Autologous stem cell transplant (ASCT) for newly diagnosed multiple myeloma (MM) in the era of novel agents: A meta-analysis of phase III randomized controlled trials.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8022-8022
Author(s):  
Binod Dhakal ◽  
Saurabh Chhabra ◽  
Mehdi Hamadani ◽  
Anita D'souza ◽  
Saad Zafar Usmani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Meta Analysis ◽  
Phase Iii ◽  
Novel Agents ◽  
High Dose ◽  
Significant Heterogeneity ◽  
Cell Transplant ◽  
The Novel ◽  
Novel Agent

8022 Background: Given the unprecedented deep response rates with the novel agent induction, the role of high dose therapy (HDT) followed by ASCT in MM pts. has been questioned, and was re-evaluated in a number of randomized clinical trials (RCTs). Although, the results of most studies suggest the continued benefit of HDT/ASCT, some RCTs suggest no overall survival (OS) benefit. We undertook a systematic review and meta-analysis of phase III randomized RCTs evaluating the role of HDT compared to standard therapy (SDT) in the context of novel agent induction Methods: We searched the PubMed, Scopus and Cochrane Collection of Controlled Trial databases using the term myeloma combined with autologous or transplant or myeloablative or stem cell from 2000-2016. A total of 2480 articles identified, of which 4 large phase III RCTs compared upfront HDT with SDT with novel agents use. Two individuals independently extracted the data. Reported hazard ratio (HR) and survival data were pooled using random effects models (STATA v14, College Station, Tx). Heterogeneity was assessed using I2. Results: Four studies comprising 2421 patients were included (Table 1). One study did not report the HR for death and hence OS analysis was limited to 3 studies. The combined hazard for progression with HDT was 0.55 (95% CI 0.40-0.71) (p < 0.005). The combined hazard for death with HDT was 0.65 (95% CI 0.29-1.0) (p = 0.007). Sensitivity and sub-group analysis showed no difference in PFS (p = 0.06) and OS (p = 0.22) with HDT. Significant heterogeneity was demonstrated by I2 of 71.4% for PFS (p = 0.01) and 68.4% for OS (p = 0.04). Conclusions: Based on our analysis, even in the novel agent era, HDT appears to be beneficial and should be considered standard of care for all transplant eligible MM pts. [Table: see text]

Stem Cell Transplant in Multiple Myeloma: Impact of Response Failure in the Era of Novel Therapies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1878-1878
Author(s):  
Morie A Gertz ◽  
Shaji Kumar ◽  
Martha Q. Lacy ◽  
Angela Dispenzieri ◽  
David Dingli ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Induction Therapy ◽  
Stem Cell Transplant ◽  
Progression Free Survival ◽  
Novel Agents ◽  
High Dose ◽  
Cell Transplant ◽  
Free Survival ◽  
Novel Agent

Abstract Abstract 1878 Poster Board I-900 Autologous stem cell transplant as a platform for multiple myeloma treatment is the standard of care for patients who can safely withstand the procedure. Before novel agents were introduced, one-third to one-half of patients did not achieve partial response at transplant. Previously published medical literature has showed that in this past era, absence of initial response to induction therapy had no impact on progression-free survival and overall survival after high-dose therapy. Lack of response to initial induction did not preclude a good response after stem cell transplant. With the introduction of novel agents—immunomodulatory drugs and proteasome inhibitors—response rates with initial therapy are now between 70% and 100%. This retrospective study analyzes progression-free survival and overall survival in patients who do not have a partial response after induction therapy with a regimen that contains a novel agent. Unlike patients in reports published previously—before novel agents—patients who do not achieve partial remission have a significantly shorter overall survival from transplant (74.0 vs 43.5 months) and a shorter progression-free survival (22.6 vs 13.1 months; P<.001). Absence of a response to induction therapy with a novel agent predicts a poorer outcome after high-dose therapy.{abstabft}.b CR+VGPR for plateau, P<.001 compared with other 3 categories. Failure to respond to novel-agent induction leads to shorter posttransplant progression-free survival (PFS). Failure to respond to novel-agent induction leads to shorter posttransplant overall survivalDisclosures: Gertz: celgene: Honoraria; millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Kumar: celgene: Honoraria; millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Lacy: celgene: Honoraria; millenium: Honoraria.TableMultivariable Analysis of Posttransplant Progression-Free SurvivalVariableP ValuePlateau vs relapsed-refractory.003Albumin.86Sex.94b2-Microglobulin.89Bone marrow plasma cells.18Age.75Abnormal cytogenetics.002CTX mobilization.51Labeling index.002

