Therapy of Acquired Aplastic Anemia (AA) with Rabbit Antithymocyte Globulin (rATG): A Retrospective Analysis by the Working Group on Non-Malignant Disorders of Hematopoiesis of the German Society of Hematology and Oncology (DGHO),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3434-3434
Author(s):  
Britta Höchsmann ◽  
Christiane Neher ◽  
Ulrich Germing ◽  
Janne Vehreschild ◽  
Juliane Eggermann ◽  
...  
Keyword(s):  
Data Collection ◽  
Aplastic Anemia ◽  
Research Funding ◽  
Response Rate ◽  
Retrospective Data ◽  
First Line ◽  
Off Label ◽  
Best Response ◽  
Retrospective Data Collection

Abstract Abstract 3434 Introduction: Several clinical trials established treatment with horse ATG (hATG) and cyclosporine A (CsA) as standard treatment of AA in patients (pts) who are not candidates for stem cell transplantation (SCT). In 2007 the hATG brand Lymphoglobulin® was withdrawn from the market. As the hATG brand ATGAM®, is not approved in Europe, hATG was replaced by rabbit ATG (rATG). Recently a large prospective randomized one-center study from NIH, USA comparing hATG ATGAM®/CsA and rATG Thymoglobulin®/CsA in untreated AA showed significantly lower response rates and survival with rATG. To obtain further information on rATG treatment in an unselected AA population, especially with a higher median of age and use of different rATG dosages we performed a retrospective data collection of first line rATG therapy on several centers. This shall reflect outcome after rATG in a real-world situation. Methods: Retrospective data collection and analysis of first line rATG treatment of AA after approval by Ethical Committee. Results: Up to now retrospective data of 64 pts from 18 centres in Germany were analysed. Characteristics of the pts: 30 male, 34 female; median age at time of therapy 54 years (6–80 years); 87.5% of pts had idiopathic AA. 51.6% of pts had severe AA, 32.8% very severe AA and 15.6% non-severe AA. Median granulocyte count was 0.3 G/l. 86% of the pts required red blood cell and 92% platelet transfusions. 56 of the evaluable pts received Thymoglobulin® and 5 pts Fresenius ATG S®. 52 of the 56 Thymoglobulin®-treated pts got this therapy in the years 2007–2011, i.e. not as deliberate primary choice of rATG but because hATG was no longer available. Median daily dose of Thymoglobulin® was 3.5 mg/kg (range from 2.5 – 3.75 mg/kg) for 5 days. 62 of 64 pts received additional immunosuppressive therapy with CsA and 19 of 64 pts received G-CSF. The median follow-up for surviving pts was 558.5 days (range, 78–3800 days). Response rates at time of best response of pts were CR in 10/58 pts (17%), PR in 18/58 pts (31%) and NR in 30/58 pts (52%) (only surviving patients with a minimum follow-up of 120 days were analyzed). Median interval to best response was 217 days. Response rate (PR+CR) was 16/33 (48.5%) in pts who received a Thymoglobulin® dose of > 3.5 –3.75 mg/kg/day versus only 4/14 (28.6%) group of 14 pts with a dose of > 2.5 to < 3.5 mg/kg/day (p=0.17; Fisher`s exact test). Relapses occurred in 3/28 responders and clonal evolution was observed in 3 pts (2 PNH, 1 MDS). Eighteen of 63 evaluable pts received allogenic SCT after ATG-therapy and were censored at the date of SCT. 23% of 44 pts without SCT died. In 6 of these 10 pts death was caused by infections. Other causes of death were bleeding, cardiac event, acute respiratory distress syndrome, adynamia. Overall probability of survival at 3 years was 75.8% (95% confidence interval (CI): 61.8 – 89.9%) and survival censored for SCT was 79.9% (CI: 66.0–92.8%). Survival was significantly better in responders (PR and CR) (94.1% at 3 years; CI: 82.9–100%) than in non-responders (58.0% at 3 years; CI 34.0 – 81.3%) (p=0.04; log-rank test). Adverse events were reported in 79.4% of 63 evaluable pts consisting of anaphylaxis/allergy in 27.3%, serum sickness in 12.7%, fever/chills in 34.5%, and bacterial/viral/fungal infections in 54.5% of pts. Conclusion: Response rate and survival after rATG+CsA in this retrospective analysis is lower than in historical controls (e.g. hATG+CsA treatment in previous controlled studies of the German AA Study Group and the EBMT AA Working Party; Frickhofen et al., Blood 2003; Tichelli et al., Blood 2011) and rate of (early) infections seem to be high. Our results are in accordance with recent reports from other groups. Additionally the results of this retrospective data analysis suggest a benefit for the patient group treated with a Thymoglobulin® dosage of > 3.5 –3.75 mg/kg/day compared to lower doses (< 3.5 mg/kg/day). There is growing evidence that best results in terms of response and survival are obtained by hATG-based immunosuppression. hATG can not be replaced by rATG without negative impact on patient outcome. There is need for action to achieve availability of hATG worldwide. If hATG is not available, treatment with rATG should be considered instead of no treatment or treatment with CsA alone since still about half of the patients respond to rATG. Disclosures: Höchsmann: Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: The use of the horse ATG ATGAM in Aplastic Anemia is off-label in Europe. At the moment no horse ATG with approval is available in Europe. Schrezenmeier:Genzyme: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Research Funding.

scholarly journals A Single-Center Retrospective Cohort Analysis of Venetoclax in Relapsed/Refractory Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5576-5576 ◽  
Author(s):  
Swetha Kambhampati ◽  
Derek Galligan ◽  
Guy Ledergor ◽  
Thomas G. Martin ◽  
Jeffrey Wolf ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Off Label Use ◽  
Final Dose ◽  
Advisory Committees ◽  
Off Label ◽  
Best Response

