scholarly journals Safety and Efficacy of JAK Inhibitor Therapy in BCR-ABL Negative MPN Patients with Underlying Portal Hypertension

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3652-3652
Author(s):  
Marta Davidson ◽  
Elliot Smith ◽  
Dawn Maze ◽  
Hassan Sibai ◽  
Vikas Gupta ◽  
...  
Keyword(s):  
Overall Survival ◽  
Portal Hypertension ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Splanchnic Circulation ◽  
Inhibitor Therapy ◽  
Jak Inhibitor ◽  
Advisory Committees ◽  
Safety And Efficacy

Abstract Background The BCR-ABL-negative Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by constitutive activation of the JAK-STAT pathway that include Polycythemia Vera, Essential Thrombocytosis, Primary (PMF) and Secondary Myelofibrosis (SMF). Splenomegaly is a characteristic feature of MPNs that can be ameliorated by JAK inhibitors (JAKi). Up-to one-third of MPN patients also experience portal hypertension (PH). Thrombosis of the splanchnic circulation is the most widely recognized etiology of PH in MPNs, however PH also occurs in the absence of intra-abdominal thrombosis. The influence of PH on outcomes of JAKi therapy in MPN patients has not been characterized. To this end, we aimed to determine the safety and efficacy of JAKi therapy in MPN patients complicated by PH with and without underlying splanchnic circulation thrombosis (ST). Methods All patients with MPNs assessed at Princess Margaret Hospital between 01/1998 and 01/2021 were identified from the MPN program's database. Patients who had undergone esophagogastroduodenoscopy (EGD) and had endoscopic evidence of PH, namely esophageal or gastric varices or portal hypertensive gastropathy were included. The study population was further limited to patients who started JAKi therapy following diagnosis of PH. Outcomes were compared between patients with and without underlying ST. The primary endpoint was palpable spleen reduction at 24 weeks. Secondary endpoints included best palpable spleen reduction within one year of starting JAKi, improvement in PH severity as determined by serial EGD assessments during JAKi therapy, overall survival, and ≥grade 3treatment emergent adverse events. Statistical differences in the frequencies of baseline characteristics were assessed using the Wilcoxon rank sum and Chi-Square tests. Overall-survival (OS) estimates were calculated by the Kaplan-Meier method using STATA/IC 16.1 software. Results All MPN patients with evidence of PH on endoscopy who started JAKi therapy after diagnosis of PH were included (n=33). Thirteen patients experienced ST prior to the start of JAKi. The proportion of younger patients and those with PH-related complications (i.e., variceal bleeding and/or ascites) was higher in patients with underlying ST (5/20 [25%] vs 9/13 [69%], p=0.01). The median palpable spleen change at approximately 24 weeks of therapy and the best palpable spleen reduction within the first year of therapy was -40.5% ([-100%[ -[+100%]) and -50% ([-100%]-0%) in the entire cohort, respectively. Better spleen responses with JAKi therapy were observed in PH patients without prior ST compared to those with underlying ST (median palpable spleen change at approximately 24 weeks was -58% (-24%-(-100%)] (n=13) vs -26.5% ([-100%]-[+100%]) (n=9), p=0.062; median best palpable spleen change at any time within 1 year of JAKi therapy start was -71% ([-14%]) -[-100%]) (n=17) vs -35% ([0%-[-100%]) (n=9), p=0.045). Of 21 patients with serial EGDs during JAKi treatment, improvement in PH severity as observed in 8 (38%). There were no differences in survival between patients with and without prior ST. Grade 3 treatment-emergent adverse events included anemia (5/33 [15%]), thrombocytopenia (5/33 [15%]), neutropenia (1/33 [3%]), and suspected Wernicke encephalopathy associated with Momelotinib (1/33 [3%]). Conclusion: In this observational study, JAK inhibitor therapy appears to be safe and effective in MPN patients complicated by PH, with a trend towards improved spleen responses among portal hypertensive patients without splanchnic circulation thrombosis. Disclosures Maze: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria; Takeda: Research Funding; PharmaEssentia: Research Funding; Kronos Bio: Research Funding. Gupta: AbbVie: Consultancy, Honoraria; Incyte: Honoraria, Research Funding; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Constellation Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Pfizer: Consultancy; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Unexpected Toxicities When Nivolumab Was Given after Allogeneic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1956-1956
Author(s):  
Amy Wang ◽  
Justin Kline ◽  
Wendy Stock ◽  
Satyajit Kosuri ◽  
Andrew S. Artz ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Stem Cell ◽  
Adverse Events ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Checkpoint Inhibitors ◽  
Advisory Committees ◽  
Relapsed Disease

Background:Treatment options are limited for patients (pts) with hematologic malignancies who relapse after allogeneic stem cell transplantation (allo-SCT). We hypothesized that checkpoint inhibitors may offer a novel approach for maintaining remission after allo-SCT. Data from pre-clinical studies have suggested a potential role for PD-1/PD-L1 inhibitors in acute myeloid leukemia (AML) (Zhang et al., Blood 2009), so it is possible that immunomodulation with checkpoint inhibitors could stimulate the donor anti-leukemia immune response and prevent disease relapse. However, the safety of checkpoint blockade early after allografting remains to be established. Methods:We conducted a pilot study to assess the tolerability and efficacy of Nivolumab, a PD-1 inhibitor, as maintenance therapy after allo-SCT (NCT02985554). Pts were eligible if they were post allo-SCT without evidence of relapse or active graft-vs-host disease (GVHD) or history of prior greater than stage I skin acute GVHD. Nivolumab was to be administered intravenously at 1mg/kg every 2 weeks for 4 doses followed by dosing every 12 weeks. Treatment started 4 weeks after routine immunosuppression was discontinued until 2 years after the transplant. The primary objective was to determine the tolerability of Nivolumab on this schedule. Secondary objectives were evaluation of adverse events, relapse, and overall survival. Results:Four pts were enrolled from December 2017 through November 2018. (Table 1)All pts experienced immune-related adverse events (irAE) from Nivolumab, and 2 (50%) pts experienced serious adverse events. (Table 2)One pt developed grade (G) 4 neutropenia soon after the first dose. (Figure 1)The absolute neutrophil count nadired at 20 cells/µL, at which point pegfilgrastim was administered. An interim bone marrow biopsy (BMBx) confirmed no evidence of relapsed disease. Full neutrophil recovery occurred approximately 3 months after the initial dose, and no subsequent toxicities occurred. Another pt developed G3 autoimmune encephalopathy concurrently with G2 transaminitis and G2 thrombocytopenia after one dose of Nivolumab. (Figure 2)Intravenous methylprednisolone (1mg/kg daily for 3 days) and immunoglobulin (2g/kg in 4 divided doses) were administered, followed by a 7-week steroid taper with full resolution of symptoms. Relapsed disease was ruled out by a BMBx. A third pt developed G2 skin rash approximately 10 days after the first dose of Nivolumab. Skin biopsy demonstrated drug hypersensitivity reaction vs GVHD, and the pt was treated with a 3-week prednisone course (starting at 1mg/kg followed by a taper). A mild flare recurred 2 weeks later, which was treated with topical steroids only. However, Nivolumab was not resumed. The fourth pt developed G2 elevated TSH approximately 2 months into therapy and after 4 doses of Nivolumab. Thyroid hormone replacement was initiated with subsequent symptom improvement and normalization of TSH over a 4-month period. As a result of these unexpected severe toxicities, the study was closed to further enrollment, and further Nivolumab administration ceased. Thus far, one pt (#1) relapsed after a total remission duration of 530 days; the remission duration after starting Nivolumab was 318 days. One pt has mild chronic skin GVHD. All 4 patients remain alive with a median overall survival of 2.3 years (range, 1.9-4.7). Conclusions:Even at low doses, the use of Nivolumab as maintenance therapy in the post allo-SCT setting was not tolerable at the current dosing and schedule due to an unexpected number of high grade irAEs. Additional studies of dose and timing after allo-SCT are needed to improve safety and tolerability, in conjunction with correlative studies to better understand the immunomodulatory processes in the post-transplant setting. Disclosures Kline: Merck: Honoraria; Merck: Research Funding. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Artz:Miltenyi: Research Funding. Larson:Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy. Riedell:Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau. Bishop:CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Arog: Other: PI of clinical trial; BMS: Research Funding; Agios: Honoraria; Novartis: Other: PI of clinical trial; Karyopharm: Research Funding. OffLabel Disclosure: Nivolumab used as maintenance therapy in the post-transplant setting