Maintenance Therapies for Multiple Myeloma (MM): A Direct Meta-Analysis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4271-4271
Author(s):  
Helen Mahony ◽  
Ambuj Kumar ◽  
Rahul Mhaskar ◽  
Branko Miladinovic ◽  
Keith Wheatley ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Meta Analysis ◽  
Phase Iii ◽  
Novel Agents ◽  
Controlled Trials ◽  
Cochrane Central Register ◽  
The Novel ◽  
Significant Difference ◽  
American Society

Abstract Abstract 4271 Background: The role of various maintenance therapies in the management of MM is unclear and evidence on the efficacy of these regimens is conflicting. In order to provide the totality of available randomized evidence on the role of maintenance therapy in MM, we conduct a comprehensive systematic review and meta-analysis of all RCTs studying maintenance therapy. Here, we report the pooled results of trials which directly examined the novel agents of bortezomib, lenalidomide, or thalidomide and reported the outcomes of overall survival (OS) and/or progression-free survival (PFS). Methods: A comprehensive literature search of MEDLINE (PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and meetings abstracts from American Society of Hematology, American Society of Clinical Oncology, European Society for Medical Oncology and European Hematology Association was undertaken to identify all phase III randomized controlled trials (RCTs) of maintenance therapy published until July 2012. We extracted data on OS and PFS. Time to event data were pooled under the random effects model as hazard ratios (HR) and its corresponding 95% confidence interval (CI). Heterogeneity was assessed using the chi square test and I2statistic. All analyses were done in Review Manager 5.1. Results: Twenty-two RCTs met the inclusion criteria. (Figure 1) However, only data from the following RCTs were able to be pooled for the direct head-to-head comparison: 2 RCTs of bortezomib maintenance therapy enrolling 792 patients, 5 RCTs of lenalidomide maintenance therapy enrolling 1776 patients, 11 RCTs of thalidomide maintenance therapy enrolling 3952 patients. The pooled HR and 95% CI, number of RCTs, and number of patients for each comparison are presented in Figure 2. Only two trials compared the novel agents of bortezomib and thalidomide head-to-head. There was no significant different in terms of PFS. For the novel agent of lenalidomide, there was no significant difference is OS compared to placebo. The pooled PFS was in favor of lenalidomide maintenance compared to placebo. For thalidomide, OS was significantly in favor of the intervention when compared to placebo or prednisone/dexamethasone. There was no significant difference in OS between thalidomide maintenance when compared to interferon control. For the outcome of PFS, the pooled results favored thalidomide when compared to prednisone/dexamethasone or interferon control. There was no significant difference between thalidomide and placebo. Conclusion: To date, the largest number of trials has been among thalidomide as maintenance therapy. In our meta-analysis, thalidomide is the only agent which improves survival compared to no treatment. Other novel agents have been evaluated in a smaller number of trials and current data does not allow for firm conclusions that any agent is superior to the other. An indirect, network meta-analysis is called for to provide additional insights regarding comparative efficacy of the novel agents as the maintenance treatment for MM. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Stem-cell transplantation in multiple myeloma: how far have we come?

