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  • American Society of Hematology  (14)
  • 1
    Online Resource
    Online Resource
    Spleen and Symptom Responses of JAK Inhibitors in Myelofibrosis; A Systematic Review of Phase 2 and 3 Trials
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 26-27
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 26-27
    Abstract: Background: The JAK-STAT pathway is a vital signaling pathway for various cytokines and growth factors. An abnormal upregulation of this pathway is seen in myeloproliferative disorders, especially the classic BCR-ABL negative myelofibrosis (MF). Janus kinase inhibitors (JAKi) have been evaluated in various clinical trials regarding their efficacy in improving the outcomes for MF patients. In this review, we looked at the reduction of splenomegaly and symptom improvement as markers for efficacy of JAKi. Methods: We did a comprehensive literature search, following PRISMA guidelines, on PubMed, Cochrane, clinicaltrials.gov and Embase databases. We used MeSH terms and related keywords for MF and JAKi, including generic and trade names. We screened 3261 articles and selected 23 trials for our study. Case reports, case series, meta-analysis, review articles, observational studies, phase I trials and studies not reporting spleen response were excluded. Spleen and symptom responses were used to determine the efficacy of JAK inhibitors. Spleen volume reduction (SVR) by & gt;35%, spleen length reduction (SLR) by & gt;50% and total symptom score (TSS) improvement by & gt;50% were set as benchmarks for a positive response. Results: We included 23 trials (n= 4739) in our review. There were 15 phase II trials (n=964) and 8 phase III trials (n=3775). Of these 23 trials, 7 trials (n=598) included patients with median age below 65 years, while 16 trials (n=4141) included patients of median age more than 65 years. Of the 9 of trials of ruxolitinib, 4 were phase III trials (n= 2809) and 5 were phase II trials (n= 416). The dose of ruxolitinib used in these trials ranged from 5 mg twice daily to 20 mg twice daily. The percentage of patients who achieved spleen response ranged from 15.6% to 71.7%. There were 5 trials (n= 861) that evaluated efficacy of momelotinib. Three were phase II trials (n= 221), while 2 were phase III trials (n=326). The doses ranged from 150mg to 300mg. The splenic response in patients ranged from 7% to 48%. In one phase 3 randomized control trial, efficacy of momelotinib (N=215)and roxulotinib (N=217) were compared, and were found to be equally efficacious in terms of spleen response (26.5% in the momelotinib group while 29% in the ruxolitinib group) and symptom response (28.4% in the momelotinib group and 42.2% in the ruxolitinib group). In 4 trials (n= 453) of fedratinib, there were 2 phase II trials (n= 127) and 2 phase III trials (n=326). The splenic response ranged from 31% to 73% of the patient population. In phase II JAKARTA2 study, patients who were resistant or intolerant to ruxolitinib showed SVR of 31%. Lestaurtunib, Ilgitanib, pacritinib and itacitinib were studied in 2,1,1, and 1 phase II trials, respectively. The splenic response was 75%, 31%, 31%, and 68.8% respectively. Symptom response was reported in 12 studies (N=1477). The percentage of patients who achieved symptom response receiving roxulotinib were 20.8-49%, momelotinib (28.4-30.7%), ictatinib (51.1-59.4%), practinib (48%), and fedratinib (27-36%). In terms of safety, the most common hematological side effects seen were anemia (15% - 65%), thrombocytopenia (1.3% - 64%) and neutropenia (1% - 28%). These side effects were seen equally with different medications. The most common non hematological adverse effects included diarrhea (4% - 32%), abdominal pain (2.6% - 27.1%) and fatigue (1.3% - 10%). Conclusion Splenomegaly and associated symptoms are major source of morbidity in MF patients. The rapid advancement in novel agents in the last decade changed the treatment paradigm in this disorder. Our systematic review summarizes the effect of JAKi on spleen and symptom responses. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau. Fazal:Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Karyopharm: Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Gilead/Kite: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Janssen: Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-140131
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
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    Online Resource
    CD-19 Specific CAR-T Cell Therapy in Relapsed/Refractory ALL in Pediatrics and Young Adults; Safety and Efficacy Outcomes: A Systematic Review and Meta-Analysis
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 10-11
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 10-11
