scholarly journals Engaging the Innate and Adaptive Antitumor Immune Response in Lymphoma

2021 ◽  
Vol 22 (7) ◽  
pp. 3302
Author(s):  
Clifford M. Csizmar ◽  
Stephen M. Ansell
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
Therapeutic Strategy ◽  
Overall Response Rate ◽  
Response Rate ◽  
Tumor Biology ◽  
Antitumor Immune Response ◽  
Checkpoint Inhibition ◽  
Major Histocompatibility Complexes ◽  
Immunosuppressive Cytokines

Immunotherapy has emerged as a powerful therapeutic strategy for many malignancies, including lymphoma. As in solid tumors, early clinical trials have revealed that immunotherapy is not equally efficacious across all lymphoma subtypes. For example, immune checkpoint inhibition has a higher overall response rate and leads to more durable outcomes in Hodgkin lymphomas compared to non-Hodgkin lymphomas. These observations, combined with a growing understanding of tumor biology, have implicated the tumor microenvironment as a major determinant of treatment response and prognosis. Interactions between lymphoma cells and their microenvironment facilitate several mechanisms that impair the antitumor immune response, including loss of major histocompatibility complexes, expression of immunosuppressive ligands, secretion of immunosuppressive cytokines, and the recruitment, expansion, and skewing of suppressive cell populations. Accordingly, treatments to overcome these barriers are being rapidly developed and translated into clinical trials. This review will discuss the mechanisms of immune evasion, current avenues for optimizing the antitumor immune response, clinical successes and failures of lymphoma immunotherapy, and outstanding hurdles that remain to be addressed.

scholarly journals FINAL Results of an Phase, Multicenter, Randomied, Controlled OPEN LEVEL Trial: Decitabine Therapy in Patients with Myelodysplastic Syndromes

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3865-3865
Author(s):  
Zonghong Shao ◽  
Hui Liu ◽  
Hao Jiang ◽  
Hongyan Tong ◽  
Ruixiang Xiang ◽  
...  
Keyword(s):  
Clinical Trials ◽  
High Risk ◽  
Adverse Events ◽  
Myelodysplastic Syndromes ◽  
Overall Response Rate ◽  
Response Rate ◽  
Conflicts Of Interest ◽  
Study Drug ◽  
Overall Response ◽  
To Receive

Abstract Background: DNA hypomethylating agent, decitabine, has become the current standard therapy for patients with higher-risk myelodysplastic syndromes (MDS). Decitabine was launched in China in August 2009 without clinical trials. According to some retrospective studies, the efficacy and safety are similar to those reported in other countries, but there is still a lack of large-scale prospective clinical trials. So we start a prospective clinical trial in China to compare the effect and safety of decitabine in MDS, which was registered at clinicaltrials.gov (NCT02013102). Design: Adults with intermediate or high risk MDS by the International Prognostic Scoring System (IPSS≥0.5) were randomized to receive either decitabine 20 mg/m2 IV daily for 5 days (arm Ⅰ) or decitabine 12 mg/m2 IV daily for 8 days (arm Ⅱ) every four weeks. Patients continued to receive study drug for 4 cycles until death, disease progression, intercurrent illness preventing further administration of treatment, unacceptable adverse event or decision by the patient to withdraw from the study. And supportive care were permitted. The primary end point was overall response rate (ORR, CR+mCR+PR) by International Working Group (IWG 2006) criteria, secondary end points included CR, mCR, PR, HI, safety, et al. Results: We enrolled a total of 198 patients between 8/2013 and 12/2017, among which 7 patients didn't take decitabine, and 191 were included in the analysis. 94 in arm Ⅰ recieved decitabine and 97 in arm Ⅱ. 32.8% of patients withdrew from the study for a variety of reasons, including progression and death (5.1%), personal decision (13.6%), adverse events (6.6%), and other causes (7.6%). The median age of patients in arm Ⅰ was 54.88 years old and 54.82 years old in arm II. The median follow-up was 106 days for patients in both arms. The patients received a mean 2.5 cycles of decitabine therapy for arm Ⅰ and 2.0 cycles for arm Ⅱ. The overall response rate was 39.3% in total, and 41.5% and 38.1% (p=0.6598) for patients in arm Ⅰ and arm Ⅱ, respectively. And CR was 18.1% and 14.4% (p= 0.5584) , PR was 6.4% and 3.1% (p=0.3257) , mCR was 17.0% and 20.6% (p=0.5814) , HI was 3.2% and 1.0% (p=0.3633) , for patients in armⅠand armⅡ, respectively (Table 1). Among all patients, 38.7% were intermediate-1 risk, 40.3% were intermediate-2 risk, 20.4% were high risk. Analysis of response by MDS patient subtypes is shown in Table 2. Those who were higher risk experienced higher ORR and CR, while the difference is not significant between two arms (p>0.05). As expected, cytopenias were the most frequent complications (76.4%). Grade 3-4 neutropenia, thrombocytopenia and anemia considered to be at least possibly related to the study drug occurred at rates of 23.0%, 34.6%, and 34.6% of patients, respectively. Nonhematologic adverse events were also common including abnormal metabolism and nutrition (23.40% vs 18.56%), abnormal gastrointestinal function (29.79% vs 41.24%), cardiac disorders (11.70% vs 14.43%), infection and infectious diseases (32.98% vs 36.08%), abnormal skin and subcutaneous tissue and so on, which were no significant differences between two ams. During the study there were 17 SAE, only 7 cases were possibly related to drug therapy, such as pulmonary infection, Sepsis, myelosuppression, intracranial hemorrhage, hepatic failure, and arrhythmia. Conclusions: The use of 5-day and 8-day schedule decitabine is safe and effective in patients with intermediate and high risk MDS, among which there was no significant differences. Disclosures No relevant conflicts of interest to declare.

