Front-line management of indolent non-Hodgkin lymphoma in Australia. Part 2: mantle cell lymphoma and marginal zone lymphoma

Mantle cell lymphoma (MCL) and the marginal zone lymphoma (MZL) subtypes (nodal MZL, extra-nodal MZL of mucosa-associated lymphoid tissue (MALT lymphoma) and splenic MZL) are uncommon lymphoma subtypes, accounting for less than 5-10% of all non-Hodgkin lymphoma. The evidence base for therapy is therefore limited and enrolment into clinical trials is preferred. Outcomes for patients with MCL have been steadily improving mainly due to the adoption of more intense strategies in younger patients, the use of rituximab maintenance and the recent introduction of bendamustine in older patients. MZL is a more heterogeneous group of cancer with both nodal, extra-nodal and splenic subtypes. Extranodal MZL may be associated with autoimmune or infectious aetiologies, and can respond to eradication of the causative pathogen. Proton pump inhibitor plus dual antibiotics in Helicobacter pylori positive gastric MALT lymphoma is curative in many patients. Watchful waiting is appropriate in most patients with asymptomatic advanced stage disease, which tends to behave in a particularly indolent manner. Other options for symptomatic disease include splenectomy, chemoimmunotherapy with rituximab and, more recently, targeted therapies

Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia

Background: chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. Methods: we randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. Results: the median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. Conclusions: ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.)

Targeted Therapy in Leukaemia, Lymphoma and Myeloma

Historically, most advances in cancer therapy have been pioneered by clinicians managing the blood diseases [...

Front-line management of non-Hodgkin lymphoma in Australia. Part 1: follicular lymphoma

Outcomes with follicular lymphoma (FL) have improved in the modern era and median survival is now beyond 15 years. Therapeutic decisions need to consider this increased survival as well as recent clinical trial data and emerging treatments. In this context, we present here current approaches to front-line management of FL in Australia. Treatment choices depend on the disease stage, tumour burden, the patient's age, symptoms, comorbidities and preferences. Only about 10–15% of patients with FL are diagnosed with early stage disease. For patients with low-grade, early stage disease, radiotherapy (RT) is recommended. The addition of chemotherapy has been shown to increase progression-free survival (PFS) but without demonstrated overall survival advantage. For patients with low-tumour-burden, advanced-stage FL, immediate treatment may not be required and we recommend considering active monitoring. For stage III/IV disease that is symptomatic and/or with high tumour burden, established first-line treatment is chemotherapy in combination with rituximab, often followed by rituximab maintenance. The listing of bendamustine and now obinutuzumab on the Pharmaceutical Benefits Scheme has expanded the first-line treatment options in Australia to include bendamustine in combination with rituximab (without rituximab maintenance permitted) or with obinutuzumab plus 2 years obintuzumab maintenance. In the FL subgroup of the Study group indolent Lymphomas (StiL) trial, therapy with bendamustine plus rituximab significantly increased PFS compared with rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisolone, without rituximab maintenance. Initial tolerability may be more favourable with bendamustine in combination with anti-CD20 antibody therapy than other therapies overall, but clinical vigilance is still required because of concerns of late infectious toxicities associated with prolonged T-cell depletion

Management of patients with previously untreated chronic lymphocytic leukaemia with obinutuzumab and chlorambucil

Patients with chronic lymphocytic leukaemia (CLL) are generally older, with many considered ‘unfit’ for fludarabine–cyclophosphamide–rituximab therapy. In these patients, the combination of obinutuzumab–chlorambucil may be an appropriate therapeutic choice. Obinutuzumab–chlorambucil has been demonstrated to improve overall survival rates compared to chlorambucil alone and to improve progression-free survival and overall response rates compared to rituximab–chlorambucil. This combination can lead to certain toxicities that need to be addressed through appropriate patient selection, pre-medication and management. In this paper, we discuss evidence-based and author-recommended practical management of first-line CLL patients receiving obinutuzumab–chlorambucil

Zanubrutinib: past, present, and future

Abstract In recent years, Bruton tyrosine kinase (BTK) inhibitors have provided significant advances in the treatment of patients with B-cell malignancies. Ibrutinib was the first BTK inhibitor to be approved, and it changed the standard-of-care treatment for diseases such as chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia, improving efficacy outcomes and safety compared to chemotherapy. In this article, we review the development of zanubrutinib, a next-generation BTK inhibitor, from molecular design to patient-related outcomes. We start this journey by providing insights into the discovery of BTK and the physiologic, genetic, and molecular characterization of patients lacking this kinase, together with the brief treatment landscape in the era of chemo-immunotherapies. Zanubrutinib was originally developed by applying a structure-activity strategy to enhance the specificity as well as enzymatic and pharmacokinetic properties. Preclinical studies confirmed greater specificity and better bioavailability of zanubrutinib compared with that of ibrutinib, which supported the initiation of clinical trials in humans. Preliminary clinical results indicated activity in B-cell malignancies together with an improved safety profile, in line with less off-target effects described in the preclinical studies. The clinical program of zanubrutinib has since expanded significantly, with ongoing studies in a wide range of hemato-oncological diseases and in combination with many other therapies. Zanubrutinib currently is approved for various B-cell malignancies in multiple countries. This story highlights the importance of multidisciplinary collaborative research, from bench to bedside, and provides an example of how the commitment to finding improved treatment options should always run parallel to patient care

Disseminated Enteroviral Infection Associated with Obinutuzumab

Two cases of disseminated enteroviral infection occurred in patients who received the CD20 monoclonal antibody obinutuzumab. Clinical features included hepatitis, edema, and a dermatomyositis-like syndrome. These manifestations may be unfamiliar to clinicians and are possibly responsive to intravenous immunoglobulin. Clinicians should remain vigilant for enteroviral infections in patients receiving obinutuzumab