anti-CD20 Monoclonal Antibody Ofatumumab Research Articles

Early-Stage Follicular Lymphoma: Learnings from the Final Analysis of the Multicenter Phase II FIL (Fondazione Italiana Linfomi) “Miro” Trial, Combining Local Radiotherapy and MRD-Driven Immunotherapy

Introduction. Early-stage follicular lymphoma (FL) is usually managed with involved field radiotherapy (IFRT), allowing a complete and long-lasting eradication of the disease in 40-50% of patients (pts). The aim of this multicenter phase II prospective study was to evaluate if a minimal residual disease (MRD)-driven immunotherapy consolidation after IFRT can improve the outcome of pts unlikely to be cured by IFRT only, and to assess the therapeutic effect of IFRT and anti-CD20 consolidation by MRD evaluation. Methods. One hundred and ten pts with stage I/II FL were enrolled; 106 were evaluable and treated with 24 Gy IFRT. Peripheral blood (PB) and bone marrow (BM) samples were centralized to the FIL (Fondazione Italiani Linfomi) MRD Network of EuroMRD-certified laboratories. In pts BCL2::IGH+ at baseline by both nested PCR (NEST) and RQ-PCR (RQ) in the BM and/or (a/o) PB, MRD was analyzed after IFRT and every 6 months over a 3-year period. Pts who were MRD+ by both NEST and RQ in the BM a/o PB after IFRT or who became MRD+ during the follow-up were treated with 8 weekly doses of the anti-CD20 monoclonal antibody ofatumumab (OFA). The primary objective of the study was to define the efficacy of immunotherapy in obtaining a negative MRD. Results. Of the 106 evaluable pts, 50 were males (47%). Median age was 55.5 years (29-83). The FLIPI score was 0 in 60% of pts, 1 in 34%, 2 in 6%; 69% of pts had inguinal site involvement, significantly more frequent in young patients. At baseline, 30.5% of pts had a BCL2::IGH rearrangement (30 MBR, 1 MBR and mcr, 1 mcr) in the BM a/o PB; the concordance between compartments was 87%. BCL2::IGH+ and BCL2::IGH- pts were not significantly different, except for a younger age (p 0.009) and a more frequent FLIPI 0 (p 0.052) among marker negative cases. All but 1 pt achieved a clinical response after IFRT; 1 pt died soon after IFRT of unrelated causes. MRD evaluation after IFRT revealed the persistence of BCL2::IGH+ cells in the PB a/o BM in 60% of pts. MRD+ pts, either after IFRT (n=18) or in case of conversion to MRD+ during the follow-up (n=8), received OFA, obtaining a conversion to MRD- in 23/25 evaluable pts (92%, CI 74-99%), significantly superior to the expected 50%. After a median follow-up of 46.3 months (m) (range 11-66), of the 23 pts who achieved a MRD- with OFA, 5 returned MRD+ (4 underwent OFA re-treatment, achieving a second MRD-, 1 relapsed as a transformation), 4 relapsed being MRD-, 14 remain in complete remission and MRD-, with a duration of molecular response at the last molecular assessment of 30 months (range 6-36). Overall, a clinical relapse was observed in 29 pts submitted to IFRT and 1 patient progressed soon after IFRT. A confirmed histologic transformation to DLBCL was observed in 5 of these patients. Among the 73 “marker negative” patients, 20 relapsed (27.4%) over time, whilst among the 32 BCL2::IGH+ at baseline 9 (28.1%) were resistant or relapsed (p=0.939). The administration of OFA was associated to a significantly reduced risk of POD24 (p= 0.035). Overall, the 24-m and 36-m overall survival (OS) were 100% and 98.9%, respectively; the 24-m and 36-m PFS were 83.7% and 77.4%, respectively. PFS was not different according to the presence or absence of BCL2::IGH at enrollment (p=0.820). PFS was significantly different according to the FLIPI score (p=0.041), but not different according to gender (p=0.696), stage I-II (p=0.122), histological grade (p=0.212), inguinal nodal site vs others (p=0.492). The Kaplan Meier landmark analysis, stratified by MRD, at m+6 (p=0.228), m+12 (p=0.003), m+18 (p=0.0002), m+24 (p=0.004) showed that PFS significantly improved from m+12 onwards when a negative MRD was present (Figure 1). Conclusions. IFRT alone is often insufficient to eradicate FL, inducing a MRD- status only in 40% of pts, long-lasting only in a third of them. An immunotherapy consolidation with OFA after IFRT in MRD+ pts was capable of increasing the molecular responses to 92%, allowing to achieve the primary objective of the study, though this effect was not always persistent. The achievement of a molecular remission correlated significantly with a reduction in the incidence of relapse over time, although this strategy was applicable only to 30% BCL2::IGH+ PET/CT staged FL pts. A consolidation strategy with more effective agent should be advisable. With these limits, a clinical advantage of the MRD-driven treatment strategy is suggested, although not largely applicable.

