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 Outcome of Autologous Stem Cell Transplantation in Waldenström's Macroglobulinemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2149-2149
Author(s):  
Romil Patel ◽  
Neeraj Y Saini ◽  
Ankur Varma ◽  
Omar Hasan ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Advisory Committees ◽  
First Remission ◽  
Relapsed Disease

Abstract Introduction: The role of autologous hematopoietic stem cell transplantation (auto-HCT) in the management of patients with Waldenström Macroglobulinemia (WM), a rare, indolent lymphoma, has not been established. We had previously published our experience with auto-HCT in a small cohort of WM patients1. Here, we present an updated analysis of auto-HCT with a larger cohort of WM patients. Methods and study population: The study cohort was comprised of 29 patients who underwent high-dose chemotherapy and auto-HCT at MD Anderson Cancer Center (MDACC). The Kaplan-Meier method was used to create survival curves. Overall survival (OS) was defined as the duration from date of transplant to death or last date of follow-up in living patients. Progression-free survival (PFS) was defined as the duration from date of transplant to either progressive disease or death, whichever occurred first. Results: Median age at auto-HCT was 60 (range, 43-75 years). Eight patients (28%) had concurrent light chain amyloidosis (AL). Of the five patients who had MYD88 testing completed, 3 were positive for the MYD88 mutation. Additionally, of these 3 patients, 2 were also positive for CXCR4 mutation. Patients received a median of 2 lines (range 1-6) of therapy prior to auto-HCT; 3(10%) patients had primary refractory disease, 8(28%) were in first remission, and 18 (62%) had relapsed disease. Median time from transplant to last follow-up for the surviving patients was 5.3 years. Preparative regimens received by the patients were: Melphalan (n=20), BEAM-R (n=2), Busulfan/Melphalan (n=1), Cyclophosphomaide/Etoposide/total body irradiation (n=1), Thiotepa/Busulfan/Cyclophosphamide (n=1), and Carmustine/Thiotepa (n=1). Three patients further went on to receive allogeneic transplant either after relapse from auto-HCT or due to disease transformation to aggressive lymphoma. Twenty-eight patients achieved engraftment with a median time to neutrophil engraftment of 11 days (range, 10-15 days). One patient suffered primary graft failure due to progression of disease and died 84 days after transplant. Non-relapse mortality was 3.4% at 1 year. All patients were eligible for response evaluation. The median OS from diagnosis was 12.2 years. Overall response rate was 96%: complete response (n=8, 27.6%), very good partial response (n=5, 17.3%), partial response (n=15, 51.7%), and progressive disease (n=1, 3.4%). PFS and OS at 5 years were 43.3% and 62.9%, respectively. Median PFS and OS from auto-HCT were 4.1 and 7.3 years (Fig. 1A). The median OS from auto-HCT in first remission + primary refractory and relapsed disease was 8.2 years and 4.1 years, respectively.16 patients were alive at the time of censoring while 13 patients had died. Causes of death include relapsed disease (n=6), secondary malignancy (n=2), infection (n=1), chronic graft-versus-host disease (n=1), and unknown (n=3). 8 patients (28%) were positive for concurrent AL amyloidosis. The sites of amyloid involvement were kidneys (n=2), lungs (n=1), bone marrow (n=1), heart(n=1), lymph nodes(n=1), gastrointestinal tract (n=1) and subcutaneous fat aspirate(n=5). The median overall survival for patients with amyloid involvement (n=8) was 12 years. On univariate analyses, the number of chemotherapy regimens prior to transplant (≤ 2 vs >2 lines) was the strongest predictor of overall survival (p=0.03, HR 0.3, CI: 0.09-0.9, log-rank) and PFS (p=0.001, HR 0.24, CI: 0.07-0.85, log-rank). The median PFS in patients with ≤ 2 lines and > 2 lines of therapy was 71 months versus 19 months, respectively (Fig. 1B). Conclusion: Auto-HCT is safe and feasible in selected patients with WM, with a high response rate and durable remission even in patients with relapsed or refractory disease. References: Krina Patel et.al. Autologous Stem Cell Transplantation in Waldenstrom's Macroglobulinemia. Blood 2012 120:4533; Disclosures Thomas: Celgene: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Array Pharma: Research Funding; Amgen Inc: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Takeda: Consultancy; Celgene: Consultancy; Spectrum Pharma: Research Funding; Janssen: Consultancy; Kite Pharma: Consultancy; Sanofi-Aventis: Consultancy; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

