A Systematic Review and Network Meta-Analysis to Evaluate the Comparative Efficacy of Interventions for Unfit Patients with Chronic Lymphocytic Leukemia.

INTRODUCTION: Rituximab plus fludarabine and cyclophosphamide (RFC) is the standard of care for fit patients with untreated chronic lymphocytic leukemia (CLL); however, its use is limited in 'unfit' (co-morbid and/or full-dose F-ineligible) patients due to its toxicity profile. We conducted a systematic review and Bayesian network meta-analysis (NMA) to determine the relative efficacy of commercially available interventions for the first-line treatment of unfit CLL patients. METHODS: For inclusion in the NMA, studies had to be linked via common treatment comparators, report progression-free survival (PFS), and/or overall survival (OS), and meet at least one of the five inclusion criteria: median cumulative illness score >6, median creatinine clearance ≤70 mL/min, existing co-morbidities, median age ≥70 years, and no full-dose F in the comparator arm. A manual review, validated by external experts, of all studies that met at least one of these criteria was also performed to confirm that they evaluated first-line therapeutic options for unfit patients with CLL. RESULTS: In unfit patients, the main NMA (five studies for PFS and four for OS) demonstrated clear preference in terms of PFS for obinutuzumab + chlorambucil (G-Clb) versus rituximab + chlorambucil (R-Clb), ofatumumab + chlorambucil (O-Clb), fludarabine and chlorambucil (median hazard ratios [HRs] 0.43, 0.33, 0.20, and 0.19, respectively), and a trend for better efficacy versus rituximab + bendamustine (R-Benda) and RFC-Lite (median HR 0.81 and 0.88, respectively). OS results were generally consistent with PFS data, (median HR 0.48, 0.53, and 0.81, respectively) for G-Clb versus Clb, O-Clb, and R-Clb 0.35 and 0.81 versus F and R-Benda, respectively); however, the OS findings were associated with higher uncertainty. Treatment ranking reflected improved PFS and OS with G-Clb over other treatment strategies (median rank of one for both endpoints). CONCLUSION: G-Clb is likely to show superior efficacy to other treatment options selected in our NMA for unfit treatment-naïve patients with CLL. FUNDING: F. Hoffmann-La Roche Ltd

Marginal zone lymphoma in elderly and geriatric patients

Approximately 50% of patients with newly diagnosed marginal zone lymphoma (MZL) are of advanced age. For the three subtypes of MZL (extranodal MZL of mucosa-associated lymphoid tissue, splenic MZL, nodal MZL), the median age at diagnosis is around 65-70 years. Due to the lack of larger studies in MZL, little is known of the prevalence of co morbidity, polypharmacy, or geriatric syndromes in older patients with MZL. The impact of these concurrent conditions on the tolerability and feasibility of diagnostic or therapeutic procedures used in MZL has not been specifically investigated. However, some extrapolations can be made from other studies in cancer, thereby raising questions about potential benefits of geriatric assessment in older patients with MZL. Core of this article is a review of recommended diagnostic and therapeutic procedures in MZL in light of potential barriers and complications that might be encountered in elderly and geriatric patients with MZL. (C) 2016 Elsevier Ltd. All rights reserved

Pharmacotherapeutic Management of Chronic Lymphocytic Leukaemia in Patients with Comorbidities: New Agents, New Hope

Chronic lymphocytic leukaemia (CLL) is mostly considered a disease of the elderly. As such, many patients present with comorbidities. Several scores allow for a qualitative and quantitative assessment of comorbidity in patients with CLL. Although our knowledge about the impact of comorbidity on outcomes in patients with CLL is still incomplete, it is becoming increasingly apparent that comorbidities could negatively interfere with CLL treatment. Recently, a number of new agents have been approved for use in patients with previously untreated CLL and comorbidities (i.e. obinutuzumab, ofatumumab), as well as in patients with previously treated or high-risk CLL (i.e. idelalisib, ibrutinib). This review discusses the role of comorbidity in patients with CLL, together with the changing treatment landscape for CLL in this patient population

Which haemato-oncological Drugs are dispensable or unsuitable in Old Age?

