Blinatumomab and donor lymphocyte infusion (DLI) combination is a promising cancer therapy, whereby blinatumomab might achieve an initial reduction in leukemic-cell burden using T cells, and after tumor clearance, DLI can potentially stimulate the donor immune system to achieve longer lasting remission. Here, we present a 51-year-old female with mixed phenotype acute leukemia who had a hematologic relapse 3 months after she received total body irradiation-based myeloablative allogeneic hematopoietic stem cell transplantation from an unrelated human leukocyte antigen matched (10/10) donor and achieved complete remission with minimal residual disease negativity by multi-parameter flow cytometry using the combination of blinatumomab and DLI. To the best of our knowledge, this is the first report to describe the use of blinatumomab and DLI combination therapy in the treatment of B/myeloid mixed phenotype acute leukemia.
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.
Background: Treatment for post-transplant relapsed/refractory acute lymphoblastic leukemia (R/R-ALL) is not well defined. A majority of ALL relapses occur within two years after allogeneic stem cell transplantation (allo-SCT). Blinatumomab, an anti-CD19/CD3 bispecific antibody, exerts cytotoxic activity leading to apoptosis of CD19 positive B cells. Blinatumomab and DLI combination therapy is a promising new concept in cancer treatment, whereby blinatumomab might achieve an initial reduction in ALL tumor burden using T-cells, and after tumor clearance, DLI can potentially stimulate the donor immune system to achieve longer lasting remission. Methods: Literature search was performed using PubMed, EMBASE, Cochrane and Web of Science databases up to 3 July 2018. MeSH terms and keywords of blinatumomab, DLI and ALL were used. Results: Comprehensive search retrieved over 150 articles. After exclusion criteria were applied, three studies (n=15 patients) met our inclusion criteria. We summarized data on 15 patients (table 1). Outcomes were not reported homogeneously. Two studies (Ueda, M. et al. 2016; Paul, S. et al. 2017) reported CR in months and one study (Bondarenko, SN. et al. 2017) reported the response rate (RR). Before starting blinatumomab therapy, 12 patients had post-transplant bone marrow relapse, 1 patient had an extramedullary relapse and 2 patients had a minimal residual disease (MRD) without marrow relapse. Total cycles of blinatumomab ranged from 2 to 4. Total cycles of DLI ranged from 1 to 2 given after at least one cycle of blinatumomab. DLI was mostly given with blinatumomab during cycle 3 (ranged from cycle 2 to cycle 4). Blinatumomab doses were not uniformly reported. DLI doses varied between 1x107 and 5x107. Complete remission (CR) with MRD negative status was achieved after 2 cycles of blinatumomab in 3 patients, 2 of them remained in CR for 7 and 13 months. One patient achieved CR and negative MRD status 7 months after initiation of blinatumomab (total cycles of combination therapy=2). Ten patients who had median number of 2 cycles of blinatumomab showed RR of 70%. Grade I acute skin GVHD was reported in one patient during the cycle 3 of blinatumomab before the first combination therapy. One patient developed grade II aGVHD after the combination therapy (cycles were not reported). One patient developed GVHD involving mouth and skin during the second cycle of combination therapy (cycle 3). Grade 3 late-onset acute skin and gut GVHD were reported in one patient after the first dual therapy (cycle 3). No fatalities were observed with combination therapy. Therapy was stopped in one patient who had isolated central nervous system (CNS) relapse detected in the cerebral spinal fluid and orbit following allo-SCT; the patient was treated with intrathecal chemotherapy and radiation. One patient died of extramedullary and hematologic relapses seen at 6 and 11 months after initiating blinatumomab, respectively. This patient previously had a marrow relapse before starting therapy. One patient having an extramedullary disease progressed despite blinatumomab and DLI. Conclusion: Blinatumomab and DLI combination therapy appears to be safe and effective, specially for patients with MRD positive status after stem cell transplantation. Large prospective studies are required to completely understand the efficacy and safety of this combination therapy. Disclosures No relevant conflicts of interest to declare.