scholarly journals Trial in Progress: Phase 1b Bridging Study of the Pharmacokinetics (PK), Safety, and Efficacy of Orally Administered Olverembatinib (HQP1351) in Patients with Refractory Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph⁺ ALL)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2551-2551
Author(s):  
Elias J. Jabbour ◽  
Hagop Kantarjian ◽  
Ghayas C. Issa ◽  
Joseph Thaddeus Beck ◽  
Rebecca B. Klisovic ◽  
...  
Keyword(s):  
Adverse Events ◽  
Treatment Failure ◽  
Board Of Directors ◽  
Research Funding ◽  
Second Generation ◽  
Chinese Patients ◽  
Publicly Traded ◽  
Independent Contractor ◽  
Advisory Committees ◽  
Safety And Efficacy

Abstract Background: Management of CML using tyrosine kinase inhibitors (TKIs) is often constrained by treatment failure, which portends a poor prognosis, particularly among patients who fail second-generation TKIs because of resistance. Treatment failure may be due to therapeutic resistance (whether BCR-ABL1 mutation-dependent or independent), intolerance, and/or suboptimal adherence. The BCR-ABL1 T315I ("gatekeeper") genotype is insensitive to first- and second-generation TKIs, and compound mutations complicate management with all members of the class (including third-generation TKI ponatinib). Olverembatinib (HQP1351) is a novel, potent, orally active BCR-ABL1 TKI with promising activity against CML, including antitumor activity regardless of genotype, and a preliminarily favorable safety profile. Methods: This open-label bridging trial is evaluating the PK, efficacy, and safety of olverembatinib administered orally every other day (QOD) in adults who have chronic-phase, accelerated-phase, or blast-phase CML (CP-CML, AP-CML, or BP-CML) and Ph⁺ ALL, with or without the T315I mutation, and have experienced resistance to or intolerance (including NCI CTCAE v5.0 grade ≥ 2 adverse events) of at least 3 TKIs. Eligible patients have no residual grade ≥ 2 adverse events (other than alopecia or skin pigmentation change) due to prior treatments, a maximum ECOG performance status of 2, and a minimum life expectancy of 3 months. Study participants are being randomly allocated in a 1:1:1 ratio to 3 dose cohorts: 30, 40, or 50 mg of oral olverembatinib QOD over a cycle length of 28 days, with 10 patients per cohort and randomization stratified according to CML phase (CP-CML, AP-CML, or BP-CML) or Ph⁺ ALL and T315I mutational status. Study endpoints comprise the PK profile of olverembatinib at Cycle 1 Day 1 and Day 27; efficacy endpoints of major cytogenetic and hematologic responses; and safety. The recommended phase 2 dose of olverembatinib will be determined based on a comprehensive assessment of PK, safety, and efficacy data in US and Chinese patients. As of July 14, 2021, 14 of 30 patients have been enrolled. Internal study identifier HQP1351-CU-101. Clinicaltrial.gov identifier: NCT04260022. Disclosures Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Kantarjian: Aptitude Health: Honoraria; Daiichi-Sankyo: Research Funding; Ascentage: Research Funding; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; BMS: Research Funding; NOVA Research: Honoraria; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz: Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Issa: Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Mukherjee: Genentech: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Acceleron: Membership on an entity's Board of Directors or advisory committees; Partnership for Health Analytic Research: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; BioPharm: Consultancy; AAMDS in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria; Eusa Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Teaching and Speaking; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research/Independent Contractor, Research Funding; McGraw Hill: Honoraria, Other: Editor of Hematology Oncology Board Review (ongoing); Bristol-Myers Squibb Co.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research/Independent Contractor, Research Funding; Jazz Pharmaceuticals: Research Funding. Oehler: OncLive: Honoraria; Pfizer: Research Funding; Takeda: Consultancy; BMS: Consultancy. Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Lu: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Fu: Ascentage Pharma Group Inc: Current Employment, Current equity holder in publicly-traded company. Zhai: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

scholarly journals Impact of Genomic Alterations on Outcomes in Myelofibrosis Patients Undergoing JAK1/2 Inhibitor Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4263-4263
Author(s):  
Jay Spiegel ◽  
Caroline Jane McNamara ◽  
Andrea Arruda ◽  
Tony Panzarella ◽  
James A. Kennedy ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Board Of Directors ◽  
Research Funding ◽  
Univariate Analysis ◽  
Inhibitor Therapy ◽  
Jak Inhibitor ◽  
Jak Inhibitors ◽  
Advisory Committees ◽  
Number Of Patients