    Abstract: BACKGROUND: Acute Lymphoblastic leukemia (ALL) has good prognosis when treated with multiagent chemotherapy in pediatrics and young adolescents. Treatment of relapsed/refractory (R/R) ALL remains a challenge. Even after stem cell transplantation (SCT), the prognosis of R/R ALL is still grave. Chimeric antigen receptor- T cell (CAR-T) therapy, uses T cells engineered for cancer therapy. CD-19 specific Car-T cell is a recent advancement, FDA approved use of tisagenlecleucel in 2017 for R/R- B cell ALL in patients under 25years of age. In this systematic review we will discuss efficacy and safety of CD-19 specific CAR-T cell therapy in R/R B-ALL in pediatrics and young adults. There are still 30 clinical trials that are going on the CD-19 CAR-T cell therapy in R/R ALL in pediatrics and adults MATERIALS and METHODS: We searched PubMed, Embase, Clinical Trials, Web of Science and Cochrane. We searched without any filters and used Mesh Terms for "ALL" and "Chimeric antigen receptor". After screening of 2381 articles, we included 12 clinical trial and 3 prospective studies evaluating the role of CD-19 specific CAR-T cell in Relapsed/ Refractory ALL in pediatrics and young adults under 30years only. We followed PRISMA guidelines in literature search and selection of studies. We used "R" for meta-analysis. RESULTS: A total of 448 patients received a CD-19 specific CAR-T cell product and 446 patients were evaluable. The age range was 0-30 years. The female population in reported studies was 42.8% (n=111/259). Fludarabine and cyclophosphamide lymphodepleting therapy was used as a conditioning regimen followed by a single infusion of CAR-T cell product. Second generation CAR-T cell with a 4-1BB signaling domain was used in 66.7% of studies (n=10/15). High Risk cytogenetics was seen range from 4%-32% (n=53/220) and CNS disease in 66.9% (n=73/109) of the population. Median number of prior therapies ranges from 1 to 8 and 43.5%(n=186/247) had previous allo-HSCT. The median follow-up ranges from 3 to 14.4months. [Table 1] Complete remission (CR) and complete remission with incomplete count recovery (CRi) range from 50%-95% of the total participants. CR with minimal residual disease (MRD) negative status was reported in 50% to 86% of total participants. The Relapse rate range from 26%-100% of the total participants. Of 82 cases of relapse, 27 had CD19 positive disease, 42 had CD19 negative, 10 had unknown status. There were 3 AML transformations. Median overall survival at 12months ranges from 63%-84%. Median event free survival ranges from 46%-76%. [Table 1] The cumulative incidence of complete remission is 82% (heterogeneity,I2=27%) (95%CI; 0.82[0.76; 0.87]). Cumulative incidence of relapse after CD19 CAR-T cell therapy is 36% (heterogeneity,I2=10%), (95%CI; 0.36[0.29;0.43] ). Similarly pooled cumulative incidence of ≥Grade 3 adverse events of neutropenia, thrombocytopenia, neurotoxicity, infections and cytokine release syndrome was 38%(95%CI; 0.38[0.09; 0.72]), 23%(95%CI; 0.23 [0.09; 0.39] ), 18%(95%CI; 0.18[0.10; 0.26]) , 29%(95%CI; 0.29[0.16; 0.46] ),19%(95%CI; 0.19[0.08;0.33]) respectively. [Table 2, Fig 1] CONCLUSION: CAR-T cell therapy against R/R B-ALL can achieve CR in significant pediatric patient population. The relapse rate is also high, about 36% pooled cumulative incidence. Being a bridging therapy, there is a need for additional therapy such as HSCT or maintenance targeted chemotherapy after CAR-T cell therapy while the patient is in remission. While most studies are phase-1 and there are still 30 ongoing clinical trials, we will be in a better position in near future to evaluate the effect of CAR-T cell therapy on overall survival and relapse rate after CAR-T cell therapy. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-134059
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
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    The Role of Checkpoint Inhibitors in Adults with Classical Hodgkin Lymphoma; A Systematic Review and Meta-Analysis of Phase II and III Clinical Trials
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 25-26
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 25-26
    Abstract: Introduction The ability of the neoplastic cells to escape from immune surveillance has been considered as a hallmark of cancer. The upregulation of programmed death-1 (PD-1) and programmed death ligand-1/2 (PDL-1) axis is a major immune escape pathway in multiple malignancies including classical hodgkin lymphoma (cHL). Disruption of PD1-PDL1/2 pathway using checkpoint inhibitors (CPIs) leads to reactivation of immune cells to attack malignant cells. CPIs have been studied in cHL in different settings. Here in, we did a systematic review and meta-analysis of phase II and III clinical trials that looked at the efficacy of CPIs in cHL Methods We did a comprehensive literature search, using 4 major databases (pubmed, embase, chocrane, and clinialtrials.gov). We used MeSH terms and related keywords that included all CPIs in generic and trade names, and cHL. We included phase II and III prospective clinical trials in patients & gt; 18 year-old. We excluded case reports, case series, review articles, retrospective and observational studies, and phase I clinical trials. Initial search resulted in 1647 articles. After applying the inclusion and exclusion criteria, we had 13 articles that we explored in details. We stratified the articles according to CPIs and did a pooled-analysis of the complete response (CR) rate. Medcalc was used to do the statistical analysis. Results Of those 13 clinical trials, we had 12 phase II trials and 1 phase III trial. Nivolumab was studied in 7 trials (n=568), pembrolizumab in 5 trials (n=427), and camrelizumab in 1 trial (n=86). Table 1 shows the characteristics of these trials. (table 1) Four