A Case Series Of Continuous Low Dose Lenalidomide In Patients With Relapsed Or Refractory Classical Hodgkin Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5134-5134 ◽  
Author(s):  
Ahmed Sawas ◽  
Sean Clark-Garvey ◽  
Ellen Neylon ◽  
Ameet Narwal ◽  
Kathleen Maignan ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Stem Cell ◽  
Dose Reduction ◽  
Low Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Median Number ◽  
Classical Hodgkin Lymphoma ◽  
Time To Progression ◽  
Overall Response

Abstract Background Relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) remains a clinical challenge with limited effective treatments after high dose therapy with autologous stem cell transplantation (ASCT). Lenalidomide (Revlimid®) is an approved anti-neoplastic therapy for multiple myeloma, mantle cell lymphoma and myelodysplastic syndrome with del(5q). It has emerged as an agent with a manageable toxicity profile and promising clinical activity in a number of B cell malignancies. Two clinical trials have evaluated lenalidomide in rel/ref patients with cHL at a dose of 25mg daily for 21 days of a 28 day cycle. One study reported an overall response rate of 14%, a median time to progression of 3.2 month, with a median number of prior therapies of 2. The second study reported an overall response rate of 19%, a cytostatic response rate (CR+PR+SD> 6 month) of 33%, with a median number of prior therapies of 4. The most common reported grade 3-4 side effects in these studies respectively were: neutropenia 28% and 47%, thrombocytopenia 28% and 27%, and anemia 21% and 27%. We report on our experience in this case series with continuous low dose (10-20mg) lenalidomide in rel/ref cHL patients. Methods Twelve rel/ref cHL patients (pts) who previously underwent (or were not candidates for) ASCT and/or clinical trials were administered a daily dose of lenalidomide. Pts received 10mg and were titrated up to 20mg, if tolerated, with continuous dosing for 30 day cycles. Treatment continued until disease progression or the development of unacceptable adverse event at the lowest administered dose (5mg) of lenalidomide. Results The median age at treatment was 33 (range 24-61) years with 5 females. Median number of prior therapies was 8 (range 3-16). Ten pts had received a prior stem cell transplant (9 ASCT, 1 allogenic, and 1 both ASCT and allogeneic). Of the 12 pts, we observed 3 PR (25%), and 9 SD (8 for more than 6 months) for an overall response rate of 25% and an overall cytostatic response rate (CR+PR+SD> 6 month) of 92%. Median number of cycles received was 6 (range 2-15); six patients remain on therapy. One patient with a PR after 2 cycles of therapy underwent allogeneic stem cell transplant. The median time to progression for the remaining 11 patients was 7.5 months (range 4-15 months). Three patients had progression of disease, all of whom were able to enroll on clinical trials. One patient discontinued therapy because of exacerbation of preexisting neuropathy and was able to transition to chemotherapy. A second patient discontinued therapy after experiencing significant fatigue. In general, the treatment was well tolerated, and the most common clinically significant adverse events were: neutropenia in 4 patients which was managed by GCSF support and dose reduction, exacerbation of neuropathy in 2 patients with one patient discontinuing therapy and dose reduction in the second, and diarrhea in one patient managed with dose reduction. Conclusions Despite a far more heavily treated patient population, continuous, low dose, single agent lenalidomide was both tolerable and effective in patients with rel/ref cHL. Continuous low dose lenalidomide is able to provide meaningful time to progression and bridge to further therapy. A clinical trial to evaluate the efficacy of continuous daily dosing of lenalidomide in rel/ref cHL is warranted. Disclosures: Off Label Use: Lenalidomide in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma. O'Connor:Celgene: Consultancy, Research Funding.