Abstract Introduction: The advent of next generation sequencing (NGS) has brought intense interest to the complex genetic landscape of myeloproliferative neoplasms (MPN). However, data regarding clinical outcomes in the context of novel MPN therapies such as JAK inhibitors are scarce. Limited data indicate that high molecular risk signature (HMR, presence of at least one mutation in ASXL1, EZH2, IDH1/2, SRSF2) or multiple mutations may be associated with decreased spleen response and a shorter time to discontinuation of Ruxolitinib in myelofibrosis (Patel et al, Blood 2015). Methods: All myelofibrosis patients seen in the MPN program at Princess Margaret Hospital between November 2009 and May 2016 and treated with JAK1/2 inhibitor therapy were identified. NGS molecular profiling of 54 genes (39 hotspot region; 15 complete coding region coverage) was performed on peripheral blood or bone marrow samples using the TruSight Myeloid Sequencing Panel. Reporting was restricted to well-covered, exonic nonsynonymous, intronic splice site, and known pathogenic synonymous variants. Variants with global mean allele frequency >1% were identified using multiple population databases (1000 genomes, ESP, ExAC) and excluded. The primary endpoint was time from start of JAK1/2 inhibitor therapy to treatment failure (TTF) defined as treatment discontinuation, progression to accelerated phase or leukemic transformation, spleen progression or death. Secondary endpoints included best spleen, anemia and IWG response achieved by 48 weeks of treatment and overall survival. Response was assessed according to the 2013 revised IWG-MRT criteria. Transfusion dependency was assessed as any transfusion in 12 weeks prior to treatment or being identified as transfusion dependent in medical history. Results: Of 159 patients treated with JAK1/2 inhibitors at our institution, 102 met the inclusion criteria (see Table 1). Patients were excluded if; no sample was available for analysis (19), short use of JAK inhibitor prior to transplant (9), active clinical trial (5), in accelerated phase/acute leukemia (4) and others (20). First JAK inhibitor used was ruxolitinib in 77 patients and momelotinib in 25. At least one mutation was identified in every patient. Twenty (20%) patients had one mutation, 32 (31%) had 2 mutations and 50 (49%) patients had ≥ 3 mutations. Eighty (82%) patients had the JAK2V617F mutation, 15 (15%) had mutations in CALR, 4 (4%) had MPL mutations and one patient was triple negative. One patient had mutations in both CALR and JAK2 while another had mutations in MPL and CALR. Forty-eight (47%) patients had mutations consistent with HMR profile. Mutation profile is summarized in Table 2. With median follow-up of 2.5 years, 51 (50%) patients experienced treatment failure. On univariate analysis, TTF was associated with DIPSS, pre-treatment transfusion status and Hb <100 prior to initiating JAK inhibitor therapy. However, TTF was not associated with specific driver mutations, the number of mutations or HMR profile. Exploratory analysis of genes mutated in ≥5% of the population showed EZH2 (p=0.004) and CBL (p=0.005) mutated patients had shorter TTF. Multi-variable analysis employing anemia <100 and DIPSS with either of the number of mutations or HMR profile did not show any association with TTF. There was a trend towards TTF in patients with Hb<100 (HR 2.21, 95%CI: 0.99-4.95, p=0.05). Of 102 patients, 91 were evaluable for spleen response with 43 (47%) achieving a spleen response by 48 weeks of treatment. Twelve (23%) of the 53 patients evaluated met criteria for anemia response. Neither spleen nor anemia response was associated with the use of a particular JAK inhibitor. Of the 95 patients with at least 48-week follow-up, best response while on treatment was clinical improvement and spleen response in 29 (31%) and 19 (20%) patients respectively. Conclusions: In this study of myelofibrosis patients treated with JAK inhibitors, EZH2 and CBL mutated patients had shorter TTF. We did not find any association between TTF and number of mutations or other high risk mutations such as ASXL1/SRSF2. Anemia was the only significant independent predictor of shorter TTF. Our findings highlight the need for multicenter collaborative studies on a large number of patients and cautious use of mutation profiling results in routine clinical decision making with current treatment approaches. Spiegel and McNamara are co-primary authors. Disclosures Panzarella: Cellgene: Consultancy. Schimmer:Novartis: Honoraria. Schuh:Amgen: Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kamel-Reid:BMS: Research Funding. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

scholarly journals First Report of the Gimema LAL1811 Phase II Prospective Study of the Combination of Steroids with Ponatinib As Frontline Therapy of Elderly or Unfit Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 99-99
Author(s):  
Giovanni Martinelli ◽  
Alfonso Piciocchi ◽  
Cristina Papayannidis ◽  
Stefania Paolini ◽  
Valentina Robustelli ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adverse Events ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Advisory Board ◽  
Intrathecal Therapy ◽  
Advisory Committees ◽  
Unfit Patients ◽  
Travel Grant

