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  • American Society of Hematology  (18)
  • Anwer, Faiz  (18)
  • 1
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    Antibodies in Development for Multiple Myeloma: A Systematic Review
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5656-5656
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5656-5656
    Abstract: Introduction Immunotherapy using monoclonal antibodies (mAbs) have been gaining significance in the treatment of multiple myeloma (MM). These include naked antibodies, checkpoint inhibitors (CPIs), novel bispecific mAbs targeting two epitopes and antibody-drug conjugates (ADCs) having a mAb conjugated to a cytotoxic drug. This review aims to summarize phase I and I/II clinical trials using mABs for the treatment of MM. Methods A comprehensive literature search using data from PubMed, Embase, AdisInsight and Clinicaltrials.gov was performed for identification of early phase (I and I/II) trials of mAbs in MM treatment (January 2008 to December 2017). Studies involving mAbs including targeting antibodies, ADCs, CPIs and bispecific mAbs were included, without considering the geo-location, age, sex or specific eligibility criteria. Drugs already approved by FDA were excluded. Results Total of 2537 phase I and phase I/II studies were identified. After screening by two reviewers and categorization by their mechanism of action, 74 clinical trials (CTs) that involved mAbs as monotherapy or in combination with other chemotherapeutic drugs for the treatment of newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). 41 CTs are active, completed or discontinued (Table 1) and 33 CTs are recruiting, approved for recruitment or planned. Most explored mechanism of action in these trials was mAb therapy directed against CD38, IL-6, huCD40, PD-L1 and PD-1. Isatuximab (Anti-CD38) has shown objective response rate (ORR) of 〉 50% in combination with lenalidomide (R) or pomalidomide (P) plus dexamethasone (d) in ongoing phase I trials NCT01749969 (n=57) and NCT02283775 (n=89) respectively. According to Vij et al. (2016) and Mikhael et al. (2018), 54% ORR (n=31) and 62% ORR (n=28) was shown by combination of isatuximab with Rd and Pd in 57 and 45 evaluable RRMM patients, respectively. In Vij et al. (2016) study, stringent complete response (sCR) in 2 (3%) patients, very good partial response (VGPR) in 13 (23%) and partial response (PR) in 16 (28%) patients was observed. In Mikhael et al. (2018) study, sCR in 1 (2%) patient, CR in 1 (2%), VGPR in 10 (21%) and PR in 16 (34%) patients was observed. In comparison, Martin et al. (2014) mentioned ORR of only 24% with isatuximab monotherapy in 34 RRMM patients. Grade (G) ≥3 pneumonia (n=4) was the most common high-grade adverse events (AEs) being reported (Table 2). Siltuximab (Anti-IL-6) has shown clinical efficacy in combination with bortezomib (V) + d and RVd in phase I and I/II CTs. Shah et al. (2016) and Suzuki et al. (2015) found ORR to be 90.9% and 67% in 11 (NDMM) and 9 (RRMM) patients when siltuximab was given combined with RVd and Vd, respectively. Clinical benefit response (CBR) i.e. ≥ minimal response (MR) was 100% with siltuximab + RVd in NDMM patients. In comparison, siltuximab monotherapy in 13 RRMM patients yielded an ORR of 15% (2 CR) as reported by Kurzrock et al. (2012). G≥3 neutropenia (n=9), G≥3 thrombocytopenia (n=6) and G≥3 lymphopenia (n=8) were most common reported high-grade AEs. Checkpoint inhibitors including pembrolizumab (anti-PD-1) and pidilizumab (anti-PD-L1) are being investigated in RRMM treatment. According to Otero et al. (2017) and Ribrag et al. (2017), 50% ORR was obtained with pembrolizumab combined with Rd compared to 0% with monotherapy, respectively. However, combination therapy was associated with G≥3 neutropenia (n=17), thrombocytopenia (n=9) and anemia (n=6) while no high-grade AEs were observed with monotherapy. Antibody-Drug conjugates including lorvotuzumab mertansine and indatuximab ravtansine have been investigated in CTs for MM treatment. Lorvotuzumab mertansine has shown clinical efficacy in combination with Rd in a phase I trial (NCT00991562). Berdeja et al. (2012) reported an ORR of 59% (1 sCR, 1 CR, 8 VGPR, 9 PR) in 32 RRMM patients. In a phase I/II trial (NCT01638936) of indatuximab ravtansine combined with either Rd or Pd, Kelly et al. (2016) showed ORR of 77% with Rd (n=43) including at least 1 CR and 4 VGPR and 79% with Pd (n=14) including 4 VGPR in total 57 RRMM patients. Conclusion Combination regimens including monoclonal antibodies, CPIs and ADCs have shown clinically significant response in RRMM and NDMM patients. The mAbs caused hematological and nonhematological AEs like cytopenias and infections which needs to be monitored closely. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-114224