Background Myelodysplastic Syndrome (MDS) represents a heterogeneous group of diseases with clonal proliferation, bone marrow failure and increase risk of progression to acute leukemia. Histone deacetylase inhibitors (HDACi) modulate the epigenetics of cancer cells to promote differentiation and programmed cell death. Our aim is to study the efficacy and safety of HDACi in patients with MDS/ acute myeloid leukemia (AML). HDACi can be a safer alternative in patients with high risk MDS who are not eligible for stem cell transplantation or high intensity chemotherapy. Methods A comprehensive literature search was done using following 5 databases: (Pubmed,Embase,Web of Science,Cochrane library,Clinical Trials.Gov) in accordance with the PRISMA guidelines. We included 21 trials (Phase II/III ) with a total 1654 patients,of which 1030 patients recieved HDACi and were evaluable for respone. Our primary objective was to determine efficacy of HDACi based regimen in terms of overall response rate (ORR) and composite complete response rate (CCR). A meta-analysis was done for regimen that were evaluated in more than one trials to report ORR and CRR.CMA software V.3 was used to run metaanalysis to calculate the response and the heterogenity among studies were assesed by using I2 test.A random -effect model was applied. Results: The pooled analysis (95% CI) with 1030 evaluable patients in MDS/ AML showed an overall response rate of 37.1% (32.3-42.3 : I2= 86.105 )with composite response (comp CR=CR+Cri+mCR) of 30.8%(26.8-35.1) .The median overall survival of those who received HDACi ranges from 8 -25 months.The Base line Characterstics,Outcome and Toxicity of HDACi in MDS/AML are summarized in Table 1. In the meta-analysis (n=57) of two trials (Garcia et al, 2007 & Luger et al. 2013), combination regimen of Mocetinostat- Azacytidine had an ORR of 54%(95% CI: 10.2-92.3) and composite complete response (CCR) of 18.9% (95% CI :9.3-34.7) in patients with MDS/AML. Combination of Vorinostat-Cytarabine-Idarubicin had an ORR of 50.7% (95% CI :40.7-96.5) and CCR of 30.1% (95% CI: in 111 patients with MDS/AML in a meta-analysis of trials by Prebet et al. 2013 and Manero et al. 2012. The meta-analysis of 3 trials evaluating Vorinostat-Azacitadine regimen (Craddock et al. 2017; Sekers et al. 2017 & Montalbano et al. 2016) had an ORR 38.3%( 95 % CI :18-63) CCR of 29%(95% CI: 11-58) in a total patient population of 274 patients. The regimen of Valproate- Deictibine/Cytarabine was evaluated in 3 separate trials with a total patient population of 156 which showed an ORR of 41.6% (95 % CI :20.9-65.6)and a CCR of 28.3%(95% CI 18.9-42.7) in the metanalysis. The meta-analysis of 3 trials evaluating a three-drug regimen of Valproate-Azacytadine-All trans retinoic acid(ATRA) showed an ORR of 32.2%(95% CI :24.2-41.3) and CCR of 23.7%(95 %CI 13.1-39.0) in 144 MDS/AML patients. In a trial by Manero et al (2017), the combination of Pracinostat and Azacitadine had an ORR of 67.5% (95% CI :51.7-80.01) CCR of 60%(95% CI 44.3-73.8) in 51 AML/MDS patients. A single trial evaluating regimen of Panobinostat and Azacitadine (n=40) had an ORR of 37.5% and CCR of 27.5%. Combination of Panobinostat and Decitabine in a trial by Geoffry et al in 2017 (n=52), the ORR was 21.2% and CCR of 19.2%.The Overall response rate and Composite response rate of HDACi in MDS/AML are mentioned in Table 2 and Table 3. Conclusion: Most of the HDACi like Mocetinostat,Valproic acid ,Pracinostat when used in combination with either Hypomethylating agents(Azacytidine ,decitabine) or purine analogs (cytarabine/idarubicin) produced a good response.Pracinostat in combination with azacytidine showed the best ORR among the studies but there was only single study mentioning this combination.Single agent studies with resposne were also not evaluable.Most of MDS patients get resistant to hypomethlating agent thus there is need to explore newer agents and HDACi agents is a promising group. Disclosures No relevant conflicts of interest to declare.
Coronary cameral fistula (CCF) is a rare congenital abnormality of abnormal communication between coronary arteries and cardiac chambers. Most patients are asymptomatic, while symptomatic patients are usually present in childhood. Adult patients can present with angina, heart failure, or arrhythmias. We report a rare case of CCF with associated recurrent torsade de pointes (TdP) in the absence of ischemic heart disease and electrolyte abnormalities.
Fossil fuels are the major source of energy in the world, which are being depleted day by day. Fossil fuels are also polluting the environment by releasing greenhouse gases such as carbon dioxide. To overcome environmental pollution as well as energy crisis, exploration of new ways of storing energy is the need of the time. In the presented work, reduced graphene oxide/Strontium selenate nanocomposite has been synthesized as an electrode material for energy storage devices. The structure of rGO/ SrSeO 4 nanocomposite was confirmed by x-ray diffraction while the morphology was investigated by scanning electron microscopy. The electrochemical measurements, such as cyclic voltammetry, galvanostatic charge/discharge, electrochemical impedance spectroscopy and cyclic stability, were also carried out. The synthesized nanocomposite showed excellent specific power of 684.16 W/kg with 3.67 Wh/kg specific energy, which is significantly much better than already reported metal selenide materials.