scholarly journals A Phase II Single Arm Study of Nivolumab As Maintenance Therapy after Autologous Stem Cell Transplantation in Patients with Hodgkin Lymphoma at Risk of Relapse or Progression

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2455-2455
Author(s):  
Carlos Bachier ◽  
Henning Schade ◽  
Behyar Zoghi ◽  
Aravind Ramakrishnan ◽  
Nirav N. Shah
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Residual Disease ◽  
Refractory Disease ◽  
Advisory Committees ◽  
Extranodal Disease

Abstract Introduction: Autologous stem cell transplants (ASCT) are standard of care for patients with primary refractory or recurrent Hodgkin lymphoma (HL). While transplant results in cure for some patients, others relapse and succumb from their disease. Studies have found high expression of programmed death ligand 1 (PD-L1) in HL cells. The anti-PD-1 monoclonal antibody, nivolumab, has been safe and efficacious in the treatment of relapsed, refractory HL (Ansell et al. 2015). We evaluated the safety and efficacy of nivolumab maintenance therapy post-ASCT in high risk for relapse Hodgkin disease. Methods: Patients with HL with high risk of residual disease following ASCT ( high risk defined as refractory disease, relapse <12 months, or relapse ≥12 months with extranodal disease after frontline therapy) received nivolumab (240 mg IV every 2 weeks) starting 45-180 days post-transplant for a maximum of 6 months of treatment. Patients were followed for AEs through 100 days after the last dose of drug. PET-CT response assessments were performed 1-3 month, 6 month, and 12 month post-ASCT. The primary objective was to evaluate the safety and tolerability of nivolumab as maintenance therapy early after ASCT. The secondary objective was to evaluate progression-free survival (PFS) at 12 months post-transplant. Results: To date, 37 patients were enrolled; median age 36 years; 25 patients (68%) male. The median number of prior systemic regimens was 2 (range 2-4). 25 patients (68%) had relapsed disease, and 12 patients (32%) had primary refractory disease. 18 patients (49%) had extranodal disease at relapse, 6 patients (16%) had B-symptoms at relapse, and 11 patients (30%) had residual disease after salvage, including 10 patients (27%) of whom had 2-3 prior salvage therapies. 22 patients (60%) had received prior brentuximab, and 3 patients (8%) had received prior nivolumab or pembrolizumab. 36 patients received ASCT and 1 patient received tandem ASCT. At the time of data cutoff, 28 patients (76%) had discontinued nivolumab treatment, 22 patients (60%) because they had completed the 6-month treatment course, 4 patients (11%) due to an adverse event (AE) (1 patient each with pain, pneumonitis, rhabdomyolysis, or hypothyroidism), and 2 patients (5%) due to disease progression. The median duration of treatment was 22.1 weeks. 17 patients (46%) experienced a treatment-related AE (TRAE), of which 5 patients (14%) experienced a ≥Grade 3 TRAE. The most common (≥5%) TRAEs were diarrhea, fatigue, bone pain, neutrophil count decreased, pruritus, rash, and vomiting. 2 patients experienced a treatment-related serious AE (pneumonitis, rhabdomyolysis). There were no treatment-related deaths. With a median follow up of 9.2 months, the median PFS and overall survival (OS) have not been reached. The 6 month PFS is 92.1% and the 12-month OS is 100%. There were no differences in OS when stratified based on prior treatment. Conclusions: The use of nivolumab maintenance early after ASCT is safe and tolerable in this high risk patient population. Early efficacy data is promising, but data need to mature to determine the 12 month PFS. Figure 1 Figure 1. Disclosures Bachier: CRISPR: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Shah: Umoja: Consultancy; Incyte: Consultancy; Legend: Consultancy; Kite: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy.