2019 ◽  
Vol 10 ◽  
pp. 204062071988811 ◽  
Author(s):  
Cinnie Y. Soekojo ◽  
Shaji K. Kumar
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Residual Disease ◽  
Phase Iii ◽  
Novel Agents ◽  
Optimal Timing ◽  
High Dose ◽  
Phase Iii Trials

High-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) has historically been an essential part of multiple myeloma (MM) management since early studies demonstrated its efficacy in relapsed disease, and subsequent phase III trials demonstrated better responses and improved survival with this modality compared with standard chemotherapy. With further advances in the MM treatment landscape, including the development of potent novel agents, there has been an increasing debate around various aspects of ASCT, including the optimal timing, role of single versus tandem ASCT, and the practice of consolidation and maintenance therapy post-ASCT. Routine incorporation of the novel agents at each of the treatment phases, induction, consolidation when used, and maintenance has led to better responses as reflected by increasing rates of minimal residual disease (MRD) negativity, longer progression-free survival (PFS) with improvement in overall survival (OS) and in some of the trials. The phase III trials over the last decade have provided significant clarity on the current approach, and have raised important questions regarding the applicability of this modality in all patients. This review aims to summarize the latest literature in the field and discusses how these findings impact the practice of ASCT today.

Role of High-Dose Chemotherapy with Autologous Stem Cell Transplantation in Primary Systemic Amyloidosis: A Systematic Review and Meta-Analysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2872-2872
Author(s):  
Madhusmita Behera ◽  
Ambuj Kumar ◽  
Mohamed A. Kharfan-Dabaja ◽  
Benjamin Djulbegovic
Keyword(s):  
Systematic Review ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplant ◽  
Meta Analysis ◽  
High Dose Chemotherapy ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Conventional Chemotherapy

Abstract Background: Primary systemic amyloidosis (AL) is a rare plasma cell clonal disorder(8/million) characterized by extracellular deposits of material composed mainly of fragments of light chain immunoglobulin throughout a body. Standard chemotherapy (e.g. melphalan and prednisone) is associated with poor outcomes (typical median survival is between 12–18 months with less than 5% survive 10 years). Autologous stem cell transplant (ASCT) has been increasingly advocated for treatment of AL. However, it is uncertain whether ASCT is better than standard chemotherapy. To address this uncertainty, we undertook a systematic review/meta-analysis to evaluate the efficacy of high-dose chemotherapy and autologous stem-cell transplant (HSCT) versus conventional chemotherapy in patients with AL. Methods: Data search of published studies included Medline [all randomized controlled trials (RCTs)], Cochrane library and hand search of references. Studies were included if they were comparison trials of HSCT versus conventional chemotherapy, regardless if they were RCTs, prospective studies with historical control, or single arm studies. The studies were eligible if patients had biopsy proven AL with at least one major organ involved. Data were extracted on benefits as well as harms (overall survival, event-free survival, response, treatment related mortality, treatment-related morbidity). Results: Out of 34 identified studies only 13 met the inclusion criteria for the current systematic review (2 RCTs, 2 prospective non-randomized trials involving historical control, and 9 single arm trials). Altogether these trials enrolled 1056 patients. Pooled data from 4 trials with controls (RCT and non-RCT) found similar overall survival for ASCT and conventional therapy arms [hazard ratio (HR) of 1.10 (95% CI 0.88, 1.36, p=0.4); p= 0.6]. Analysis of data according to trial design also did not find any difference in survival [HR for RCTs was 1.10 (95% CI 0.88, 1.37) and for non RCTs HR was 0.98 (95% CI 0.29, 3.35)]. The complete hematological response was also similar in both arms in RCTs (Odds ratio [OR]=1.38, 95%CI 0.67, 2.85; p=0.4) and non RCTs (OR=1.78, 95%CI 0.22, 14.65; p=0.32). The pooled proportion of treatment-related deaths in the single arm studies for AHCT was 0.119 (95% CI = 0.09 to 0.14)]. Conclusion: The results from the meta-analysis indicate that there is no statistically significant difference between the treatment effects from high-dose chemotherapy with ASCT and conventional chemotherapy. Hence, the efficacy of ASCT in improving overall survival and complete hematological response remains to be proven.

