Carfilzomib (CFZ) is a proteasome inhibitor currently approved for the treatment of relapsed and refractory multiple myeloma (RRMM). Multiple trials are ongoing to evaluate its efficacy and safety in newly diagnosed multiple myeloma (NDMM). The use of CFZ-based two- or three-drug combination regimens as induction for the management of NDMM is an emerging approach. CFZ-based regimens include combinations of immunomodulators, alkylating agents, and monoclonal antibodies along with dexamethasone. In this review, we assess the efficacy and toxicity of CFZ-based regimens in NDMM. We reviewed a total of 27 studies (n=4538 patients) with overall response rates (ORR) ranging between 80% and 100%. Studies evaluating the combination of CFZ with daratumumab reported an ORR of approximately 100%. Achievement of minimal residual disease (MRD) negativity, measured by multi-parameter flow cytometry (MPFC), ranged between 60% and 95% in 4 (n=251) out of 6 studies that measured MRD-negativity. The interim results of the ENDURANCE trial failed to show superior efficacy and progression-free survival (PFS) of carfilzomib-lenalidomide when compared to bortezomib–lenalidomide combination, albeit with a lower incidence of neuropathy. Hematological toxicity was the most common adverse event observed with these regimens, and the most common non-hematological adverse events were related to cardiovascular and electrolyte disturbances. We need to further evaluate the role of CFZ in NDMM by conducting more Phase III trials with different combinations.
The most common etiology of malignant brain tumors is metastatic lesions. They usually present as multiple lesions at the gray‐white matter junction. However, they can unconventionally present as a single space‐occupying lesion mimicking meningioma.
Introduction: Nasopharyngeal carcinoma (NPC) is defined as the cancer of squamous epithelium lining nasopharynx. The single most common culprit of undifferentiated NPC is the Epstein-Barr virus (EBV). Recurrent local-regional or metastatic NPC cannot be treated with repeated chemo-radiotherapy because of poor overall survival and profound effect of these therapies on quality of life. One safer approach is immunotherapy with autologous EBV specific cytotoxic T lymphocytes (EBV-CTLS) targeted to the EBV antigens EBNA1, latent membrane protein LMP1, and LMP2 expressed by most NPC tumors. This study aims to review the efficacy and toxicity of adoptive immunotherapy with EBV-CTLS in patients with EBV induced NPC. Methods: A systematic search of PubMed, Embase, Clinicaltrials.gov, and Web of Science was performed for adoptive immunotherapy in EBV induced NPC patients from inception to May 28, 2020. Out of 604 studies, 07 phase I and II clinical trials were selected for the systematic review. Results: A total of 134 patients (pts) were evaluated out of 157 pts. 56 had a locoregional disease, 63 had distant metastasis, 15 had both locoregional disease as well as distant metastasis, 8 were in remission and disease status was unknown in 5 pts. Li et al. (2015) in their phase I clinical trial on 20 NPC pts with ECOG performance status of <3 after chemoradiotherapy (CCRT) showed overall response rate (ORR) of 95% with complete response (CR) in 19 patients. One patient showed progressive disease (PD). Median progression-free survival (PFS) was observed to be 16 months. Eighteen (90%) pts showed disease-free survival of greater than 12 months after adoptive cell therapy (ACT). Grade (G) ≥3 adverse events (AEs) included leukopenia (5%) and neutropenia (5%). Phase I/II dose-escalation trial by Louis et al. (2010) on 23 pts showed ORR of 48.7% (20% CR, 13.3% undetermined complete response [Cru], 15.4% PR) among pts with active disease. Eight pts remained in remission while 10 had metastatic disease at the time of infusion. PD was 21.7%, Stable Disease (SD) 13%, and 3 pts (13%) had recurrent disease. The median time to progression was 1059 days with PFS of 65% and 52% at 1 and 2 years respectively while the (Overall Survival) OS was 87% and 70% at 1 year and 2 years respectively. There was a higher risk of disease progression (HR: 3.91, P= 0.015) and decreased overall survival (HR: 5.55, P=0.022) in metastatic disease as compared to locoregional disease. Huang J. et al (2017) conducted a phase I/ II trial in 21 pts with a mean waiting period of 71 days after chemotherapy. Two CTL infusions were given 2 weeks apart. Two pts (9.5%) maintained SD but all other pts (85%) showed PD after 8 weeks follow- up. One patient achieved CR (4.8%). Hence, ORR was 4.8% while median PFS and OS were of 2.2 months and 16.7 months respectively. In a phase II trial, 24 patients completed 6 EBV- CTL therapy cycles after receiving chemotherapy cycles of Gemcitabine and Carboplatin. ORR was observed to be 42.9% (CR 5.7%, PR 31.7%). SD was 20% while PD was 31.4%. Median OS was 29.9 months (95% CI 20.8-39.3) with 1, 2, and 3-year rates being 77.1%, 62.9%, and 37.1 % respectively. Median PFS was 7.6 months (95% CI 7.4-8.4). All G≥3 AE occurred during chemotherapy. (Chia et al, 2014) Secondino et al. (2011) conducted a phase I/II study in 11 NPC patients who also received chemotherapy consisting of cyclophosphamide and fludarabine. After a mean follow-up of 4 weeks, ORR was 27% (PR 18%, Minor Response [MR] 9%). PD was reported to be 45% and SD 27%. Median PFS at 6 months was 54% (6/11 pts). Only G≥3 AE reported was neutropenia (36%). Phase I/II trial by Comoli et al. (2005) evaluated 10 EBV-related stage IV NPC in progression after CCRT. After receiving two to twenty-three EBV-specific CTLs infusions, 2 patients showed PR (20%), 40% of pts maintained SD and all others showed evidence of PD (40%) at 1-2 months follow up. Median PFS was 6.5 months. Smith et al (2012) in their phase I trial on 14 patients with locoregional and metastatic NPC reported SD 71.4% and PD 28.6% of patients at a median follow up of 1 month. Median OS and PFS were 17.4 months and 4.5 months respectively. No G≥3 AEs were reported. Conclusion : Adoptive Immunotherapy with EBV-CTLS has shown impressive efficacy with improvement in median PFS and OS and a favorable safety profile. Key Words: Adoptive cell therapy, Cytotoxic T lymphocytes, nasopharyngeal carcinoma, Phase I/II clinical trials, Epstein-Barr virus. Disclosures Anwer: Celgene: Research Funding; AbbVie Pharmaceuticals: Research Funding; Incyte Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Astellas Pharma: Research Funding; Acetylon Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Millennium Pharmaceuticals: Research Funding.