The Abundance of Certain Bacteria in the Intestinal Flora Is Associated with Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 744-744 ◽  
Author(s):  
Jonathan Peled ◽  
Eric R. Littman ◽  
Lilan Ling ◽  
Satyajit Kosuri ◽  
Molly Maloy ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Intestinal Flora ◽  
Advisory Board ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Streptococcus Anginosus ◽  
Conditioning Intensity

Abstract The major causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are relapse, graft-versus-host disease (GVHD), and infection. We have previously reported that changes in the intestinal flora can affect GVHD, bacteremia, and overall survival. As intestinal bacteria are potent modulators of systemic immune responses, and since GVHD is correlated with graft-versus-tumor activity, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HSCT. We applied a biomarker-discovery approach and performed a retrospective observational analysis of 160 adults who received an unmodified (T-cell-replete) allograft. Patients were prospectively enrolled in a fecal biospecimen-collection protocol. For this analysis, we selected patients who had at least one specimen during the first 3 weeks following allo-HSCT. The primary diseases in this cohort were AML (37%), Non-Hodgkin's Lymphoma (33%), ALL (8%), MDS (7%), CLL (6%), Hodgkin's Lymphoma (6%), CML (2%), and myeloproliferative neoplasm (2%). The mean age of the patients was 52 years (range 21-75). They were conditioned with ablative (17%), reduced-intensity (64%), and nonmyeloablative (19%) regimens. They received grafts from cord blood (46%), unrelated adults (33%), or related adults (22%). Among adult grafts, 92% were from peripheral blood and 8% were from bone marrow. A census of the bacterial species in each stool sample was generated by 16S rRNA deep-sequencing as previously described (Jenq et al., BiolBone Marrow Transplant 2015). The area under the curve of bacterial abundance over time was used as a measure of each patient's cumulative exposure to each bacterial taxon. Bacterial taxa of each patient present at a frequency >1% were evaluated for association with the outcome of relapse or progression of disease within the first year after allo-HSCT using linear discriminant analysis of effect size (LEfSe), a common approach in microbiota studies (Segata et al., Genome Biology, 2011). Among the taxons most significantly associated with freedom from relapse were members of the human oral flora including Streptococcus anginosus. After stratifying the patients by median abundance, we found that those with higher abundance of this bacterium had less relapse after transplantation (Left figure, p = 0.0014). We also identified bacteria associated with increased risk of relapse, such as Enterococcus faecium (Right figure, p = 0.0103). We evaluated these bacteria as biomarkers in multivariate Cox models adjusted for three factors that were associated with relapse in this cohort: Refined Disease Risk Index (RDRI, Armand et al., Blood 2014), conditioning intensity, and graft source (cord blood vs. adult donor). Streptococcus anginosus predicted relapse in a multivariate model adjusted for all three factors (HR 0.39, 95% CI 0.16-0.96, p = 0.041). Enterococcus faecium predicted relapse in a model adjusted for RDRI and conditioning intensity but failed to do so in a model additionally adjusted for graft source. In this analysis there was no formal adjustment for multiple comparisons; these data are now being validated in an additional cohort of patients whose samples are being sequenced. Finally, although we have previously reported that low bacterial diversity is associated with decreased overall survival after allo-HSCT (Taur et al., Blood 2014), we did not find an association between bacterial diversity and relapse as assessed by reciprocal Simpson diversity index (p > 0.1). Thus, the results of this retrospective analysis have identified an association between relapse after allo-HSCT and the abundance of two bacteria in the intestinal flora. These might serve as potential novel diagnostics or therapeutic targets to prevent relapse and improve overall survival after allo-HSCT. Figure 1. Figure 1. Disclosures Peled: Merck: Research Funding. Giralt:SANOFI: Consultancy, Honoraria, Research Funding; TAKEDA: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; CELGENE: Consultancy, Honoraria, Research Funding. Perales:Merck: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Astellas: Honoraria; NMDP: Membership on an entity's Board of Directors or advisory committees. van den Brink:Boehringer Ingelheim: Consultancy, Other: Advisory board attendee; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tobira Therapeutics: Other: Advisory board attendee; Regeneron: Honoraria; Merck: Honoraria.