Effect of ofatumumab on pregnancy, parturition, and lactation in cynomolgus monkeys

Knowledge of the impacts of the anti-CD20 monoclonal antibody ofatumumab on the developing immune system is limited. This study examined the effects of intravenous ofatumumab on pregnancy, parturition, and lactation, and on pre- and postnatal survival and development in cynomolgus monkeys, an established model for developmental toxicity assessment. Pregnant cynomolgus monkeys (n = 42) were randomized to receive vehicle only (control group; n = 14), low-dose ofatumumab (n = 14), or high-dose ofatumumab (n = 14). Survival, clinical outcomes, and clinical pathology investigations were evaluated regularly until lactation day (maternal animals) and postnatal day 180±1 (infants). Anatomic pathology was investigated in euthanized infants and unscheduled terminations of maternal animals and infants. Ofatumumab treatment was not associated with maternal toxicity or embryotoxicity and had no effect on the growth and development of offspring. As expected, B-cell depletion occurred in maternal animals and their offspring, with a reduced humoral immune response in infants of mothers on high-dose ofatumumab. Both effects were reversible. In the high-dose group, perinatal deaths of 3 infants were attributed to infections, potentially secondary to pharmacologically induced immunosuppression. The no-observed adverse-effect level for initial/maintenance ofatumumab doses was 100/20 mg, and 10/3 mg/kg for pharmacological effects in infant animals, which are associated with exposures significantly higher than those following therapeutic doses in humans. In this study with cynomolgus monkeys, ofatumumab treatment was not associated with maternal toxicity or embryotoxicity and had no effect on the growth and development of offspring.

B cell-depleting therapy with rituximab or ofatumumab in immunoglobulin A nephropathy or vasculitis with nephritis.

BackgroundApproximately 30% of adult patients with immunoglobulin A (IgA) nephropathy (IgAN) or IgA vasculitis with nephritis (IgAVN) develop end-stage renal disease during long-term follow-up. In particular, patients with nephritic–nephrotic syndrome have an increased risk of rapid progression. Conventional immunosuppressive therapy with corticosteroids (CSs) may be insufficient for disease control and is associated with a number of side effects. Rituximab (RTX) has been shown to be well tolerated and effective in a range of glomerular diseases, but there is little information on its therapeutic potential in IgAN. The humanized anti-CD20 monoclonal antibody ofatumumab (OFAB) may be an alternative drug for patients intolerant or unresponsive to RTX, but so far there is no report on its use in IgAVN or IgAN.MethodsWe describe clinical outcomes after 17–22 months in four adult patients with biopsy-confirmed IgAVN or IgAN treated with RTX or OFAB as well as CS soon after diagnosis. All presented with nephritic–nephrotic syndrome and one had crescentic IgAN. Rebiopsy was performed in two cases.ResultsRTX and OFAB were well tolerated. Albuminuria was <250 mg/day in three patients at last evaluation and two regained normal renal function. In all cases, renal function improved after therapy. In one patient with severe IgA vasculitis, rebiopsy showed disappearance of subendothelial but not mesangial immune complexes. In the case with crescentic IgAN, rebiopsy after 9 months showed no active necrotic lesions.ConclusionsB cell–depleting therapy may be an alternative treatment for patients with IgAN or IgAVN and nephritic–nephrotic syndrome. A possible CS-sparing effect should be further evaluated in randomized controlled clinical trials.