Nanomedicine Approach to Immunotherapy of Hepatocellular Carcinoma

2021 ◽  
Vol 17 (5) ◽  
pp. 771-792
Author(s):  
Hongbo Ni ◽  
Jian Xue ◽  
Fan Wang ◽  
Xiaohan Sun ◽  
Meng Niu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Response ◽  
Tumor Cell ◽  
Response Rate ◽  
Advanced Technology ◽  
Antitumor Immune Response ◽  
Immune Microenvironment ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Immunosuppressive Microenvironment

In recent years, the growing studies focused on the immunotherapy of hepatocellular carcinoma and proved the preclinical and clinical promises of host antitumor immune response. However, there were still various obstacles in meeting satisfactory clinic need, such as low response rate, primary resistance and secondary resistance to immunotherapy. Tackling these barriers required a deeper understanding of immune underpinnings and a broader understanding of advanced technology. This review described immune microenvironment of liver and HCC which naturally decided the complexity of immunotherapy, and summarized recent immunotherapy focusing on different points. The ever-growing clues indicated that the instant killing of tumor cell and the subsequent relive of immunosuppressive microenvironment were both indis- pensables. The nanotechnology applied in immunotherapy and the combination with intervention technology was also discussed.

Clinical Efficacy of Lenalidomide in Fludarabine-Refractory Chronic Lymphocytic Leukemia Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3108-3108 ◽  
Author(s):  
Asher A. Chanan-Khan ◽  
Myron S. Czuczman ◽  
Swaminathan Padmanabhan ◽  
Michael J. Keating ◽  
Susan M. O’Brien ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chronic Lymphocytic Leukemia ◽  
Phase Ii ◽  
Clinical Efficacy ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Refractory Disease ◽  
Overall Response

Introduction: Fludarabine treatment has been shown to be beneficial for patients with Chronic Lymphocytic Leukemia (CLL), and fludarabine-based combinations may even further improve outcomes in patients with CLL. However, most CLL patients eventually become fludarabine refractory, a state which is associated with a relatively short survival. Treatment of fludarabine-refractory patients is challenging, with a median survival of about 10 months. Recently, 2 phase II clinical trials (Chanan-Khan et al. JCO 2006 and Ferrajoli et al. ASH 2006) demonstrated the clinical efficacy of lenalidomide, an immunomodulatory agent, in relapsed/refractory CLL patients. We conducted a subset analysis to examine the efficacy of lenalidomide in patients who are fludarabine refractory. Methods: All patients enrolled on the 2 phase II single agent lenalidomide clinical trials were evaluated and patients with fludarabine-refractory disease (progressed while on or within 6 months of fludarabine-based therapy) were assessed for clinical efficacy of lenalidomide. Lenalidomide was given orally either at 10 mg daily for 28 days followed by 5 mg increments every 28 days to a maximum dose of 25 mg or given at 25 mg on days 1–21 of each 28-day cycle. Response was assessed using the NCI-WG 1996 criteria. Results: A total of 80 patients were collectively enrolled in these clinical studies. Among these, 29 were identified to have fludarabine-refractory disease. Important clinical characteristics of these patients are reported in Table 1. The overall response rate in fludarabine-refractory patients was 34.5% (10/29). Complete remission was observed in 2 (6.8%) patients. Conclusion: Lenalidomide is a novel agent with immunomodulating properties demonstrating clinical efficacy in relapsed or refractory CLL patients. Interestingly, clinical responses to single agent lenalidomide were noted despite refractoriness to fludarabine (a subset of CLL patients with poor survival and limited therapeutic options). This observation of the clinical benefit of lenalidomide independent of responsiveness to prior fludarabine is encouraging and warrants further evaluation. Table 1 Ferrajoli et al. Chanan-Khan et al. Fludarabine-refractory (N=12) Fludarabine-refractory (N=17) ORR, overall response rate; PFS, progression-free survival; OS, overall survival. Median age, years (range) 62 (51–82) 68 (53–75) Sex, female/male 4/8 4/13 Median no. prior therapies (range) 4 (3–15) 4 (1–10) Median beta microglobulin (range) 5 (3–10) 5 (2–10) Advance Rai Stage (III/IV), n (%) 7 (58.3) 13 (76.4) ORR, n (%) 3 (25.0) 7 (41.2) Median PFS, months 12 14.9 Median OS, months All alive (range, 7–19) 23