A Phase I Study of Selinexor in Combination with Daunorubicin and Cytarabine in Patients with Newly Diagnosed Poor-Risk Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4040-4040 ◽  
Author(s):  
Kendra L. Sweet ◽  
Rami S. Komrokji ◽  
Eric Padron ◽  
Christopher L Cubitt ◽  
Leyla Khavarian ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Poor Risk

Abstract Background: Induction chemotherapy for older adults with poor-risk AML has remained largely unchanged over the past 40 years, with complete remission (CR) rates ranging from 20-50%. Five-year overall survival (OS) ranges from 2-15%, illustrating the need for novel treatment strategies. Selinexor is an oral selective inhibitor of nuclear export (SINE) that has shown promising single agent activity in AML (NCT01607892). By inhibiting the primary export protein, XPO1, selinexor localizes tumor suppressor proteins to the nucleus leading to their activation. Furthermore, selinexor inhibits DNA damage repair, rationalizing its use in combination with DNA damaging agents. Preclinical data from our institution suggest Selinexor synergizes with daunorubicin when used in CD34+ AML cells. Here we report early results from a phase I clinical trial with selinexor plus cytarabine and daunorubicin in patients (pts) with newly diagnosed, poor-risk AML. Methods: This is a single institution phase I clinical trial with a 3+3 design and an expansion phase at the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary endpoint was to determine the MTD/RP2D of selinexor. Secondary endpoints included rate of CR/CRi, overall survival (OS), relapse free survival (RFS) and toxicity assessment. Eligible pts had a diagnosis of previously untreated AML (non-M3), with poor-risk features based on karyotype, mutational profile, secondary AML (sAML) arising from an antecedent hematologic disorder (AHD) or prior chemotherapy, or age ≥60 years. Prior treatment for an AHD was allowed. Induction included daunorubicin 60 mg/m2/day on days 1-3 and cytarabine 100 mg/m2/day CIVI days 1-7 (7+3) with two dose cohorts of selinexor: 60 mg and 80 mg PO. Selinexor was given on days 1, 3, 8, 10, 15 and 17. Re-induction with 5+2 plus selinexor was allowed if indicated. Once in CR, pts received 1-2 cycles of consolidation with 5+2 plus selinexor followed by maintenance selinexor on days 1 and 8 of a 21 day cycle for up 12 months. Selinexor was given at the same dose for all phases of the study. Pts could proceed to hematopoietic stem cell transplant (HCT) at any time after achieving CR. Results: 21 pts (14 (67%) M / 7 (33%) F) were enrolled from June 2015 to June 2016. Median age was 68 years (range 37-77); 18 (86%) were age ≥60 and 9 (43%) were age ≥70. Nineteen (90%) pts were considered poor-risk (unrelated to age), and two (10%) were eligible due to age ≥60 only. Each cohort enrolled 4 pts, and 13 pts were enrolled in the expansion. One pt in each cohort was replaced before completing the 28-day DLT period; one withdrew consent and the second died on day 23 from acute renal failure related to antibiotics. At data cutoff, 18 pts were included in the safety and efficacy assessment. Three additional patients have not completed induction. The early death rate (≤60 days) was 4.8%. No DLTs occurred in the dose-escalation cohorts. The MTD of selinexor was not reached and the RP2D was 80 mg twice weekly. The most common grade 3/4 non-hematologic, treatment emergent AEs in all pts were febrile neutropenia (56%), diarrhea (22%), hyponatremia (22%) and sepsis (17%). Nine patients (50%) achieved CR/CRi. Of the 14 pts treated at the RP2D (selinexor 80 mg), 6 (43%) achieved CR/CRi. In the entire cohort, the median age of the responders was 69 (61-77) and 4 (44%) were age ≥70. Seven (78%) were considered high-risk. Four (44%) had sAML. Two (22%) required a second induction. The median time to response was 47 days (range 28-77) At a median follow up of 8.7 months in the 9 responding pts, 7 (78%) remain in remission. Overall, 4 pts (44%) underwent HCT, and 1 (11%) relapsed just prior to HCT. Conclusion: Results from this phase I trial suggest that selinexor 80mg PO twice weekly can be safely administered in combination with induction chemotherapy using cytarabine and daunorubicin to pts with poor-risk AML, including older pts. The most prominent AEs were febrile neutropenia, diarrhea and hyponatremia. Response rates are encouraging and many elderly pts proceeded to transplant, suggesting this regimen warrants further investigation in this challenging population. Disclosures Sweet: Karyopharm: Honoraria, Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sullivan:Karyopharm: Research Funding. Shah:Incyte: Research Funding; Rosetta Genomics: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria; Pfizer: Honoraria.

