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The Complement 1 trial investigated the efficacy and safety of ofatumumab + chlorambucil with chlorambucil monotherapy in patients with previously untreated chronic lymphocytic leukaemia (CLL). On long-term follow-up in the chemoimmunotherapy arm vs. the chemotherapy arm there was an estimated 12% (not significant) and 39% risk reduction in overall survival and progression-free survival, respectively. A high rate (61%) of treatment with next-line therapies in both the treatment arms may dilute any potential OS difference and confound the interpretation of the OS results. Addition of ofatumumab to chlorambucil demonstrated clinical benefit and tolerability as a frontline treatment option in patients unfit for fludarabine-containing therapy, with no new safety concerns., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

The purpose of this study is to assess the safety and efficacy of the combination of ofatumumab and bendamustine in patients with previously untreated or relapsed chronic lymphocytic leukemia. Patients received IV ofatumumab (cycle 1: 300 mg day 1 and 1,000 mg day 8; cycles 2-6: 1,000 mg on day 1 every 28 days) and IV bendamustine 90 mg m(-2) (previously untreated) or 70 mg m(-2) (relapsed) on days 1 and 2 of each 28-day cycle, for up to 6 cycles. Forty-four previously untreated and 53 relapsed patients were enrolled. Median age was 62.5 years (previously untreated) and 68 years (relapsed); relapsed patients had received a median of 1 (range 1-11) prior therapy. The investigator-assessed overall response rate was 95% (43% complete response [CR]) for the previously untreated, and 74% (11% CR) for the relapsed patients. The regimen was well tolerated with 89% (previously untreated) and 85% (relapsed patients) receiving all 6 cycles. No unexpected toxicities were reported. Grade 3/4 events occurred in 57% of previously untreated, and 72% of relapsed patients. At ∼29 months' follow-up, the median progression-free survival (PFS) was not reached for the previously untreated population, and the 28-month PFS estimate was 72.3%. The median PFS for the relapsed population was 22.5 months (95% CI: 14.0-27.3 months). The combination of ofatumumab and bendamustine was well tolerated and effective in these previously untreated or relapsed populations. Am. J. Hematol. 91:900-906, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

In the phase III MM-003 trial, pomalidomide plus low-dose dexamethasone (POM+LoDEX) improved overall survival (OS) versus high-dose dexamethasone (HiDEX) in 455 patients with relapsed and refractory multiple myeloma (RRMM) after treatment with bortezomib and lenalidomide. Here, a two-stage Weibull method was used to adjust for the crossover of patients in the HiDEX arm to pomalidomide-based therapy. The adjusted difference in median OS between patients in the POM+LoDEX and HiDEX arms was 7·0 months (12·7 vs. 5·7 months, respectively). These findings provide important evidence for understanding the clinical efficacy of pomalidomide on OS benefits seen in RRMM patients., (© 2014 John Wiley & Sons Ltd.)

Follicular Lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) subtype and its course is heterogeneous. At diagnosis, some patients with FL manifest a detectable leukaemic phase (FL-LP), but this feature has been seldom described and is poorly characterized. Among 499 patients diagnosed with FL in Lyon-Sud hospital, 37 (7·4%) had characteristic FL-LP (by cytological blood smears and flow cytometric analysis). In addition, 91/1135 FL patients from the PRIMA study presented FL-LP at study entry. In order to evaluate the outcome of this Lyon-Sud cohort, FL-LP patients were matched with 111 newly diagnosed FL without LP according to the Follicular Lymphoma International Prognostic Index (FLIPI) score, age and treatment. Presence of FL-LP was associated with shorter progression-free survival (PFS) and overall survival (OS) (P = 0·004 and P = 0·031, respectively). Presence of FL-LP and high FLIPI score remained independent prognostic factors in a Cox model for time to progression (TTP). A number of circulating lymphoma cells (CLC) >4 × 10(9) /l was the most significant predictor for a shorter TTP in this Cox model. The prognostic impact of FL-LP on TTP was validated in the PRIMA cohort (P = 0·0004). In conclusion, FL-LP is a rare event associated with shorter PFS and patients with CLC >4 × 10(9) /l have a poorer outcome. These patients should be monitored carefully to consider alternative therapeutic options., (© 2013 John Wiley & Sons Ltd.)