Background Despite recent advances, treatment of relapsed refractory multiple myeloma (RRMM) remains a challenge. Venetoclax, a BH3 mimetic, is an oral, specific, and potent small molecule inhibitor of BCL-2 that has been approved for treatment of 17p-deleted CLL and in combination with azacitidine or decitabine in AML patients >/= 75 years of age.Pre-clinical and clinical studies suggest that bcl-2 inhibition can induce MM cell death and may synergize with bortezomib and dexamethasone. Based on this, several prospective clinical trials of venetoclax in RRMM have been performed. However, clinical use of this targeted therapeutic for salvage therapy in RRMM has not been well described. Methods We performed a single-center, retrospective chart review of all patients with RRMM diagnosed after January 1, 2009 who were treated with off-label use of venetoclax. The goal of this study was to describe the clinical characteristics of these patients, assess the response to salvage treatment with venetoclax as determined by the International Myeloma Working Group (IMWG) criteria, and assess the toxicities during salvage treatment with venetoclax in an academic practice setting. Results 43 patients were identified. Median number of lines of prior therapy was 7 (range 2-13). 12 patients had documented high risk cytogenetics, defined as the presence of a 17p deletion, t(14;16), t(14;20), t(4,14), gain (1q), or nonhyperdiploidy. Of the 36 patients with cytogenetics/FISH available, 8 had t(11;14). 34 patients were refractory to bortezomib. 40 patients had progressed after carfilzomib, 36 after pomalidomide, and 41 after anti-CD38 antibody therapy. 39 patients were treated with venetoclax in combination with a proteasome inhibitor (bortezomib (n=36); carfilzomib (n=3)). 23 patients were treated with venetoclax, proteasome inhibitor, and dexamethasone. Patients were started at 400 mg daily for 7 days then increased to the median dose of 800mg daily (11 received < 800mg/daily as a final dose and one received >800 mg/daily as final dose). Overall patients were on treatment for a median of 67 days (range 2-855). 2 patients received intermittent venetoclax therapy, defined as being off venetoclax for at least 3 months before restarting. Best response by IMWG criteria include; CR 5%( 2/43), VGPR 12% (5/43) and PR 16% (7/43) for an overall response rate of 33% (14/43). In addition, MR was seen in 5% (2/43) and stable disease in 9% (4/43). Fifty-one percent (22/43) had progressive disease (PD). Out of the 8 patients who had t(11;14), best responses were: 2 VGPR, 2 PR, 1 SD, and 3 PD for a response rate of 50% (4/8) in this subgroup. Median time to best response for all responding patients was 90 days (range 15-305) and median duration of response was 206 days (range 28-820). At time of data collection, median follow-up time from venetoclax treatment initiation was 192 days (range 8-1058). Four patients have not progressed and remain on therapy, 23 patients remain alive, and 4 patients have been lost to follow-up for over 6 months. The most common treatment related AEs were cytopenias including leukopenia in 26 /43 (60%) patients, neutropenia in 19/43 (44%) patients, and thrombocytopenia in 22/43 (51%) patients. Non-hematologic toxicities included diarrhea in 12/43 (30%) patients, nausea/vomiting in 15/43 (35%) patients, infections in 11/43 (26%) patients, and fatigue in 23/43 (53%) patients. 8/43 (19%) patients required dose reduction, 7/43 (16%) patients required temporary discontinuation of treatment, and 4/43 (9%) patients required permanent discontinuation due to treatment related AEs. 38/43 (88%) patients had any grade treatment related AEs, 27/43 (63%) patients had grade >/= 3 AEs and 2/43 (5%) patients had treatment related SAEs. One patient had a treatment related death from an infectious complication (CMV pneumonitis). Conclusions Venetoclax is an active and well-tolerated agent in relapsed multiple myeloma. Furthermore, it is easily administered in the outpatient setting. Additional areas of research with this therapy include understanding the importance of t(11:14) for response and selecting the best anti-MM partner for combination therapy. Disclosures Ledergor: Venetoclax: Other: off-label use; Immunai: Consultancy. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Wolf:Takeda: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Wong:Celgene Corporation: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Fortis: Research Funding; Juno: Research Funding. Shah:Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment; Indapta Therapeutics: Equity Ownership; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This study is looking at the safety and efficacy of venetoclax in relapsed refractory myeloma patients who are treated off-label since venetoclax is not currently approved for multiple myeloma

scholarly journals Real-World Effectiveness and Safety of Eltrombopag in Patients with Aplastic Anemia: A Chinese Nationwide Survey

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5020-5020
Author(s):  
Wenrui Yang ◽  
Bing Han ◽  
Hong Chang ◽  
Bingyi Wu ◽  
Fankai Meng ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Real World ◽  
Overall Response Rate ◽  
Response Rate ◽  
Line Treatment ◽  
First Line ◽  
Overall Response ◽  
Treatment Naïve ◽  
First Line Treatment