Abstract Background. The incorporation of tyrosine kinase inhibitors (TKIs) in treatment schemes of Ph+ ALL has remarkably improved survival. In adult patients with Ph+ ALL, ponatinib in combination with chemotherapy showed a 3-year event-free survival rate of 69%, a 3-year overall survival (OS) of 83%, and a higher rate of response when compared with dasatinib plus chemotherapy. However, in unfit or elderly ALL patients, TKIs combined with chemotherapy are associations with higher toxicity. Therefore, we examined the efficacy and safety of steroids plus ponatinib alone for the treatment of elderly or unfit patients with Ph+ ALL in a multi-center Phase II prospective clinical Italian trial, GIMEMA LAL1811 (EudraCT number 2012-002761-35). Methods. From March 2014 to December 2016, we enrolled 44 patients with untreated Ph+ ALL, ≥ 60 years or unfit (i.e. for intensive chemotherapy and stem cell transplantation). Two out of 44 patients were not elegible for the study. Patients received oral administration of 45 mg/day of ponatinib for 8 consecutive courses of 6 weeks (w). Steroids were administered from day -14 to day 29 during course 1. Intrathecal therapy with methotrexate, cytarabine and dexametasone was performed every 28 days for central nervous system (CNS) disease prophylaxis. In patients with CNS disease at diagnosis, intrathecal therapy was administered twice a week until complete remission. Dose reduction of ponatinib was allowed for adverse events. Patient samples were obtained at diagnosis and at every course, BCR-ABL mutational analisys and BCR-ABL/ABL ratio by quantitative real time PCR was performed. Complete molecular response (CMR) was defined as BCR-ABL/ABL ratio below 0.01 or undetectable, and with a sensitivity of at least 30,000 molecules of ABL. Results. Forty-two patients were eligible for the study. Median age was 68 years (range 27-85). Nine out of 42 patients were &lt;60 years and were considered unfit. Twenty-six out of 42 patients had the p190 fusion transcript, 4/42 had p210, 12/42 had p190/p210. Steroid pretreatment was administered to 39; 14/39 patients had a reduction in circulating blasts of 75% or more before starting ponatinib. Primary endpoint (Complete hematological response (CHR) at 24w in 75% of patients) was prematurely reached. CHR was obtained in 40/42 patients (95,2%) after course 1 (6w). Thirty-eight out of 42 patients (90,5%) were in CHR after 8 courses (24w); 2 patients stopped treatment after 6w for disease relapse (1) and for excessive toxicity (1). Two patients dropped out after 12w for medical decision. A CMR was detected in 11/24 patients at 24w (45.8%; 14/38 patients not evaluable). Considering a CMR test sensitivity of at least 10,000 ABL molecules and testing peripheral blood whenever a bone marrow was not obtained, 20/33 patients (60.6% 5/38 patients not evaluable) were in CMR at 24w (figure 1). The median follow-up of the enrolled patients was 11.4 months (range 6-34.5). Overall survival (OS) at 6 months and 1 year was 97.6% (C.I 95%: 93.1%-100.0%) and 87.5% (C.I. 95%: 76.5%-99,9%) respectively (figure2). At week 24, 15/42 patients still received 45 mg of ponatinib daily, only 4/42 patients permanently withdrew study drug. During the study, 75 adverse events (AE) were reported; 36 of the 75 AEs were considered related to ponatinib. Twenty-six of the 75 AEs were considered serious (SAE); 13/26 SAEs were considered related to ponatinib. A death was suspected to be related to ponatinib. We performed BCR-ABL mutational analysis in 22 patients at diagnosis, and 15 patients at 24w. T315L (abundance 100%) was detected in a patient relapsed during ponatinib therapy. We could not identify the emergency of other mutations. Conclusions. Ponatinib and steroid show a high efficacy in newly diagnosed unfit/elderly Ph+ ALL patients. Toxicities were manageable and cardiovascular AEs were limited. In the small cohort of patients relapsed in the study, relapse mechanisms were unclear; only one patient had evidence of mutations that caused resistance to ponatinib. The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway could explain the therapeutic effectiveness. Acknowledgments. GIMEMA, ELN, AIL, AIRC, Regione-Università 2010-12, FP7 NGS-PTL, HARMONY, Fondazione del Monte BO e RA. Disclosures Soverini: Bristol-Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy. Bocchia: Novartis: Other: Travel grant; Celgene: Other: Travel grant; Roche: Other: Travel grant; Jansen: Other: Travel grant. Cuneo: Abbvie: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board; Roche: Honoraria, Other: Advisory Board. Bonifacio: Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Falini: Roche: Research Funding. Galieni: Takeda: Other: Advisory Board; Abbvie: Other: Advisory Board. Foà: Sandoz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Baccarani: Pfizer: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

Safety and Efficacy Of Long-Term Open-Label Romiplostim Dosing In Thrombocytopenic Pediatric Patients With Immune Thrombocytopenia (ITP)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3530-3530
Author(s):  
Michael D. Tarantino ◽  
James B. Bussel ◽  
Amy Geddis ◽  
Michael F. Guerrera ◽  
Alan K. Ikeda ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Pediatric Patients ◽  
Open Label ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Platelet Counts ◽  
Equity Ownership

Abstract Background Chronic pediatric ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production, resulting in low platelet counts. Romiplostim is a peptibody that stimulates platelet production via activation of the thrombopoietin (TPO) receptor. Romiplostim increased and maintained platelet counts in thrombocytopenic children with ITP in a phase 1/2 trial. Patients who completed this study or an ongoing phase 3 trial were given the option of rolling over into an open-label long-term extension study. Objectives To evaluate the safety and efficacy of long-term use of romiplostim in pediatric ITP. Methods Patients received weekly subcutaneous injections of romiplostim; the starting dose was the last dose in the prior study. Patients who had received placebo started at 1 μg/kg. Dose adjustments targeted platelet counts in the range of 50–200 x 109/L. The maximum allowed romiplostim dose was 10 µg/kg. Assessments of adverse events, concomitant medications, and local platelet counts were performed weekly. The primary endpoint was incidence of adverse events. The protocol did not require bone marrow biopsies to be performed, but when performed, specimens were submitted to a central lab for analysis. Patients who were on a stable dose had the option to receive romiplostim at home; patients and their caregivers then recorded dosing date, time, volume administered, and any dosing errors. Patients who turned 18 years of age during this study were permitted to remain on study. Results Twenty-two patients (N = 12 from the phase 1/2 study and N = 10 from the phase 3 study) were treated with romiplostim for up to 172 weeks (3.3 years). Baseline demographics included a median age of 12.0 years (range 3–16), 50% male, and 18.2% with prior splenectomy. Median romiplostim treatment duration was 89.0 weeks (range 3–172); median total number of doses was 64 (range 3–171); median average weekly romiplostim dose was 4.0 µg/kg (range 1–10), including ramp up to stable dose; and median maximum dose was 8.0 µg/kg (range 1–10). Of the 4 patients who discontinued the study, 3 withdrew consent and 1 was noncompliant; no patients withdrew due to safety issues and 18 continued on study. After the first week of this extension study, which for some patients was the first week of romiplostim, median platelet counts remained above 50 x 109/L throughout the study, and were in the target range of 50–200 x 109/L for all visits but weeks 76 and 156 (Figure). The median romiplostim dose (Q1, Q3) was 6.0 (2.0, 8.0) µg/kg at week 1 and 3.5 (0.0, 7.0) µg/kg at week 168 (Figure). Four patients discontinued romiplostim. Eight patients received rescue medications (defined as medications used for platelet counts < 10 x 109/L, bleeding/wet purpura, or investigator decision) which included immunoglobulins (3 patients), tranexamic acid (3 patients), platelet transfusion (1 patient), aminocaproic acid (1 patient), and prednisone (1 patient). Four patients had serious adverse events (asthma, hemangioma, hypotension, infection, thrombocytopenia, and transfusion reaction) and 1 had life-threatening adverse events (infection and thrombocytopenia). None of the serious adverse events were deemed treatment-related by the investigators. There were no fatal adverse events. Twelve patients had bleeding adverse events; 2 of which were deemed treatment-related (gingival bleeding and petechiae). Bleeding adverse events included epistaxis (4 patients); petechiae (3 patients); gingival bleeding (2 patients); hemorrhage (2 patients); and bleeding from the anus, injection site, lip, and mouth (1 patient each). No bone marrow biopsies were performed as part of this study. Conclusion In this open-label extension study, long term treatment with romiplostim maintained platelet counts in pediatric patients with chronic ITP without significant toxicity. Future results from this ongoing study will provide additional safety and efficacy data regarding long-term use of romiplostim in children with ITP. Disclosures: Tarantino: Pfizer: Membership on an entity’s Board of Directors or advisory committees; Octapharma: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; BPL: Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Romiplostim is approved for the treatment of adults with chronic ITP. Romiplostim is not approved for the treatment of pediatric patients with chronic ITP. Bussel:Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees. Nie:Amgen: Employment, Equity Ownership. Eisen:Amgen: Employment, Equity Ownership.