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    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 2
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    A Decade of Anti-Myeloma Vaccine Development through Early Phase Trials: A Systematic Review
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5635-5635
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5635-5635
    Abstract: Introduction: Rationale for anticancer vaccine therapy is based on humoral and/or cellular response against unique tumor antigens (Ag). Peptide vaccines specific for Ag are under investigation for patients with multiple myeloma (MM). Among cell-based vaccines, monocyte derived dendritic cell (MDDC) fused with myeloma cells serve as Ag presenting cells to develop an immune response against a variety of targets. The purpose of this study is to report clinical response and tolerability of anti-myeloma vaccines. Methods: We included phase I and I/II trials developed between January 2008 to December 2017, where vaccines or viruses were used against MM, irrespective of the geo-location, age, and sex. We performed a comprehensive literature search (last update 3-30-2018) using the following databases: PubMed, Embase, AdisInsight, and Clinicaltrials.gov. Results: The initial search identified 2537 early phase studies. After screening by 2 reviewers and categorization by mechanism of action, 25 clinical trials (CT) that involved vaccines and/or viruses were included. We added 1 CT after the manual search. Therapy was given to 3 distinct classes of patients: patients without prior treatment (high risk smoldering MM or stage I MM, 4 CT), as an adjunct therapy for patients undergoing FDA approved treatments [high dose chemotherapy (HDT), allogeneic (allo-SCT) or autologous stem cell transplant (ASCT), 9 CT], and patients with residual or relapsed/refractory (RR) disease after FDA approved therapies (11 CT). Of the included 25 CT, 14 have published results available for analysis. For patients without prior treatments, PVX-410, a multi-peptide vaccine, resulted in at least minimal response (MR) in 50% of patients when combined with lenalidomiden and achieved stable disease (SD) for 60% of patients when used alone at 12 months follow up. Treatment with Idiotype-pulsed mature MMDC targeting idiotype proteins in MM showed MR in 30% of patients and SD in 43% of patients at 12 months. For patients receiving vaccines as an adjuvant treatment, recMAGE-A3 resulted in complete response (CR) and very good partial response (VGPR) in 46% and 54% respectively, at 3 months post ASCT follow up. By 12 months post ASCT, these responses were 38% CR and 23% VGPR. Treatment with MDDC (MAGE3 + Survivin + BCMA) resulted in SD in 42% of patients at a median of 25 months post vaccination and 55 months post ASCT. ScFv-FrC, a DNA fusion vaccine, resulted in CR in 50% and MR/SD in 21% at 52 weeks post vaccination. Ongoing CR/PR was maintained for 3+ years in 57 % patients, 4+ years in 36%, and 5+ years in 14% of patients following ASCT; OS was 64% after a median follow up of 85.6 months . Patients treated with MDDCs/tumor cells fusion vaccine had 69% SD after vaccination and 20% SD at a median of 26 months. When vaccines were given as a salvage therapy in RR MM, ImMucin vaccine showed a CR in 30% of patients during treatment, 20% maintained CR, and 13% had SD at a median of 24 months. Galinpepimut-S vaccine showed CR or very good partial response (VGPR) in 37% of patients at a median of 12 months, and 26% CR and VGPR at 18 months, with a progression free survival rate of 23.6 months. Patients receiving mHag loaded host MDDC vaccination also showed 8% CR for 〉 6 years (n=1) and 8% PR for 19 weeks (n=1); 33% had SD. Reolysin (wild-type reovirus), a virus-based vaccine, was used in 3 trials for RR MM patients. When alone, 42% of patients had SD and 58% had PD. When combined with dexamethasone and bortezomib 37% of patients had SD lasting for 3 