studies evaluated the efficacy of nivolumab in the relapsed/refractory (RR) setting. Armand et al (2018) evaluated the efficacy of nivolumab after autologous hematopoietic stem cell transplantation (auto-HSCT), the cohort in this study was divided into 3 groups: patients who received brentuximab vedotin (BV) after auto-HSCT, patients who are BV naïve, and patients who received BV before and/or after auto-HSCT. Overall response rate (ORR) and CR were 68% and 13%, 65% and 29%, 73% and 12%, respectively. Maruyama et al (2017) reported ORR and CR of 81.3% and 25%, in 16 Japanese patients received nivolumab in combination with BV. The ORR and CR in the remaining 2 trials were: 82% and 59%, and 85% and 67%. In the frontline setting, nivolumab showed ORR and CR of 84% and 67% (Ramchandren et al, 2019), 96%-100% and 53-85% (Brockelmann et al, 2019 in 2 different dosing regimens), and 100% and 72% (Yasenchack et al, 2019). Pooled analysis of all nivolumab trials showed CR rate of 47.4 % (95% CI 29.0-66.1) (figure 1) Pembrolizumab was evaluated in 4 clinical trials in the RR setting. Armand et el (2019) reported CR rate of 83% in 25 patients. Chen et al (2019) reported ORR and CR of 76.8 % and 26.1% in patients who relapsed after auto-HSCT and BV, 66.7% and 25.9% in patients ineligible for HSCT, and 73.3% and 31.7% in patients who relapsed after auto-HSCT with no prior exposure to BV. In combination with gemcitabine, vinorelbone , and doxorubicin, pembrolizumab showed ORR and CR of 100% and 93%, respectively. The only phase III clinical trial compared pembrolizumab vs BV in the RR setting showed ORR of 65.6% vs 54% and CR of 24.5% vs 24%, respectively. Only one study evaluated pembrolizumab in the frontline setting, ORR and CR of 100% in 30 patients received 3 cycles of pembolizumab followed by 4-6 cycles of doxorubicin, vinblastine, and dacarbazine. Pooled analysis of all pembrolizumab trials showed CR rate of 54.4% (95% CI 32.6-77.2) (figure 2) Only one trial evaluated the role of camrelizumab as monotherapy or in combination with decitabine. The combination regimen showed ORR and CR of 95% and 71% in CPIs naïve patients, and 52% and 28% in patients previously received CPIs. Camrelizumab monotherapy showed ORR and CR of 90% and 32% in CPIs naïve patients. Conclusion CPIs in cHL have showed high rates of response in the frontline and RR settings, with fairly acceptable toxicity profile. Their efficacy was studied post HSCT and BV, in BV naïve patients, and in HSCT-ineligible patients. Pembrolizumab and nivolumab were the 2 most studied CPIs. Future direction should focus on more studies in the frontline setting, the role of combined CPIs with other CPIs or with novel agents, to spare this relatively young population the long term toxicity of chemotherapy. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.Fazal:Jansen:Speakers Bureau;Jazz Pharma:Consultancy, Speakers Bureau;Stemline:Consultancy, Speakers Bureau;Glaxosmith Kline:Consultancy, Speakers Bureau;Gilead/Kite:Consultancy, Speakers Bureau;Amgen:Consultancy, Speakers Bureau;Novartis:Consultancy, Speakers Bureau;Agios:Consultancy, Speakers Bureau;BMS:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene:Speakers Bureau;Karyopham:Speakers Bureau;Incyte Corporation:Consultancy, Honoraria, Speakers Bureau;Takeda:Consultancy, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-140591
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
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    Efficacy and Safety of Voxelotor in Sickle Cell Disease: A Systematic Review
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 35-35
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 35-35
    Abstract: Introduction: Sickle cell disease (SCD) is caused by mutation of beta-globin chain alleles, with the involvement of at least one sickle mutation. Sickling of red cells leads to hemolytic anemia, vaso-occlusions, and inflammation. Voxelotor (GBT440) is a hemoglobin modulator that prevents polymerization by increasing the affinity of hemoglobin with oxygen. We performed a systematic review to evaluate the efficacy and safety of voxelotor in SCD patients. Methods: PRISMA guidelines were followed to perform the literature search and selection of articles for this systematic review. A search was performed using databases including PubMed, Cochrane, Web of Science, Embase, and clinicaltrials.gov. We used the following keywords, "Voxelotor" OR "Benzaldehydes" OR "GBT440" AND "Sickle Cell Anemia" from the inception of literature till 04/25/2020. Out of 475 articles, we screened and included three clinical trials and a case series measuring the efficacy (i-e, change in Hemoglobin (Hb), Hb modification, etc.) and safety (adverse events) in clinical terms (N=359). We excluded case reports, pre-clinical studies, review articles, and meta-analysis. RESULTS: We included data on 359 patients, with 12-67 years of age. In Blyden et al. 2018, authors presented a case series of 7 patients with advanced SCD treated with 700 mg-1500 mg voxelotor. With treatment, vaso-occlusive episodes related hospitalizations decreased by 67%, hemoglobin levels, and markers of hemolysis improved in all patients. Authors in Hutchaleelaha et al. 2019 randomly assigned 24 participants to a once-daily dose of 900 mg, 600 mg, 300 mg voxelotor, and