Phase III Randomized Stem Cell Mobilization Trial Comparing Standard Vs Double-Dose G-CSF Vs Standard Doses of G-CSF Plus GM-CSF in Hard to Mobilize Patients Undergoing An Autologous Hematopoietic Stem Cell Transplant (HSCT).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3228-3228
Author(s):  
Elizabeth Berger ◽  
Christopher Seet ◽  
Mala Parthasarathy ◽  
Tulio Rodriguez ◽  
Scott E. Smith ◽  
...  
Keyword(s):  
Stem Cell ◽  
Standard Dose ◽  
Stem Cell Mobilization ◽  
Phase Iii ◽  
Control Group ◽  
High Dose ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Cell Mobilization

Abstract Abstract 3228 Poster Board III-165 Introduction Using standard dose G-CSF (10 μg/kg) for stem cell mobilization, 25-40% of patients, deemed to be hard to mobilize based on prior therapy, will not collect sufficient HSC (> 2-2.5 × 106 CD34/kg) to proceed to a prompt autotransplant. Strategies to improve CD34/kg yields have included dose escalating G-CSF up to 30 μg/kg or combining G-CSF and GM-CSF. While dose escalated G-CSF is effective in increasing CD34 yields in normal donors as is the combination of G-CSF and GM-CSF, their comparative value in pre-treated patients has not been tested. To determine the value of these strategies, we performed a randomized comparison of high dose G-CSF (30 μg/kg as 2 doses 12 hours apart), to the combination of simultaneous single daily doses of G-CSF (10 μg/kg) plus GM-CSF (5 μg/kg), to a control group receiving G-CSF at an equivalent total dose of cytokine to the combination arm (15μg/kg) as a single dose. Patients and Methods Patients were eligible if heavily pre-treated, defined as: a minimum of 10 total cycles of combination chemotherapy and two prior regimens, or a total of 6 chemotherapy cycles if the patient also received RT to marrow bearing sites, platinum-based chemotherapy or 2 or more cycles of any BCNU or fludarabine containing regimen. Baseline WBC had to be > 3000/μl, ANC > 1500/μl and a platelets > 100,000/μl. Twelve liter aphereses began on day 5 of mobilization, and continued until ≥ 4 × 106 CD34/kg were collected or a maximum of 5 aphereses. Patients typically proceeded to transplant if they had ≥ 2.5 × 106 CD34/kg collected and were always re-mobilized if they collected < 2.0 × 106 CD34/kg. CD34 subsets (CD34+/CD33- and CD34+/CD38-) were also assessed for the 3 groups to determine if more primitive HSC were mobilized by the 2 novel strategies. The sample size was calculated based as follows: 60% of the control group would collect 2.5 × 106 CD34/kg and this would rise to 90% in one or both study arms. The detection of such differences with a power of 80% and a 2-sided alpha level of 0.025 required a total sample of 120 patients. Results A total of 120 patients were randomized; 119 were eligible. Patient demographics, shown in the Table, were matched among the three groups: The % of patients collecting ≥2.5 × 106 CD34/kg was: standard G: 60%, high dose G: 57% (p = 1.0), G + GM: 41% (p = 0.1). Median CD34 collected in first mobilization were, 3.6 × 106/kg, 3.0 × 106/kg (p = 0.22) and 2.0 × 106/kg (p = 0.05) respectively in a median of 4, 4, and 5 aphereses (p = NS). Re-mobilization rates: standard G; 37.5%, high dose G: 35%; G + GM: 50% (p = NS). Total median CD34 collected from first and any second mobilizations were: standard G: 4.8 × 106/kg, high dose G: 3.9 × 106/kg, and G + GM: 3.5 × 106/kg. One patient in the standard G arm and 3 in high dose G did not proceed to transplant due to poor initial mobilization and progression in 2, and one each for progression or poor mobilization alone. There were no significant differences in median engraftment times: for ANC, 10, 11 and 15 days respectively for the standard G-, high dose G- and G + GM arms and for platelets, 11, 13 and 14 days respectively. The overall survivals @ the median f/u time of 37 months were 59.8%, 61.8% and 48.1% respectively (p = 0.272) for the three groups. The % primitive HSC (CD34+/CD33- and CD34+/CD38-) from the first mobilization were identical in the 3 patient groups. Conclusions We found no advantage to dose escalated G-CSF nor to the combination of G-CSF and GM-CSF to mobilize HSC for autotransplantation in heavily pre-treated patients. We also did not find higher numbers of more primitive CD34 subsets mobilized by these newer strategies. Alternative approaches, e.g. the combination of plerixifor + standard dose G-CSF (Stiff et al: BBMT; 15:249-56, 2009) would appear to be the preferred method of initial HSC mobilization for heavily pre-treated patients. Disclosures Stiff: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Efficacy of Novel Agents in Multiple Myeloma in Comparison to Autologous Stem Cell Transplant: A Retrospective Study in a Single Inner City Institution

