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  • Anwer, Faiz  (5)
  • Aslam, Shehroz  (5)
  • 1
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    Beyond JAK2 Inhibitors: A Systematic Review of Management Strategies for Myelofibrosis
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5484-5484
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5484-5484
    Abstract: Introduction Drugs that target activating mutations of Janus Kinase 2 (JAK2) have been the backbone of myelofibrosis (MF) management. With recent advancements in our understanding of the underlying molecular mechanisms involved in myelofibrosis (MF) pathogenesis, numerous novel agents have been developed in the last decade. We have systematically reviewed the mechanisms of actions, efficacy and safety of these drugs. Methods A comprehensive literature research was performed using PubMed, Cochrane, EMBASE, Web of Science and Clinicaltrials.gov. We included all trials that were under development in phase I/II/III trials. Our search identified 1642 full-length manuscripts or abstracts with published results in the last decade were screened for relevant studies. Of these, 212 articles were finalized for our final analyses. Results Hedgehog inhibitors (saridegib, glasdegib and sonidegib) targets signaling membrane protein, smoothened. The combination of sonidegib + ruxulotinib (RUX) elicited the best response. Spleen volume reduction (SVR) ≥35% and spleen length reduction (SLR) ≥50% was reported in 15 (55.6%) and 25 (92.6%) patients. Histone deacetylase inhibitors (panobinostat, pracinostat, vorinostat, givinostat) target JAK2-H3Y41-HP1 pathway involved in hematopoiesis and leukemogenesis. The combination of pracinostat + RUX demonstrated the best response in a phase II trial (n=22), with clinical improvement (IWG-MRT) in splenomegaly, symptoms and both were reported in four (18%), two (9%), and ten (45%) patients that were durable for a median of 7.5 months. Immunomodulators: Lenalidomide has shown anemia responses in 32% of patients in combination with prednisone, in a phase II trial (n=40). Improvement in bone marrow fibrosis (10/11 patients with G4 reduced to G2 or better) was also seen. Pomalidomide with or without prednisone has shown anemia responses varying from 17-24% across different trials. However, a recent phase III trial (n=32) comparing pomalidomide vs. placebo, found no difference in transfusion independence rates (16% vs. 16%, p=1.00). Azacytidine (AZA) and decitabine (DCB) are hypomethylating agents. An objective response rate (ORR) of 69% (n=39) with AZA+RUX was noted. DCB+RUX demonstrated an ORR of 57% with a median overall survival of 10.4 months, in a phase I trial (n=21). Imetelstat is a telomerase inhibitor that has shown an ORR of 21% among 33 MF patients. Responses were characterized by BMF improvement (n=4) and transfusion independence (3/7 responders). Anti Fibrotics: PRM 151, a recombinant pentraxin-2, has shown an ORR of 35% in a phase II trial (n=27). Anemia response was noted in 6/15 (40%) patients and BMF improvement in two patients, durable up to 72 weeks. Simtuzumab, an antibody lysysl oxidase like-2 (LOXL2) enzyme, failed to show any clinical benefit in a phase II study of 54 patients. Sotatercept and luspatercept are ligand "traps" that limit the activity of TGF-B superfamily ligands, involved in erythroid differentiation. Sotatercept monotherapy achieved transfusion independence (TI) in six (35%) of 17 evaluable patients. Luspatercept has recently been under investigation in patients with MF (NCT03194542). LCL-161 is a second mitochondrial activator of caspases (Smac)-mimetic, A phase II clinical trial (n=33) found an ORR of 30% (n=9). Five (56%) of the nine responders achieved anemia responses. Buparilisib and everolimus targets the PI3K/mTOR pathway. Buparilisib, a PI3K inhibitor, demonstrated a SLR ≥ 50% in 72% patients whereas everolimus, an mTOR inhibitor, showed an ORR of 23%. Conclusion The combination of ruxolitinib with some of these novel agents such as hedgehog inhibitors and hypomethylating agents have shown promising efficacy with response rates of more than 40%. LCL-161 and sotatercept has been reassuring with respect to anemia management, achieving response rates of more than 30%. PRM-151 has shown durable responses and will be the first antifibrotic for MF, if approved. Even though initial results with some of these novel agents have been ground breaking, there is a need to further explore pathways that can be targeted to help prolong survival and modify the disease course in MF 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-2018-99-115867
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 2
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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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  • 3
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    Clinical Response and Tolerability of Selinexor in Acute Myeloid Leukemia and Other Hematologic Malignancies - a Systematic Review
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5231-5231
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5231-5231
    Abstract: Introduction Selinexor, a SINE (selective inhibitor of nuclear export) compound, inhibits exportin 1 (XPO1) involved in transport of tumor suppressor proteins leading to apoptosis of tumor cells. XPO1 is overexpressed in variety of cancer including ovarian cancer, pancreatic cancer, glioma, osteosarcoma, leukemia, lymphoma, and multiple myeloma. The aim of this study is to summarize clinical response and adverse events of selinexor in hematological neoplasms. Methods A comprehensive literature search on PubMed, Embase, AdisInsight and Clinicaltrials.gov was completed on July 12, 2018. Studies focusing on efficacy and/or adverse events of selinexor in patients with hematological neoplasms were included for the review. Results Out of 321 studies found on initial search, we finalized 15 studies (8 phase I and 7 phase I/II) after screening by two reviewers. AML: Selinexor in combination with high-dose cytarabine and mitoxantrone has shown overall response rate (ORR) of 70% among 20 patients with acute myeloid leukemia (AML), Wang et al., 2018. Out of 12 newly diagnosed AML (ND AML) patients, 11 (92%) patients showed response with complete response (CR) in 7, CR with incomplete recovery (CRi) in 3 and partial response (PR) in 1 patient. Among 8 relapsed/refractory AML (R/R AML) patients, only 3 patients showed CR while 5 had treatment failure (TF), ORR in this subset was 38%. In 81 evaluable R/R AML patients receiving selinexor as monotherapy only 14% of the patients showed response while 31% patients had disease progression (PD) along with grade ≥3 hematological adverse events (AEs) of thrombocytopenia, anemia and neutropenia in 19%, 15% and 13% patients, respectively (Garzon et al., 2017). MM: Relapsed refractory multiple myeloma patients receiving selinexor combined with pomalidomide and dexamethasone have achieved ORR of 60% with CR in 1 and PR in 5 patients (Chen et al., 2016 n=10) with grade ≥3 neutropenia in 8 patients. In another regimen with doxorubicin and dexamethasone the clinical benefit rate (CBR) was 26% with 15% overall response (Rachid et al., 2017 n=27). Grade ≥3 neutropenia, thrombocytopenia and hyponatremia occurred in 33%, 33% and 30% of patients, respectively. NHL: Kuruvilla et al. observed ORR in 31% patients with relapsed refractory non-Hodgkin lymphoma with single-agent selinexor. Grade ≥3 thrombocytopenia, neutropenia and anemia occurred in 47%, 32% and 27% patients, respectively. The efficacy of selinexor in phase I and I/II clinical trials is given in table 1 while toxicity is mentioned in table 2. With selinexor, the most common hematological and nonhematological AEs noted were thrombocytopenia and hyponatremia, respectively. Conclusion: Selinexor based combination regimens have shown better clinical response against AML as compared to monotherapy. The efficacy results in multiple myeloma and other hematological malignancies are also encouraging. The adverse events like cytopenias were common as in other chemotherapy regimens. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-116819
    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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    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
    detail.hit.zdb_id: 80069-7
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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
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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