placebo for 15 days. With treatment, hemoglobin modification was maximum in the 900 mg voxelotor group. Headache and diarrhea were the only adverse events related to voxelotor treatment. No grade 3 adverse events were reported. In phase I/II trial by Howard et al. 2019, (n=54) 38 patients were followed for 28 days, and 16 patients were followed for & gt;90 days. The compliance for study drug was 91%. In the 28-day cohort, treatment with 1000 mg of voxelotor showed maximum improvement in hemoglobin level, reticulocyte count, and unconjugated bilirubin. In & gt;90-day cohort, the improvement in hemoglobin, unconjugated bilirubin, and reticulocyte count were statistically significant in favor of 900 mg voxelotor treatment as compared to placebo (p & lt;0.05). LDH showed variability with treatment. Vaso-occlusive episodes seen in voxelotor groups were reported when the treatment was on hold or after the last dose. No grade ≥3 adverse events were reported. In a randomized placebo-controlled phase III clinical trial by Vichinsky et al. 2019, two doses of voxelotor 1500 mg (N=90) and 900 mg (N=92) were compared with placebo (N=92). 12-65 years old SCD patients were followed for 24 weeks. After treatment, improvement in hemoglobin was statistically significant in favor of 1500 mg voxelotor vs. placebo. Moreover, markers of hemolysis, reticulocyte count, and indirect bilirubin levels were also significantly improved in favor of 1500mg voxelotor treatment vs. placebo. The incidence of vaso-occlusive crisis episodes was similar in 1500 mg, 700 mg, and placebo groups (p & gt;0.05). Treatment-related adverse events were seen in 94%, 93%, and 89% of participants in 1500mg, 700mg, and placebo groups, respectively. (Table 1) There are 6 ongoing clinical trials registered on clinicaltrials.gov (n=665) to determine the efficacy and safety of high doses of voxelotor and its use in children below 12 years. (Table 2) Conclusion: Voxelotor has an acceptable safety profile in sickle cell disease patients of 12 years or older. Voxelotor has shown a dose-dependent improvement in hemoglobin levels and markers of hemolysis, which is associated with a reduction in end-organ damage. Moreover, the increase in hemoglobin was not associated with an increase in vaso-occlusive crisis episodes, in contrast to the other hemoglobin modulator (senicapoc). Additional large prospective multicenter randomized clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-135960
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
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    Anti-Thymocyte Globulin (ATG) for Prophylaxis of Severe Graft Vs. Host Disease after Hematopoietic Stem Cell Transplant: A Systematic Review and Meta-Analysis
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 35-36
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 35-36
    Abstract: Introduction: Hematopoietic stem cell transplantation (HSCT) is used for the treatment of multiple hematologic diseases. The donor cells kill the host malignant cells, but unfortunately, the immune response can cause graft vs. host disease (GvHD). Anti-thymocyte globulin (ATG) is an antibody derived from rabbits or horses. It targets antigens expressed on T-cells, B-cells, macrophages, natural killer cells, and dendritic cells, and used for the prevention of GvHD. We conducted a meta-analysis to assess the efficacy of ATG in preventing high-grade GvHD after hematopoietic stem cell transplant. Methods: A search was performed on PubMed, Cochrane, Embase, and Web of Science. We used the following mesh terms and Emtree terms, "antilymphocyte globulin" OR "antithymocyte globulin" AND "graft vs. host disease" from the inception of literature till 06/01/2020. We screened 5767 articles and included 10 randomized clinical trials (N=1,227) and 31 observational studies (N=14,895) in this meta-analysis. We extracted data for severe acute GvHD (grade III-IV or grade II-IV) and severe chronic GvHD (an extensive disease by Seattle criteria or moderate to severe disease according to NIH criteria). We excluded case reports, case series, preclinical trials, single-arm studies, review articles, meta-analysis, and controlled studies not providing any information about high-grade GvHD. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results: In 41 included studies (N=16,122), the median age was ≥40 years in 22 studies (N=12,099), ≤40 years in 16 studies (N=3536), and ≤18 years in 3 studies (N=487). 2986 patients had at least one HLA allele mismatch. Out of 41 studies, data for high-grade acute GvHD was available in 40 studies (N=16,047), and data for high-grade chronic GvHD was available in 33 studies (N=14,206), see Figure 1, 2. For high-grade acute GvHD, risk ratio (RR) was 0.68 (I2=24%, 95% CI=0.61-0.75) in favor of the use of ATG vs. no use of ATG in the prophylaxis of GvHD with HSCT. In 9 RCTs (N=1,152), RR was 0.59 (I2=38%, CI=0.42-0.82) in favor of ATG use. High-grade acute GvHD significantly improved in all subgroups, i-e., peripheral blood (PB) /bone marrow (BM) HSCT from related donors (RR=0.73; 95% CI=0.61-0.88), PB/BM transplant from unrelated donors (RR=0.62; CI=0.52-0.72) and umbilical cord blood (UC) HSCT (RR=0.61; CI=0.43-0.88). For high-grade chronic GvHD, RR was 0.47 (I2=49%, 95% CI=0.40-0.55) in favor of the use of