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5118-5118
Author(s):  
Tareq Braik ◽  
Dayra Avila ◽  
Shivi Jain ◽  
Manila Gaddh ◽  
Barabara Yim ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Median Survival ◽  
Standard Of Care ◽  
High Dose Chemotherapy ◽  
Novel Agents ◽  
High Dose ◽  
Cell Transplant ◽  
Conventional Chemotherapy ◽  
Novel Therapy

Abstract Abstract 5118 Introduction: Since the mid 1990s, high dose chemotherapy with hematopoietic stem cell rescue has been considered the standard of care for front-line treatment in younger patients with multiple myeloma. This standard of care has been based on randomized controlled trials that compared autologus stem cell transplant (ASCT) with conventional chemotherapy. During the past decade, novel agents (NA), thalidomide, bortezomib and lenalinomide, have replaced conventional chemotherapy in the treatment of myeloma. These agents, used frontline, have shown promise in improving the outcome of myeloma patients without increasing toxicity. There are no studies to date comparing NA therapy to ASCT to determine whether there is a survival difference or whether NA therapy may reduce the need for transplantation. Many of our patients have no health insurance coverage and transplant is not a therapeutic option for them. We have attempted to compare the outcome of such patients receiving NA therapy with those in the literature who received conventional chemotherapy followed by ASCT. Methods: Ninety nine patients with multiple myeloma were treated at John H Stroger Hospital of Cook County between 2001 and 2011. All patients received novel agents (thalidomide, bortezomib and lenalinomide) as part of their therapy. Only 18/99 (18.2%) went for high-dose chemotherapy with ASCT and the remaining 81/99 (81.8%) received novel therapy without ASCT. We compared the outcome of patients who received novel therapy alone to a historical control group from the literature who received ASCT with conventional therapy (N Engl J Med 2003;348:1875–83). Overall survival was determined by Kaplan-Meier estimates. Results: We evaluated 99 consecutive myeloma patients (38% males and 61% female) of which 65% were African Americans, 19% Hispanics and 7% whites. All 3 stages (international staging system) of myeloma were equally represented. The median age at diagnosis was 60 years (40–85yr). Median follow up was 48 months (12–120). During the ten year follow up period, 60 patients (60.4%) have died. Twenty four out of 99 patients (24.2%) received only one line of therapy. 75 patients received more than one line of therapy. 75% received thalidomide-based therapy, 13% received bortezomib-based therapy and 12% received lenalinomide-based therapy. The median survival of patients who received novel therapy without ASCT (n=81) was 60 months, which is higher than the median survival of the historical controls who received ASCT reported by Child et al, N Engl J Med 2003;348:1875–83, (median survival = 54.1 months), the difference was statistically significant (P=0.0329). There was no statistically significant difference between the two groups by sex (p=0.927) and race (p=0.421). The 5-year survival of patients who received novel therapy without ASCT (n=81) was 48.2%. For those who were younger than 65 years (n=54), the median survival was 72 months and the 5-year survival was 58.1% in comparison to those who were 65 years and older (n=27), the median survival was 46 months and the 5-year survival was 29.2% (P=0.029). Conclusion: Novel agents are effective frontline therapy for multiple myeloma, especially in patients younger than 65. Our cohort had remarkable results in comparison to a historical population of patients who had ASCT with conventional chemotherapy. Since there is no curative therapy to date, a prospective randomized trial comparing NA with ASCT will be essential to clarify the role of ASCT in the era of novel therapy. Disclosures: No relevant conflicts of interest to declare.