Targeting DNA damage response and repair genes to enhance anticancer immunotherapy: rationale and clinical implication

2020 ◽  
Author(s):  
Giuseppe Lamberti ◽  
Elisa Andrini ◽  
Monia Sisi ◽  
Alessandro Di Federico ◽  
Biagio Ricciuti
Keyword(s):  
Immune Response ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Immune Checkpoint ◽  
Therapeutic Strategy ◽  
Checkpoint Inhibitors ◽  
Metastatic Cancer ◽  
Antitumor Immune Response ◽  
Endogenous Factors ◽  
Damage Response

DNA damage response and repair ( DDR) genes play a central role in the life of actively replicating cells, cooperating to maintenance of genomic integrity. However, exogenous or endogenous factors, including deficiency in DDR genes, can cause different degrees of DNA damage that profoundly impacts the tumor immunogenicity and enhance antitumor immune response through neoantigen-dependent and neoantigen-independent mechanisms. Inhibition of DDRs is already an effective therapeutic strategy in different cancer types. In addition, because DDR inhibition can also induce and amplify DNA damage in cancer cells, with a deep impact on antitumor immune responses, combining DDR inhibitors with immune checkpoint inhibitors represent an attractive therapeutic strategy to potentially improve the clinical outcomes of patients with metastatic cancer. In this review, we provide an overview of the rational and potential of combining DDR and immune checkpoint inhibition to exploit the enhanced antitumor immune response induced by DNA damage.

Real-world experience of talimogene laherparepvec in patients receiving immunotherapy in metastatic melanoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22003-e22003
Author(s):  
Tapas Ranjan Behera ◽  
Jung Min Song ◽  
Jennifer S. Ko ◽  
Michael J. McNamara ◽  
Pauline Funchain ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Metastatic Melanoma ◽  
Treatment Response ◽  
Median Time ◽  
Real World ◽  
Overall Response Rate ◽  
Response Rate ◽  
Talimogene Laherparepvec ◽  
Overall Response

e22003 Background: Talimogene laherparepvec (TVEC) is an oncolytic herpes virus approved by the FDA for intralesional therapy in unresectable metastatic melanoma. However, little is known regarding the effectiveness of TVEC+checkpoint inhibition (CPI) outside of clinical trials. We present outcomes of the largest single institution experience with TVEC in the context of different immune checkpoint inhibitors. Methods: All patients with stage III-IV unresectable melanoma having received TVEC were evaluated. Patient demographics, clinicopathological characteristics, TVEC treatment response and outcomes were assessed. Final analysis included those who received TVEC adjacent to CPI with a minimum 6-month follow-up, excluding patients on clinical trials. Response was estimated by sequential measurement of injectable on-target lesions. Results: A total of 62 patients received TVEC from 2016 to 2019, of which 43 remained excluding Merkel cell carcinoma, patients on trials, and TVEC monotherapy. Of 30 patients with available treatment response data and at least 6-months follow-up, median age was 68.5 years (30-99 years), 40% were female, 16 (53.3%) stage IV. Median follow-up was 17.5 months (6-43 months). At 6 months, 20 (67.7%) patients were alive; at 1 year, 17 (56.7%) patients were alive. Eighteen patients received pembrolizumab, 7 nivolumab and 5 ipilimumab/nivolumab. Median number of TVEC doses received was 8 (3-31 doses). Median time on TVEC therapy was 4 months (1-26 months). Overall response rate for on-target lesions was 24 (80%), with complete local response (CR) in 15 (50%), partial response (PR) in 9 (30%), and progressive disease (PD) in 6 (20%). Median time to response was 6 weeks (2-17 weeks); 5 in CR, 6.5 in PR and 5.5 in PD groups. Adverse events were mostly mild and limited to constitutional symptoms. Conclusions: To our knowledge this is the largest real-world experience assessing TVEC in patients receiving CPI. Local overall response rate appears higher in comparison to historic numbers for TVEC monotherapy. The findings demonstrate that TVEC is an effective and safe treatment for metastatic melanoma and has robust outcomes in real-life clinical settings.