cycles. Whereas, when combined with dexamethasone and carfilzomib, all patients had decrease in monoclonal proteins, with VGPR reported in 28%, PR in 43%, MR in 8%, and SD in 8% patients after 8 cycles. Most vaccines were well tolerated by patients, only grade (G) 1 and G2 side effects (SE), which were mostly flu-like symptoms and local skin reactions. G3 SE included pneumonia with mHag DC and Bcl2 peptide vaccine, GVHD with hTERT tumor vaccine, DVT and rash seen with scFv-FrC DNA vaccines. G4 SE were rare, but seen with reolysin, requiring 2 patients to be removed from study, and with DC/tumor cell fusion vaccine (1 pulmonary embolism). Conclusion Anti-myeloma vaccination therapy appears to be well tolerated, which makes it a promising adjuvant therapeutic agent against MM. Current data reveals positive immunologic activity in most patients and there is possibility of promising clinical responses with further drug development. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-115922
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 3
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    Safety and Efficacy of Venetoclax in Relapsed Refractory Multiple Myeloma: A Systematic Review and Meta-Analysis
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5625-5625
    Details
    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
    URL: Article
    DOI: 10.1182/blood-2018-99-109925
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 4
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    Sequencing Therapy for Elderly Chronic Lymphocytic Leukemia Patients in the Era of Novel Therapies: An Overview of Randomized Clinical Trials
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5559-5559
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5559-5559
    Abstract: Background: For most of the elderly or unfit CLL patients, treatment algorithms focus on achievement of clinical response, relief of symptoms and prolongation of life expectancy. Comorbidities, frailty and reduced functional status in elderly patients make some of the standard treatments intolerable and less efficacious. However, recent advancements in understanding of CLL biology, approval of target agents including novel monoclonal antibodies and kinase inhibitors have expanded the horizons for treatment of CLL in elderly. Methods: We conducted a literature search on PubMed, Embase, Web of Science and ClinicalTrials.gov which was completed on July 1, 2018. To assess the CLL treatment protocols in the elderly population, we included data from phase II and phase III clinical trials from the last decade (Jan 2008 to Jan 2018). Results: From a total of 1259 studies, we selected 34 studies (n=3122) after inclusion criteria were met. The patients included are from the age group of ≥65 years with the mean age of 68.8 years. Male to female ratio was 3:2. On comparison of different parameters to look for the drug or regimen efficacy, we found that ibrutinib is very effective and tolerable in older (aged ≥65 years) treatment-naïve (TN) as well as relapsed refractory patients (RR), with overall response rate (ORR) of 91% for combined group in one study when compared to ofatumumab. When used in combination with ublituximab, the ORR peaked to 80% as compared to ibrutinib alone in patients with high risk cytogenetics (ORR=47%, p 〈 0.001). Phase III RESONATE trial showed a comparison between ibrutinib and chlorambucil treated del 17p negative elderly patients; ibrutinib was superior in terms of ORR (86% vs. 35%) and overall survival (OS) (2-year OS, 98% vs. 85%, p=0.001). The OS with ibrutinib turned out to be 89% showing better disease control as compared to idelalisib (OS= 61%) when used in combination with rituximab, with a 33% reduction in mortality with ibrutinib as compared with idelalisib in RR patients. The combination of rituximab with idelalisib has shown promising results in patients with specific mutations (i.e. 100% ORR in those with del (17)/ Tp53 mutations, 97% ORR in those with unmutated IGHV). Similarly, when compared with placebo and rituximab combination progression free survival (PFS) was 13%, idelalisib is found to have PFS of 66% at 12 months in patients with del 17p/ Tp53 mutations and unmutated IGHV status. Moreover, in a phase II study, ofatumumab monotherapy showed ORR of 72%. In newly diagnosed (ND) CLL, an ORR of 98% is found with the