scholarly journals A Pilot Study of the Anti-SLAMF7 Monoclonal Antibody, Elotuzumab, in Myelofibrosis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3635-3635
Author(s):  
Prithviraj Bose ◽  
Taghi Manshouri ◽  
Sharon D. Bledsoe ◽  
Nitin Jain ◽  
Lucia Masarova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Current Status ◽  
Jak Inhibitor ◽  
Advisory Committees ◽  
Allele Burden

Abstract Background: Prior work from our group has shown that fibrocytes, the cells driving bone marrow (BM) fibrosis in patients with primary myelofibrosis (PMF), are neoplastic (clonal) and derived from monocytes (Verstovsek, J Exp Med 2016). These findings led to the clinical development of PRM-151 (recombinant human pentraxin-2) as an anti-fibrotic agent for patients with myelofibrosis (MF) (Verstovsek, EHA 2019). Our observations were extended by others to show that thrombopoietin receptor (MPL) activation induces fibrocyte differentiation and that blood monocytes highly expressing MPL and signaling lymphocyte activation molecule family member 7 (SLAMF7) were possible fibrocyte precursors (Maekawa, Leukemia 2018). Furthermore, patients with JAK2V617F+ MF have a significantly elevated SLAMF7 high monocyte percentage, which correlates with the JAK2V617F allele burden (Maekawa, Blood 2019). Finally, elotuzumab, a SLAMF7-targeting monoclonal antibody, inhibited the differentiation of MF patient-derived fibrocytes in vitro and romiplostim-induced MF and splenomegaly in vivo. Study design and methods: This is a single-institution, investigator-initiated, pilot phase 2 study of elotuzumab monotherapy in patients with JAK2V617F+ PMF or post-polycythemia vera/essential thrombocythemia MF who need treatment but are not candidates for JAK inhibitor therapy. Baseline BM fibrosis grade must be 2 or 3 per the European consensus (Thiele, Haematologica 2005). Prior JAK inhibitor treatment is permitted. Elotuzumab is dosed intravenously weekly at 10 mg/kg per dose for the first 8 doses, followed by 20 mg/kg every 4 weeks, per the label for its use in multiple myeloma in combination with pomalidomide and dexamethasone. Patients may continue elotuzumab until disease progression or unacceptable toxicity, up to a maximum of 36 cycles. Premedication and management of infusion reactions are carried out according to the elotuzumab package insert. Spleen and liver sizes are measured by palpation and the MPN-SAF-TSS questionnaire (Emanuel, J Clin Oncol 2012) is administered on day 1 of each cycle. Patients receive a BM biopsy at screening and every 6 cycles while on-study. Plasma cytokines are measured at baseline and every 3 cycles while on-study. The primary endpoint is overall response rate according to the revised IWG-MRT-ELN criteria (Tefferi, Blood 2013). A total of 15 patients are planned to be enrolled. Elotuzumab is provided by Bristol-Myers Squibb. Adverse events are graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. The method of Thall, Simon and Estey (Thall, Stat Med 1995) is used for toxicity monitoring. Correlative studies: These include quantification of SLAMF7 highCD16 neg circulating monocytes by flow cytometry, measurement of serum interleukin-1 receptor alpha (IL-1Rα) concentrations and correlation of these with each other and with the mutant JAK2 allele burden, culture of human fibrocytes from peripheral blood mononuclear cells (PBMCs) in vitro, engraftment of BM cells from patients in non-obese diabetic, severe combined immunodeficient gamma (NSG) mice, and quantitation of fibrocytes in the BM of participants at baseline and every 6 cycles. Current status: The study (clinicaltrials.gov identifier: NCT04517851) is ongoing; 2 participants have been enrolled and treated thus far. Updated enrollment information will be provided. Disclosures Bose: Astellas: Research Funding; Sierra Oncology: Honoraria; Constellation Pharmaceuticals: Research Funding; Novartis: Honoraria; Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Blueprint Medicines: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Pfizer: Research Funding. Jain: TG Therapeutics: Honoraria; Janssen: Honoraria; Servier: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Beigene: Honoraria; Adaptive Biotechnologies: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pfizer: Research Funding; Cellectis: Honoraria, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding. Pemmaraju: Roche Diagnostics: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Springer Science + Business Media: Other; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Sager Strong Foundation: Other; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Plexxicon: Other, Research Funding; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Kantarjian: Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Astra Zeneca: Honoraria; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria; Daiichi-Sankyo: Research Funding; Jazz: Research Funding; Immunogen: Research Funding; BMS: Research Funding; Astellas Health: Honoraria; AbbVie: Honoraria, Research Funding; Ascentage: Research Funding; Novartis: Honoraria, Research Funding; Aptitude Health: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Verstovsek: Blueprint Medicines Corp: Research Funding; Promedior: Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; CTI BioPharma: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; NS Pharma: Research Funding; Ital Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; Sierra Oncology: Consultancy, Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. OffLabel Disclosure: Elotuzumab is a monoclonal antibody targeting SLAMF7, previously known as CS-1. It is approved for the treatment of multiple myeloma in combination with an IMiD and dexamethasone. This trial studies it as a single agent in patients with myelofibrosis.

Safety and Efficacy of Subcutaneous-Administered Omacetaxine Mepesuccinate in Chronic Myeloid Leukemia (CML) Patients Who Are Resistant or Intolerant to Two or More Tyrosine Kinase Inhibitors – Results of A Multicenter Phase 2/3 Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 861-861 ◽  
Author(s):  
Jorge Cortes-Franco ◽  
Digumarti Raghunadharao ◽  
Purvish Parikh ◽  
Meir Wetzler ◽  
Jeffrey H. Lipton ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Median Overall Survival ◽  
Cytogenetic Response ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Hematologic Response ◽  
Grade 3