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.
Introduction Allogenic hematopoietic stem cell transplantation (Allo-HSCT) used for the treatment of multiple hematological malignancies requires immunosuppression, that can lead to the reactivation of viruses like EBV, CMV, adenovirus (AdV). These viruses pose a life-threatening risk to an individual like Graft vs Host Disease (GVHD) and other virus-specific complications. Adoptive T cell therapy (ATC) is an approach to treat refractory post-Allo-HSCT transplant viral infections. The aim of this study is to assess the efficacy of various ATCs being developed against various viruses. Methods A systematic search on PubMed, Embase, Clinicaltrials.gov, and Web of Science was performed for adoptive immunotherapy in viral infections after stem cell transplantation from inception to May 28, 2020. Out of 604 studies, 13 phase I and II clinical trials were selected for the systematic review. Results A total of 13 studies were included of which two studies included data on the pediatric population (n=13). A total of 335 patients (pts) were enrolled in 13 studies of which 264 were evaluable. CMV Perruccio et al. (2005) in a randomized controlled trial (RCT) assessed the efficacy of ATC against both Aspergillus and CMV after alloSCT. Median follow up (f/u) was six months. For Aspergillus (n=23), 90% and 54% achieved clearance, while for CMV (n=68) 92% and 9% didn't develop CMV reactivation in treatment and control group respectively. Overall Survival (OS) and progression-free survival (PFS) rate at two years were 92% and 80% respectively. Smith et al. (2018) (n=21) in a phase I trial studied the transfusion of virus-specific T cells (VST) (n=13) against CMV infection after undergoing alloSCT. After a median f/u of 28 weeks, overall response rate (ORR) was 85%. Bao et al. (2012) (n=10) conducted a study with VST transfusion against CMV infection (n=7). ORR was 85% of which 3 pts who were on immunosuppressive had shown reactivation. Miej et al. (2012) in phase I/II study (n=6) assessed the response of VST against refractory CMV with CR of 100% Neuenhahn et al. (2017) studied a phase I/II prospective trial (n=17) (CMV Seropositive graft donor (D+) 9/17 and CMV Seronegative graft donor (D-) 8/17) with CR of 62% in D+ group. In D- group only 37% developed T cells after Third-Party Donor transfer and only these achieved CR, while pts with no T cell detection in D- group (63%), only one achieved CR. Micklethwaite et al. (2008) did a phase I clinical trial (n=12) of CMV specific T cells given prophylactically. Only four pts showed CMV reactivation. Adenovirus Feucht et al. (2019) performed a phase I/II clinical trial (n=30) of VST against refractory AdV infection. 47% showed CR, 13% with negative blood AdV cleared virus from other sites, 10% showed PR. OS at six months was 71%. Winnie et al. (2018) (n=8) conducted phase I/II RCT among pediatric pts. Median f/u was six months. All patients have shown a decrease in AdV viral load. Qasim et al. (2013) conducted a prospective trial (n=5) among pediatric pts with CR of 60% until six weeks f/u. 20% died due to AdV viremia. Multi-virus CTLs Gerdemann et al. (2013) (n=36) did a clinical trial by infusing multi-virus cytotoxic T lymphocytes (CTLs) (n=10), reactive against CMV, EBV, and AdV. CR in 80% of the pts. Muranski et al. (2017) performed a phase I trial (n=9) and infused multi-virus CTLs prophylactically. No AdV, BK, or EBV related disease was observed in any pts while 11% pts had asymptomatic AdV viremia. Only those pts who received steroid therapy had CMV reactivation (44%). Ma et al. (2015) performed a phase I/II RCT with an intervention group (n=19, evaluable=10) and control group (n=33) with an infusion of multi-virus CTLs against CMV, EBV, AdV, and VZV after alloSCT, prophylactically. Pts in the intervention group had no reactivation of EBV, AdV, or VZV. 6 (60%) pts with CMV had reactivation; four before T cell therapy and two in the context of steroid therapy. OS at one year was 89% and 81% in the intervention and control group respectively. Third-Party Donor T-cells Tzannou et al. (2017) (n=37) in a phase II study demonstrated ORR of 92% (95% CI, 78.1% to 98.3%) in various viruses with ORR for BK virus 100%, CMV 94%, Adv 71%, EBV 100% and HHV-6 67%. Conclusion Adoptive T cell therapy for viral infections has shown efficacy in Post- allo-SCT pts who achieved complete clearance of infection in many cases, showed only minimal adverse events, and no major risk for GVHD related to this therapy was noted. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.
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