Immunosuppressive therapy (IST) based on antithymoglobin (ATG) and cyclosporin (CsA) is the first-line treatment for severe aplastic anemia (SAA) patients who are unfit for transplantation,and the overall response rate (ORR) is about 70%.The utility of eltrombopag (EPAG),a TPO receptor agonist, achieved robust hematologic response in refractory and treatment-naïve SAA patients in clinical trials and some other studies. However, only a few data came from Asia countries where higher incidence of AA has been reported. A retrospective study on the use of EPAG in AA was conducted in mainland China. Aplastic anemia (transfusion dependent non-severe, severe, and very severe) patients who started eltrombopag before Feb 2019 and continued for at least 3 months either as first-line treatment or as rescue treatment, were enrolled. The maximum daily dosage of EPAG used continuously for at least 2 weeks is defined as the stable dosage. Response criteria were referred to that used in previous reports (Townsley DM, NEJM 2017; BCSH, BJH 2016). Fifty-six patients from eleven centers were enrolled in this study, including 26 males and 30 females at the median age of 39 (7-80) years. All patients were transfusion-dependent by the time of EPAG administration, and there were 14 VSAA, 24 SAA and 18 transfusion dependent non-severe aplastic anemia (TD-NSAA). Nineteen treatment-naïve patients received EPAG and IST (ATG+CsA, n=10; CsA/CsA+androgen, n=9) as first-line treatment. Thirty-seven patients were refractory to IST. Eltrombopag was administered at a median dose of 75 (25-150) mg per day for 7 (3-31) month. The median follow-up time was 9 (3-40) months. The overall response rate in patients receiving EPAG as first-line therapy was 78.9% (15/19), and most patients achieved complete response (CR) (10/15). Among the 10 patients receiving ATG+CsA, 6 patients achieved hematologic response (HR) at 3 months post-treatment, including 3 CR. Six patients were diagnosed as VSAA and three achieved HR. For the 9 patients treated with CsA/CsA+androgen, 8 achieved HR (88.9%) and 4 were CR (44.4%) at 3 months. By last follow-up, the cumulative HR rate was 70% in ATG+CsA group and 89% in CsA/CsA+ androgen group. Among the 14 responders, 11 patients receiving EPAG at a stable dosage ≤75mg/d and achieved HR at 3 months. The overall response rate in IST-refractory patients was 46% (17/37), with trilineage response in 27% patients at 3 months. For the 18 ATG+CsA refractory SAA patients,trilineage HR occurred in 4 patients (22.2%, 4/18), bi-lineage HR in one patient and single lineage HR in one patient. Thus, the total HR was 33.3% (6/18) at 3 months and increased to 44% (8/18) by last follow-up. Among the 19 CsA/CsA+ androgen refractory patients, 6 (31.5%, 6/19) achieved trilineage HR, one achieved bi-lineage HR and 4 achieved single lineage response. Total HR rate was 57.9% (11/19) at 3 months after EPAG initiation and 68% (13/19) by last follow-up, including 9 patients with trilineage HR. Among 17 responders, 13 received a stable EPAG dose of≤75mg/d. Most patients tolerated EPAG well. Adverse events occurred in 29 patients (52%) and most were mild to moderate, including gastrointestinal symptom (n=15, e.g. abdominal pain, nausea), impaired liver function (n=5), skin changes (n=7, e.g. skin pruritus and rash) and musculoskeletal pain (n=6), and venous thrombus (n=2). Eltrombopag dosage was reduced in 2 patients due to severe digestive symptoms at 100 mg/d and discontinued in one patient who suffered from upper limb venous thrombus. In conclusion, EPAG is effective and safe in treating Chinese AA patients at a daily dose of 75mg and less. The real-world result of EPAG in Chinese patients is similar to those reported in Western countries. Disclosures No relevant conflicts of interest to declare.

Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2310-2310 ◽  
Author(s):  
Christina S Lee ◽  
Allison Imahiyerobo ◽  
Micha Thompson ◽  
Marina Izak Karaev ◽  
Waleed Ghanima ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Response Rate ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Best Response

Abstract Background Adults with newly-diagnosed and persistent ITP usually respond to steroid based treatments such as prednisone but relapse with tapering. One 4-day cycle of Dexamethasone (dex) at 40 mg/day in newly diagnosed ITP resulted in a lasting effect in 50% of patients (pts) in 1 study. An Italian study showed that 3 cycles of dex are better than 1 cycle. Approximately 50% of pts with chronic ITP experience a complete or partial response (CR & PR) to rituximab, yet only 20% of pts have a lasting, unmaintained response after 3 years. Mechanistically, rituximab (which depletes B cells but not plasma cells) and dexamethasone (which may be the most potent anti-plasma cell agent) are a logical combination in treatment of antibody-mediated diseases such as ITP. In 2 studies of newly-diagnosed pts, dex 40mg/day x 4 followed by rituximab was more effective than dex alone (one study added more dex half way through). In our pilot study, pts at Weill Cornell Medical College (WCMC) with all stages of ITP were treated with a combination of rituximab (R) and usually 3 cycles of dex. The outcome of this combination was retrospectively analyzed. Methods Combination of standard-dose rituximab (weekly x 4) and usually 3 4-day cycles of 28mg/m2 (max. 40mg) dex at 2-week intervals (R+3Dex) was explored in 67 pediatric and adult pts with ITP at WCMC. Patients were monitored with CBCs obtained weekly and then at less frequent intervals if a response was achieved. Best response (after 8 weeks to avoid transient effects of dex) was determined. Patients were categorized as CR (platelet count≥100x109/L) or PR (50-100x109/L). Relapse was defined as either two consecutive platelet counts <50x109/L and/or need for additional therapy. The duration of response was calculated from date of first rituximab administration to relapse or latest follow-up as of July 31st 2013. Results Overall, 50 of 67 pts treated with R+3Dex achieved a best response of either a CR (n=43) or a PR (n=7) at 8 weeks or later from start of therapy for an overall response rate of 75%. Seventy-three percent of pts received R+3Dex; variations were primarily in the timing and amount of dex given. Fifteen responders, 9 CRs and 6 PRs, relapsed at a median of 9 months. Seventy percent of the responders (or 52% of all pts treated) maintain a continuous response with platelet counts ≥ 50 x 109/L as of their last visit at a median f/u of 20 months. Kaplan Meier Analysis estimates 44% of all pts treated (Figure) and 59% of responders (Figure) maintained a best response without relapse at 67 months after initiating treatment. If only those with ITP ≤ 24 months are included, the estimated long term response rate is 59% (p=0.0017) versus only 19% for those with a duration of ITP > 24 months (Figure). Of 36 responding children and adults who had ITP ≤ 24 months, 29 continued to respond as of last follow up. Adults initially responded better than children (p=0.0019) but the long-term responses were not different (Figure). Pts achieving a CR had longer response than those achieving a PR. Adverse events related to R+Dex were usually mild-moderate, although 3 pts had serum sickness and 2 had transient colitis. IgG levels fell to below the lower limit of normal for age in 14 of 67 pts, 10 of whom had their IgG levels return to normal. In 6 of 14, IgG levels were < 400 mg/dl, some of whom received IVIG. Fifteen patients had serial BK/JC levels without ever detecting virus. Conclusions R+3Dex provides clearly superior results to rituximab alone. Notably, there was a 75% response rate overall (50/67 pts) compared to 50% with R alone. The 5 year response rate was almost 50% of all patients and 3/5 of responders. In patients who had had ITP for ≤ 2 years, the response is comparable to what has been reported with splenectomy. Specifically the results in the ≤ 2 year group suggest that R+3Dex is an effective way to induce indefinitely normal platelet counts in pts with a “short” duration of ITP. R+3Dex was tolerable although patients had difficulty with 3 cycles of dex. The 21% rate of hypogammaglobulinemia, higher than that seen with R alone, is also evidence of the mechanism of R+3Dex affecting both B cells and plasma cells. The lasting, long-lived, unmaintained responses observed in this study suggest that this combination therapeutic strategy should be further tested in a controlled trial in patients with newly diagnosed, persistent, and early chronic ITP, whether or not they have been previously treated with other agents. Disclosures: Bussel: Sysmex: Research Funding; Cangene: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Patterns of disease and severity in bipolar disorder: Retrospective data from a large multinational longitudinal study (WAVE-bd)

