Lukas Smolej

Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia.

We conducted an international phase 2 trial to evaluate 2 dose levels of ofatumumab, a human CD20 mAb, combined with fludarabine and cyclophosphamide (O-FC) as frontline therapy for chronic lymphocytic leukemia (CLL). Patients with active CLL were randomized to ofatumumab 500 mg (n = 31) or 1000 mg (n = 30) day 1, with fludarabine 25 mg/m(2) and cyclophosphamide 250 mg/m(2) days 2-4, course 1; days 1-3, courses 2-6; every 4 weeks for 6 courses. The first ofatumumab dose was 300 mg for both cohorts. The median age was 56 years; 13% of patients had a 17p deletion; 64% had β2-microglobulin > 3.5 mg/L. Based on the 1996 National Cancer Institute Working Group (NCI-WG) guidelines, the complete response (CR) rate as assessed by an independent review committee was 32% for the 500-mg and 50% for the 1000-mg cohort; the overall response (OR) rate was 77% and 73%, respectively. Based on univariable regression analyses, β2-microglobulin and the number of O-FC courses were significantly correlated (P < .05) with CR and OR rates and progression-free survival (PFS). The most frequent Common Terminology Criteria (CTC) grade 3-4 investigator-reported adverse events were neutropenia (48%), thrombocytopenia (15%), anemia (13%), and infection (8%). O-FC is active and safe in treatment-naive patients with CLL, including high-risk patients. This trial was registered at www.clinicaltrials.gov as NCT00410163.

Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study

BACKGROUND Ofatumumab is a human anti-CD20 monoclonal antibody that has proven efficacy as monotherapy in refractory chronic lymphocytic leukaemia. We assessed the efficacy and safety of ofatumumab maintenance treatment versus observation for patients in remission after re-induction treatment for relapsed chronic lymphocytic leukaemia. METHODS This open-label, multicentre, randomised phase 3 study enrolled patients aged 18 years or older from 130 centres in 24 countries who had chronic lymphocytic leukaemia in complete or partial remission after second-line or third-line treatment. Eligible patients had a WHO performance status of 0-2, had a response assessment within the previous 3 months, did not have refractory disease, autoimmune haemolytic anaemia requiring treatment, chronic or active infection requiring treatment, and had not previously received maintenance treatment or autologous or allogeneic stem-cell transplant. Using a randomisation list generated by a central computerised system and an interactive voice recognition system, we randomly assigned (1:1) patients to receive ofatumumab (300 mg followed by 1000 mg 1 week later and every 8 weeks for up to 2 years) or undergo observation. Randomisation was stratified by number and type of previous treatment and remission status after induction treatment (block size of four). Treatment assignment was open label. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. We report the results of a prespecified interim analysis after two-thirds of the planned study events (disease progression or death) had happened. This trial is closed to accrual but follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00802737. FINDINGS Between May 6, 2010, and June 19, 2014, we enrolled 474 patients: 238 patients were randomly assigned to receive ofatumumab maintenance treatment and 236 to undergo observation. One (<1%) patient in the ofatumumab group did not receive the allocated intervention (withdrawal of consent). The median follow-up was 19·1 months (IQR 10·3-28·8). Progression-free survival was improved in patients assigned to the ofatumumab group (29·4 months, 95% CI 26·2-34·2) compared with those assigned to observation (15·2 months, 11·8-18·8; hazard ratio 0·50, 95% CI 0·38-0·66; p<0·0001). The most common grade 3 or higher adverse events up to 60 days after last treatment were neutropenia (56 [24%] of 237 patients in the ofatumumab group vs 23 [10%] of 237 in the observation group) and infections (31 [13%] vs 20 [8%]). 20 (8%) of 237 patients in the ofatumumab group and three (1%) of 237 patients in the observation group had adverse events that led to permanent discontinuation of treatment. Up to 60 days after last treatment, two deaths related to adverse events occurred in the ofatumumab treatment group and five deaths related to adverse events occurred in the observation group; no deaths were attributed to the study drug. INTERPRETATION These data are important for the development of optimum maintenance strategies in patients with relapsed chronic lymphocytic leukaemia, notably in the present era of targeted drugs, many of which are to be used until progression.

Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial

Summary Background Bendamustine and rituximab (BR) has been a standard of care for the management of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). We evaluated the efficacy and safety of adding idelalisib, a first-in-class targeted PI3Kδ inhibitor, to BR in patients with R/R CLL Methods This trial was a global, multicenter, double-blind, placebo -controlled trial in adult patients (≥18 years) with R/R CLL requiring treatment for their disease. Patients had to have measurable lymphadenopathy (≥1 nodal lesion ≥2.0 cm in the longest diameter and ≥1.0 cm in the longest perpendicular diameter) by computer tomography or magnetic resonance imaging, disease progression within <36 months since last prior therapy, a Karnofsky Performance Status score ≥60 and adequate bone marrow, liver and kidney function. Key exclusion criteria included histological transformation to an aggressive lymphoma (eg, Richter transformation) or disease refractory to bendamustine. Patients were randomised 1:1 using a central interactive web response system that assigned a unique treatment code for each patient, to receive intravenous BR infusions for a maximum of 6 cycles in addition to blinded study drug matching the assigned treatment of either twice-daily oral idelalisib 150 mg or placebo administered continuously until disease progression or intolerable study drug-related toxicity. Randomisation was stratified based on high-risk features (IGHV, del(17p)/TP53 mutation) and refractory vs relapsed disease. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee in the intent-to-treat population. Overall survival was a key secondary endpoint. Crossover was not permitted to the idelalisib arm at progression. The trial is ongoing (ClinicalTrials.gov # NCT01569295). Findings Between 26 June 2012 and 21 August 2014, 416 patients with R/R CLL were enrolled; 207 patients were randomised to the idelalisib and 209 to the placebo arm. After the prespecified interim analysis, the Independent Data Monitoring Committee (IDMC) recommended discontinuation and unblinding of the trial due to efficacy. Updated data are presented in this manuscript with a cutoff date of 07 October 2015. Median (95% CI) PFS was 20·8 (16·6, 26·4) and 11·1 (8·9, 11·1) months in the idelalisib and placebo arms, respectively (hazard ratio [HR], 0·33; 95% CI, 0·25, 0·44; P<0·0001) at a median (Q1, Q3) follow-up of 14 (7, 18) months. The most frequent grade 3 or greater AEs were neutropenia (124/207 [60%]) and febrile neutropenia (48/207 [23%]) in the idelalisib arm and neutropenia (99/209 [47%]) and thrombocytopenia (27/209 [13%]) in the placebo arm. Serious AEs included febrile neutropenia, pneumonia and pyrexia and were common in both treatment arms. An increased risk of infection was observed in the idelalisib vs placebo arm. Interpretation Idelalisib plus BR is superior to BR alone, improving PFS and OS. This regimen represents an important new treatment option for patients with R/R CLL.

Central nervous system involvement in mantle cell lymphoma: clinical features, prognostic factors and outcomes from the European Mantle Cell Lymphoma Network

BACKGROUND Central nervous system (CNS) involvement in mantle cell lymphoma (MCL) is uncommon, and the manifestations and natural history are not well described. PATIENTS AND METHODS We present the data on 57 patients with MCL who developed CNS involvement, from a database of 1396 consecutively treated patients at 14 institutions. RESULTS The crude incidence of CNS involvement was 4.1%, with 0.9% having CNS involvement at diagnosis. Blastoid histology, B-symptoms, elevated lactate dehydrogenase, Eastern Cooperative Group performance status ≥2 and a high Mantle Cell Lymphoma International Prognostic Index score were enriched in the cohort with CNS involvement, and the presence of ≥1 of these features defined a high-risk subset (an actuarial risk of CNS involvement 15% at 5 years) in a single-institution subset. The median time to CNS relapse was 15.2 months, and the median survival from time of CNS diagnosis was 3.7 months. The white blood cell count at diagnosis <10.9 × 10⁹/l, treatment of CNS involvement with high-dose anti-metabolites, consolidation with stem cell transplant and achievement of complete response were all associated with improved survival. CONCLUSIONS In MCL, CNS involvement is uncommon, although some features may predict risk. Once manifest outlook is poor; however, some patients who receive intensive therapy survive longer than 12 months.

Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial

BACKGROUND In many patients with chronic lymphocytic leukaemia requiring treatment, induction therapy with rituximab plus chemotherapy improves outcomes compared with chemotherapy alone. In this study we aimed to investigate the potential of rituximab maintenance therapy to prolong disease control in patients who respond to rituximab-containing induction regimens. METHODS In this randomised, international, multicentre, open-label, phase 3 clinical trial, we enrolled patients who had achieved a complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) to first-line or second-line rituximab-containing chemoimmunotherapy and randomly assigned them in a 1:1 ratio (central block randomisation in the electronic case report form system) to either intravenous rituximab 375 mg/m(2) every 3 months, or observation alone, for 2 years. Stratification was by country, line of treatment, type of chemotherapy added to the rituximab backbone, and degree of remission following induction. The primary endpoint was progression-free survival. Efficacy analysis was done in the intention-to-treat population. This is the final, event-triggered analysis. Final analysis was triggered by the occurrence of 92 events. This trial is registered with ClinicalTrials.gov, number NCT01118234. FINDINGS Between April 1, 2010, and Dec 23, 2013, 134 patients were randomised to rituximab and 129 to observation alone. Median observation times were 33·4 months (IQR 25·7-42·8) for the rituximab group and 34·0 months (25·4-41·9) for the observation group. Progression-free survival was significantly longer in the rituximab maintenance group (47·0 months, IQR 28·5-incalculable) than with observation alone (35·5 months, 95% CI 25·7-46·3; hazard ratio [HR] 0·50, 95% CI 0·33-0·75, p=0·00077). The incidence of grade 3-4 haematological toxicities other than neutropenia was similar in the two treatment groups. Grade 3-4 neutropenia occurred in 28 (21%) patients in the rituximab group and 14 (11%) patients in the observation group. Apart from neutropenia, the most common grade 3-4 adverse events were upper (five vs one [1%] patient in the observation group) and lower (three [2%] vs one [1%]) respiratory tract infection, pneumonia (nine [7%] vs two [2%]), thrombopenia (four [3%] vs four [3%]), neoplasms (five [4%] vs four [3%]), and eye disorders (four [3%] vs two [2%]). The overall incidence of infections of all grades was higher among rituximab recipients (88 [66%] vs 65 [50%]). INTERPRETATION Rituximab maintenance therapy prolongs progression-free survival in patients achieving at least a PR to induction with rituximab plus chemotherapy, and the treatment is well tolerated overall. Although it is associated with an increase in infections, there is no excess in infection mortality, suggesting that remission maintenance with rituximab is an effective and safe option in the management of chronic lymphocytic leukaemia in early treatment phases. FUNDING Arbeitsgemeinschaft Medikamentöse Tumortherapie gemeinnützige GmbH (AGMT), Roche.

Ofatumumab in poor-prognosis chronic lymphocytic leukemia: a Phase IV, non-interventional, observational study from the European Research Initiative on Chronic Lymphocytic Leukemia

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.

Biological prognostic markers in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most frequent leukemic disease of adults in the Western world. It is remarkable by an extraordinary heterogeneity of clinical course with overall survival ranging from several months to more than 15 years. Classical staging sytems by Rai and Binet, while readily available and useful for initial assessment of prognosis, are not able to determine individual patients ongoing clinical course of CLL at the time of diagnosis, especially in early stages. Therefore, newer biological prognostic parameters are currently being clinically evaluated. Mutational status of variable region of immunoglobulin heavy chain genes (IgVH), cytogenetic aberrations, and both intracellular ZAP- 70 and surface CD38 expression are recognized as parameters with established prognostic value. Molecules regulating the process of angiogenesis are also considered as promising markers. The purpose of this review is to summarize in detail the specific role of these prognostic factors in chronic lymphocytic leukemia.

Ofatumumab added to dexamethasone in patients with relapsed or refractory chronic lymphocytic leukemia: Results from a phase II study

The treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical issue. An important treatment option is the use of high‐dose corticosteroids. The purpose of this clinical trial was to determine the efficacy and toxicity of an ofatumumab–dexamethasone (O‐Dex) combination in relapsed or refractory CLL. The trial was an open‐label, multicenter, nonrandomized, Phase II study. The O‐Dex regimen consisted of intravenous ofatumumab (Cycle 1: 300 mg on day 1, 2,000 mg on days 8, 15, and 22; Cycles 2–6: 1,000 mg on days 1, 8, 15, and 22) and oral dexamethasone (40 mg on days 1–4 and 15–18; Cycles 1–6). The O‐Dex regimen was given until best response, or a maximum of six cycles. Thirty‐three patients (pts) were recruited. Twenty‐four (73%) pts completed at least three cycles of therapy. The remaining nine pts were prematurely discontinued owing to Grade 3/4 infections (seven pts), disease progression (one pt), or uncontrollable diabetes mellitus (one pt). Overall response rates/complete remissions (ORR/CR) were achieved in 22/5 pts (67/15%). The median progression‐free survival (PFS) was 10 months. In pts with p53 defects (n = 8), ORR/CR were achieved in 5/2 pts (63/25%) with a median PFS of 10.5 months. The median overall survival (OS) was 34 months. The Grades 3–5 infectious toxicity in 33% of pts represented the most frequent side effect during the treatment period. In conclusion, the O‐Dex regimen shows a relatively high ORR and CR with promising findings for PFS and OS. The study was registered at www.clinicaltrials.gov (NCT01310101). Am. J. Hematol. 90:417–421, 2015.

