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  • Durer, Seren  (4)
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  • 1
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5625-5625
    Abstract: Background: Management of relapsed or refractory multiple myeloma (RRMM) is challenging. Venetoclax (ABT-199) is an oral selective inhibitor of an anti-apoptotic protein Bcl-2 that showed activity in preclinical studies, especially for t(11;14) MM cell lines or in the cells with high bcl-2 expression. We conducted a systematic review and meta-analysis to evaluate the outcomes of venetoclax in RRMM. Method: Literature databases (Medline, Embase, and Cochrane) were searched for studies published up to June 19, 2018. Our search strategy included MeSH terms and key words for multiple myeloma and venetoclax including trade names and generic names. CMA software v.3 was used for analysis. Random-effects model was applied. Results: 163 patients (n=115 in dose escalation, n=48 in safety expansion) were identified from two clinical trials (phase Ib study by Moreau, P. et al. 2017, n=66 and phase I/II study by Kumar, S. et al. 2017, n=66) and one retrospective study (Galligan, D. et al. 2017, n=31). The median age was 63, 64, N/A in phase Ib, phase I/II and retrospective study, respectively. 47 patients (29%) had t(11;14). Other cytogenetic aberrations were del(17p) [n 〈 25]; t(4;14) [n=5] ; del(13q) [n=41]; t(14;16) [n 〈 5]; t(14;20) [n 〈 5]. 124 patients (76%) were refractory to bortezomib and/or lenalidomide; most patients had ≥3 prior therapies. Venetoclax doses escalated from 50 mg/day to 1200 mg/day in phase Ib and phase I/II studies. Safety expansion doses were 800 mg and 1200 mg in phase Ib and phase I/II studies, respectively. Median dose of venetoclax for the retrospective study was 800 mg daily. Bortezomib and dexamethasone doses from phase Ib study were 1.3 mg/m2 subcutaneous and 20 mg, respectively. The median duration on venetoclax and median time on study ranged from 2 to 6 months. Median duration of response (DOR) and median time-to-progression (TTP) were reported higher with combination therapy of bortezomib and dexamethasone (9.7 months and 9.5 months, respectively). 62% of patients have discontinued the therapy due to: progressive disease (48%), adverse events (6%), and various other reasons (8%). There were 13 deaths; 6 were due to disease progression. Most common side effect from three studies was gastrointestinal problems such as nausea, diarrhea and vomiting. The median duration of response was 9.7, 9.7, 2 months and the median time to progression was 9.5, 2.6, NA months for phase Ib, phase I/II and retrospective study, respectively. The pooled overall response rate (ORR) for all patients was 43% (n=163) with the highest rate (67%) being reported from phase Ib study using combined venetoclax, bortezomib and dexamethasone (Figure 1 and 2). Among 44 patients with t(11;14), ORR was 40% and 78% in phase I/II and phase Ib studies, respectively. Twenty-eight patients who expressed high-bcl2 showed ORR rates of 80% and 94%, whereas 50 patients who had low-bcl2 level showed ORR rates of 8% and 59% in phase I/II and phase Ib studies, respectively (Table 1). Conclusion: Single-agent venetoclax showed an ORR of 21%, the addition of bortezomib produced an ORR of 32%, and the addition of bortezomib and dexamethasone improved an ORR to 67%. Better ORR was observed in patients with t(11;14) and with high-bcl2 expression. The highest median DOR (9.7 months) and TTP (9.5 months) were reported with a combination therapy of venetoclax, bortezomib and dexamethasone. Most reported adverse events were related to gastrointestinal system. More clinical studies evaluating the combination therapies using venetoclax are needed. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5640-5640