scholarly journals Efficacy of Venetoclax Based Regimens in Relapsed Refractory Multiple Myeloma: A Systematic Review and Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Laila Hashim ◽  
Muhammad Salman Faisal ◽  
Zahoor Ahmed ◽  
Insija Ilyas Selene ◽  
Moazzam Shahzad ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Overall Response Rate ◽  
Retrospective Studies ◽  
Response Rate ◽  
Phase Iii ◽  
Median Dose ◽  
Phase Iii Trial ◽  
Overall Response ◽  
Duration Of Response

Background: Clonal plasma cells in multiple myeloma (MM) over express b-cell lymphoma-2 protein (BCL2). Which is the target for venetoclax (VEN). VEN has a promising efficacy and a favorable safety profile in MM patients. This review highlights the efficacy of VEN for the treatment of relapsed refractory (RR) MM. Methodology: We performed a comprehensive database search on four major databases(PubMed, Embase, Cochrane, and Clinical trials.gov). Our search strategy included MeSH terms and keywords for multiple myeloma and VEN, including trade names and generic names, from the date of inception of the database to April 2020.The initial search revealed 782 articles. After excluding review articles, duplicates, and non-relevant articles,we included six studies(four clinical trials and two retrospective studies), which reported an overall response rate (ORR) in RRMM patients. Proportions along with 95% Confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.0.2) to report the efficacy of VEN. We pooled the results of the experimental arms of included trials using the inverse variance method and logit transformation. Between studies,the variance was calculated using Der Simonian-Laird Estimator. Results: We identified 568 patients from four clinical trials [Moreau et al.2019, the BELLINI trial, (n=291, venetoclax arm= 194, placebo arm= 97)], Costa et al. 2018 (n=42), Kumar et al. 2017(n=66), and Moreau et al. 2017 (n=66)] and two retrospective studies (Kambhampati et al. 2020 (n= 47) and Sidiqi et al.2019 (n=56)). Among which 563 patients were evaluable for the treatment outcomes. One hundred and forty two patients (25%) had t(11:14)mutation. The median age of the patients ranged from 64-66 years, and the median number of prior therapies was ≥2. The median dose of venetoclax ranged from 50 mg/day to 1200 mg/day in dose-escalation cohorts of clinical trials while in the retrospective study by Kambhampati, S et al., the median dose of venetoclax was 800 mg/day. The pooled overall response rate (ORR) for all patients who received venetoclax (n=466) was 57% (95% confidence interval (CI) 0.34-0.77, p<0.01; I2=95%), with the highest rates of 84% and 79% being reported from phase III trial using VEN + bortezomib (V) + dexamethasone (d) by Moreau et al.(2019), and VEN + carfilzomib + d in phase II clinical trial by Costa et al. (2018), respectively (Figure 1A). A minimum ORR of 21% was observed in a retrospective study by Siddiqi et al. (2019). Among 142 patients with positive t(11:14) in all studies, ORR was 56% (95% CI 0.44-0.68, p<0.11; I2=44%) (Figure 1B) with the highest rate of 100% being reported from Costa et al., though the number of patients was small. Among 362 patients with no t(11:14) ,ORR was 33% (95% CI 0.16-0.55, p<0.01: I2=89%), with the highest rate of 56% being reported from Moreau et al. in a phase III trial using VEN-Vd (Figure 1C). The highest median duration of response (DOR) (23.4 months) was reported with combination therapy of VEN-Vd. Two hundred and thirty eight (42%) of the patients discontinued VEN, among whom 132 (55%) were reported to have progressive disease. The most common grade≥3 hematological adverse effects were neutropenia, thrombocytopenia, and anemia. The gastrointestinal distress was the most common non-hematological toxicity reported in all the studies. Sixty four (33%) patients died on VEN arm vs. 24 (25%) on placebo in the BELLINI trial, the trend of OS is non-significantly better in VEN arm in t(11:14) while OS is non-significantly worse in non t(11:14) group. Conclusion: VEN is an effective treatment option for relapsed and refractory multiple myeloma patients with t(11:14) translocation. The overall response rate and the duration of response are better in patients with t(11:14). The CANOVA trial is ongoing now to better answer the debatable question of VEN efficacy in t(11;14) MM patients. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau. Fazal:Jansen: Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Gilead/Kite: Consultancy, Speakers Bureau; Glaxosmith Kline: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria, Speakers Bureau; Karyopham: Speakers Bureau; Celgene: Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharma: Consultancy, Speakers Bureau.

