The Effect of Zoledronic Acid on the Prevention of Bone Loss in Lymphoma Patients Receiving First-line Therapy

Patients with lymphoma are at high risk of osteoporosis. The majority have osteopenia at baseline, and the risk increases when treated with alkylating agents or corticosteroids. We conducted a randomized phase III trial to evaluate the effect of zoledronic acid on bone mineral density (BMD) in patients with lymphoma undergoing chemotherapy.Full AbstractIntroductionOsteoporotic bone cannot easily be restored to normal levels of strength; thus, the prevention of bone loss is crucial. Pamidronate can reduce the risk of bone loss and vertebral fractures in patients with lymphoma receiving chemotherapy. Zoledronic acid, a bisphosphonate approximately 100-fold more potent than pamidronate, has not been evaluated in lymphoma patients to date. We conducted a prospective trial to determine whether zoledronic acid reduces the risk of developing osteoporosis in this patient population.Patients and MethodsAll patients with newly diagnosed lymphoma seen at our institution from 2005 to 2009 were evaluated for protocol eligibility. Exclusion criteria included bone fractures, bone mineral density (BMD) T-scores poorer than ?2.0, creatinine clearance < 60 mL/min, dental problems, and recent steroid or bisphosphonate use. Patients on study were stratified according to sex and menopausal status. Accrued patients received randomized therapy of either: (1) oral calcium and vitamin D (Ca + D), or (2) Ca + D and 4 mg zoledronic acid intravenously (I.V.) at baseline and at 6 months.ResultsTo date, 33 patients have completed the study and have evaluable data. Patient characteristics included 17 men; 4 pre-menopausal women; 12 post-menopausal women; and median age, 62 years (range, 33–80 years). Seventeen patients had mild osteopenia upon enrollment. Patients who received zoledronic acid had stable median T-scores at all locations during the 12-month observation, whereas the T-scores of the control group decreased at every location evaluated (location: L1-4, P = .004; L neck, P = .001; L hip, P = .118; R neck, P = .009; R hip, P = .04).ConclusionTreatment with zoledronic acid in patients with newly diagnosed lymphoma prevents the BMD loss commonly seen in this population. Bone mass loss is difficult to restore, thus necessitating effective prevention strategies; additional studies should be conducted to confirm these findings.     

Selective targeting of Toll‐like receptors and OX40 inhibit regulatory T–cell function in follicular lymphoma

Immunotherapeutic strategies are promising approaches for the treatment of follicular lymphoma (FL). However, their efficacy may be limited by immunosuppressive elements in the immune system and tumor microenvironment. Therefore, strategies to reverse the effects of the immunosuppressive elements are needed. We observed that regulatory T cells (Tregs) were increased in the peripheral blood at diagnosis and persisted in high numbers after induction of clinical remission with a cyclophosphamide and doxorubicin‐containing chemotherapy regimen in FL patients. High levels of peripheral blood Tregs prior to therapy were associated with decreased progression‐free survival in FL patients treated with either chemotherapy or combination immunotherapy that targeted CD20 and PD‐1 with monoclonal antibodies rituximab and pidilizumab, respectively. Intratumoral and peripheral blood Tregs potently suppressed autologous antitumor effector T cells in FL. However, the effects of FL Tregs could be reversed by triggering Toll‐like receptors (TLR) with TLR ligands Pam₃CSK4 (TLR 1/2), flagellin (TLR 5), and CpG‐B (TLR 9), and/or OX40. The TLR ligands synergized with each other as well as OX40 signaling to inhibit Tregs. Furthermore, they restored the function of FL tumor‐specific effector T cells. Our results suggest that a state of tolerance exists in FL patients at diagnosis and after induction of clinical remission, and agents that activate TLRs 1/2, 5, and 9, and OX40 may serve as adjuvants to enhance the efficacy of antitumor immunotherapeutic strategies and preventive vaccines against infectious diseases in these patients.     