    Abstract: Background: Elotuzumab (elo) is a humanized monoclonal antibody, which has been approved by the FDA for use in combination with lenalidomide (lena) and dexamethasone (dexa) in patients (pts) with relapsed and refractory multiple myeloma (RRMM). Elotuzumab is effective as a single agent, as well as in combination for multiple myeloma treatments, supporting the use of elo in pts with RRMM and newly diagnosed multiple myeloma (NDMM) pts. Method: After review of literature using database searches was done on 6/27/18 (Pubmed, Embase, Cochrane Library, Web of Science and Clinical Trials.gov), 9 prospective and 1 retrospective study with 1128 enrolled pts met the inclusion criteria to date in RRMM and 2 clinical trials including 123 pts in NDMM (Table 1). CMA software v.3 was used for meta-analysis. A random-effect model was applied. Result: Regimens used in RRMM: Based on pooled analysis (95% CI), an overall response rate (ORR) of 66% (54-76.2) was calculated in 685 evaluable pts treated with elo based regimens in RRMM (Figure 1). Most common grade (G) ≥ 3 hematological adverse events (HAE) and non-hematological adverse events (NHAE) based on regimen were calculated using pooled analysis in RRMM pts (Table 2). Anemia was noted in 12.1% ( 7.7-18.6) in 559 pts, while neutropenia in 14.5% (7.5-26.4) out of 591 pts and thrombocytopenia (tcp) in 11.9% (7.9-17.4) in 198 evaluable pts. Diarrhea 5.5% (3.6-8.3), pyrexia 2.4% (1.5-4), peripheral neuropathy (PN) 8.4% (3.8-17.8) were measured in 626, 668 and 143 pts respectively. Elotuzumab as monotherapy: 1 study (n=34) evaluated the efficacy of elo as single agent in RRMM. The median age, time from diagnosis and number of prior therapies were 64.5 years (y) (46-87), 4.4 y (0.9-12.8) and 4.5 y (2-10) respectively. It produced an ORR of 1.4% (0.1-19.1 95% CI) in 34 evaluable pts. Adverse events recorded were pyrexia and fatigue in 17.6% and 8.8% pts respectively. Elotuzumab in two drug regimen: In RRMM, 2 clinical trials (n=49) evaluated the efficacy (95% CI) of elo, ORR of 25% (4.1-72.3) was calculated. The best PFS (progression free survival) produced was in combination of elo 20 mg with bortezumib (bort) 1.3mg/m2 of 9.46 months as compared to 1.8 months when elo10mg/kg + dexamethasone (dexa) 28mg was used. In our analysis for safety, common G≥ 3 HAE calculated were, thrombocytopenia 8.7% (3.3-21.1) n=49, neutropenia 10.7 % (3.5-28.4) n=28 pts and anemia 7.1% (1.8-24.5) n=28 pts. NHAE included diarrhea 1.7% (0.1-22.3), PN 10.7% (3.5-28.4), pyrexia 1.7% (0.1-22.3) in 28 evaluable pts each. Elotuzumab in three drug regimen: In RRMM, 10 clinical trials including 602 pts evaluated the efficacy of elo as a part of triple drug regimen, producing an ORR of 72.2% (54-76.2). The best results were produced with the combination of elo 10-20mg/kg + lenalidomide (lena) 25mg + dexa 40mg producing a PFS of 32.2 mo and 28.62 mo in its phase I and II cohorts respectively. Based on pooled analysis (95% CI) common HAE calculated were neutropenia 17.5% (7.6-35.4) in n=563, thrombocytopenia 12.7% (8.2-19.4) in n=149 and anemia 13% (8-20.5) in n=531 pts. Common G ≥ 3 NHAE estimated were diarrhea 5.7% (3.7-8.6), PN 6.6% (2-19.2), pyrexia 2.5% (1.5-4.1) in 598, 115 and 640 pts respectively. Elotuzumab based regimen in NDMM: A currently ongoing clinical trial NCT02272803 has produced promising results in NDMM pts. As a part of three drug regimen with dose of elo 10mg/kg-20mg/kg, lena 25mg, dexa 20mg in 40 pts produced an ORR of 87.5% (73.2-95.8) versus control group of lena 25mg plus dexa 40mg in 42 pts with an ORR of 73.8% (58-86.1). The PFS rate recorded at 1 year was 93% (79-98%) and 91% (73-97%) respectively. The HAE G ≥ 3 included, neutropenia 18% and leukopenia 15%. In another study with 41 pts, elo was used in combination with lena, bort and dexa producing an ORR of 100% and greater than grade 3 adverse events including Tcp 15%, PN 2%. Conclusion: Results produced in our study suggest that elotuzumab is highly effective when used in pts with RRMM and NDMM. Combination regimens for elo produces an ORR ranging from 79-83% with elo + lena+ dexa, proving that the best results were produced by three drug regimens. Large prospective studies are required to evaluate efficacy and safety of elotuzumab in combination therapies. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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  • 3
