Kevin R Imrie

A meta-analysis and systematic review of thalidomide for patients with previously untreated multiple myeloma

A systematic review and meta-analysis was performed to determine the efficacy and toxicity of thalidomide in previously untreated patients with myeloma. Medline, Embase, Cochrane Controlled Trials Register, and abstracts from the American Society of Hematology and the American Society of Clinical Oncology were searched for randomized controlled trials (RCTs) of either induction or maintenance thalidomide in adults with previously untreated myeloma. Nine RCTs of induction thalidomide, three RCTs of maintenance thalidomide, and one RCT of induction and maintenance thalidomide were identified, involving a total of 4144 subjects. When thalidomide was added to standard, non-transplantation myeloma therapy, overall survival (OS) improved (HR 0.67; 95% CI 0.56-0.81). When thalidomide was given as maintenance following autologous transplantation (ASCT), there was a trend to improved OS (HR 0.61, 95% CI 0.37-1.01); when the only trial which combined induction and maintenance thalidomide was excluded from this analysis, a significant survival advantage emerged (HR 0.49, 95% CI 0.32-0.74). The relative risk of venous thromboembolism (VTE) with induction thalidomide was 2.56 (95% CI 1.88-3.49). A meta-analysis of trials/sub-groups administering low molecular weight heparin (LMWH) as VTE prophylaxis, suggested a persistently increased relative risk of VTE with induction thalidomide (RR 1.54, 95% CI 1.07-2.22). The relative risk of VTE was substantially lower, but still elevated, when thalidomide was given as maintenance therapy following ASCT (RR 1.95, 95% CI 1.15-3.30). In summary, thalidomide appears to improve the overall survival of patients with newly diagnosed myeloma both when it is added to standard, non-transplantation therapy, and when it is given as maintenance therapy following ASCT. However, thalidomide is associated with toxicity, particularly a significantly increased risk of VTE.

Bortezomib in multiple myeloma: systematic review and clinical considerations

We conducted a systematic review to determine the appropriate use of bortezomib alone or in combination with other agents in patients with multiple myeloma (mm). We searched medline, embase, the Cochrane Library, conference proceedings, and the reference lists of included studies. We analyzed randomized controlled trials and systematic reviews if they involved adult mm patients treated with bortezomib and if they reported on survival, disease control, response, quality of life, or adverse effects. Twenty-six unique studies met the inclusion criteria. For patients with previously untreated mm and for candidates for transplantation, we found a statistically significant benefit in time to progression [hazard ratio (hr): 0.48, p < 0.001; and hr: 0.63, p = 0.006, respectively] and a better response with a bortezomib than with a non-bortezomib regimen (p < 0.001). Progression-free survival was longer with bortezomib and thalidomide than with thalidomide alone (p = 0.01). In non-candidates for transplantation, a significant benefit in overall survival was observed with a bortezomib regimen (hr compared with a non-bortezomib regimen: 0.61; p = 0.008), and in transplantation candidates receiving bortezomib, the response rate was improved after induction (p = 0.004) and after a first transplant (p = 0.016). In relapsed or refractory mm, overall survival (p = 0.03), time to progression (hr: 1.82; p = 0.000004), and progression-free survival (hr: 1.69; p = 0.000026) were significantly improved with bortezomib and pegylated liposomal doxorubicin (compared with bortezomib alone), and bortezomib monotherapy was better than dexamethasone alone (hr: 0.77; p = 0.027). Bortezomib combined with thalidomide and dexamethasone was better than either bortezomib monotherapy or thalidomide with dexamethasone (p < 0.001). In previously untreated or in relapsed or refractory mm patients, bortezomib-based therapy has improved disease control and, in some patients, overall survival.

Bortezomib in multiple myeloma: a practice guideline.

AIMS Bortezomib (Velcade™, PS-341), a first-in-class proteasome inhibitor, has been extensively studied either alone or in combination with other agents for the treatment of multiple myeloma. We created a provincial guideline for the use of bortezomib, in newly diagnosed individuals (both eligible and ineligible for transplant) and in individuals with relapsed or refractory multiple myeloma. MATERIALS AND METHODS A systematic review was conducted searching MEDLINE, EMBASE, the Cochrane Library and relevant meeting abstracts. Outcomes of interest were survival, disease control, response rate, response duration, quality of life and adverse effects. Members of the Cancer Care Ontario Hematology Disease Site Group (CCO HDSG), comprising physicians with content expertise, epidemiologists and consumers, developed a guideline through a systematic process that involved assessment of the best available evidence, consensus interpretation of the evidence and a validation process involving practitioners across the province. RESULTS The CCO HDSG recommends the use of bortezomib-based combinations in previously untreated patients with multiple myeloma who are candidates for autologous stem cell transplantation and in individuals who are ineligible for autologous stem cell transplantation. The group further recommends the use of bortezomib, alone or in combination, for patients with relapsed/refractory disease. The evidence did not establish a subgroup of patients with myeloma that should be uniquely targeted for therapy with bortezomib. Qualifying statements by the HDSG address alternative dosing options, the management of cytopenias and the prevention of toxicities, including herpes zoster reactivation. CONCLUSIONS Bortezomib alone or in combination with other agents can be recommended for both previously untreated or relapsed/refractory patients with multiple myeloma. Guidelines for monitoring and reducing toxicity are provided.