Rituximab in combination with high-dose dexamethasone for the treatment of relapsed/refractory chronic lymphocytic leukemia

BACKGROUND High-dose methylprednisolone is active in treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) but infectious toxicity is serious. The aim of this project was to retrospectively assess efficacy and safety of high-dose dexamethasone combined with rituximab (R-dex) in this setting. PATIENTS AND METHODS We treated 54 patients (pts) with relapsed/refractory CLL using R-dex regimen at two tertiary centers. Two schedules of rituximab were used (not randomized - based on the choice of the center): group 1, rituximab 500 mg/m(2)day 1, 8, 15, 22 (375 mg/m(2) in 1st dose) every 4 weeks (n=29); group 2, 500 mg/m(2)day 1 (375 mg/m(2) in 1st cycle) repeated every 3 weeks (n=25). The target dose of dexamethasone was 40 mg on days 1-4 and 10-13 or 15-18. Rai III/IV stages were present in 82%, unmutated IgVH genes in 82%, del 11q in 38% and del 17p in 19% pts; 46% had bulky lymph nodes; 82% were pretreated with fludarabine and 29% with alemtuzumab. RESULTS Overall response rate/complete remissions were 62/21% (Group 1) and 72/4% (Group 2). In three patients, R-dex was successfully used for debulking before nonmyeloablative allogeneic stem cell transplantation. R-dex was particularly effective in improvement of anemia and thrombocytopenia (p=0.0055 and p=0.0036); B-symptoms resolved after treatment in 11/17 pts. Hematological toxicity was mild. Serious infections occurred in 32% pts. At the median follow-up of 9 and 10 months, median progression-free survival was 6 months in Group 1 and 6.9 months in Group 2 (p=ns); median overall survival was 14.1 months in Group 1 vs. not reached in Group 2 (p=ns). CONCLUSIONS R-dex appears to be an active and feasible treatment for relapsed/refractory CLL. Infectious toxicity remains an important issue. Further investigation of this regimen in larger studies appears fully warranted.

Prothrombotic changes due to an increase in thyroid hormone levels.

OBJECTIVE With increasing free thyroxine levels, a gradually rising risk of venous thromboembolism has been described in case-control studies. However, reports on the influence of thyroid hormones on haemostasis, while suggesting a hypercoagulable state in thyrotoxicosis, have often been inconclusive. This study evaluates multiple markers of haemostasis and fibrinolysis in a paired design, making it more sensitive to changes in thyroid hormone levels. DESIGN We analysed multiple variables in patients who shifted from severe hypothyroidism to mild hyperthyroidism during thyroid cancer treatment. Those with possible residual disease were excluded. METHODS Ninety patients following total thyroidectomy were tested on two occasions: i) before radioiodine remnant ablation and ii) 6 weeks later, on levothyroxine (lT4) suppression treatment, and the results were compared using the Wilcoxons test for paired data. RESULTS During lT4 treatment, significant increases (all P<0.001) in fibrinogen (from median 3.4 to 3.8 g/l), von Willebrand factor (from 85 to 127%), factor VIII (from 111 to 148%) and plasminogen activator inhibitor 1 (from 6.5 to 13.9 μg/l) were observed. In addition, the activation times of platelet adhesion and aggregation stimulated with collagen and epinephrine (EPI)/ADP, i.e. closure times in platelet function analyser (PFA-100), were significantly shortened (P<0.001): for EPI from median 148 to 117 s and for ADP from 95 to 80 s. Changes in other tests were less prominent or insignificant. CONCLUSIONS An increase in thyroid hormone levels shifts the haemostatic balance towards a hypercoagulable, hypofibrinolytic state. This may contribute to the increased cardiovascular morbidity and mortality observed even in mild thyrotoxicosis.