Profile of obinutuzumab for the treatment of patients with previously untreated chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a hematologic malignancy derived from a clonal population of mature B-lymphocytes characterized by relatively low CD20 antigen expression. Although the disease often takes an indolent course, the majority of patients will eventually require therapy. Standard treatment for medically fit patients includes purine analogs and/or alkylating agents in addition to the type I anti-CD20 monoclonal antibody, rituximab. This therapy is inherently myelosuppressive and can result in significant morbidity and even mortality in patients with impaired performance status due to age and/or medical comorbidities. Historically, treatment options for the elderly or frail patient population were limited to mono-therapy with the oral alkylating agent, chlorambucil, rituximab, or another type I anti-CD20 monoclonal antibody ofatumumab. Recently, a newer-generation anti-CD20 monoclonal antibody, obinutuzumab, was developed for patients with CLL. Obinutuzumab is a humanized type II monoclonal antibody that appears to have more direct antibody-dependent cell-mediated cytotoxicity (ADCC) and possibly more direct cytotoxicity in vitro than previously available type I antibodies. A large Phase III prospective randomized clinical trial for older patients with impaired renal function and/or significant medical comorbidities demonstrated that when compared to conventionally-dosed rituximab and chlorambucil, the combination of chlorambucil and obinutuzumab administered at a dose and schedule involving early loading doses improved response rates and progression-free survival without significantly increasing toxicity. Results of this pivotal trial led to the FDA (US Food and Drug Administration) approval of obinutuzumab in combination with chlorambucil for frontline treatment of CLL. Obinutuzumab expands the armamentarium of active and less-toxic targeted agents in the evolving treatment landscape of CLL, providing physicians and patients with an additional therapeutic option.

Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The Orcharrd Study (OMB110928)

Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The Orcharrd Study (OMB110928)

Ofatumumab for refractory opsoclonus-myoclonus syndrome following treatment of neuroblastoma

Opsoclonus-myoclonus syndrome (OMS) may be associated with ANNA-1 (anti-Hu) autoantibodies. The standard treatment with IVIG, steroids, and anti-CD20 monoclonal antibody may fail, and optimal therapy is unknown. A patient developed OMS with high-titer ANNA-1 following recovery from neuroblastoma. She failed standard therapy and had only transient response to rituximab. Treatment with the humanized anti-CD20 monoclonal antibody ofatumumab combined with methotrexate resulted in transient neurologic improvement and decrease of ANNA-1. This suggests that ofatumumab combined with methotrexate should further be considered OMS patients, particularly in refractory disease.

Ofatumumab retreatment and maintenance in patients with fludarabine-refractory CLL.

6584 Background: In Study 406, the anti-CD20 monoclonal antibody ofatumumab (ofa), given as monotherapy over 6 months, showed 47% overall response rate (ORR) in patients (pts) with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab (FA-ref), or to fludarabine with bulky (&gt;5cm) lymphadenopathy (BF-ref). The effects of ofa retreatment (retx) and maintenance (mt) are unknown. Methods: Pts who responded to ofa and then progressed or had stable disease (SD) in Study 406, were offered retx in Study 416 (NCT00802737; GSK/Genmab) with ofa 1 x 300 mg + 7 x 2000 mg weekly followed by mt with ofa 2000 mg monthly for up to 2 years (if SD or better). Primary endpoint was ORR (1996 NCI-WG). Safety and time to event outcomes were also assessed. Results: Of 29 pts enrolled, 7 had SD and 22 had partial response (PR) and progressed in Study 406. Pts were defined per Study 406: 17 FA-ref, 11 BF-ref, 1 “other”. Pretreatment characteristics were similar between groups. Pts received a median of 12 doses (range 3-32); 86% had 8 doses, 3% received all 32 doses. 72% of pts had infusion-related adverse events (AEs), 41% at 1st infusion, mostly grade 1-2. The most common grade &gt;3 AE occurring up to 60 days after last tx was infection (38%); the most common was pneumonia (17%). 3 pts (10%) had fatal infections, all bronchopneumonia. Clinical efficacy is shown in Table. Comparative analysis to Study 406 is ongoing. Conclusions: The response to ofatumumab (ofa) as induction retreatment and progression-free survival in this limited number of pts was similar to 1st treatment (Study 406). Ofa maintenance had some clinical benefit for pts with advanced CLL. Ofa was well-tolerated with no unexpected toxicities. [Table: see text]