Abstract Abstract 861 Background: Omacetaxine is a first-in-class cetaxine with clinical activity against Ph+ CML and a mechanism of action independent of tyrosine kinase inhibition. The development of TKI resistance and intolerance is an emerging problem and patients (Pts) who have failed multiple TKIs may benefit from an alternative therapy for CML. Study Goals: To evaluate the safety and efficacy of SC omacetaxine in CML Pts who are resistant and/or intolerant to two or more TKIs. Methods: Eligible Pts included adult CML Pts in chronic, accelerated, or blast disease phase (CP, AP, BP) with resistance and/or intolerance to at least two TKIs. Bcr-Abl mutational analysis was performed at one of 2 central reference laboratories and Pts harboring the T315I Bcr-Abl mutation were enrolled in a separate clinical trial. Induction schedule: 1.25 mg/m2 SC omacetaxine twice daily for 14 days every 28 days until hematologic response. Maintenance dosing: 1.25 mg/m2 SC omacetaxine twice daily for 7 days every 28 days. Study Results: To date, 99 Pts have enrolled, with data available for analysis on 65 Pts (30 CP, 20 AP and 15 BP). The median age was 57 yrs (23-78) with 52% male and a median disease duration of 77 mo (1-197). Nearly all (64/65, 99%) Pts failed prior IM therapy and 57% failed 3 or more prior TKIs. Baseline mutations were identified in 21 (32%) Pts with 10 non-P Loop, 7 P Loop and 4 compound mutations. Baseline clonal evolution was evident in 5 (17%) CP, 8 (40%) AP, and 13 (87%) BP Pts. Six CP Pts entered the study in CHR. The median follow-up for all Pts is 4.0 mo (0.3 to 14.7). Efficacy: In CP Pts, CHR was achieved in 18 Pts and maintained for more than 8 weeks in the 6 Pts enrolled with baseline CHR, for an overall CHR rate of 80%; median duration 4.7+ mo (1.4 to 13). Major cytogenetic response (MCyR) was achieved in 6 (20%) CP Pts (1 complete, 5 partial); median duration 1.6+ mo (0.0 to 2.9). Major molecular response was achieved in 10% of CP Pts. In AP Pts, overall hematologic response was achieved in 15 (75%) Pts; 12 CHR and 3 return to chronic phase (RCP); median duration 2.5+ mo (1.8 to 10.5). One (5%) AP Pt achieved a complete CyR, identified immediately prior to data cut-off and ongoing. In BP Pts, overall hematologic response was achieved in 8 (53.3%); 6 CHR and 2 RCP. Three Pts (2 CP, 1 AP) received bone marrow/stem cell transplants after achieving major cytogenetic response, a therapeutic option not available to them at study enrollment. No deaths occurred in CP Pts. The median overall survival for AP Pts has not been reached and 13 Pts were alive at the time of data cut-off. Median overall survival was 14.5 mo for BP Pts. Median time to progression was 11.1, 5.7, and 2.6 mo for CP, AP, and BP Pts, respectively. Safety: Grade 3/4 related events occurred in 47/65 (72%) of Pts. The most commonly reported events (>15%) were thrombocytopenia (43%), neutropenia (29%), and anemia (22%). Non-hematologic toxicities were generally grade 1/2 with the most frequently reported; diarrhea (32%), nausea (26%), pyrexia (23%), headache (20%), fatigue (19%), vomiting (17%), and asthenia (17%). Grade 3/4 non-hematologic toxicities were uncommon with no events occurring in >5% of Pts and fatigue (3%) the most common event. Treatment delays occurred in approximately 50% of the Pts with median duration of approximately 9 days for all disease phases and cycles (CP=7, AP=11, and BP=12 days). The primary causes of delay were thrombocytopenia, neutropenia and pancytopenia. Deaths occurred in 6 (9.2%) Pts, including 2 (10%) AP pts and 4 (26.7%) BP Pts. Of the deaths, one occurrence in an AP Pt was considered to be possibly related to omacetaxine treatment (febrile neutropenia). Conclusions: Omacetaxine administered by SC injection produced hematologic and cytogenetic responses with a safety profile primarily consisting of hematologic toxicities. This study demonstrated that omacetaxine may be a potential treatment option for CML Pts who have failed multiple TKIs. Disclosures: Cortes-Franco: ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Raghunadharao:ChemGenex: Research Funding. Parikh:ChemGenex: Research Funding. Wetzler:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lipton:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jones:ChemGenex: Research Funding. Hochhaus:ChemGenex: Research Funding. Kantarjian:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Craig:ChemGenex: Employment. Benichou:ChemGenex: Employment. Humphriss:ChemGenex: Employment. Nicolini:ChemGenex: Research Funding.

PRM-151 in Myelofibrosis: Durable Efficacy and Safety at 72 Weeks

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 56-56 ◽  
Author(s):  
Srdan Verstovsek ◽  
Ruben A. Mesa ◽  
Lynda M Foltz ◽  
Vikas Gupta ◽  
John O. Mascarenhas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Negative Slope ◽  
Computer Assisted ◽  
Jak Inhibitor ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Grade 3