Early Response Using Serum Immunoglobulin Free Light Chain (sFLC) Measurement Predicts Response to Therapy in Waldenstrom Macroglobulinemia (WM)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3755-3755
Author(s):  
Xavier Leleu ◽  
Aldo M. Roccaro ◽  
Renee Leduc ◽  
Stephanie Poulain ◽  
Anne-Sophie Moreau ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Light Chain ◽  
Overall Response Rate ◽  
Response Rate ◽  
Early Response ◽  
Free Light Chain ◽  
Response To Therapy ◽  
Overall Response ◽  
M Spike

Abstract Background. Measurement of serum M-spike is used to determine response to therapy and treatment free survival in Waldenstrom Macroglobulinemia (WM). However, there are many limitations to the use of IgM M-spike, and new sensitive markers are needed to determine early response or progression in these patients. We have previously shown that involved serum free light chain (sFLC) accurately diagnosed patients with WM, and correlated with markers of poor prognosis, specifically beta- 2 microglobulin (B2M). In this study, we sought to determine the role of levels of involved in the response to therapy in patients with WM treated on clinical trials, and compare it to the response observed using the traditional M-spike measurement. Methods. We prospectively studied involved sFLC in 61 WM patients enrolled on 2 clinical trials, at diagnosis (N=8) and with relapse/refractory disease (N=53). Patients were treated on one of two clinical trials: either perifosine (N=30; given 150mg oral daily) or combination of bortezomib and rituximab (N=30; given IV bortezomib 1.6mg/m2 at days 1, 8, 15 q 28 days × 6 cycles and rituxan 375 mg/m2 at days 1, 8, 15, 22 on cycles 1 and 4). Response was assessed after cycle 2, confirmed on 2 consecutive measurements, and included minor response (MR), partial response (PR) or complete remission (CR). Results. The baseline characteristics of the patients were as follows: the median age was 65 years (44–83), male/female ratio 2.38, serum B2M 3.0mg/L (1.00–7.30), hemoglobin 11.0g/dL (7.00–14.90), platelet count 216 ×109/mm3 (46–563), serum M-spike 2.24g/L (0.41–4.62), and involved sFLC 95.2mg/L (4.92–868). The WM International staging system (WM-ISS) showed that 28% of patients had low ISS, 31% intermediate, and 41% high ISS scores. The overall response rate for the entire cohort was 62.3%, assessed by M-spike measurement (MR=23, PR=13, nCR=2). The overall response rate using involved sFLC level was 72.1% (MR=14, PR=29, and CR=1), (p<0.001). We then investigated the role of sFLC in predicting early response to therapy in patients treated with bortezomib and rituximab. We studied the level of sFLC weekly for the first month of therapy. Interestingly, early measurement of sFLC in the first month of therapy significantly predicted response; 93% of the patients who obtained at least an MR within the first 3 weeks of therapy by sFLC demonstrated a response on further follow up using serum M-spike (p=0.024). Conclusion. In this study, we identified that involved sFLC is a new and reliable marker for monitoring response to therapy in WM disease, especially to determine early response in these patients.

scholarly journals Encouraging Outcomes for Patients with Multiple Myeloma Treated in Early Phase Clinical Trials: A Single Centre and Meta-Analysis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5663-5663
Author(s):  
Anna Cowley ◽  
Jenny O'Nions ◽  
Hakim-Moulay Dehbi ◽  
Dima El-Sharkawi ◽  
William Townsend ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Overall Response Rate ◽  
Response Rate ◽  
Meta Analysis ◽  
Phase 1 ◽  
Rank Test ◽  
Overall Response ◽  
Trial Entry ◽  
Clinical Research Facility