pentostatin, cyclophosphamide, rituximab, and lenalidomide regimen. Other worth sharing results include; complete remission (CR) in 71% (24 out of 34 included) patients who were given lenalidomide as an initial therapy, with OS of 88% and ORR of 65%. The OS is surprisingly as high as 97.9% in those who were given pentostatin and cyclophosphamide in combination with ofatumumab. Traditional chemotherapy with fludarabine and rituximab (FR) showed OS of 67% in one study with rates of grades II and III-IV acute GVHD as 60% and 15% respectively. The most common hematological side effects seen with ibrutinib in one of the studies are neutropenia (12%), thrombocytopenia (4%) and anemia (7%). The non-hematological complications may be secondary due to cytopenias (infections, pneumonia, bleeding, and neutropenic fever) or due to constitutional symptoms like myalgia, fatigue, vomiting, or nausea. Conclusion: The rapid clinical development of novel therapy agents has changed the prognosis for CLL patients. Ibrutinib is considered as a standard option and an up front therapy for high risk CLL patients especially who are elderly and have del 17p, despite its significant toxicity profile in very elderly patients (80 years and above) where multiple deaths were reported. Future prospects include ibrutinib combinations with frontline chemo-immunotherapy (CIT) and other novel agents for TN and RR del 17p negative patients. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-117084
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 5
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    Efficacy and Safety of Histone Deacetylase Inhibitors in Multiple Myeloma - a Systematic Review of Early Phase Clinical Trials
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5629-5629
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5629-5629
    Abstract: Introduction Recent studies in novel therapies have created opportunities for new treatment regimens to be used in the management of multiple myeloma. Histone deacetylase (HDAC) inhibitors lead to epigenetic manipulation of multiple myeloma (MM) cells by reducing resistance to pro-apoptotic signals. Panobinostat is an FDA approved HDAC inhibitor for multiple myeloma. The aim of this article is to study the safety, efficacy and dose limiting toxicities of HDAC inhibitors in the early phase clinical trials in multiple myeloma. Methods We performed a comprehensive literature search for phase I & I/II trials of HDAC inhibitors during last ten years using following databases: PubMed, Embase, AdisInsight, and Clinicaltrials.gov. Studies involving HDAC inhibitors in multiple myeloma other than panobinostat irrespective of the age, sex or specific eligibility criteria were included. Results Out of 2537 studies, we included 25 trials (23 phase I, 2 phase I/II) of HDAC inhibitors in this systematic review having a total of 518 patients. Of these, 471(90.9%) patients were evaluable for response. Vorinostat (Vor) is the most studied drug used in 13 trials (n=281). Two trials had Vor-only regimen and the remaining 11 had combination regimens mostly with lenalidomide and bortezomib. Vor, in combination with lenalidomide (R), bortezomib (V) and dexamethasone (d) has showed 100% overall response rate (ORR) in 30 newly diagnosed multiple myeloma (NDMM) patients, (Kaufmann et al., 2016), fifty two percent patients achieved very good partial response (VGPR) and 28% patients showed complete response (CR). Another study using Vor + R regimen after autologous stem cell transplant in 16 NDMM patients showed VGPR in 7, stringent complete response (sCR) in 4, partial response (PR) in 2 and CR in 3 patients (Sborov et al.). Grade 3 neutropenia was seen in 1 patient in this study. Richter et al, 2011 showed an ORR of 24% in 29 relapsed refractory multiple myeloma (RRMM) patients with Vor only regimen. Another study (Kaufmann et al., 2012) with Vor only regimen used in 10 RRMM patients showed stable disease (SD) in 9 and minimal response (MR) in 1 patient. ORR of 65% was achieved in 31 RRMM patients receiving Vor in combination with doxorubicin & bortezomib (Vorhees et al, 2017). Thrombocytopenia & neutropenia were reported in 94% and 59% patients respectively. Ricolinostat in combination with Rd and Vd achieved an ORR of 55% and 29% respectively in two studies with 38 and 57 evaluable patients (NCT01583283, NCT01323751). Another