Abstract Background: PRM-151 (PRM) is a recombinant form of pentraxin-2, an endogenous human protein that acts at sites of tissue damage, inducing macrophage differentiation to prevent and reverse fibrosis. 27 patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, or post-polycythemia vera MF and Grade 2 or 3 bone marrow (BM) fibrosis enrolled in the first stage of a 2-stage adaptive trial in which PRM-151 10 mg/kg IV was administered for 24 weeks in four different arms: PRM-151 QW (n=8), PRM-151 Q4W (n=7), PRM-151 QW + ruxolitinib (RUX) (n=6), or PRM-151 Q4W + RUX (n=6). At 24 weeks, reductions in BM fibrosis, improvements in hemoglobin (Hgb) and platelets (PLT), decreases in symptoms (MPN-SAF Total Symptom Score [TSS]), and modest reductions in spleen size by palpation were observed in all arms, with a favorable safety profile (Verstovsek, ASH 2014, Abstract 713). Patients experiencing clinical benefit were allowed to continue beyond 24 weeks. We now report efficacy and safety in 13 patients who have completed at least 72 weeks of treatment. Bone marrow fibrosis status by morphologic WHO grading and computer-assisted image analysis (CIA) are available up to 48 weeks in some patients, as assessed by central hematopathologist reviewers blinded to patient, treatment, and timepoint. BM data through 72 weeks is pending. WHO response was defined as ≥1 grade reduction in MF grade at any time and CIA response was defined as a decrease in the % fibrosis compared to baseline with a negative slope > 1. (Pozdnyakova, EHA 2015, Abstract P677). Baseline Demographics (N=13): Median age 60 (51-76); 46% DIPSS Int-1, 54% DIPSS Int-2; 62% PMF, 15% post-ET MF, 23% post-PV MF; 46% grade 3 BM fibrosis, Hgb < 100 g/L in 38%, PLT < 100 x 109/L in 69% and <50 x 109/L in 38%; 31% JAK inhibitor-naive and 69% received a prior or current JAK inhibitor. Study treatment (N=13): In the first 24 weeks, treatment was PRM-151 QW (n=5), PRM-151 Q4W (n=3), PRM-151 QW + RUX (n=2), PRM-151 Q4W + RUX (n=3). At 28 weeks, treatment changed to PRM-151 QW (n=2), PRM-151 Q4W (n=7), and PRM-151 Q4W + RUX (n=4), with 1 patient stopping RUX for thrombocytopenia. Both PRM-151 QW patients switched to PRM-151 Q4W after 40 and 52 weeks. Two patients missed weeks 64 and 68 due to complications of a motor vehicle accident and abdominal surgery, respectively, but are continuing treatment as of week 72. BM (n=13): 54% had a morphologic response, and 85% had a CIA response. Hgb (g/L): In 5 pts with baseline Hgb < 100, median Hgb increased by 24% from 86 (range 77-97) at baseline to 107 (range 71-113) at Week 72. 3 of 5 patients who were receiving transfusions at baseline became transfusion independent, with durations of 32-60 weeks. (Figure 1) PLT (x 109/L): In 9 pts with baseline < 100, median PLT count increased by 37% from 38 (range 10-89) at baseline to 52 (range 26-159) at Week 72. All 4 patients who were receiving PLT transfusions at baseline became transfusion independent, with durations of 24-44 weeks. (Figure 2) Symptoms (N=13): 69% and 38% of patients had ≥ 50% and 100% reductions from baseline in TSS between 24 and 72 weeks, with durations of up to 48 and 12 weeks, respectively. (Figure 3) Spleen (N= 9 with palpable spleens at baseline): 50% of pts had ≥25% reduction, 2 of whom had ≥50% reduction lasting > 12 weeks. (Figure 4) Safety (N=13): Most common adverse events (AEs) regardless of relatedness were fatigue (4), nausea (3), fever (3), cough (2), diarrhea (2), tooth infection (2), headache (2), upper respiratory infection (2), hyperglycemia (2), and hyperuricemia (2). There were 13 possibly or probably related adverse events in 3 patients from beginning of study through 71 weeks, 11 Grade 1, 1 Grade 2 and 1 Grade 3, with no event occurring in > 1 patient. There were no related serious AEs in these patients. Conclusion: In 13 patients completing at least 72 weeks, PRM-151 treatment was well tolerated, and improvements in Hgb, PLT, symptoms and spleen appeared to increase with longer treatment duration. Disclosures Mesa: Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Genentech: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Pfizer: Research Funding. Foltz:Promedior: Research Funding. Gupta:Incyte Corporation: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Promedior: Research Funding. Mascarenhas:Kalobios: Research Funding; Roche: Research Funding; Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding. Ritchie:Incyte: Speakers Bureau; Celgene: Speakers Bureau. Hoffman:All Cells, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding. Silver:Promedior: Research Funding. Pozdnyakova:Promedior: Consultancy. Hasserjian:Promedior: Consultancy. Trehu:Promedior: Employment, Equity Ownership. Salama:Promedior: Consultancy. Gotlib:Allakos, Inc.: Consultancy.

scholarly journals Mitoxantrone, Etoposide and Cytarabine (MEC) Can Induce Deep Complete Remission and Is an Effective Bridge Therapy to Allotransplantation (SCT) in Refractory/Relapsed Acute Myeloid Leukemia (AML) Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4036-4036
Author(s):  
Giovanni Marconi ◽  
Annalisa Talami ◽  
Maria Chiara Abbenante ◽  
Stefania Paolini ◽  
Chiara Sartor ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Median Overall Survival ◽  
Rescue Therapy ◽  
Treatment Schedule ◽  
Advisory Committees ◽  
Number Of Patients

Abstract Introduction Relapsed/refractory (R/R) AML patients continue to be a formidable clinical challenge, mainly in consideration of associated very poor outcome, with a median overall survival (OS) of less than 12 months. SCT represents the only curative option for these patients. Although, there is no standard-of-care approach which may serve as a bridge to SCT. Our study aims to investigate the effectiveness of MEC regimen as a rescue therapy for R/R AML patients by specifically addressing the CR rate, including minimal residual disease (MRD) negativity, the number of patients who subsequently underwent SCT and the presence of predictive factors of response. Methods Fifty-five consecutive adult AML patients were treated with MEC regimen in our Institution. In patients under 66 years old, we administered mitoxantrone 6 mg/sqm/die from day 1 to day 6, etoposide 100 mg/sqm/die from day 1 to day 6 and cytarabine 1000mg/sqm/die from day 1 to day 6, whereas in patients over 66 years old, the treatment schedule was reduced to 4 consecutive days. Data were retrospectively collected by using RedCap in accordance with Helsinki declaration and GCP. We used Kaplan-Meyer to estimate survival, and log rank to test differences in survival. Chi-squared, fisher's exact test and linear-by-linear correlation were used to test differences in proportions and distributions. Response was defined in accordance with 2017 ELN recommendations. CTCAE 4.03 was used to grade adverse events. MRD was assessed with WT1 or specific fusion transcripts. Results Fifty-five patients received MEC from 2008 to 2018. Age at diagnosis ranged from 17 to 72 years, with a median age of 51 years. Our set was enriched for high-risk patients. Interestingly, twenty percent of patients harbored FLT3-ITD at diagnosis (table 1). Two main groups were included: resistant AML, 28/55 patients (50,9%), and relapsed AML, 27/55 patients (49,1%). At induction, almost half of patients received "3+7" (n=25, 45,5%), while fludarabine-based regimens were administered to 14 patients (25,5%). In our set, after MEC median duration of hospitalization was 30 days (14-78); PMN >500/mm3 was reached after 26 days (range 18-67). Fever and febrile neutropenia was the most recurrent adverse events (AE). AEs were low in grade; out of 80 graded AEs, 38 (47,5%) were grade 2, 27 (33,8%) were grade 3, 9 (11,3%) were grade 4 and only 3 events resulted in death (3,8%). E. coli was the most recurrent cause of infection (10 cases). Overall, 25/55 patients (45,5%) achieved a complete remission (CR) after one course of MEC chemotherapy. Twelve patients (21.9%) achieved MRD negativity and 13 patients (23,6%) obtained an MRD+ CR or had no MRD test. Six patients (10,9%) had a partial response (PR) and 1 patient (1,8%)had hematological improvement (HI). Four patients (7.3%) died during post-MEC aplastic phase. Disease risk at diagnosis and R/R status did not influence the chance to obtain CR (figure 1 A). In 12 patients, a second MEC was administered. Four out of 12 patient improved their response with the 2nd MEC (2 patients obtained MRD - from MRD+ CR, 1 patient obtained PR and 1 patients obtained CR from hematological improvement). MEC was an effective bridge to SCT, 32/55 patients (58,2%, figure 1 B), received SCT; 15/32 patients (46,9%) received SCT directly after the 1st course of MEC, 9/32 patients (28,1%) after the 2nd course of MEC and 2 patients (6,3%) after an additional course of post-remission chemotherapy. Of note, only 6 patients (18,8%), who were not responsive to MEC, underwent SCT after an alternative rescue therapy. Median overall survival (OS) from MEC was 455 days (95% C.I. 307-602 days.); 1-year OS, 3-year OS and 5-years OS were 57,9%, 33,2% and 23,1%, respectively (std. error ± 0,067). Patients who responded to MEC (CR MRD+ or CR MRD- after 1 or 2 courses) had better OS than non-responders (median OS 1389 vs 160 days, p=.003). Stepwise multiple logistic regression analysis with COX-HR model established that pre-MEC R/R status, diagnosis class risk, response to one or two courses of MEC, and SCT were independent predictors of survival in the optimal model. Conclusions Taken together, our data indicate that MEC is an effective salvage regimen with affordable toxicity, and gives a high chance to obtain CR. MEC is particularly useful as a bridge to SCT, and has to be considered as a rescue therapy whenever a clinical trial is not available. *GM and AT equally contributed Disclosures Martinelli: Ariad/incyte: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Roche: Consultancy. Cavo:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Safety and Efficacy of Sars-Cov-2 Vaccines in Hodgkin Lymphoma Patients Receiving PD-1 Inhibitors