Abstract Introduction:The overall survival (OS) for patients with multiple myeloma (MM) continues to improve with advances in therapies such as second-generation proteasome inhibitors (PI), immunomodulatory agents (IMiDs) and monoclonal antibodies. Advanced therapeutics (eg chimeric antigen receptor (CAR-T) cells), immunotherapies and 3rd generation agents are also under evaluation. Therefore, interest in Phase 1 clinical trials has increased as patients may benefit from exposure to a novel therapy. Also, increasingly data has been used to obtain breakthrough designation from regulatory authorities as part of accelerated approvals. However, these therapies have unproven efficacy, may cause potentially severe toxicities and patients may receive sub-optimal doses. We therefore analysed the outcomes of our patients and to complement this performed a meta-analysis of publicly available Phase I MM trials. Methods: This was a retrospective review of patients with MM enrolled onto phase I and I/II trials at the NIHR/UCLH Clinical Research Facility, London, UK. Patients received at least one dose of study drug, AEs were graded by CTCAE 4.0 and response criteria evaluated as per protocol. Individual-patient survival data were analysed using the Kaplan-Meier method and survival curves compared with the log-rank test. A meta-analysis using Medline, EMBASE and clinicaltrials.gov was performed to identify abstracts/papers reporting phase I trials from January 2016 to December 2017. Data was extracted by two independent reviewers using the same inclusion and exclusion criteria with significant overlap to ensure inter-observer consistency. Meta-analyses of Overall Response Rate (ORR) were performed using random-effect models. Results: 50 patients were enrolled onto 7 phase I or I/II clinical trials between March 2012 to June 2018 at the NIHR/UCLH Clinical Research Facility. 6 participated in 2 trials (each trial entry considered a separate event). IMPs were: monoclonal antibody (Mab) (1), HDAC inhibitor (1), immune-modulator (1), proteasome pathway inhibitors (2), kinase pathway inhibitor (1), epigenetic modifier (1). 3 trials were monotherapy and 4 as combinations. The median age was 54 years (33-73), 46% were female. The median time from diagnosis to trial entry was 58.5m (IQR 36-104.5) and median prior lines of therapy was 3 (0-7). Patients received a median of 10 cycles (1-34) over a median duration of 176 days (IQR 112-425). Study withdrawal was due to progressive disease (50%), autograft (16.1%), toxicity (12.5%), completion of study (12.5%) and other (3.6%) (Table 1). 30.4% of patients experienced G3-4 toxicity and 28.6% had dose interruptions of ≥7 days. The overall response rate (≥PR) was 55.3%, ≥VGPR: 26.7% (see Table 1).The median PFS was 14.2 m (95% CI:7.6-15.9) and OS 37.3m (95% CI:29.2-not reached) with a median follow-up of 26.5m. Median OS for those with < 4 prior lines was better (48.1m) vs those ≥ 4 prior lines (30.6m, p-value log-rank test=0.03). Those with adverse risk cytogenetics appeared to do worse vs standard risk: PFS 14.2 vs 7.6m (log rank not significant); OS 37.3 vs 30.6m (log rank: not significant). Most patients (80.3%) received further treatment after trial (12.5% received another trial, 46.4% chemotherapy; 21.4%: autograft). 8.9% were managed expectantly and 5.4% palliated. 110 trial abstracts & publications were selected for meta-analysis that included 3222 patients with a median age of 64 years (30-75), 42% female, median 4 prior lines. 64.6% of reports were combination studies. 17% targeted the proteasome, 17% were MAbs, 10.9% were epigenetic modifiers, 5.5% were cellular therapies and 24.6% were other small molecule inhibitors (Table 2). The overall response rate across all studies was 52.2% (95% CI 46-58.2). Higher responses were described for immunotherapy studies: BCMA CAR-T cells, 74.2% (95%CI 42.3- 91.8) and monoclonal antibodies, 64.2% (95% CI 56.2- 71.4). PFS and OS was not consistently reported across studies. Conclusions: Patients derive benefit from phase 1 trials with clinically significant responses reported from this single centre and meta-analysis. Additionally, most received further treatment after. The best responses were reported for immunotherapy studies. Despite this, in our data there was an overall trend for worse outcomes for adverse risk cytogenetics and for those treated later in their disease course. Disclosures Townsend: Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Yong:Takeda: Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau. Popat:Amgen: Honoraria.

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