2011 ◽  
Vol 26 (S2) ◽  
pp. 258-258
Author(s):  
E. Vieta ◽  
M.L. Figueira ◽  
F. Bellivier ◽  
D. Souery ◽  
E. Blasco-Colmenares ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Longitudinal Study ◽  
Data Collection ◽  
Total Population ◽  
Mood State ◽  
Disease Status ◽  
Retrospective Data ◽  
Retrospective Data Collection ◽  
Insight Into

IntroductionThe Wide AmbispectiVE study of the clinical management and burden of bipolar disorder (BD) (WAVE-bd; NCT01062607) is ongoing to address limitations of longitudinal BD studies to-date focused on single disease phases or treatment.Aim/ObjectiveTo describe baseline bipolar mood state and severity in a cohort of patients with BD.MethodsMultinational, multicentre, non-interventional, longitudinal study of patients diagnosed with BD-I or BD-II with ≥1 mood event in the preceding 12 months (retrospective data collection from index mood event to enrolment, followed by 9-14 months’ prospective follow-up). Site and patient selection provided a sample representative of bipolar populations. The study includes descriptive analyses of demographics, diagnosis and medical history.Results2880 patients (mean age 46.5 years [SD: 13.3]; 62.0% female) were recruited March to September 2010: 1989 (69.1%) BD-I and 891 (30.9%) BD-II. Time (years) from first symptoms to diagnosis was 2.9 [SD: 6.6] (BD-I) and 4.4 [SD: 8.0] (BD-II). Of the total population, 20.8% lived alone (13.9% BD-I, 6.9% BD-II), 36.7% were employed (24.0% BD-I, 12.7% BD-II) and 13.3% unemployed (9.5% BD-I, 3.8% BD-II). Disease status at inclusion (BD-I, BD-II, respectively [mild, moderate, severe]) included hypomania (7.9% [67.7%, 31.0%, 1.3%], 6.5% [70.7%, 29.3%, 0%]), mania (7.1% [26.1%, 47.2%, 26.8%], 0%), euthymia (58.6%, 60.3%), depression (19.7% [38.8%, 47.7%, 13.5%], 31.1% [41.2%, 46.9%, 11.9%]) and mixed (5.7% [30.1%, 46.9%, 23.0%], 0%).ConclusionsThis ongoing study provides detailed insight into a large BD population, showing the majority with euthymia and an important proportion with depression both in BD-I and BD-II patients.

scholarly journals Eltrombopag for the Treatment of Aplastic Anemia in Europe

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1304-1304
Author(s):  
Beatrice Drexler ◽  
Matyas Ecsedi ◽  
Etienne Lengline ◽  
Cora Knol ◽  
Paul Bosman ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Combination Therapy ◽  
Aplastic Anemia ◽  
Research Funding ◽  
Strong Predictor ◽  
Model Combination ◽  
First Line ◽  
Transfusion Independence ◽  
Previous Therapy

Abstract Background Eltrombopag (ELT), an oral thrombopoetin-receptor agonist, has recently emerged as an encouraging and promising agent in acquired aplastic anemia. It has shown efficacy within clinical trials exploring its role in the first - line therapy in addition to standard immunosuppressive therapy as well as in the refractory setting (Townsley et al, NEJM 2017; Olnes et al, NEJM 2012). How ELT is used outside of clinical trials in the real-world setting after approval in Europe and results of this treatment are not known. Methods We conducted a retrospective survey on the use of thrombopoietin agonists for AA among EBMT member centers. Thirty-one centers provided data on 137 patients treated between 11/2011 to 10/2017. We merged our dataset with the cohort from the French Reference Center for Aplastic Anemia (Lengline et al., Haematologica 2017). Here we report the outcome 165 patients having received at least 30 days ELT and having a follow up of at least 2 months, patients with a shorter duration of treatment or follow up, as well as three patients receiving romiplostim were excluded. The following response criteria were used: complete response (CR) defined as hemoglobin >100g/l, neutrophil count >1.5 x106/ml and platelet count >100 x106/ml; partial response (PR) corresponding to transfusion independence and minimal response (MR) to some improvement in one or more lineage but not fulfilling the criteria of PR. Results The median follow-up was 14 months (IQR 7-24 months). Before starting ELT, AA was classified as severe or very severe in 68.6% respectively 13.8 % of patients. At last follow-up 87.3% of patients were alive, of those 47.2% continued ELT (maximum median dose: 150mg/day). A minority of the patients (n=22, 13.3 %) received ELT upfront, i.e. within 60 days following initiation of first-line treatment, whereas most patients were treated with ELT as a rescue treatment either for insufficient response to previous treatment(s) (n= 122, 73.9%) or relapse (n=21, 12.7%). ELT was applied both as monotherapy (n= 56, 33.9%) and in combination with IS (ELT+ CYA: n= 87/52.7%, ELT+CYA/ATG: n=20/12.1% , Fig. 1 a). Importantly, 69.7% of patients received ELT outside the FDA/EMA label, either in the first line setting or as part of a combination therapy. The reported overall response rate in our cohort was 64.6 %, with 19.5 % CR, 28% PR and 17.1% minimal response. Best response was achieved in median after 252 days (95% CI 181-366 days). In univariate models, we could not identify any baseline characteristics associated with better response in the whole cohort, although severity of AA before start of ELT was significantly associated with death without a response (p= 0.024). In the multivariate model, combination therapy was a predictor (p=0.049) of response, with a hazard ratio for response of 3.32 for the ELT/CYA/ATG group compared to ELT monotherapy (p=0.008). In the subgroup of patients with previous therapy, response to previous therapy was a strong predictor of response (HR 2.2, p<0.001), whereas previous exposure to ATG, interval from diagnosis or interval from last treatment were not significantly associated with response. The median survival was not reached in our cohort, the 1-year survival from start of ELT was 87.9%. Twenty-one (12.7 %) patients died during follow-up, seven (33%) of these had undergone allo-HSCT and in six (28.6%) deaths were classified as HSCT-related. In univariate and multivariate analysis, AA severity at ELT start and response to ELT were associated with OS. Interestingly, the better survival of patients responding to ELT was driven by CR and PR, as patients with a minimal response to ELT had the same survival as patients without a response (Fig 1b.). Adverse events (AEs) were reported in 30.6% of patients, although severe (grade III-IV) AEs were rare (8.9%) and ELT was stopped only in 2 patients due to AEs. Cytogenetic abnormalities were assessed systematically only at diagnosis and showed a normal karyotype in 70.9% of patients and an abnormal karyotype in 11 cases (7.9%) including 3 cases of trisomy 8 and 1 case of inv(3;3q26). Only 2 cases of MDS diagnosed 2 and 5.5 months after ELT start were reported. Conclusions ELT is used widely in Europe to treat AA patients, mostly in the relapsed/refractory setting. Whereas patients achieving at least transfusion independence with ELT have an excellent survival, the outcome of patients refractory to ELT remain unsatisfactory. Disclosures Cortelezzi: janssen: Consultancy; abbvie: Consultancy; novartis: Consultancy; roche: Consultancy. Gaidano:Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Morphosys: Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Peffault De Latour:Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding.