Zoledronic Acid for Prevention of Bone Loss in Patients Receiving Primary Therapy for Lymphomas: A Prospective,Randomized Controlled Phase III Trial

BackgroundPatients with lymphoma are at risk of development of bone mineral density (BMD) loss from therapy with high-dose corticosteroids and alkylating agents. Zoledronic acid (ZA), a bisphosphonate, may prevent this complication of therapy. We evaluated the effect of ZA on the change in BMD and surrogate biomarkers in patients with lymphoma receiving initial chemotherapy.Patients and MethodsOur phase III trial randomized 74 patients with newly diagnosed lymphoma and a baseline BMD of ≥ ?2.0 to receive oral calcium and vitamin D daily with or without ZA at enrollment and at 6 months after enrollment. BMD was evaluated at baseline and 1 year after enrollment. Secondary biomarker endpoints were collected at baseline and at 3, 6, 9, and 12 months after enrollment.ResultsForty-three percent of patients had baseline osteopenia. Fifty-three patients were evaluable for response: 24 received ZA and had stable BMD during the observation period, whereas 29 patients in the control group had decreased BMD (P < .05 at lumbar spine and bilateral femoral neck). Twenty-one randomized patients were not evaluable for response because of lymphoma progression or death, withdrawn consent/incomplete testing, or ineligibility. Bone biomarkers were higher in the control group at all intervals after treatment (P < .001). No fractures or intervention-related toxicities were observed during this trial.ConclusionsNewly diagnosed patients with lymphoma are at risk of low BMD, which may worsen with therapy. Treatment with ZA effectively stabilizes BMD and prevents bone loss. Our data suggest that BMD testing and prophylaxis should be considered as an early intervention for a preventable problem.     

90Y‐ibritumomab tiuxetan radiotherapy as first‐line therapy for early stage low‐grade B‐cell lymphomas,including bulky disease

⁹⁰Y‐ibritumomab‐tiuxetan (⁹⁰YIT) was used as a first‐line therapy for patients with early‐stage follicular lymphoma (FL) or marginal zone B‐cell lymphoma (MZL). Thirty‐one patients were treated, with an overall 3‐month response rate of 100% (68% complete response, 29% unconfirmed complete response and 3% partial response). At a median follow‐up of 56 months, ten patients (32%) had disease relapse or progression. The progression‐free rates at 3 and 5 years were lower in males, patients with FL, stage II diseaseand non‐bulky disease, although they did not reach statistical significance. Grade 3–4 neutropenia, thrombocytopenia and anaemia were 61%, 35%, and 3%, respectively. ⁹⁰YIT was well tolerated, including in those patients over 60 years old, and achieved high response rates in patients with early‐stage low‐grade B‐cell lymphomas. Bulky disease did not adversely affect tumour response.     

Phase II trial of the combination of denileukin diftitox and rituximab for relapsed/refractory B-cell non-Hodgkin lymphoma

Denileukin diftitox plus rituximab was evaluated in relapsed/refractory B-cell non-Hodgkin lymphoma patients. Of the 38 evaluable patients, 30 (80%) were rituximab-refractory. The overall response rate (ORR) was 32%, with six complete responses (CR) and six partial responses (PR). The median time to progression for responders was 8 months (range: 2–36+); two patients with rituximab-refractory follicular lymphoma were in CR at 25 and 36+ months. The ORR was 55% (4 CRs, 2 PRs) in 11/14 patients with rituximab-refractory follicular lymphoma, and 100% in the three patients with rituximab-sensitive tumour. Most toxicities were low grade and transient, and myelotoxicity was uncommon.     

Lenalidomide plus rituximab (R2) in previously untreated marginal zone lymphoma: subgroup analysis and long-term follow-up of an open-label phase 2 trial

Lack of consensus for first-line marginal zone lymphoma (MZL) treatment and toxicities associated with currently available systemic therapies have inspired evaluation of immunotherapeutic agents yielding robust outcomes with improved tolerability. We previously reported durable efficacy with first-line lenalidomide and rituximab (R²) in follicular lymphoma, MZL and small lymphocytic lymphoma with a subsequent long-term follow-up shown here in MZL patients. This phase 2 investigator-initiated study included previously untreated, stage III/IV MZL patients treated with lenalidomide 20 mg/day on days 1–21 and rituximab 375 mg/m² on day 1 of each 28-day cycle, continuing in responders for ≥6–12 cycles. The primary endpoint was overall response rate (ORR); secondary endpoints were complete and partial response (CR, PR), safety, and progression-free survival (PFS). The ORR was 93% with 70% attaining CR/CR unconfirmed. At median follow-up of 75·1 months, median PFS was 59·8 months and 5-year OS was 96%. Most non-haematological adverse events (AE) were grade 1/2. Grade 3 haematological AEs were neutropenia (33%) and leucopenia (7%), and grade 4 were leucopenia (3%) and thrombocytopenia (3%). Two patients died of secondary malignancies; no treatment-related fatalities occurred. With extended follow-up, outcomes for MZL patients receiving R² were robust with no unexpected late or delayed toxicities.