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2445-2445
Author(s):  
Jakub Svoboda ◽  
Hatcher J Ballard ◽  
Carrie I Ho ◽  
Mitchell E. Hughes ◽  
Elise A Chong ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Median Time ◽  
Research Funding ◽  
Igg Antibody ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Patient Reported ◽  
Antibody Titers

Abstract Background: Patients (pts) with cancer are at higher risk for complications and mortality related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although mRNA vaccines have been granted Food and Drug Administration emergency use authorization (EUA) for prevention of COVID-19, the pivotal trials largely excluded pts with active cancer. Emerging data suggests suboptimal efficacy of these vaccines in pts with hematologic malignancies. There are also theoretical concerns that programmed cell death protein 1 inhibitors (PD-1i) could potentiate vaccine-related adverse events (AEs); conversely, these vaccines could activate the immune system, increasing the risk for immune-related reactions (IRRs) after PD-1i treatment. Pts with classic Hodgkin lymphoma (cHL) receiving PD-1i represent a unique cohort and should be investigated for safety and efficacy issues with SARS-CoV-2 vaccines. Methods: We conducted a retrospective analysis of pts with cHL who were treated with PD-1i within the past 12 months. Our primary objective was to determine the frequency of vaccine-related AEs and also subsequent IRRs to PD-1i after vaccination as reported in the medical records. Our secondary objective was to determine efficacy based on post-vaccine COVID-19 infection rates and by presence of adequate receptor binding domain (RBD) IgG antibody level to the SARS-CoV-2 spike protein. This assay was a clinically available institutional assay developed under EUA. While the level of antibody that is associated with immune protection has not yet been defined, we used RBD IgG &gt; 0.700 AU as positive since it was previously correlated with virus neutralization titer in vitro. Results: From July 1, 2020 through June 31, 2021, we identified 27 pts who received PD-1i for cHL and were seen at the University of Pennsylvania. Seventeen (63%) pts received nivolumab and 10 (37%) received pembrolizumab. The median age was 42 years (23-86), median number of therapies was 4 (2-15), and 7 (26%) had prior history of COVID-19 infection (none required hospitalization). Twenty-three pts (85% of total) were vaccinated: 17 (74%) received Pfizer-BioNTech BNT162b2 and 6 (26%) had Moderna mRNA-1273 formulations. Of 19 (83%) pts who received at least one dose of PD-1i prior vaccine, the median time between last PD-1i infusion and first vaccine administration was 20 days (2-157). Of 19 (83%) pts who received any PD-1i after vaccine, the median time to infusion was 18 days (4-89). In pts who had prior COVID-19 infection, the median time between the prior infection and vaccine was 91 days (range 78-350). There were no unexpected toxicities noted and no severe adverse events or hospitalizations directly related to vaccination. No patient discontinued the vaccination series due to side effects. In 12 vaccinated pts who had vaccine-related AEs solicited by the medical provider, 7 (58%) developed injection site reaction/pain: grade 1 (6/12) and grade 2 (1/12). Six (50%) pts had systemic AEs: grade 1 fatigue (4/12), grade 2 fatigue (1/12), transient generalized lymphadenopathy (1/12), fever (1/12). No new IRRs occurred in pts receiving subsequent PD-1i after vaccination. Two weeks after second vaccination, 1 patient developed worsening cough with imaging suggestive of pneumonitis but improved with antibiotics. There were no post-vaccine COVID-19 infections noted. RBD IgG antibody levels were available in 12/23 (52%) of all vaccinated pts; 11/12 (92%) pts had positive antibody titers. The only patient who did not mount positive RBD IgG antibody titers received brentuximab vedotin concurrently with PD-1i prior to vaccination. There were insufficient events to correlate pre-vaccine factors with AEs or efficacy. Conclusion: Pts with relapsed/refractory cHL on PD-1i who received SARS-CoV-2 vaccines had no unexpected toxicities and tolerated subsequent PD-1i without new IRRs. The efficacy based on post-vaccination COVID-19 rates and RBD IgG levels is encouraging in these heavily pretreated pts. We plan an additional prospective component of this study using patient reported outcomes and long-term safety and efficacy follow-up. Disclosures Svoboda: Incyte: Research Funding; Genmab: Consultancy; Merck: Research Funding; Pharmacyclics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; TG: Research Funding; Imbrium: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Atara: Consultancy; Adaptive: Consultancy, Research Funding. Dwivedy Nasta: Roche: Research Funding; Merck: Other: Data safety monitoring board; Incyte: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; ATARA: Research Funding; Millenium: Research Funding; Rafael: Research Funding; Debiopharm: Research Funding. Ruella: AbClon: Consultancy, Research Funding; BMS, BAYER, GSK: Consultancy; Novartis: Patents & Royalties; Tmunity: Patents & Royalties; viTToria biotherapeutics: Research Funding. Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; ADCT: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; Morphosys: Membership on an entity's Board of Directors or advisory committees. Barta: Seagen: Honoraria; Daiichi Sankyo: Honoraria; Acrotech: Honoraria; Kyowa Kirin: Honoraria. Gerson: TG Therapeutics: Consultancy; Kite: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy. Schuster: Loxo Oncology: Consultancy; Nordic Nanovector: Consultancy; Genentech/Roche: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acerta Pharma/AstraZeneca: Consultancy; BeiGene: Consultancy; Juno Theraputics: Consultancy, Research Funding; Tessa Theraputics: Consultancy; Pharmaclyclics: Research Funding; Abbvie: Consultancy, Research Funding; Alimera Sciences: Consultancy; Adaptive Biotechnologies: Research Funding; Merck: Research Funding; Incyte: Research Funding; TG Theraputics: Research Funding; DTRM: Research Funding.

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