Monoclonal antibodies (mAbs) - rituximab, ofatumumab and alemtuzumab - have been approved for use in the therapy of chronic lymphocytic leukemia (CLL). Recently, a new generation of anti-CD20 mAbs has become available for preclinical studies and clinical trials. These antibodies were engineered to have augmented antitumor activity by increasing complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity and Fc-binding affinity for the low-affinity variants of the Fcγ receptor IIIa. The most promising mAb directed against CD20 is obinutuzumab (GA-101). mAbs directed against CD22, CD37 and CD40 have also shown some activity in CLL. In addition, small modular immunopharmaceuticals - TRU-015 (anti-CD20) and TRU-016 (anti-CD37) - that retain Fc-mediated effector functions have been developed and investigated in preclinical studies and clinical trials. Antibody-drug conjugates and recombinant immunotoxins are also being evaluated in lymphoid malignancies. Further studies will elucidate the role of these agents in the treatment of CLL.
Chronic lymphocytic leukaemia (CLL) accounts for 25% of all leukaemias and is the most common lymphoid malignancy in western countries. Standard treatments include mono- or polychemotherapies, usually combined with monoclonal antibodies such as rituximab or alemtuzumab. However, the impact of these agents remains unclear, as there are hints for increased risk of severe infections.
Non-Hodgkin’s lymphoma (NHL) comprises a clinically and biologically heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer (NK) cells. The disease course may range from indolent to aggressive. Zevalin(®) (ibritumomab tiuxetan) is a radioactive drug product, which is the combination of a β-emitting isotope, (90)Y, linked to the anti-CD20 monoclonal antibody (mAb), rituximab. It has demonstrated therapeutic efficacy with durable responses and allows delivery of ionizing radiation directly to the tumor site, while minimizing toxicity to normal tissue. Ibritumomab tiuxetan is indicated for treatment of patients with relapsed or refractory low-grade, follicular NHL, including patients who are refractory to rituximab, and as consolidation therapy in previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy. Despite the efficacy and acceptable safety profile of ibritumomab tiuxetan, utilization has not been broadly adopted in practice due to a number of factors. This manuscript will review the literature available for ibritumomab tiuxetan, including several new trials that are currently being studied, and discuss the rationale for use of ibritumomab tiuxetan in NHL.
Hairy cell leukemia (HCL) is a lymphoproliferative B-cell disorder characterized by pancytopenia, splenomegaly, and characteristic cytoplasmic hairy projections. Precise diagnosis is essential in order to differentiate classic forms from HCL variants, such as the HCL-variant and VH4-34 molecular variant, which are more resistant to available treatments. The current standard of care is treatment with purine analogs (PAs), such as cladribine or pentostatin, which provide a high rate of long-lasting clinical remissions. Nevertheless, ~30%-40% of the patients relapse, and moreover, some of these are difficult-to-treat refractory cases. The use of the monoclonal antibody rituximab in combination with PA appears to produce even higher responses, and it is often employed to minimize or eliminate residual disease. Currently, research in the field of HCL is focused on identifying novel therapeutic targets and potential agents that are safe and can universally cure the disease. The discovery of the BRAF mutation and progress in understanding the biology of the disease has enabled the scientific community to explore new therapeutic targets. Ongoing clinical trials are assessing various treatment strategies such as the combination of PA and anti-CD20 monoclonal antibodies, recombinant immunotoxins targeting CD22, BRAF inhibitors, and B-cell receptor signal inhibitors.
The underlying in vivo mechanisms of rituximab action remain incompletely understood in chronic lymphocytic leukemia. Recent data suggest that circulating miRNAs correlate with chronic lymphocytic leukemia progression and response to rituximab. Our study aimed at identifying circulating miRNAs that predict response to rituximab monotherapy in chronic lymphocytic leukemia patients. Using a hierarchical clustering of miRNA expression profiles discriminating 10 untreated patients with low or high lymphocyte counts, we found 26 miRNAs significantly deregulated. Using individual RT-qPCR, the expression levels of miRNAs representative of these two clusters were further validated on a larger cohort (n=61). MiR-125b and miR-532-3p were inversely correlated with rituximab-induced lymphodepletion (p=0.020 and p=0.001, respectively) and with the CD20 expression on CD19+ cells (p=0.0007 and p<0.0001, respectively). In silico analyses of genes putatively targeted by both miRNAs revealed a central role of IL-10 pathway and CD20 (MS4A1) family members. Interestingly, both miRNAs were negatively correlated with MS4A1 expression, while they were positively correlated with MS4A3 and MSA47. Our results identify novel circulating predictive biomarkers for rituximab-mediated lymphodepletion efficacy in chronic lymphocytic leukemia, and suggest a novel molecular mechanism responsible for the rituximab mode of action that bridges miR-125b and miR-532-3p and CD20 family members.