Impact Of FISH Abnormalities On Response To Lenalidomide In Patients With Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3210-3210 ◽  
Author(s):  
Shivlal Pandey ◽  
S. Vincent Rajkumar ◽  
Prashant Kapoor ◽  
Rhett P Ketterling ◽  
Martha Q Lacy ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Response Rate ◽  
Molecular Subtype ◽  
Wide Spectrum ◽  
Current Data ◽  
Genetic Abnormality ◽  
Best Response ◽  
Lower Response Rate

Abstract Background Multiple myeloma (MM) is a heterogeneous disease with variable responses to different therapeutic regimens and wide spectrum of survival. Much of the heterogeneity in the outcomes appear to be related to the underlying primary genetic abnormality, which in the majority of patients consist of either translocations involving the heavy chain region on chromosome 14 (IgH translocation) or trisomies of odd numbered chromosomes. We hypothesized that the response to lenalidomide (Len) therapy would vary significantly based on the underlying molecular subtype of myeloma. Methods We examined a cohort of 518 patients with available FISH results, who had been exposed to Len-based regimens. Medical records were reviewed and data regarding the best response and time to next therapy following treatment with Len-based regimen was obtained. Data from the first use of Len was collected. Len was given in combination with dexamethasone (Dex) with or without alkylators in combination. Patients who received a combination of IMiD and bortezomib as their first exposure to Len were excluded. Patients were grouped according to whether FISH showed a trisomy or an IgH translocation. Results The median age was 62 (28-91), and the median estimated follow up from diagnosis was 52 months (95% CI; 50, 54) with 359 (69%) alive at the time of analysis. An IgH translocation was seen in 129 (30%) of patients and a trisomy in 268 (62%) of patients. IgH translocations included t(11;14) in 92 (18%), t(4;14) in 45 (9%), t(14;16) in 21 (4%); 34 (8%) had both translocations and trisomies. For the current analysis, we included only patients with either a translocation or trisomy (n=397) excluding those with neither or both of the abnormalities. The median time to start of Len from diagnosis was 0 months (range, 0-64). A PR or better was seen in 80% of patients with trisomy compared with 63% of the patients with translocation (p<0.001); and the response rate was similar among the different translocation types. The median TTNT was 28 months among trisomy pts compared with 17 months for translocated patients (p<0.001, figure). The median TTNT was similar across the different types of translocations (Figure). Among this group, 134 patients proceeded to an autologous SCT after Len induction. Among these patients, no difference was seen in terms of TTNT (29 months for patients with translocation vs. 28 months for those with trisomy (p=0.8). Finally, the TTNT was no different if Len was used with Dex or as part of an alkylator combination. Conclusion The current data supports the hypothesis that the underlying primary genetic abnormality can affect the response to a particular therapy. In this study response to Len was significantly higher in myeloma with trisomy compared with IgH translocated myeloma. Although the routine use of combinations of a proteasome inhibitor plus Len in frontline therapy in all patients with myeloma may overcome the lower response rate in IgH translocated patients, in most countries such a regimen is not approved or economically feasible. Based on our study, newly diagnosed patients with evidence of trisomy on FISH could be considered for a Len-based regimen such as lenalidomide-low dose dexamethasone. Additional studies should examine if use of bortezomib in patients with IgH translocation will lead to better outcomes compared with Len based therapies. Disclosures: Lacy: Celgene Corporation: Research Funding. Gertz:Celgene: Honoraria. Dispenzieri:Celgene, Millenium, Jansenn, Pfizer: Research Funding. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Novartis: Research Funding; Genzyme: Research Funding.

In Multiple Myeloma Progression Free and Overall Survival in the Relapsed Setting Remains Poor with Early Exposure to Novel Agents: Experience from a Real-World Cohort

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4261-4261 ◽  
Author(s):  
Christopher P. Venner ◽  
Nizar J Bahlis ◽  
Paola Neri ◽  
Irwindeep Sandhu ◽  
Peter Duggan ◽  
...  
Keyword(s):  
Research Funding ◽  
Response Rate ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Third Line Therapy ◽  
First Relapse ◽  
Third Line ◽  
Line Of Therapy