Maintenance Therapies for Multiple Myeloma (MM): A Network Meta-Analysis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 236-236
Author(s):  
Helen Mahony ◽  
Ambuj Kumar ◽  
Rahul Mhaskar ◽  
Branko Miladinovic ◽  
Keith Wheatley ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Phase Iii ◽  
Novel Agents ◽  
Controlled Trials ◽  
Cochrane Central Register ◽  
Randomized Controlled ◽  
American Society ◽  
Novel Agent

Abstract Abstract 236 Background: There is little consensus on which maintenance therapy clinicians should choose for their patients. Since 1999, the three novel agents of bortezomib, lenalidomide, and thalidomide have been approved for use among patients with MM. These agents have been increasingly used as maintenance therapy. To date, only two randomized controlled trials of maintenance therapy have examined the efficacy of these novel agents head-to-head. Here, we conduct a network meta-analysis of bortezomib, lenalidomide, and thalidomide to determine which of these novel agents could potentially increase overall survival (OS) and progression-free survival (PFS). Methods: A comprehensive literature search of MEDLINE (PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and meetings abstracts from American Society of Hematology, American Society of Clinical Oncology, European Society for Medical Oncology and European Hematology Association was undertaken to identify all phase III randomized controlled trials (RCTs) of maintenance therapy published until July 2012. We applied the Bayesian mixed treatment comparison (MTC) method under the random-effects model. The indirect comparisons were constructed from trials that have one treatment in common. For each included RCT, we calculated the hazard ratio (HR) and its corresponding standard error and used this to calculate the indirect estimates of HR and corresponding credible intervals (CrI). We also ranked the treatments according to the probability of best treatment and calculated the surface underneath the cumulative ranking curve (SUCRA). All analyses were conducted in WinBUGS 1.4.3 and Stata 11.2. Results: The network, number of trials for each comparison, and number of patients enrolled is shown in Figure 1. The network for OS was based on 12 RCTs enrolling 5542 patients and the network for PFS was constructed from 13 RCTs and 5784 patients. The MTC networks were consistent for both OS and PFS. For both OS and PFS, two comparisons were produced (Figure 2). For OS, the analysis showed that none of the treatments were superior. For PFS, lenalidomide was superior to thalidomide (HR = 0.58, 95% CrI [0.37, 0.94]). The estimates of SUCRA and rank probabilities (Figure 3) suggested that for OS bortezomib was best followed by lenalidomide and thalidomide. For PFS, lenalidomide was best followed by bortezomib and thalidomide. Conclusion: Using the MTC method, we found no evidence that any of the novel agents are superior to one another in terms of OS. Lenalidomide was the only novel agent which was superior to another active therapy (thalidomide). While these results provide preliminary evidence to which novel agent may be more beneficial as maintenance therapy, definitive conclusions cannot be reached until large, well designed RCTs evaluating these therapies head-to-head are conducted. Disclosures: No relevant conflicts of interest to declare.

