituximab monotherapy has produced an overall response rate of 73%. Attempts to improve response rates to rituximab by increasing the dose or frequency of dosing showed that the addition of four extra infusions of rituximab (in addition to the standard treatment schedule) resulted in an overall response rate of 76% in patients with FL. Augmenting rituximab with cytokines is also an option for increasing response rates in patients with indolent NHL. In a trial by the Nordic Lymphoma Study Group in patients with previously untreated or first-relapse indolent NHL, who had stable disease or a partial response after four doses of rituximab, 48% of the patients treated with rituximab plus interferon-alpha2a achieved a complete response. A further option is to combine rituximab with chemotherapy. Interim analyses from the East German Study Group have shown that rituximab plus mitoxantrone, chlorambucil and prednisolone (MCP) resulted in overall response rates of 89% in patients with untreated indolent lymphoma. Rituximab is therefore an excellent treatment option both as first-line and as salvage therapy for patients with indolent NHL.

This phase II study determined the efficacy and safety of alemtuzumab, a humanized anti-CD52 monoclonal antibody, delivered subcutaneously as first-line therapy, over a prolonged treatment period of 18 weeks in 41 patients with symptomatic B-cell chronic lymphocytic leukemia (B-CLL). Injections were administered subcutaneously 3 times per week, from week 2 to 3 onward. An overall response rate (OR) of 87% (95% CI, 76%-98%; complete remission [CR], 19%; partial remission [PR], 68%) was achieved in 38 evaluable patients (81% of intent-to-treat population). CLL cells were cleared from blood in 95% patients in a median time of 21 days. CR or nodular PR in the bone marrow was achieved in 66% of the patients and most patients achieved this after 18 weeks of treatment. An 87% OR (29% CR) was achieved in the lymph nodes. The median time to treatment failure has not yet been reached (18+ months; range, 8-44+ months). Transient injection site skin reactions were seen in 90% of patients. Rigor, rash, nausea, dyspnea, and hypotension were rare or absent. Transient grade IV neutropenia developed in 21% of the patients. Infections were rare, but 10% patients developed cytomegalovirus (CMV) reactivation. These patients rapidly responded to intravenous ganciclovir. One patient, allergic to cotrimoxazole prophylaxis, developed Pneumocystis carinii pneumonia. Alemtuzumab is highly effective as first-line treatment in patients with B-CLL. Prolonged treatment is important for maximal bone marrow response. Subcutaneous administration induced very few "first-dose" flulike symptoms and may reduce health care costs in comparison with the intravenous infusions.

Monotherapy with the human-mouse chimeric anti-CD20 monoclonal antibody rituximab is effective and well tolerated in the treatment of indolent non-Hodgkin's lymphoma, but the majority of patients relapse. The combination of chemotherapeutic agents with rituximab results in greater efficacy, but at the cost of the increased toxicity associated with chemotherapy. To increase the efficacy of rituximab without compromising tolerability, the cytokines interferon-alpha2a, which has multiple immunomodulatory effects and enhances antibody-dependent cell-mediated cytotoxicity, and the granulocyte-colony stimulating factor, which enhances antibody-dependent cell-mediated cytotoxicity by neutrophils, have been combined with rituximab. In a randomized comparative study in patients with relapsed or untreated indolent non-Hodgkin's lymphoma, the addition of interferon-alpha2a significantly increased responsiveness to a second course of rituximab in patients with a partial response or minor response to an initial course of rituximab monotherapy. In a single-arm study in 20 patients with relapsed disease, the combination of granulocyte-colony stimulating factor with rituximab resulted in a longer duration of response than normally seen with rituximab monotherapy. In both studies, no significant increase in adverse events compared with rituximab monotherapy was reported. Currently available data suggest that the combination of rituximab with immunomodulatory cytokines result in increased efficacy without compromising tolerability., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