ricolinostat regimen with pomalidomide & dexamethasone achieved ≥PR in 6/11 RRMM patients (Madan et al., 2016). Table 1 illustrates the efficacy, number of patients and regimens used in all the studies in this systematic review. Quisinostat in a 2017 study by Moreau P et al. (NCT01464112) showed an ORR of 88% in a combination regimen with Vd in RRMM patients (N=18). Drug related adverse events were seen in 13 patients, thrombocytopenia being most common in 11 patients, 2 patients had grade 3 cardiac disorders and 1 patient had a cardiac arrest. Romidepsin in a phase I/II study (Harrison et al., 2011) combined with Vd was used in 25 RRMM patients. ORR was 60% with VGPR n=7, CR n=2, PR n=6, SD n=5 and PD n=1. Grade ≥3 thrombocytopenia in 16, neutropenia in 9 and peripheral neuropathy in 2 patients was seen. Popat et al used combination of two HDAC inhibitors CHR 3996 and tosedostat in 20 RRMM patients. ORR was 10% and SD was seen in 30% patients. Grade 3/4 toxicities seen were thrombocytopenia (n=12), leukopenia (n=6) and diarrhea (n=5). A phase I study on AR-42 drug in 17 RRMM patients (Sborov et al., 2017) showed SD in 10, PD in 4, MR in 3 patients with progression free survival (PFS) of 8.2 months. Thrombocytopenia, neutropenia and lymphopenia were seen in 11, 10 and 6 patients respectively. A detail of all grade 3 and higher adverse events along with dose limiting toxicity is given in table 2. Three trials (NCT02576496, NCT01947140, NCT03051841) of Edo-S101, romidepsin and CKD-581 are currently recruiting with 84, 93 and 18 planned number of patients. Conclusion Regimens containing vorinostat have shown an ORR up to 100% in NDMM patients. HDAC inhibitors have also shown promising efficacy up to 88% ORR in RRMM population. Majority of the patients developed cytopenias as hematological adverse events. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-114019
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 6
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    The Comparison of Unmanipulated Bone Marrow Versus Peripheral Blood Haploidentical Stem Cell Transplantation in Adult Acute Leukemia: A Systematic Review and Meta-Analysis
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5768-5768
    Details
    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
    URL: Article
    DOI: 10.1182/blood-2018-99-109924
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 7
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    Evidence Based Recommendations for Supportive Care in Multiple Myeloma
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1952-1952
    Details
    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
    URL: Article
    DOI: 10.1182/blood-2018-99-110748
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
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  • 8
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    Efficacy of Lenalidomide Based Three Drug Versus Two Drug Regimen for Relapsed Multiple Myeloma: A Systematic Review and Meta-Analysis of Randomized Trials
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3239-3239
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3239-3239
    Abstract: Introduction: Survival of patients with multiple myeloma (MM) has improved over the last decade, mainly due to advent of newer drugs, three drug based induction, high dose chemotherapy consolidation and routine use of maintenance therapy for eligible patients. Despite advances in therapy, many cases of MM ultimately relapse and there is need to summarize evidence comparing efficacy and clinical outcome of combination regimens used in relapsed or refractory MM (RRMM) treatment. We performed a systematic review and meta-analysis of randomized controlled trials to compare the efficacy of lenalidomide based three drug regimens versus two drug regimens among relapsed and refractory myeloma (RRMM) patients. Methods: We conducted a literature search on PubMed, Embase, Wiley Cochrane Library, Web of Science and ClinicalTrials.gov which was completed on March 26, 2018. We used keywords like "relapsed multiple myeloma", "revlimid", "dexamethasone", "elotuzumab", "carfilzomib", "bortezomib", "ixazomib", "daratumumab", "doxorubicin", "pembrolizumab", "thalidomide", "cyclophosphamide" along with MeSH and Emtree terms. The primary meta-analytic approach was a random effects model using the Mantel-Haenszel