Abstract Introduction: With the widespread adoption of novel agents (NA) in all lines of therapy patients are being exposed to both proteosome inhibitors (PIs) and immunomodulatory drugs (IMiDs) early in their treatment course. This has lead to marked improvements in survival in the frontline setting. Data is limited with respect to patient outcomes after exposure to both these drug classes in the real world setting. Here we present our experience examining outcomes after each line of therapy whereby bortezomib-based induction followed by lenalidomide-based therapy at first relapse has become the standard of care. We further explored the outcomes of patients who were exposed to both active classes of drugs within their first 2 lines of therapy. Patients and methods: This series includes patients seen through the provincial Alberta Myeloma and Dysproteinemia Program in Canada. Only patients treated between 2005-2013 were included to allow at least 2 years of follow-up beyond first line therapy. Only those treated with a NA-containing regimen as part of their first line treatment were examined. The cohort was split based on eligibility for autologous stem cell transplant (ASCT). Double exposed patients were those who had been treated with, but were not necessarily refractory to both an IMiD and PI within the first 2 lines of treatment. Outcomes were measured after first, second and third line therapy. Survival outcomes were measured in months (m). OS was measured from the start of each line of therapy until death or last follow-up. PFS was from the start of each line of therapy to relapse, death or last follow-up. Response was measured as per the most recent International Myeloma Working Group criteria. Near complete response (nCR) was used when the monoclonal protein disappeared on protein electrophoresis but was not confirmed by immunofixation. Results: Two hundred forty eight patients had received upfront therapy (non-ASCT = 113 and ASCT = 135). One hundred twenty seven had received second line therapy (non-ASCT = 62 and ASCT = 65). Sixty-four had received third line therapy (non-ASCT = 31 and ASCT = 33). The median OS and PFS after each line of therapy are shown in table 1. After first line therapy the OS (p < 0.001) and PFS (p< 0.001) were significantly better in the ASCT cohort. There were no significant differences in survival outcomes based on transplant eligibility in subsequent lines of therapy (figure 1A and B). The overall response rate to third line therapy was 45% (VGPR = 14% and nCR = 7%) for non-ASCT patients and 52% (VGPR = 15% and nCR = 6%) for ASCT patients. Fifty-five percent of non-ASCT patients failed to respond during third line therapy (34% with progressive (PD) and 21% with stable disease (SD)). Forty-eight percent of ASCT patients failed to respond (PD = 27% and SD = 21%). Forty-seven patients were double exposed within the first 2 lines of therapy (non-ASCT = 26 and ASCT = 21). In this cohort, the OS and PFS after double exposure (i.e. third line therapy) was 15m and 5m respectively with no significant difference based transplant eligibility (figure 1C and D). The response rate to third line therapy was 46% (VGPR = 17% and nCR = 8%) for ASCT patients and 43% (VGPR = 14% and nCR = 5%) for non-ASCT patients. Fifty-five percent failed to respond (PD = 38% and SD = 17%) in the non-ASCT group. Fifty-seven percent failed to respond (PD = 38% and SD = 19%) in the ASCT group. Summary: The introduction of NAs earlier in the management of patients with myeloma has improved OS. This is driven by improvements in PFS to frontline therapy and after first relapse. However, with current therapeutic approaches patients will be exposed to both IMiDs and PIs much earlier in their disease. In many jurisdictions, the limited treatment options in third line and beyond, especially in double exposed patients, poses a significant therapeutic challenge. Durable responses are limited in this setting with most patients relapsing after only 6 months. In addition, approximately a third of patients have overtly progressive disease. Interestingly, front-line ASCT eligibility had no impact on outcome with subsequent relapses, emphasizing the fact that ASCT only improves the outcome for the line in which it is employed. Further study regarding resistant mechanism and clonal evolution after exposure to both IMiDs and PIs will be important in developing rationally designed therapeutic regimens for this population. Disclosures Venner: J&J: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding. Off Label Use: Some patients in this series will have received frontline lenalidomide which is not yet an approved indication for this drug in Canada.. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Johnson & Johnson: Research Funding. Neri:Celgene: Research Funding. Sandhu:Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Duggan:Jansen: Honoraria; Celgene: Honoraria. Belch:Janssen-Cilag: Consultancy. Jimenez-Zepeda:Celgene: Honoraria; J&J: Honoraria; Amgen: Honoraria.

Nationwide Survey on the Use of Eltrombopag in Patients with Severe Aplastic Anemia: Report on Behalf of the French Reference Center for Aplastic Anemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2684-2684 ◽  
Author(s):  
Etienne Lengline ◽  
Bernard Drenou ◽  
Pierre Peterlin ◽  
Olivier Tournilhac ◽  
Julie Abraham ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Dose Reduction ◽  
Research Funding ◽  
Real Life ◽  
Dyskeratosis Congenita ◽  
First Line ◽  
Reference Center ◽  
Transfusion Independence ◽  
Line Therapy