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5768-5768
    Abstract: Background: The use of peripheral blood stem cell source (PBSC) continues to grow in the setting of haploidentical hematopoietic stem cell transplantation (haplo-SCT), mainly due to the ease of collection and rapid peripheral blood count recovery. We conducted a systematic review and meta-analysis of the published literature to evaluate the outcomes of unmanipulated bone marrow (BM) and PB haplo-SCT for adult leukemia patients. Method: A comprehensive literature search of electronic databases (Medline, Embase, and Cochrane library) for studies published between 1 January 2004 to 24 June 2018 was conducted. We included the studies of unmanipulated BM and/or PB haplo-SCT in adult acute myeloid leukemia (AML) and acute lymphoblastic leukemia ( ALL) . We excluded the studies which combined PB and BM stem cell sources and the studies which did not report the results of BM and PB haplo-SCT for ALL and AML separately. CMA software v.3 was used for the analysis. Heterogeneity among studies was assessed using the I2 test. Random-effect model was applied. Publication bias was assessed using funnel plots. Primary endpoints were engraftment, 2-year overall survival (OS), disease-free survival (DFS), relapse incidence (RI); grade II-IV, III-IV acute and chronic GVHD. Results: Out of 1548 publications, 3 studies (n = 672 patients; retrospective; multi-center) met our inclusion criteria. The sample size of the studies varied between 71 and 451 patients. The median follow-up ranged from 18 to 46 months. PB haplo-SCT was used in 191 patients (Ruggeri, A. et al. 2018) and BM haplo-SCT was used in 481 patients (Arcese, W. et al. 2015; Ruggeri, A. et al. 2018; Chiusolo, P. et al. 2018). Myeloablative (MA) conditioning was used in majority of patients. The pooled (95%CI) engraftment rate was 93% (88-95) in BM group and 95% (91-97) in PBSC group. The pooled estimates (95%CI) of BM studies showed a 2-year OS rate of 56.1% (51.6-60.4), 2-year DFS of 48.9% (43.5-54.2) and 2-year cumulative RI of 24.6%(20.7-29).There was no heterogeneity in BM group (I2=0%) for 2-year OS, DFS and RI. For PBSC group, the pooled estimates (95%CI) for 2-year OS, DFS and RI were 56 % (48.9-62.9; I2=0%), 54% (46.9-60.9; I2=0%) and 22% (16.7-28.4; I2=0%), respectively. Incidences of grade II-IV, grade III-IV aGVHD and cGVHD from a pooled analysis (95%CI) were 23.1% (17.2-30.3; I2=55%), 5.4% (3.4-8.3; I2=16%) and 19.5% (9.7-35.3; I2=88%) for BM group in comparison to 38% (31.4-45.1; I2=0%), 14% (9.8-19.7; I2=0%) and 32% (25.8-38.9; I2=0%) for PBSC group. Pooled estimates were shown in figure 1. Conclusions: In this analysis, higher pooled rates of grade II-IV aGVHD (38% vs 23.1%), III-IV aGVHD (14% vs 5.4%) and cGVHD (32% vs 19.5%) were observed in PBSC group vs BM group, respectively. Based on comparable OS, DFS and RI, PB haplo-SCT appears to be a good alternative option for adult AML and ALL patients. Large prospective randomized controlled trials are required to confirm these results. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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  • 4
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1952-1952