method. It was used to calculate pooled risk ratio of objective response rates with 95% confidence interval. Cochrane Collaboration's tool was used for quality assessment of included studies. Systematic reviews, meta-analyses, combination regimen without lenalidomide, newly diagnosed MM patients, and other plasma cell dyscrasias were excluded. Results: Literature search retrieved 11,362 titles. Following initial screening, 72 articles were considered for full text review. Of these only five studies with 2844 patients met inclusion criteria and two studies qualified for meta-analysis. The study arm used daratumumab (Dara), ixazomib, carfilzomib, or elotuzumab in combination with lenalidomide (Len) and dexamethasone (Dex). The control arm used combination of Len and Dex (LenD). There was no difference in overall response rate (ORR) between ixazomib-Len-Dex regimen versus LenD (RR=1.33, 95% CI = 0.83 to 2.17, p= 0.236). However significantly higher complete response (CR) was observed in ixazomib-Len-Dex group compared to LenD (RR = 1.82, 95% CI = 1.14 to 2.93, p = 0.013). An absolute increase in ORR among carfilzomib-Len-Dex, elotuzumab-Len-Dex, and daratumumab-Len-Dex versus LenD was 20.4% (87.1% vs. 66.7%, p 〈 0.001), 13% (79% vs 66%, p 〈 0.001) and 16.5% (92.9% vs. 76.4%, p 〈 0.001) respectively. Conclusion: Daratumumab and carfilzomib in Len based three drug regimens have better clinical efficacy when compared to lenalidomide and dexamethasone based two drug regimens among relapsed and refractory multiple myeloma patients. There was no difference between the ORR of ixazomib based combination regimen and LenD but higher number of patients achieved deeper responses. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-111930
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 9
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    A Single Center Retrospective Evaluation of Daratumumab Infusion Related Reactions with Split-First Dose Day 1 and Day 2 Infusion
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5667-5667
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5667-5667
    Abstract: Introduction: Monoclonal antibody's infusion related reactions (IRRs) include anaphylaxis, anaphylactoid reactions and cytokine release syndrome. These reactions are related to the time of infusion. Incidence of IRRs in patients treated with daratumumab is reported to be about 42%. Severity of the most commonly reported IRRs, during the first dose of infusion are between grade I and II. Approved dosage of daratumumab is 16 mg/kg IV weekly given for 1 through 8 weeks, then every 2 weeks from 9th through 24th week, after which it is given every 4 weeks from 25th week onwards, its use is continued until disease progression. The goal of this study is to evaluate the IRRs at cycle 1 day 1 (C1D1) and C1D2, using split dose daratumumab (8 mg/kg) and to look for the impact of prior leukotriene receptor antagonist administration on the incidence of IRRs. Methods: To study the IRRs at day 1 using split dose daratumumab C1D1 (8 mg/kg) and C1D2 (8 mg/kg), we performed a retrospective review of medical records of relapsed/refractory (R/R) multiple myeloma patients receiving daratumumab between December 1st, 2015 to March 31st, 2018 at our center. Key variables related to each patient were recorded from Epic electronic database. Data were summarized using counts and percentages. Results: A total of 35 patients were included and the incidence of IRRs was measured. Overall, 13 (37.14%) patients developed IRRs on day 1. Out of these 13 patients, 11 (84.61%) patients had grade II IRRs, 1 (7.69%) patient had grade I IRRs and 1 (7.69%) patient had grade III IRRs. Nineteen (54.2%) patients out of a total 35 patients were pretreated with montelukast; out of these 19 patients, 5 (26.31%) patients had grade II IRRs and 1 (5.26%) patient had grade III IRRs. Thus, 31.57% patients had IRRs with montelukast pretreatment. No patient had grade I or grade IV IRRs. Sixteen (45.71%) patients out of total 35 patients were not pretreated with Montelukast; out of these 16 patients, 6 (37.5%) patients had grade II IRRs and 1 (6.25%) patient had grade I IRR. No patient had grade III or grade IV IRR. Thus, 43.75% patients had IRRs without montelukast. Overall, 12.18% reduction in IRRs was noted with pretreatment using montelukast. Conclusion: This single center study demonstrates that split dose model of daratumumab in the treatment of R/R multiple myeloma shows lower incidence of IRRs when compared to historical controls reported in the literature. Moreover, pretreatment with leukotriene receptor antagonist also appear to decreases the incidence of IRRs in our patient population. Future randomized prospective trials are needed to support these findings and improving the overall impact on tolerance for daratumumab. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-119736