ATG vs. no use of ATG in the prophylaxis of GvHD with HSCT. In 6 RCTs (N=714), RR was 0.40 (I2=58%, 95% CI=0.27-0.61) in favor of ATG use. High-grade chronic GvHD significantly improved with the use of ATG in both related donors (RR=0.44; 95% CI=0.34-0.58) and unrelated donors (RR=0.46; 95% CI=0.38-0.55) subgroups for BM / PB HSCT. However, there was no significant improvement in the risk of high-grade chronic GvHD with the use of ATG with cord blood HSCT (RR=0.98; 95% CI=0.73-1.31). Conclusion: ATG is effective in the prophylaxis of severe acute GvHD irrespective of donor relationship or type of HSCT. ATG is also effective in the prophylaxis of severe chronic GvHD with bone marrow or peripheral blood HSCT except for cord blood HSCT. Additional multicenter randomized double-blinded clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-135950
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
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  • 6
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    Efficacy and Safety of Phosphoinositide 3-Kinase (PI3K) Inhibitors in Non-Hodgkin's Lymphoma: A Systematic Review and Meta-Analysis
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 12-13
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 12-13
    Abstract: Background: Phosphatidylinositol-3-Kinase (PI3K)-oncogenic protein kinase is ubiquitously expressed in cells, however, PI3Kδ and PI3Kγ are selectively expressed in hematopoietic cells predominantly in leucocytes. Suppression of the PI3K pathway has emerged as a therapeutic strategy for non-Hodgkin lymphoma (NHL) and 3 PI3K inhibitors are already approved for therapeutic use with many others under exploration. The application of these agents in terms of risk and benefit remains scarcely explored. Therefore, a systematic review and meta-analysis was conducted to assess the efficacy and safety of PI3K inhibitors in non-Hodgkin lymphoma. Methods: A comprehensive literature search was conducted from inception to the 4th of April 2020, following PRISMA guidelines on 4 databases (PubMed, Cochrane library, clinicaltrials.gov, web of science, and Embase). A search was performed without the use of filters and the MeSH terms used were "lymphoma, non-Hodgkin" and "phosphoinositide-kinase inhibitors". Only studies with available data that were either completed or still recruiting were included. Trials with no reported efficacy or safety data were excluded. A pooled analysis of the extracted data was performed using the "meta" package by Schwarzer et al. in the R programming language (version 4.0.2). For data analysis purposes, in the case of multi-arm studies, only those cohorts where PI3K was administered were included. The event rates were pooled using the inverse variance method and logit transformation. The between-studies variance was calculated using the DerSimonian-Laird estimator. The random-effects model was used for the analysis. Results: Initial search revealed 391 articles. After a thorough screening, 22 studies involving 1123 patients with relapsed or refractory NHL that fulfilled the inclusion criteria were included (Table 1). The median age ranged from 58-70 years. The median number of prior therapies ranged from 2 to 4. Twenty studies used a selective PI3K inhibitor including voxtalisib, pilaralisib, umbralisib, duvelisib, idelalisib, copanlisib, buparlisib, and parsaclisib. The pooled overall response rate (ORR) was 50% [95% CI: 42%; 58%] with pooled complete response of 15% [95% CI: 12%; 20%] . A subgroup analysis was performed on complete responses (CR) of patients with diffuse large B cell lymphoma (DLBCL), and follicular lymphoma (FL). The CR in FL and DLBCL were 20% [95% CI: 15%-20%] and 14% [95% CI 8%-25%] respectively, and the difference between the two subgroups was statistically non-significant with the Cochran Q test yielding the p-value of 0.34. The overall survival (OS) was extractable in only 3 studies with the highest OS reported as 28.9 months. The progression-free survival (PFS) ranged from 1.9 to 37.1 months and was reported in 16 studies. In terms of safety, the most common ≥ grade 3 hematologic abnormality was neutropenia with a pooled incidence rate of 24% [18%; 32%] while the pooled incidence rates of anemia and thrombocytopenia were 11% [7%; 17%] , and 10% [7%; 13%]. Diarrhea was the most common ≥ grade 3 non-hematological adverse event, which was seen in 14.85% [12%;18%] patients. Conclusion: PI3K pathway inhibitors have shown promising efficacy. However, the therapeutic applicability is hindered by the off-target adverse events especially gastrointestinal as well as the consequences of neutropenia. Overcoming these limitations would involve exploring the selectivity of novel agents, optimizing sequencing, use in combination regimens, and varying of the doses. Table Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-134986
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 7
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    Dartumumab in Pretreated AL Amyloidosis: A Systematic Review
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 46-47
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    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 46-47