    Abstract: Introduction: Multiple myeloma (MM) is associated with end organ damage that negatively impacts the quality of life (QOL)and supportive care has a potential to improve symptoms. Methods: After detailed search on Pubmed, Cochrane, Embase and Clinical Trials.gov, we finalized total 36 articles on supportive care published after 2004. Results: Management of skeletal events: Mhaskar et al. (2017, n=3257) compared bisphosphonates (BPs) with placebo (PBO) in preventing pathological vertebral fractures, skeletal-related events (SRE), reported risk ratio (RR) of 0.74 in each; 95% CI 0.62-0.89 and 0.63-0.88 respectively. Both zoledronic acid (ZA) and clodronic acid prevent SRE, but mortality rate was better reduced with ZA (hazard ratio [HR]=0.84; p=0.0118), (Gareth et al. 2010, n=1960). In a study by Zuradelli et al. (2009, n= 240); hypocalcemia developed in 93 (38.8%) patients on ZA for a median of 2.3 months (range, 0-34.9). Vitamin D and calcium replacement is essential in patients developing hypocalcemia with BPs, (Kennel et al. 2009). Vertebral augmentation procedures improved pain after compression fracture (n=923) by 4.8, 4.6 and 4.4 points at 1 week, 1 year and beyond 1 year respectively, (Khan et al. 2014). Valerie et al. (2011, n=84) analyzed improvement in bone pain with radiotherapy (median 45 grays) in 92 % patients. Prophylaxis of infections: Leng et al. (2018, n=70,687) observed reduced risk of herpes zoster (HZ) reactivation in patients on bortezomib or carfilzomib + HZ prophylaxis (2.4%) vs 5.8% in non-prophylactic group, (attributable risk reduction: 0.42; 95% CI 0.31-0.56). Teh et al. (2016, n=199) reported reduced risk of varicella zoster virus reactivation with valacyclovir (500 mg) in patients on bortezomib based therapy and following autologous stem cell transplant (ASCT) vs no prophylaxis (HR=0.06 vs 16.9; p 〈 0.01). Dimopoulos et al. (2016, n=569) found higher risk of pneumonia, 8.2% in daratumumab group (n=286) vs 7.8% in control group (n=283). Prophylactic trimethoprim-sulfamethoxazole reduced risk of PCP in 85% patients after ASCT (RR=0.15; 95% CI 0.04-0.62), Stern et al. (2014, n=1000). Incidence of Community-acquired pneumonia (CAP), noninvasive CAP and invasive pneumococcal disease in elderly population (≥65 years) was seen in 49, 33 and 7 patients on Pneumococcal polysaccharide conjugate vaccine group as compared to 90, 60 and 28 patients in placebo group respectively, (Bonten et al. 2015, n=84,496). Role of plasmapheresis in renal impairment (RI): Alkhatib et al. (2017) showed that plasmapheresis reduced dialysis dependency by removing serum free light chains (sFLC) in patients with RI (n=147), (RR 0.45; P = 0.02). Yu-X et al. (2015, n=147), showed lower 6-month dialysis dependency ratio with plasmapheresis and chemotherapy (PP + CTH) vs CTH alone, (15.6% vs 37.2%; RR=2.02; p = 0.04). High cut-off hemodialysis lowered sFLC level in 61% (n=42) and 63% patients at day 12 and 21 respectively. Out of these, 71% and 69% patients became dialysis independent, (Hutchison et al. 2012, n=67). Peripheral neuropathy (PN): Bortezomib caused PN in 124/331 (37%) patients (Richardson et al. 2009) whereas with thalidomide, the incidence of PN was 38% and 73% at 6 and 12 months, respectively, (Mileshkin et al. 2006, n=75). PN improved in 68% patients on bortezomib with dose modifications (n=72) vs 47% patients, without dose modification (n=19). (Table 1 and 2). Significant improvement in PN was seen with duloxetine vs placebo (1.06 vs. 0.34; p= 0.003), (Smith et al. 2013, n=231). Arbaiza et al. (2007, n=36) showed improvement in neuropathic pain with tramadol (p= 〈 0.001). Epoetin and derivates for anemia: Castelli et al. (2017, n= 31; median creatinine 1.2 mg/dL (0.8-3.0)) reported hemoglobin (Hb) increase of ≥1g/dL and ≥2g/dL in 71% and 31.7% patients respectively with epoetin α, transfusions requirement reduced from 2.39 ± 1.05 to 1.23 ± 1.36 (p 〈 0.001). Begiun et al. (2013, n= 72) compared the effect of darbepoetin (D) ± iron (Fe) vs placebo on erythroid recovery after ASCT. All patients receiving D + Fe achieved Hb ≥13 g/dL (p 〈 0.0001). Tonia et al. (2012, n= 16,093) showed 35% decrease in transfusion need with erythropoietin stimulating agents (RR=0.65; 95% CI 0.62-0.68). (Table 3) Conclusion: Along with anti-myeloma chemotherapy therapy, management of complications (anemia, infections, renal insufficiency) and other associated symptoms is necessary to improve the quality of life. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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