Despite advancements in the treatment of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL), patients continue to relapse and thus a need for new targeted therapies remains. The CD40 receptor is highly expressed on neoplastic B cells and activation leads to enhanced proliferation and survival. Lucatumumab (HCD122) is a fully human antagonistic CD40 monoclonal antibody. A phase IA/II study was designed to determine the maximum tolerated dose (MTD) and activity of lucatumumab in patients with relapsed/refractory lymphoma. Determination of the MTD was the primary objective of the phase IA dose escalation portion and clinical response was the primary objective of the phase II dose expansion portion. Patients received escalating doses of lucatumumab administered intravenously once weekly for 4 weeks of an 8-week cycle. MTD was determined at 4 mg/kg of lucatumumab. A total of 111 patients with NHL (n = 74) and HL (n = 37) were enrolled. Responses were observed across various lymphoma subtypes. The overall response rate by computed tomography among patients with follicular lymphoma (FL) and marginal zone lymphoma of mucosa-associated lymphatic tissue (MZL/MALT) was 33·3% and 42·9%, respectively. Lucatumumab demonstrates modest activity in relapsed/refractory patients with advanced lymphoma, suggesting that targeting of CD40 warrants further investigation., (© 2013 John Wiley & Sons Ltd.)

Transformation of B cell chronic lymphocytic leukemia (B-CLL) to large cell lymphoma or Hodgkin's disease is known as a Richter's syndrome (RS). According to the literature, 1-10% of B-CLL patients develop this high-grade lymphoid malignancy. The relationship between the immunosuppressive effect of nucleoside analogues (NA) and monoclonal antibodies and the development of large cell transformation still remains a controversial issue. We describe a CLL patient who developed a large B cell lymphoma 94 months after diagnosis and 3 months after the start of alemtuzumab. The CLL immunophenotype was retained by the transforming cells although a different light chain was expressed. Molecular analysis of the immunoglobulin heavy chain confirmed that the CLL and the RS had a different clonal origin. Subsequent molecular analyses of stored samples showed that the clone with transforming capacity already appeared two years before the clinical appearance of the RS. We hypothesize that alemtuzumab promoted the uncontrolled growth of the latest clone by eradicating the initial B-CLL clone efficiently, and by inducing a strong T cell depletion with consequent impairment of the immunosurveillance. We also ruled out that the RS was EBV driven. In conclusion, we report a case of EBV negative RS after alemtuzumab as salvage therapy., ((c) 2006 Wiley-Liss, Inc.)

To assess the influence of high-dose chemotherapy and age on the intrinsic capacity of stem cells to generate T cells, CD34+ cells derived from bone marrow used in clinical transplantation were evaluated in an in vitro T-cell assay using a mouse thymic microenvironment. CD34+ cells were sorted from healthy donor and autologous back-up bone marrow after density gradient centrifugation and depletion for CD1, 3, 4, 7, 8, 19 and glycophorin A using magnetic beads. CD34+ cells were then introduced in day 14-15 fetal SCII) mouse thymus lobes by incubation in hanging drops for 48 h. After transfer to gelfoam rafts they were cultured for variable time periods. The lobes were then homogenized in a tissue grinder for flow cytometric analysis gating on human cells. These were evaluated for CD4, CD8, CD3 and HLA-DR surface expression. 51 samples were analysed and three patterns of T-cell precursor development could be observed. In pattern A no human cells could be recovered, in pattern B maturation stopped at the CD4+ CD8- CD3- pre-T-cell stage, and in pattern C maturation to double-positive CD4+ CD8+ thymocytes was reached. In 25 healthy donors under age 40 three showed pattern A, 12 pattern B and 10 pattern C, whereas in 16 healthy donors over the age 40 there were respectively four with A, seven with B and only five with C (P=0.01). In 10 patients who had previously received chemotherapy, none developed pattern C, five pattern B and five pattern A, in contrast to 15/41 pattern C, 19/41 pattern B and 7/41 pattern A in healthy donors. These data suggest an intrinsic loss of T-cell generation capacity from adult bone marrow stem cells in comparison to reports on stem cells of fetal origin. This loss correlated weakly with age, irrespective of thymic involution, and may be further reduced by prior chemotherapy.