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 10
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    The Use of Checkpoint Inhibitors before and after Allogeneic Stem Cell Transplantion: A Double-Edged Sword
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5722-5722
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5722-5722
    Abstract: Introduction: Allogenic stem cell transplantation (allo-SCT) is a potentially curative option for hematological malignancies. Checkpoint inhibitors (CPI) have been successful in achieving remission for patients that relapse after allo-SCT. CPI can help relapsed/refractory (RR) patients to respond and bridge towards allo-SCT after achieving remission. Check point inhibition after allo-SCT carries an increased benefit of graft vs malignancy effect (GvL) but it may exaggerate the risk of immune system related toxicity such as graft versus host disease (GvHD). Methods: To assess the safety and efficacy of CPI use in conjunction with allo-SCT, after a comprehensive literature search, we included data (n=283) from a total of twenty-four studies (11 original manuscripts, 13 case reports or case series) and analysed the results. Results: Most common indication for CPI use was Hodgkin lymphoma (n=182). CPIs used in various studies included CTLA-4 inhibitors (ipilimumab, n=93) and PD-1 inhibitors (nivolumab, n=167 and pembrolizumab, n= 27). In patients who were exposed to CPI before allo-SCT (n=107), 56% patients developed acute (a) GvHD and 29% patients developed chronic (c) GvHD. The overall mortality risk (11/107) associated with GvHD was 11%. Interval between last dose of CPI and allo-SCT ranged from 28-62 days. Median cycles of CPI therapy ranged from 4-9 cycles. The overall response rate (ORR) was observed (42/62) to be 68% patients with complete remission (CR) in 47% patients and partial remission (PR) in 21% patients. Most common adverse events reported were non-infectious febrile syndrome (12%), infections (5%), hepatic sinusoidal obstruction syndrome (4%) and encephalitis (3%). In patients (n=150) who received CPI after allo-SCT for treatment of disease relapse, 13% patients developed aGvHD and 11% patients developed cGvHD. The overall mortality risk with GvHD was around 7% in this population. The interval between allo-SCT and first dose of CPI ranged from 12.5 months to 29 months. Nivolumab was given at doses 1 mg/kg to 3 mg/kg, weekly or two-weekly. Ipilimumab dose ranged from 0.1 mg/kg to 5 mg/kg. A combination with lenalidomide was also tried. Pembrolizumab was administered at 200 mg/kg every three weeks. An ORR of 48% (59/123) was observed with CR in 34 (28%), PR in 25 (20%) and disease stabilization in 7 (6%) patients. Complications, other than GvHD, include hematological side effects (22%), most notably neutropenia followed by respiratory and hepatic complications (16% and 14% respectively). Thirteen case reports evaluated safety and efficacy of CPIs after allo-SCT. Among 26 cases, the reported ORR was 85% with fifteen and seven patients achieving CR and PR, respectively. Of the four patient deaths that occurred during the study period, one died of GvHD. Most common adverse reactions noted were in the GI tract, notably hepatitis (32%), followed by skin (25%) and pulmonary disease (25%). Conclusion: CPI use before and after allo-SCT can be highly effective for relapse disease control. For patients who received Allo-SCT, CPI exposure can lead to significantly increased risk of GvHD, GvHD related morbidity and mortality. There is need for caution while making decision for CPI use in this population. Prospective well-designed clinical trials are required to further explore the safety of CPIs in allo-SCT setting. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-110006
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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