scholarly journals Development and Testing of a Lymphoma Clinical Trials Specific Frailty Index: A Secondary Analysis of the LY.12 Clinical Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4076-4076
Author(s):  
Abi Vijenthira ◽  
Xinzhi Li ◽  
Michael Crump ◽  
Annette E. Hay ◽  
Lois E. Shepherd ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Frailty Index ◽  
Secondary Analysis ◽  
Advisory Committees ◽  
Frail Patients ◽  
The Impact

Abstract Background: Frailty is common in older patients with lymphoma. However, it remains unknown whether frailty is prevalent in patients included in clinical trials of lymphoma, as those with frailty may meet inclusion criteria of a trial which do not include functional information beyond performance status (PS). Understanding the prevalence and impact of frailty in clinical trials is important to direct future stratification criteria, as well as to have robust data to counsel frail patients on their potential outcomes. Methods: We conducted a secondary analysis using data from the phase III LY.12 clinical trial in which patients with relapsed aggressive non-Hodgkin lymphoma were randomized to gemcitabine-dexamethasone-cisplatin or dexamethasone-high dose cytarabine-cisplatin chemotherapy prior to autologous stem cell transplant. The primary objective of our study was to construct a lymphoma clinical trials specific frailty index (FI) using previously described methods (Searle. BMC Geriatr. 2008;8:24). Secondary objectives were to describe the association of frailty (binary variable) with overall survival (OS), event-free survival (EFS), hospitalization, adverse events (AE), serious adverse events (SAE), and proceeding to transplant, and to describe the association of frailty with these outcomes, controlling for important covariates (age, sex, immunophenotype, revised international prognostic index score (rIPI), Eastern Cooperative Oncology Group (ECOG) PS, stage, and response to previous chemotherapy). Results: 619 patients in the LY12 trial were used to construct the frailty index (Table 1). Using a binary cut-off for frailty (<0.2), 15% (N=93) of patients were classified as frail. There were no differences in age or sex between frail and non-frail patients; however they differed in terms of other lymphoma-related characteristics (Table 2). Frailty was strongly associated with OS (HR 2.012, 95% CI 1.57-2.58), EFS (HR 1.94, 95% CI 1.53-2.46), frequency of the worst overall Grade >3 AE (OR 2.65 (15% vs. 6%), p=0.003), and likelihood of proceeding to ASCT (OR 0.26, 95% CI 0.15-0.43), but not hospitalization (OR 1.52, 95% CI 0.97-2.40) or SAE (6% vs. 4%, p=0.3). In multivariable analysis, frailty was not significantly associated with OS, EFS, likelihood of proceeding to ASCT, nor hospitalization (Table 3), though there was a trend to significance for ASCT. However, rIPI remained significantly associated with OS and EFS, ECOG remained significantly associated with OS (Table 3) Conclusion: A potentially broadly applicable lymphoma clinical trials specific FI was constructed through secondary analysis of LY12 data. 15% of patients were classified as frail. Frailty was significantly associated with OS, EFS, frequency of grade >3 AE and likelihood of proceeding to transplant. However, this relationship no longer was significant when controlling for lymphoma-related prognostic variables, suggesting that the impact of poor prognostic features of lymphoma supersede the impact of frailty alone in this younger clinical trial population. Interestingly, rIPI and ECOG demonstrated their value as simple predictors that are highly associated with OS and/or EFS even when controlling for other important covariates including frailty. These findings require further testing in an external data set, and would be particularly valuable to test in an older population. Calibration of the FI against clinical frailty assessment (e.g. Clinical Frailty Scale, Comprehensive Geriatric Assessment) would also be meaningful to confirm its ability to classify frail versus non-frail patients. Figure 1 Figure 1. Disclosures Crump: Epizyme: Research Funding; Roche: Research Funding; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hay: Merck: Research Funding; Roche: Research Funding; Abbvie: Research Funding; Amgen: Research Funding; Karyopharm: Research Funding; Seattle Genetics: Research Funding. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria.