Abstract BACKGROUND: Few therapeutic options are currently available for patients (pts) with severe aplastic anemia (SAA) refractory to antithymocyte globulin (ATG) plus ciclosporine (CsA) and not eligible for allogeneic stem cell transplantation. It has recently been reported that eltrombopag (ELT), a TPO receptor agonist, is efficient to improve tri-lineage blood counts in this setting. However, real-life use of this drug is still largely unknown. In pts with SAA refractory to ATG, physicians can accede to ELT in France through a compassionate use program. We took advantage of this program to assess the efficacy and safety of ELT in SAA pts. PATIENTS AND METHODS: The French National Reference Center for Aplastic Anemia conducted this study in pts who received ELT for the treatment of SAA. Latest guidelines were used to define disease severity, treatment indication, and response rates (Marsh et al, BJH 2014). The diagnosis of SAA was confirmed by marrow biopsy and Camita criteria for all pts. Pts were eligible if they received at least 2 months of ELT alone or in combination with other treatment in case of relapsed/refractory disease or front-line therapy for pts not eligible to the association of ATG and CsA. Pts were identified through a national e-mailing on behalf of the French reference center for SAA and the French Society of Hematology. All data presented here were collected at the reference date of June 26th, 2016. The study was conducted according to Helsinki's Declaration. RESULTS: Forty-six pts (male, 54%) who received ELT between July 2012 and February 2016 were identified in 17 French centers. Indications for ELT were relapsed/refractory SAA in 35 pts (76%) after 1 (49%), 2 (29%) or 3 (9%) courses of CsA+ATG. Eleven pts considered unfit for ATG also received the drug as first line therapy. The characteristics of the pts according to ELT indications are shown in Table 1. Median age at time of ELT initiation was 61 years [IQR 40 to 70]. 44 pts had idiopathic SAA including 17 (37%) with a detectable PNH clone (median size 7%). Two pts (4%) with dyskeratosis congenita also received ELT. ELT was introduced 17 months [8-50] after the initial diagnosis of SAA and with a median of 6 months [3-14] after the last course of immunosuppressive therapy. The maximal dose was 150 mg/day [100-150] for a median duration time of 6 months [4-12]. At last follow-up 22(48%) pts were still on treatment, 4(9%) pts stopped because of good hematological response, 1(2%) and 15(33%) after limited toxicity and failure to improve hematological status. Before treatment, median neutrophils count was 790/mm3 [500-1215] and pts received a median number of 4 red blood cells packs [2-4] and 3 platelets apheresis units [2-4] every month. Neutrophils counts were 765 [515-1475], 1100 [600-1800], 1200 [670-1915] and 1200/mm3 [757-2300] at 1, 3, 6 months and at last follow-up respectively. The rates of transfusion independence for both red cells and platelets were 7%, 33%, 46% and 46% at 1, 3, 6 months and at last follow-up. In pts achieving transfusion independence, hemoglobin and platelets level improved of 3 gr/dL [1.4, 4.5] and 42 G/L [11, 100], respectively. The rate of transfusion independence was not different among first line and refractory pts (p=0,5). We did not observe any response in the 2 patients with dyskeratosis congenita. No factor associated with hematological response to ELT was identified. Liver toxicity (cytolysis) occurred in 11 pts (1 grade 3 that required withdrawal of the treatment and 10 grade 1 who responded to dose reduction). 2 pts had a grade 2 intestinal toxicity which improved after dose reduction. Other side effects where related to SAA (28% infections, 13% hemorrhages). Bone marrow karyotype analysis after ELT was done in twelve pts (26%) (median time 14 months [5-22] after ELT start). In 10 pts the karyotype was normal, in one, trisomy 8 was identified (already seen at SAA diagnosis), and karyotype was a failure in 1 pt. CONCLUSION: We report here the first real-life multicenter study about the use of ELT in SAA. In a particular severe pts population with no other treatment possibility, we confirm a 40% rate of hematological improvement with transfusion independence. Some of the pts who were not eligible to ATG plus CsA (comorbidities) also received ELT first line with similar response rates. Elderly pts unfit for ATG may thus benefit from this treatment which at the best should be given through prospective clinical trials. Table 1 Table 1. Disclosures Ades: Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Terriou:Novartis: Consultancy; amgen: Consultancy. Peffault de Latour:Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

scholarly journals Seven Year Follow up and Comparison of Dosing Strategies from the Pivotal Phase II Clinical Trial of Lenalidomide Plus Rituximab (R2) in Previously Untreated Follicular Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1594-1594
Author(s):  
Nathan H. Fowler ◽  
Preetesh Jain ◽  
Loretta J. Nastoupil ◽  
F. B. Hagemeister ◽  
Sheryl G Forbes ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Best Response

Abstract Introduction: We have previously reported the results of cohort A from a single arm, phase II clinical trial of lenalidomide with rituximab (R2) as frontline treatment for patients with previously untreated follicular lymphoma (FL), Fowler N et al Lancet Oncology 2014. Recent randomized studies (RELEVANCE) did not demonstrate superiority of either R2 or R-Chemo in untreated, high GELF FL, but follow up is short. We now report outcomes of an additional extended dosing cohort (12 mo of R2) and the long term follow up of the both dosing schedules in untreated FL. Methods: A total of 154 pts were included in the original clinical trial (FL, n=80; MZL, n=31; SLL, n=43). Characteristics were collected at the time of starting R2 treatment. Patients received lenalidomide 20 mg/day on days 1-21 of each 28-day cycle and rituximab 375 mg/m2 on day 1 of each cycle (6 cycles; schedule A) and lenalidomide 20 mg/day on days 1-21 of each 28-day cycle for cycles 1-6 then lenalidomide 10 mg/day on days 2-22 for cycles 7-12 with rituximab 375mg/m2 IV x1 weekly on cycle 1 and day 1 of every subsequent cycle (12 cycles; schedule B). Responders continued treatment for at least 6 but up to 12 cycles. The primary endpoint was overall response rate (ORR); secondary endpoints were complete and partial response (CR, PR), safety, and progression free survival (PFS). PFS was defined as time from starting treatment to disease progression or death, event free survival included time from starting treatment to discontinuation due to any cause and overall survival (OS) was defined from the time of initial diagnosis of FL to death/last follow up. Results: Eighty pts with FL were enrolled in study and followed a median of 86 months. Median age was 58 years (range, 29 to 84); 50% were males. 61% pts had grade 1 FL and 39% had grade 2 FL. Schedule A was administered in 50 pts and schedule B in 30 pts. Seventy seven pts were evaluable for initial response assessment and 76 (98%) responded. The best response rate was 95% (87% CR/CRu). At the time of last follow up, 23 patients experienced disease progression, 13 lost to follow up (all had CR as best response and had completed tx), 4 came off study due to pt choice/financial and 4 due to intolerance (2 arterio-thrombotic event, 1 respiratory failure, 1 intolerance) during therapy. After a median follow up of 86 mo, 23 pts (29%) progressed, 5 yr PFS was 75%. Five yr PFS was 70% and 82% for pts on cohort A vs B respectively (P=.30). Overall, 2 pts died, with a 5 year survival 97%, Figure-1 (A-B). The median event free survival in pts with FL was 85 months with a 5 year EFS of 59%. Subgroup analysis showed no statistically significant difference in PFS with FLIPI score, bulky disease and by initial bone marrow involvement. Pts who achieved CR had significantly longer PFS compared to those who did not achieve CR (not reached vs 78 months; p = 0.004), however the OS was not significantly different between the two groups Figure-1 (C-F). Grade 3 or 4 hematologic AEs included neutropenia (28%), thrombocytopenia (3%), and no anemia. Count recovery occurred in all pts with follow up and/or dose modification. Nine pts developed second primary cancers, including one melanoma in-situ, 3 localized skin cancers, and 2 secondary hematologic malignancies. Conclusions: A combination of lenalidomide with rituximab produced durable responses in pts with FL. At a follow up of 7 years, the majority of pts remain in remission and patients who achieved CR had the best outcomes. Five year PFS may be longer in pts who received 12mo of therapy, but will need larger analysis to confirm. Further studies are ongoing to analyze mutation dynamics and genomic profile to identify molecular biomarkers. Disclosures Fowler: Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Nastoupil:Novartis: Honoraria; Juno: Honoraria; Gilead: Honoraria; TG Therappeutics: Research Funding; Spectrum: Honoraria; Janssen: Research Funding; Merck: Honoraria, Research Funding; Karus: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Westin:Apotex: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Wang:Kite Pharma: Research Funding; Novartis: Research Funding; Pharmacyclics: Honoraria, Research Funding; Dava Oncology: Honoraria; Juno: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Acerta Pharma: Honoraria, Research Funding. Samaniego:ADC Therapeutics: Research Funding.