Efficacy and Safety Of Treatments For Relapsed Or Refractory DLBCL: Results Of a Systematic Literature Review

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5104-5104 ◽  
Author(s):  
Ann Colosia ◽  
Peter C Trask ◽  
Robert Olivares ◽  
Shahnaz Khan ◽  
Adeline Abbe ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplant ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Cell Transplant ◽  
Efficacy And Safety ◽  
Free Survival ◽  
Career Development Award

Abstract Background Diffuse large B-cell lymphoma (DLBCL) accounts for 30% to 40% of non-Hodgkin’s lymphoma (NHL) cases in Western countries. Although two-thirds of patients may be cured with combination chemotherapy, in the event of treatment failure and for those who are refractory to treatment, survival is usually measured in months. Several therapeutic modalities have been utilized for patients with relapsed or refractory disease, but among patients who are not eligible for high-dose chemotherapy with stem cell transplant, a comprehensive assessment of efficacy and safety is lacking. This systematic literature review (SLR) was designed to exhaustively collect and review information on the clinical efficacy and safety of the different interventions used in the treatment of refractory or relapsed DLBCL, and if possible to perform a meta-analysis. Methods Electronic databases (PubMed, Cochrane Library, Embase) were searched for relevant studies published from 1997 to August 2, 2012. In addition, conference abstracts, bibliographic reference lists of included articles and recent reviews, and the Clinicaltrials.gov database were searched for phase 2, 3, or 4 studies displaying results, potentially unpublished in peer-reviewed journals. Main efficacy outcomes included objective response rate (ORR), complete response, partial response, duration of response, progression-free survival (PFS), and overall survival (OS). Safety endpoints focused on grade 3/4 toxicities and treatment discontinuation due to toxicity. Studies had to report on relapsed or refractory DLBCL after at least one standard treatment and patients who were not eligible to receive high-dose chemotherapy or stem cell transplant (autologous or allogeneic). Mixed type NHL studies were required to report DLBCL outcomes separately for inclusion. Results A total of 3,308 publications were identified in the first pass of a broad SLR on NHL; of these, 57 provided relevant data for DLBCL representing 54 unique studies. Of the 54 studies, there was 1 phase 3 study, 33 phase 2 studies, and 4 phase 1/2 studies (15 studies did not report the study phase and 1 was an observational study). Six studies were comparative (3 randomized trials; 3 nonrandomized trials) with two treatment arms; 48 studies were single arm. Of the 48 regimens evaluated, few regimens were represented more than once. Overall survival and PFS were often not reported or not reported separately for the patients with DLBCL in studies that enrolled patients with any of the multiple lymphoma histologies. Refractory and relapsed criteria were often not defined, and definitions were heterogeneous when available. The ORR from the few comparative studies ranged from 27% to 100%, with most estimates between 40% and 70%. PFS with low and high doses of obintuzumab was 2 months and 3 months, respectively in one study, and OS was 4 months with MEP and 7 months with C-MEP in another study. There was a common regimen in two of the randomized controlled trials, but the patient populations in these studies differed too greatly to allow a valid meta-analysis to be performed. In the single-arm studies, ORR ranged from 11% to 100%, with the estimates evenly distributed across that range. Progression-free survival was approximately 1 to 10 months. Reported median OS ranged from 1 to 13 months. Main safety concerns included thrombocytopenia, leukopenia, and neutropenia. Conclusions There is a high unmet need for effective therapies for patients with relapsed or refractory DLBCL who are ineligible for stem cell transplant. Although numerous regimens have been evaluated in single-arm trials and a handful in comparative studies, there is no clearly superior regimen for patients with relapsed or refractory DLBCL, especially in third- and later lines of therapy. FA is supported by a Clinical Career Development Award from the Lymphoma Research Foundation Disclosures: Colosia: RTI Health Solutions: Employment. Trask: Sanofi: Employment. Olivares: Sanofi: Employment. Khan: RTI Health Solutions: Employment. Abbe: Sanofi: Employment. Police: RTI Health Solutions: Employment. Njue: RTI Health Solutions: Employment. Wang: RTI Health Solutions: Employment. Sherrill: RTI Health Solutions: Employment. Ruiz-Soto: Sanofi: Employment. Kaye: RTI Health Solutions: Employment. Awan: Lymphoma Research Foundation (Career Development Award): Research Funding.

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