Background: Ixazomib (Ixa) is the first FDA approved oral proteasome inhibitor to be used for relapsed and refractory multiple myeloma (MM). We conducted a comprehensive systematic review and meta-analysis of all published prospective clinical trials to analyze the efficacy and safety of ixazomib in newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma (RRMM). Method: After review of literature (last updated June 30, 2018) using database searches (Pubmed, Embase, Cochrane Library, Web of Science and Clinical Trials.gov), from a total of 1290 studies, only fifteen clinical trials (n=1387) met the inclusion criteria for RRMM and eight clinical trials (n=537) met criteria for NDMM. CMA software v.3 was used for meta-analysis. Heterogeneity among studies was assessed using the I2 test. A random-effect model was applied. Result: Based on pooled analysis, an overall response rate (ORR) of 40.6% (95% CI:19.4-66.0) with a very good partial response or better (≥VGPR) of 15.7% (95% CI: 6.8-32.1) in RRMM and ORR (CR+VGPR+PR) of 77.5% (95% CI: 73.1-81.4, I2=48.05) in NDMM was observed. Most common grade (G) ≥ 3 adverse events (AE) based on regimen were calculated using pooled analysis in MM patients. Ixazomib Based Regimen in RRMM: Ixazomib as monotherapy: Four studies (n=192) evaluated the efficacy of ixazomib as a single agent. On subgroup pooled analysis on Ixa as monotherapy, an ORR of 22.7% (95% CI: 13.3-35.9, I2=45%) was observed with ≥VGPR of 7.8% (95% CI: 2.7-20.3). Pooled analysis for safety profile on most common G ≥ 3 adverse events (AEs) were thrombocytopenia 32.3% (95% CI: 22.4-44.2), neutropenia 21.5% (95% CI: 12.6-34.1), diarrhea 13.1% (95% CI: 6.8-23.9), fatigue 11.6% (95% CI: 7.4-17.7) and peripheral neuropathy 2.2% (95% CI: 0.7-6.6). Ixazomib in two drug regimen: In RRMM, two clinical trials (n=92) evaluated the efficacy of Ixa weekly with dexamethasone (D). In this subgroup pooled analysis, ORR of 40.7% (95% CI: 22.8-61.5, I2=41.76%) with ≥VGPR of 19.5% (95% CI: 4.6-52) was calculated. One study reported event-free survival (EFS) of 8.4 months(4.5-12.8) with a 1-year overall survival rate of 96% (95% CI: 91-100). In our analysis for safety (n=102), common G≥ 3 AEs calculated was thrombocytopenia in 20% (95% CI: 7.5-43.7), neutropenia in 14.3% (95% CI: 3.7-41.6), fatigue in 9.1% (95% CI: 5.0-16.2), diarrhea in 5.7% (1.1-25.5), nausea in 5.7% (95% CI: 1.4-20.2) and peripheral neuropathy in 5.7% (95% CI: 1.4-20.2). Ixazomib in three drug regimen: In RRMM, the efficacy of Ixa was evaluated inten clinical trials (n=646), an ORR of 56.3% (95% CI: 41.8-65.5, I2=82%) with ≥VGPR of 22.8% (95% CI: 13.2-36.4) was noted. Best response was seen when Ixa was used in combination with lenalidomide (R) and dexamethasone, with reported ORR of 78.3%. Common AEs were neutropenia 23.5% (95% CI: 16-33.1), thrombocytopenia 18.8% (95% CI: 13.4-25.6) anemia 10.5% (95% CI: 8.2-13.2), diarrhea 6.3% (95% CI: 3.4 -11.3), fatigue 4.2% (95% CI:2.7-6.4), nausea 1.8% (95% CI: 0.9-3.5) and peripheral neuropathy 2.3% (95% CI: 1.3-3.9). Ixazomib Based Regimen In NDMM: Pooled analysis of subgroup study for combination regimen of Ixa as IRD, Ixa-Thalidomide (T)-D, Ixa-Cyclophosphamide (C)-D, and with Ixa -melphalan-prednisone (IMP), their estimated ORR was 83.7% (95% CI: 75.6-89.5), 80.8% (95% CI: 72.8-86.9), 75% (95% CI: 66.6-82) and 66% (95% CI: 52.4-77.4) respectively. We also measured the efficacy of Ixa as a maintenance therapy, estimated ORR was 81.5% (95% CI: 36.6-97.1, I2=90.5%). In one phase II maintenance study (n=64), a combination of IR receiving patients (n=34), an ORR of 90.4% with VGPR of 53% was reported. Median progression-free survival (PFS) was not reached after a median follow up of 37.8 months and estimated 2-year PFS was 81%. Common G≥3 AEs in NDMM patients were neutropenia 21.6% (95% CI: 11.2-37.6), thrombocytopenia 15.9% (95% CI: 4.7- 42), infections 15.2% (95% CI: 10.3-21.9) and peripheral neuropathy 7.9% (95% CI: 4.7-13). Conclusion: In our pooled analysis (95%CI), Ixazomib has shown promising efficacy both in NDMM as well as RRMM. Especially in three drug regimen it showed an estimated ORR of 84.8% in NDMM and 56.3% RRMM.Cytopenia was a common side effect.Peripheral neuropathy was noted to be a rare side-effect (2.6%) in RRMM. Further studies are required to evaluate efficacy and safety of ixazomib in combination therapies in NDMM. Disclosures No relevant conflicts of interest to declare.
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