    Abstract: Background: Amyloidosis is characterized by the deposition of misfolded lambda or kappa light chain (AL) proteins in tissue. It commonly affects the heart, which correlates with poor prognosis. Disease-modifying therapies aim to suppress the production of abnormal light chains. Daratumumab (Dara) use is associated with a reduction in light chain protein production. Dara is a human anti-CD38 monoclonal antibody approved for the treatment of newly diagnosed and Relapsed & Refractory Multiple Myeloma. AL amyloidosis plasma cells express CD38, and therefore, Dara is an attractive alternative in this setting. This review aims to assess the efficacy and safety of daratumumab in pre-treated AL amyloidosis patients. Methods: We conducted a comprehensive literature search in PubMed, Embase, Medline using MeSH terms and keywords "AL amyloidosis," "daratumumab", and "darzalex" to incorporate the studies published up to July 2020. We included studies assessing the efficacy and safety of daratumumab alone or in combination with other therapies in pretreated AL amyloidosis. After excluding duplicates, non-relevant, and review articles, we selected four prospective and twelve retrospective studies. RESULTS: In our review, data on 482 patients were included. The ages ranged from 35-88 years. The median number of prior therapies was 3 (ranges:2-6), and the most common therapy was bortezomib in 90% of patients followed by immunomodulators in 55% and stem cell transplant in 35%. A total of 260 (54%) patients received Dara monotherapy, 126 (26%) received Dara plus Dexamethasone (d), and 96 (20%) patients received other Dara containing two or three-drug regimens. The time from the diagnosis to the start of Dara therapy varied from 1 to 137 months. 71 % of patients had cardiac, and 62 % had renal involvement. There was a greater than 30 % reduction of N-terminal pro-brain natriuretic peptide (NT-proBNP) in cardiac patients responsive to therapy. 1. Daratumumab monotherapy: Dara monotherapy achieved an overall response rate (ORR) of 76% (191/249), complete response (CR) of 30% (69/224), very good partial response (VGPR) of 41% (79/192) and partial response (PR) of 14% (19/140). The overall survival (OS) ranges from 59-100% at 10-12 months were noted. Table 1. 2. Daratumumab+ Dexamethasone: Dara plus d achieved ORR of 81% (86/106), CR of 51% (53/102), VGPR of 29% (18/62), PR of 15% (15/102), and OS of 87% at 24 months. Table 1. 3. Daratumumab with combination regimens: The use of Dara based combination regimens of Dara+pomalidomide (P)+d (36% of patients), Dara+lenalidomide (R)+d (32%) and Dara+bortezomib (V)+d (18%), reported by Abeykoon et al., showed an ORR of 88% (14/16), CR of 19 % (3/16), VGPR of 63% (10/16), PR of 6 %(1/16), OS of 89 % at 10 months and progression-free survival (PFS) of 83% at 10 months. Godara et al. reported an ORR of 100% (9/9) using a combination of Dara and birtamimab. The combination of D+cyclophosphamide (c)+V+d reported by Palladini et al. achieved an ORR of 96 % (27/28), CR of 36 % (11/28), VGPR of 29 % (8/28) and PR of 14 % (4/28).Table 1. The most reported adverse event was infusion-related reactions; grade 3-4 adverse were less than 10 % and mostly related to the heart (heart failure & atrial fibrillation). The most-reported hematological adverse effects were anemia, thrombocytopenia, neutropenia, infections, and sepsis. The most common non-hematological adverse events were heart failure, bronchitis, pneumonia, fatigue, nausea, and diarrhea. Table 2. Conclusion: Dara therapy is associated with promising efficacy with a response rate of more than 70% when used alone and more than 80% when used in combination. These regimens are well tolerated in advanced cardiac disease patients with a tolerable risk of volume overload and infusion-related complications. Additional multicenter randomized, double-blind clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-138530
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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    A Systematic Review and Meta-Analysis of Luspatercept for Anemia Treatment in Low Risk Myelodysplastic Syndrome with Ring Sideroblast Subtype in Phase II and Phase III Clinical Trials
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 40-41
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 40-41
    Abstract: Background: Low-risk Myelodysplastic Syndromes (MDS) patients commonly present with anemia and may become blood transfusions dependent upon progression. Luspatercept, a targeted drug for an activin receptor ligand has emerged as new anemia treatment in MDS for patients with ring sideroblasts and the patients with SF3B1 mutation. This systemic review highlights the efficacy of luspatercept in MDS patients whom erythropoietin stimulating agents (ESA) are not effective. Methods: We conducted a comprehensive literature search using PubMed, Clinical trial.gov, Embase, Cochrane, and Web of science. Our search strategy included MeSH (Medical Subject Headings) terms and keywords for MDS and luspatercept including trade names and generic names from inception to 29 April 2020. Studies were selected according to PRISMA guidelines. The initial screening revealed 240 articles. After excluding review articles, duplicates, and non-relevant articles, finally we included two clinical trials, which reported transfusion independence (TI), an erythroid response (HI-E) in MDS patients with luspatercept. 