Alemtuzumab and CHOP Chemotherapy for the Treatment of Aggressive Histology Peripheral T Cell Lymphomas: A Multi-Center Phase I Study.

BACKGROUND Alemtuzumab has single-agent activity in relapsed peripheral T cell lymphoma (PTL), but the optimal dose and/or schedule in combination with chemotherapy for first-line use is unknown. The primary objectives were to establish the maximally tolerated dose and pharmacokinetics (PK) of alemtuzumab combined in this way. PATIENTS AND METHODS Adult patients with untreated CD52-positive (CD52(+)) PTL were enrolled in a phase I trial. Alemtuzumab was given subcutaneously in escalating doses and/or schedules in combination with CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) using a 3+3 design. Trough PK of alemtuzumab were measured on day 1 of each 21-day cycle and B and T cell subsets were serially measured. RESULTS Twenty patients were enrolled across 4 dose levels. Dose-limiting toxicities necessitated expansion at 10 mg weekly (fatal tuberculosis reactivation) and 60 mg every 3 weeks (grade 4 thrombocytopenia) dose levels. Maximally tolerated dose was not reached. Ten patients developed asymptomatic cytomegalovirus reactivations at a median of 39 days (range, 4-99 days). Two patients developed fungal pneumonias. The overall and complete response rates were 68% and 37%, respectively. Highest day 1 alemtuzumab trough levels were achieved at 60 mg (1973 ng/mL), but with significant inter- and intradose variability. Lymphopenia at baseline was common and T cell recovery was significantly delayed. CONCLUSION With monitoring and prophylaxis, alemtuzumab 60 mg combined with CHOP showed activity in CD52(+) PTL and achieved the highest drug levels.

Autologous stem cell transplant and combination immunotherapy of rituximab and interferon-α induces prolonged clinical and molecular remissions in patients with follicular lymphoma

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Targeting the follicular lymphoma microenvironment – Ready for prime-time?

Despite recent advances in the management of follicular lymphoma (FL), this disease is still characterised by tremendous heterogeneity in outcomes. While some individuals enjoy prolonged survival, others experience rapid disease progression or early transformation to diffuse large B-cell lymphoma. Previous speculation has attributed much of this clinical variability to differences in genetic lesions associated with FL; although the hallmark t(14;18) translocation is found in the majority of presentations, most FL cases demonstrate additional karyotypic abnormalities. More recent evidence, however, suggests that an exclusively genetic model to explain FL development may be inadequate. Current research supports a major role for the surrounding population of non-malignant immune regulatory cells – the microenvironment – in dictating pathogenesis and behaviour. The notion that the microenvironment figures prominently in lymphoma behaviour should not be surprising. FL malignant follicles tend to emulate the features of normal germinal centres, in which a rich supporting cast of macrophages, T-cells and follicular dendritic cells (FDCs) facilitate antigen-presentation and B-cell selection. Several lines of evidence suggest similar interactions are vital to lymphomagenesis. Microarray analyses of FL samples have identified two gene-expression signatures that are highly predictive of survival [1]. Both profiles reflect expression of genes primarily by non-malignant immune cells (T-cells versus macrophages/dendritic cells), suggesting that FL prognosis may be influenced significantly by the microenvironment. By immunohistochemistry, the density, activity and spatial distribution of cells including lymphomaassociated macrophages (CD68 positive), T-helper-1 cells (T-bet positive) and regulatory T-cells (FOXP3 positive) have been predictive in several studies for clinical behaviour, disease transformation or overall survival [2–4]. FDCs are also likely to play an essential part. These cells are ubiquitous in FL biopsy samples. Moreover, alterations in the follicular dendritic meshwork within neoplastic follicles have been noted in individuals destined for early transformation, suggesting a relationship between FDC function and FL progression [3]. Finally, in vitro studies have found that physical interactions between FDCs and lymphoma cells are able to prevent apoptosis and promote FL cell proliferation [5,6]. Such research has advanced the understanding of FL biology and raises the enticing possibility that the interactions between the microenvironment and malignant B-cells could be manipulated for therapeutic gain. In this pioneering spirit, Friedberg et al. [7] hypothesised that targeting the interplay that occurs between FDCs and FL cells could lead to control of lymphoma progression. The authors recognised the importance of tumour necrosis factor-alpha (TNFa) in facilitating FDC development and function. Mice deficient in TNFa fail to form either FDC networks or germinal centers in B-cell follicles [8]. In FL, elevated TNFa levels have been documented and are associated with poor outcome [9]. Inhibition of TNFa signaling might therefore interfere with proliferative signals provided by FDCs and shift the immune response balance in favour of host control of