scholarly journals A Phase 1a/b Dose Escalation Study of the MYC Repressor Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3411-3411
Author(s):  
Maro Ohanian ◽  
Martha L. Arellano ◽  
Moshe Y. Levy ◽  
Kristen O'Dwyer ◽  
Hani Babiker ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Grade 3 ◽  
Refractory Aml

Abstract INTRODUCTION: APTO-253 represses expression of the MYC oncogene by targeting a conserved G-quadruplex structure in its promoter, down-regulates MYC mRNA and protein levels and induces apoptosis in AML cell lines and marrow samples from patients with AML, MDS, and MPN in vitro. After injection, a large fraction of APTO-253 binds iron and transforms to the Fe(253) 3 complex which retains full activity. APTO-253 has been granted orphan drug designation for AML by the US FDA and is being studied in a Phase 1a/b clinical trial in patients with relapsed or refractory AML (R/R AML) or high-risk myelodysplasias (high-risk MDS) (NCT02267863). AIMS: Primary objectives are to determine the safety and tolerability of APTO-253, MTD, dose limiting toxicities (DLT), and the RP2D. Key secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of antitumor activity. METHODS: Eligible patients have R/R AML or high-risk MDS for which either standard treatment has failed, is no longer effective, or can no longer be administered safely. Treatment- emergent adverse events (TEAEs) and tumor responses are evaluated using International Working Group criteria. APTO-253 is administered by IV infusion once weekly on days 1, 8, 15, and 22 of each 28-day cycle; ascending dose cohorts were enrolled at a starting dose of 20 mg/m 2 with planned escalation to 403 mg/m 2. RESULTS: As of June 7, 2021, a total of 18 patients (median age 64.0 years, 16 AML and 2 high-risk MDS) with a median of 2.5 prior treatments (range of 1 - 9) have been treated with APTO-253 at doses of 20 (n=1), 40 (n=1), 66 (n=4), 100 (n=4) and 150 mg/m 2 (n=8). Most patients were RBC (87.5% of AML and 100% of MDS) and/or platelet (75% of AML and 50% MDS) transfusion-dependent. No DLTs or drug-related serious adverse events have been reported. Only 1 patient had a drug-related TEAE of grade 3 or greater (fatigue, Grade 3, probably related). Preliminary PK analysis (Figure 1) showed that serum levels of APTO-253 were dose proportional. C max and AUC 0-72h for C1D1 dosing were 0.06, 0.02, 0.36 ± 0.37, 0.44 ± 0.41 and 0.72 ± 0.70 µM and 0.11, 0.15, 3.98 ± 1.77, 4.79 ± 0.87 and 2.51 ± 1.73 µM*h for dose levels of 20, 40, 66, 100 and 150 mg/m 2, respectively. Plasma levels for Fe(253) 3 were significantly higher than those for the APTO-253 monomer. For example, C max and AUC 0-72h of Fe(253) 3 for C1D1 dosing of patients in Cohort 150 mg/m 2 were 2- and 20- fold higher than the ATPO-253 monomer at 15.09 ± 0.42 µM and 51.52 ± 28.26 µM*h, respectively. Following dosing at 150 mg/m 2, serum concentrations of Fe(253) 3 were above 0.5 µM for > 48 h, which approaches the therapeutic range based on in vitro studies. CONCLUSIONS: APTO-253 has been well-tolerated at doses of 20, 40, 66, 100 and 150 mg/m 2 over multiple cycles and escalated to 210 mg/m 2 (Cohort 6). PK analysis revealed that APTO-253 is rapidly transformed to and co-exists with the Fe(253) 3 in serum from R/R AML and high-risk MDS patients. Enrollment of patients at the 210 mg/m 2 dose level is ongoing and updated clinical data will be presented at the meeting. Figure 1 Figure 1. Disclosures Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Levy: AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Mahadevan: caris: Speakers Bureau; Guardanthealt: Speakers Bureau; PFIZER: Other: Clinical trial Adverse events committee; TG Therapeuticals: Other: Clinical trial Adverse events committee. Zhang: Aptose Biosciences, Inc.: Current Employment. Rastgoo: Aptose Biosciences, Inc.: Current Employment. Jin: Aptose Biosciences, Inc.: Current Employment. Marango: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Howell: Aptose Biosciences, Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rice: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties; Oncolytics Biotech Inc.: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Bejar: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company; Takeda: Research Funding; BMS: Consultancy, Research Funding; Gilead: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Astex: Consultancy; Silence Therapeutics: Consultancy.