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 luspatercept. We pooled the results of the experimental arms of the two trials using the inverse variance method and logit transformation. Between studies, variance was calculated using DerSimonian-Laird Estimator. Results: A total of 287 patients were enrolled and evaluated in two phases II/III trials. Platzbecker et al and Fenaux et al reported Erythropoietin stimulating agents (ESA) with one median prior line of therapy (n= 148, n=46). Fenaux et al. also reported iron chelation therapy (n=71) as a prior line of therapy. Patients having ring sideroblast positive & lt;15% (n=172) and SF3B mutation were present in 169 evaluable patients. Low-risk MDS (LR-MDS) patients are classified according to IPSS-R criteria, defined as being of very low (n=19), low (n=135), or intermediate-risk (n=44). Platzbecker et al. (2017) studied luspatercept in MDS patients (n=58) in the PACE phase II trial. Fenaux et al. (2020) studied the efficacy of luspatercept in MDS pts (n=219) in the MEDALIST phase III trial. The baseline Erythropoietin (EPO) levels were: levels & lt;200: n=191, level 200-500: n= 81, level & gt;500: n=57 for both studies. The baseline means hemoglobin (Hb) levels were eight before therapy. TI for more than eight weeks was observed in 38% of patients in both the MEDALIST trial and PACE trial. The erythroid response was 53% and 63% in both trials respectively. In a Phase II study, for LR-MDS patients, the overall erythroid response was higher among patients (n= 69%) having ringed sideroblast status ( & gt;15% ring sideroblast) and SF3B mutation (n=77%). The mean increase of Hb was observed in 29 out of 46 and 32 out of 41 pts in MEDALIST and PACE trial, respectively. Luspatercept proved to be efficacious in the pooled analysis i.e transfusion independence (TI): 38%, 95% CI 0.31-0.45; p =0.98, I2 = 0%), and erythroid response (HI-E): 54%, 95% CI 0.48-0.62; p=0.22, I2 = 32%) with an increase in mean Hb of 70% 95%: CI 0.59-0.78; I2 = 56%) (Figure 1). CONCLUSION: In patients with low risk MDS positive ringed sideroblast or SF3B1 mutation status shows good responses with luspatercept treatment, with reduced transfusion dependence, and higher erythroid response. Disclosures Anwer: Incyte Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Millennium Pharmaceuticals: Research Funding; Celgene: Research Funding; Astellas Pharma: Research Funding; Acetylon Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; AbbVie Pharmaceuticals: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-137152
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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    Risk of Serious Infections with Lenalidomide Based Regimens in Multiple Myeloma: A Network Meta-Analysis
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 12-12
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 12-12
    Abstract: Background: Lenalidomide is an immune modulator, approved for use since 2005 for the treatment of multiple myeloma (MM) patients. Its use is associated with an increased risk of infections. Combination of lenalidomide with other drugs, monoclonal antibodies, proteasome inhibitors, dexamethasone, and alkylators, can enhance the risk of serious infections. We conducted a network meta-analysis to compare the incidence of ≥Grade 3 infections among lenalidomide based regimens used in MM that can help clinicians to monitor patients for the risk of infections. Methods: A search was performed on PubMed, Cochrane, Embase, and Web of Science. We used the following keywords, "lenalidomide" AND "multiple myeloma" from the inception of literature till 06/10/2020. We screened 14,684 articles and included 23 randomized clinical trials (RCT) (N=11,174) in network meta-analysis. We extracted the data for serious (≥Grade 3) infections in lenalidomide based regimens. We excluded case reports, case series, preclinical trials, non-randomized clinical trials, observational studies, review articles, meta-analysis, and RCTs not providing any information about ≥Grade 3 infections. We used the "netmeta" package by Rucker et al. in the R programming language (version 4.0.2) to conduct frequentist network meta-analysis. Results: In 23 RCTs, the median age was ≥65years in 11 RCTs (N=5585) and ≤65 in 12 RCTs (5589). 9 RCTs were performed on relapsed/refractory multiple myeloma (RRMM) patients (N=4254), while 13 RCTs were performed on newly diagnosed multiple myeloma (NDMM) patients (N=6920). Lenalidomide regimen was used as maintenance therapy in 8 RCT (N=4255). Table 1 reviews the baseline characteristics. The pooled incidence of high-grade infections in trials with a median age of ≥65 and ≤65 years is 1010/5585 and 634/5589, respectively. The incidence of high-grade infections is 693/4254 in RRMM patients, 951/6920 in NDMM patients, and 466/4255 in NDMM patients with maintenance therapy. P-score in table 2 represents the mean extent of certainty with which a regimen is better in terms of the incidence of high-grade infections, i.e., higher P-score means a lower risk of serious infections. According to P-score, lenalidomide with carfilzomib and dexamethasone is worst in terms of the incidence of infections. Indirect comparison of placebo