Significant peripheral blood CD4+ T-cell depletion has been observed after a first cycle of rituximab, a monoclonal antibody directed against the CD20 antigen, which is currently used in rheumatoid arthritis. Of note, an absence of CD4+ T-cell decrease has been observed in non-responders. Herein, we describe CD4+ T-cell changes over repeated cycles of rituximab and their relationship with clinical outcomes.
With modern intensive combination polychemotherapy, the complete response (CR) rate in adults with acute lymphoblastic leukemia (ALL) is 80-90%, and the cure rate 40-50%. Hence there is a need to develop effective salvage therapies and combine novel agents with standard effective chemotherapy. ALL leukemic cells express several surface antigens amenable to target therapies, including CD20, CD22, and CD19. Monoclonal antibodies target these leukemic surface antigens selectively, and minimize off-target toxicity. When added to frontline chemotherapy, rituximab, an antibody directed against CD20, increases cure rates of adults with Burkitt leukemia from 40% to 80%, and those with pre-B ALL from 35% to 50%. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, has resulted in marrow CR rates of 55% and a median survival of 6-7 months when given to patients with refractory-relapsed ALL. Blinatumomab, a biallelic T-cell engaging CD3-CD19 monoclonal antibody, also resulted in overall response rates of 40-50% and a median survival of 6.5 months in a similar refractory-relapsed population. Other promising monoclonal antibodies targeting CD20 (ofatumumab, obinutuzumab), or CD19 or CD20 and bound to different cytotoxins or immunotoxins are under development. Combined modalities of chemotherapy and the novel monoclonal antibodies are under investigation.
We present the first study to explore safety and efficacy of the human CD20 monoclonal antibody ofatumumab in relapsing-remitting multiple sclerosis (RRMS).
In the rituximab era, lymphoma patients with persistent disease receiving autologous transplantation have a very poor outcome. The addition of radioimmunotherapy to the conditioning regimen may improve outcome for these patients. We have evaluated, in a prospective phase 2 study, the safety and efficacy of the addition of 90Y-Ibritumomab tiuxetan to the conditioning chemotherapy in refractory diffuse large B cell lymphoma patients. Thirty patients with induction failure (primary refractory; n=18) or refractory to salvage immunochemotherapy at relapse (n=12) were included in the study. Patients with a median age of 53 years (range, 25-67) received 90Y-Ibritumomab tiuxetan at a fixed dose of 0.4mCi/kg (maximum dose 32mCi) 14 days prior to the preparative chemotherapy regimen. Histology included de novo diffuse large B cell lymphoma (22) and transformed diffuse large B cell lymphoma (8). All patients had persistent disease at the time of transplantation, with 25 patients considered to be chemorefractory. Median time to neutrophil recovery (>500/ml) was 11 days (9-21), and to platelet recovery (>20.000/ml) was 13 days (11-35). Overall response at day +100 was 70% (95% CI, 53.6-86.4) with 60% (95% CI, 42.5-77.5) complete responses. After a median follow-up of 31 months for alive patients (range, 16-54), estimated 3-year overall and progression-free survival is 63% (95% CI, 48-82) and 61% (95% CI, 45-80), respectively. We conclude that autologous transplantation with conditioning including 90Y-Ibritumomab tiuxetan is safe, and results in a very high response rate with promising survival in this very poor prognosis group of refractory diffuse large B cell lymphoma patients. Study registered at European Union Drug Regulating Authorities Clinical Trials (EudraCT) No. 2007-003198-22.
Chemo-refractory NHL has a very poor outcome; the addiction of RIT to salvage regiment pre ASCT had recently demonstrated promising results.We performed a retrospective sequential study to determine the feasibility of standard Zevalin with BEAM in high-risk relapse/refractory NHL. A matched cohort analysis with a group treated with standard BEAM without Zevalin was performed as secondary endpoint. Between October 2006 and January 2013, 37 NHL patients at high risk for progression or early (< 1 year) or multiple relapses were treated with Z-BEAM and ASCT after R-DHAP or R-ICE as salvage therapy. Clinical characteristics were 19 refractory and 18 early or multiple relapse; 16 patients received 1, and 21 had 2 or more previous rituximab-containing chemotherapy. At the end of treatment, response was CR 22 (59%), PR 10 (27%), PD 4 (11%), and toxic death (TD) 1 (3%). With a median follow up of 61 months, 3-year PFS was 61% and OS 61%. Fifteen patients died, 12 of lymphoma. Comparison with 21 treated with BEAM alone showed a numerical higher 3-yr PFS rate in favor of Z-BEAM but not statistically significant (57 vs 48%). With the limitation of the small sample subgroup analysis, a significant benefit was observed in relapsed patients for PFS (78% Z-BEAM vs 22% BEAM p = 0.016) and OS (83% Z-BEAM vs 22% BEAM p = 0.001). In relapsed/refractory high-risk NHL, Z-BEAM+ASCT is able to achieve a good ORR. Three-year PFS is promising for early relapsed patients but is not satisfactory for those with refractory disease.