scholarly journals A Randomized Phase II, Open Label, Study of Daratumumab, Weekly Low-Dose Oral Dexamethasone and Cyclophosphamide with or without Pomalidomide in Patients with Relapsed and Refractory Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-6
Author(s):  
Michael Sebag ◽  
Nizar J. Bahlis ◽  
Christopher P. Venner ◽  
Arleigh McCurdy ◽  
C. Tom Kouroukis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Research Funding ◽  
Low Dose ◽  
Response Rate ◽  
Response Rates ◽  
First Line ◽  
Randomized Phase Ii ◽  
Line Of Therapy

Lenalidomide (Len) has become the standard first line therapeutic choices for Multiple Myeloma (MM), whether as first line for transplant ineligible patients or as maintenance post transplant. Therapies that are designed to overcome lenalidomide refractory disease are few and often give disappointing results. We previously reported the efficacy of daratumumab in combination with low dose weekly cyclophosphamide and dexamethasone with and without pomalidomide (Pom). In patients previously treated with both Proteosome Inhibitors (PIs) and Len the combination of Dara, Cyclophosphamide, Dex and pomalidomide (DCdP) produced impressive response rates. Although the same combination without the Pom had appreciably lower response rates and initial progression free survival (PFS), most patients were salvageable after the addition of Pom. Here we report an update on this trial. Patients/Methods In this phase II clinical trial, 120 patients with relapsed refractory MM, after at least one line of therapy, were randomized to receive either daratumumab (16mg/kg) weekly IV C1-2, every 2 weeks C3-6, monthly C7+, dexamethasone 40mg po weekly, cyclophosphamide 400mg po weekly and pomalidomide 4mg po days 1-21 of 28 day cycles (Arm A) or the same doses and dosing regimen of daratumumab, cyclophosphamide and dexamethasone but with Pom added only after confirmed disease progression (Arm B). All patients were exposed to PIs and Len prior to study entry. The primary endpoint of this study was the comparison of the PFS of Arm A to that of Arm B after the addition Pom (PFS2) at 36 months while secondary endpoints included overall responses, duration of responses, survival and safety. Correlative laboratory studies will be reported separately. Results As of 1 June 2020 all 120 patients have been enrolled in 11 sites across Canada. The patient characteristics were: median age 65 (range 39-82); median 2 prior lines of therapy (range 1-8); 70% had a previous ASCT; 95% Len exposed; 93% PI exposed; 90% Len and PI exposed; 25% carfilzomib exposed, Len was the last line of therapy in 65%. Median follow-up was 19 months (range 1-28), median number of cycles 16 (range 1-31). The overall response rates (ORR) were 88.6% for arm A compared with 50.8% for arm B, with 62.4% and 28.8% of patients achieving ≥VGPR in arm A and B respectively. 43 patients in Arm B have progressed by data cut-off and the ORR after adding pomalidomide was 55.8% with a median follow up time 6.6 months. The response rates for both Arm A and B (prior to Pom) did not vary much in patients in whom Len was the last line of therapy (94.5% vs 55.7%), compared to the ITT population. The response rate after the addition of Pom to Arm B patients after first progression was also similar in patients in whom Len was used last (58.3%). The median PFS of Arm A was an impressive 20.5 months (regardless of previous Len exposure) while it was considerably shorter for Arm B prior to addition of Pom at 11.5 months and 16.7 months overall after addition of Pom. Median OS has not yet been reached, however, time to subsequent therapies from randomization was similar in both groups at 18.1 (Arm A) and 20.2 months (Arm B). Rates of grade 3/4 hematologic toxicities included a high incidence of neutropenia, 85.2% in Arm A and 50.8% in Arm B overall; however, the rates of febrile neutropenia were low at 13.1% and 16.9% respectively. The most common infection was pneumonia, seen in 13% of Arm A and 6.8% of Arm B prior to Pom and 20.3% overall for Arm B. Conclusions The results of this randomized phase II trial demonstrate that in a highly pretreated MM population (2 lines of therapy but range 1-8) that the four-drug combination (DCdP) confers impressive ORR (88.6%) and a median PFS (20.5 months) that compares favourably to other studies with anti-CD38 antibodies combined with Pomalidomide (11.5 months for Isatuximab-Pom-Dex, albeit in patients with 3 median lines of prior therapy). In Len exposed patients, DCdP demonstrates an ORR of 93% and a PFS of 20.5 months which is similar to what has been reported recently in Len exposed patients with Dara-pom-dex but after only one previous line of therapy. Although the 3 combination (DCd) showed an inferior initial response rate, over half of patients recaptured a response after the addition of Pom. Finally, while the overall PFS is lower in Arm B, the times to subsequent therapies are so far similar in both arms of this study opening a sequential-based approach as a feasible and economic option for further study. Disclosures Sebag: Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. Bahlis:Genentech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. McCurdy:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Honoraria. Shustik:Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Kotb:Amgen: Honoraria; Celgene: Honoraria; Sanofi: Research Funding; Karyopharm: Current equity holder in publicly-traded company; Merck: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria. White:Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Stakiw:BMS: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Roche: Research Funding; Lundbeck: Honoraria. Laferriere:Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Camacho:Janssen: Consultancy; AbbVie: Consultancy; Bausch-Health: Consultancy. Reece:Otsuka: Research Funding; Merck: Honoraria, Research Funding; Janssen, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen, Bristol-Myers Squibb, Amgen, Takeda: Consultancy, Honoraria.

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