with lenalidomide shows a risk ratio of high-grade infections of 2.87 (95% CI: 1.96; 4.23) in favor of placebo. Fig 1 outlines the indirect comparison of the incidence of high-grade infections with different lenalidomide based regimens vs. placebo. Table 3. shows the calculated indirect comparison of high-grade infections in each lenalidomide based regimen. Heterogeneity was not statistically significant. For serious infections, lenalidomide dexamethasone showed a risk ratio of 0.86, 0.70*, 0.76*, 0.78*, 0.77, and 0.77 in comparison with the combination of lenalidomide dexamethasone with bortezomib, carfilzomib, daratumumab, elotuzumab, ixazomib, and pembrolizumab respectively (*statistically significant). Conclusion: This network meta-analysis suggests an increase in the risk of high-grade infections with the addition of bortezomib, monoclonal antibodies, ixazomib, and carfilzomib to lenalidomide in multiple myeloma patients with the highest increase in risk with the addition of carfilzomib. Additional randomized clinical trials are needed on the toxicity of lenalidomide based regimens to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-136455
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 10
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    Safety and Efficacy of Ruxolitinib in Steroid-Resistant Graft Versus Host Disease: A Systematic Review and Meta-Analysis
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 23-24
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    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 23-24
    Abstract: Introduction: Stem cell transplantation (SCT) is used to treat multiple malignancies, but a major complication of the procedure is graft versus host disease (GvHD), which is a significant cause of morbidity and death in SCT patients. Methylprednisolone is the first-line therapy of GvHD. Ruxolitinib is a Janus kinase (JAK) inhibitor that can dampen the effect of inflammatory cytokines involved in GvHD and may be used in patients refractory to steroid treatment. In this systematic review and meta-analysis, we assessed the safety and efficacy of Ruxolitinib in steroid-resistant (SR) acute (a) and chronic (c) GvHD. Methods: We performed a search on PubMed, Cochrane, Embase, and Web of Science. We used the keywords, "Ruxolitinib" AND "Graft vs Host Disease" from the inception of literature till 7/10/2020. We screened 694 articles and included 1 randomized clinical trial (RCT) (N=309), 4 non-randomized trials (NRCT) (N=232), and 13 observational studies (N=481) in this meta-analysis. We extracted data for efficacy (i-e, OS, CR, ORR) and safety (≥grade 3 treatment related adverse events (TRAE). We excluded case reports, case series, review articles, meta-analysis, and preclinical trials. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results: In the 18 included studies (N=1022), Ruxolitinib was used in patients with the age range of 6 months to 70 years. 417 participants had grade III-IV acute GvHD, and 272 participants had moderate to severe chronic GvHD (Table 1). In an RCT (N=309), patients aged between 12-73 years with SR aGVHD were randomized 1:1 to receive either Ruxolitinib or physician's choice drug. Overall response rate (ORR) and complete response (CR) were significantly higher in the Ruxolitinib group as compared to the physician's choice drug. The results were consistent for all grades of GvHD. Grade 3 or higher treatment-related adverse events (TRAEs) were 78% in the two groups. 22% of the patients died of GvHD related adverse events in the Ruxolitinib group vs. 25% of the patients in the control group. In 12 clinical trials and observational studies, among SR GvHD patients (N=443), pooled ORR was 0.74 (CI=0.65-0.81, I2=61%) with Ruxolitinib treatment. Similarly, pooled CR was 0.45 (CI=0.34-0.68, I2=81%). The most common adverse events were cytopenias, viral reactivation, and infections. (Fig 1, 2) In 9 early phase trials and observational studies (N=282) in SR- chronic GvHD patients, pooled ORR and pooled CR were 0.75 (CI=0.64-0.83, I2=64%) and 0.11 (CI=0.08-0.16, I2=0), respectively. The most common adverse events were cytopenias and viral reactivation (Fig 3, 4). In a non-randomized trial (N=64), Ruxolitinib was used in combination with Etanercept for SR- acute GvHD patients. The ORR and CR were 87.5% and 72%, respectively. High rates of hematological adverse events and infections were reported in these patients. In an observational study (N=18), Ruxolitinib was used in combination with Extracorporeal Photopheresis (ECP). The combination was well-tolerated, and ORR and CR were 55% and 44%, respectively (Table 1). Conclusion: Ruxolitinib was well tolerated by patients with acute or chronic SR-GvHD. Ruxolitinib showed a higher efficacy compared to the physician's choice drug in SR acute GvHD. Ruxolitinib was also effective in SR cGvHD patients. The addition of etanercept to Ruxolitinib increased the efficacy in SR-acute GvHD patients but resulted in an increased incidence of infections. Ruxolitinib with ECP was effective and well tolerated in SR-acute GvHD. Additional multicenter, randomized, double-blind clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-137485
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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