AbstractThere is a vast amount of drugs and therapeutic regimens available today to treat hemato-oncological diseases. This offers new opportunities to close known gaps of undertreatment in older individuals with cancer, but also increases the risk of overtreatment in this patient group. Currently available criteria (drug listings) for potentially inadequate prescribing in the elderly are not matured enough to serve hemato-oncologists as a guidance when trying to identify unnecessary or inappropriate cancer medication in routine clinical practice. In some clinical situations (e. g., decision-making for adjuvant treatment), online tools that allow for a rough prediction of remaining life expectancy (without or with cancer) as well as chemotherapy toxicity could help to detect risks of overtreatment in individual patients, however. Avoiding chemotherapy in distinct therapeutic situations has become possible for some hematological and solid tumors due to a growing number of novel targeted (i. e. non-cytostatic) drugs. This development appears of particular benefit for elderly patients. The present review discusses tools that generally could support the identification of overtreatment in older patients with such diseases. Drug examples are presented for some common hemato-oncological entities.</jats:p

New treatment approaches in CLL: Challenges and opportunities in the elderly

The majority of patients with chronic lymphocytic leukemia (CLL) are over 70 years old. These patients vary in their vulnerability toward treatment efforts. Heterogeneity in fitness of older patients with CLL is mainly determined by individual differences in physiological aging and pathological conditions such as comorbidities and geriatric syndromes. Various options exist to treat older patients with CLL outside and inside clinical trials. Among these are new treatment approaches, including chemoimmunotherapy with engineered CD20 antibodies (e.g., obinutuzumab), single agent therapy with Icinase inhibitors (e.g., ibrutinib, idelalisib), other targeted drug therapy (e.g., venetoclax, lenalidomide), and combinations of these novel compounds. Treatment recommendations for older patients take patient-related as well as disease-related risk factors into consideration. Emerging new treatment approaches in older patients offer novel opportunities, but also novel challenges which are discussed in this review. (C) 2016 Elsevier Ltd. All rights reserved

Management of unfit elderly patients with chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a disease characterized by an increasing incidence with age reaching 35/100,000 in patients over 85 years. Elderly CLL patients carry several challenges, which have to be considered particularly in advanced stages including a higher risk of infections and individual differences in comorbidities and geriatric syndromes. Although no specific tool for geriatric evaluation in CLL has been developed so far, several of them (e.g. CIRS or Charlson-Score) have been tested in CLL patients. Several treatment options exist for frontline and relapse therapy in unfit CLL patients. Less intensive chemoimmunotherapy with engineered CD20 antibodies (e.g. obinutuzumab) is one of the treatment options, if TP53 mutation or deletion has been ruled out by genetic testing. Single agent treatment with the Btk-inhibitor ibrutinib is not only approved in relapsed CLL; but also for frontline therapy. The kinase inhibitor idelalisib (plus rituximab) and the bcl2 inhibitor venetoclax are other novel compounds, which showed great efficacy in relapsed CLL even in unfit patients. Treatment decisions in unfit patients have to take patient-related as well as disease-related risk factors into consideration

Obinutuzumab (GA101) for the Treatment of Chronic Lymphocytic Leukemia and Other B-Cell Non-Hodgkin's Lymphomas: A Glycoengineered Type II CD20 Antibody

Obinutuzumab (GA101) is a humanized, monoclonal type II CD20 antibody modified by glycoengineering. The glycoengineered Fc portion enhances the binding affinity to the Fc gamma RIII receptor on immune effector cells, resulting in increased antibody-dependent cellular cytotoxicity and phagocytosis. In addition, the type II antibody binding characteristics of obinutuzumab to CD20 lead to an efficient induction of direct non-apoptotic cell death. Preclinical data demonstrated more efficient B-cell depletion in whole blood and superior antitumor activity in xenograft models of obinutuzumab as compared to the type I CD20 antibody rituximab. In previously untreated patients with chronic lymphocytic leukemia (CLL) and comorbidities, obinutuzumab plus chlorambucil increased response rates and prolonged progression-free survival compared with rituximab plus chlorambucil. Obinutuzumab had an acceptable and manageable safety profile, with infusion-related reactions during the first infusion as the most common adverse event. Further phase I/II clinical trials have also shown promising activity in other CD20-positive B-cell non-Hodgkin's lymphomas (NHL). Therefore, several clinical studies are planned or ongoing to investigate obinutuzumab with different combination partners in both untreated and relapsed/refractory patients with different B-cell NHL entities, which in addition to CLL include diffuse large B-cell lymphoma and follicular lymphoma