A phase II study was undertaken to evaluate the efficacy and toxicity of a new schedule of cladribine administration (10 mg/m2 orally daily for 3 d every 3 weeks) in 107 patients with B-cell chronic lymphocytic leukaemia (CLL). To minimize toxicity, treatment withdrawal criteria were defined. The results of the 63 previously untreated patients were retrospectively compared with 63 from an earlier study using a 5-d monthly schedule. The compiled data were analysed for prognostic factors for survival. No significant difference regarding response were seen in the two cohorts of the 126 previously untreated patients. The complete response (CR), nodular partial response (nPR) and partial response (PR) rates were 15%, 21% and 41%. Quality of response had no impact on survival. The 3- and 5-year overall survival for previously untreated patients was 73% and 58%, respectively, with a median follow-up of 54 months. Pretreatment haemoglobin <11.0 g/dl and elevated beta-2-microglobulin had a negative influence on survival. Major infections occurred in 21% of patients in the 3-d study compared with 35% in the 5-d study. The overall response (OR) and CR rates in the 40 previously treated patients were 34% and 5% respectively. Median overall survival was 24 months and median progression-free survival for responding patients was 14 months. Cladribine used as a single agent is an effective treatment with an acceptable safety profile for pretreated and untreated B-CLL. The achievement of complete remission was not a prerequisite for long-term survival.

We present health-related quality of life (HRQoL) data from GADOLIN, comparing bendamustine (B) alone or combined with obinutuzumab (G-B) in rituximab-refractory indolent non-Hodgkin lymphoma patients. The Functional Assessment of Cancer Treatment-Lymphoma (FACT-Lym) questionnaire was administered on day 1 of cycles 1, 3, and 5 during treatment, at end of induction (EOI), bi-monthly for 2 years during maintenance/follow-up, and annually during extended follow-up until progression/death. Time to first ≥6-point worsening from baseline in the FACT-Lym trial outcome index (TOI) was estimated. Minimally important differences at individual subscale and total score level were used to define the proportion of patients reporting improvement on the FACT-Lym lymphoma-specific subscale (≥3 points), FACT-Lym TOI (≥6 points), and FACT-Lym total score (≥7 points). Overall, 396 patients were randomized. Analysis was conducted when 175 Independent Review Committee-assessed progression-free survival (PFS) events were observed. Questionnaire completion rates were generally balanced between arms at baseline, EOI, and final follow-up. Median time to ≥6-point worsening from baseline on the FACT-Lym TOI was 8.0 months in the G-B arm and 4.6 months in the B arm (HR 0.74; 95% CI 0.56-0.98). More G-B patients reported meaningful improvements on the FACT-Lym questionnaire subscales. Results were similar when follicular lymphoma patients were analyzed separately. The delayed time to worsening and greater proportion of patients reporting meaningful improvement in HRQoL in the G-B arm suggest that benefit in PFS is not at the expense of an increase in treatment-related toxicity that could lead to reduced HRQoL. [ABSTRACT FROM AUTHOR]

Background: Posttransplant lymphoproliferative disease (PTLD) is a serious complication after organ transplantation associated with a high mortality, and is often caused by a primary or reactivated Epstein-Barr virus (EBV) infection. The incidence of PTLD ranges from 1% to 10%, depending on the type of organ transplanted and the immunosuppressive regimens used.Methods: In this retrospective study from a single center, 12 (2.4%) of 500 consecutive recipients of liver grafts developed lymphoma. Patient data were obtained by chart review. All diagnostic biopsies were reviewed by two hematopathologists.Results: The median time between transplantation and the diagnosis of lymphoma was 19.5 (1.5-148) mo. Nine of the patients had been treated with OKT-3 and/or ATG after the transplantation. Two patients had a pretransplant diagnosis of lymphoma. The PTLD was of high grade in all patients, and was associated with EBV in 6 of 9 examined cases. No relation with human herpesvirus-8 could be detected. In all patients, immunosuppression was reduced at the time of lymphoma diagnosis. Chemotherapy was used in all patients, mostly upfront but in one patient after lymphoma progression after reduction of immunosuppression. Nine patients also got antiviral therapy. Immunotherapy with the monoclonal antibody rituximab was used in one patient. Half of the patients are alive, in complete continuous remission, more than 4 yr after the lymphoma diagnosis. Two patients died of neutropenic sepsis, three of persistent lymphoma, and one of recurrent cirrhosis while in complete remission.Conclusions: PTLD is a significant complication in liver-transplanted patients. Intensive chemotherapy can induce long-term remissions in a substantial number of patients. The role for monoclonal antibodies in this setting should be investigated further. [ABSTRACT FROM AUTHOR]