scholarly journals Bortezomib, Lenalidomide and Dexamethasone (VRD) Followed By Autologous Stem Cell Transplant for Newly Diagnosed Multiple Myeloma; The Mayo Clinic Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2147-2147
Author(s):  
M Hasib Sidiqi ◽  
Mohammed A Aljama ◽  
Angela Dispenzieri ◽  
Eli Muchtar ◽  
Francis K. Buadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
High Risk ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Mayo Clinic ◽  
Research Funding ◽  
Advisory Committees ◽  
Post Transplant ◽  
Standard Risk

Abstract We retrospectively reviewed all patients receiving bortezomib, lenalidomide and dexamethasone induction followed by autologous stem cell transplantation (ASCT) within 12 months of diagnosis for multiple myeloma at the Mayo Clinic. 243 patients treated between January 2010 and April of 2017 were included in the study. Median age was 61 (interquartile range, 55-67) with 62% of patients being male. High risk cytogenetic abnormalities (HRA) were present in 34% of patients. 166 (68%) patients received some form of maintenance/other therapy post transplant (no maintenance (NM, n=77), lenalidomide maintenance (LM, n=108), bortezomib maintenance (BM, n=39) and other therapy (OT, n=19)). Overall response rate was 99% with complete response (CR) rate of 42% and 62% at day 100 and time of best response post transplant respectively. The four cohorts categorized by post transplant therapy were well matched for age, gender and ISS stage. HRA were more common amongst patients receiving bortezomib maintenance or other therapy post transplant (NM 18% vs LM 22% vs BM 68% vs OT 79%, p<0.0001). Two year and five year overall survival rates were 90% and 67% respectively with an estimated median overall survival (OS) and progression free survival (PFS) of 96 months and 28 months respectively for the whole cohort. OS was not significantly different when stratified by post-transplant therapy (Median OS 96 months for NM vs not reached for LM vs 62 months for BM vs not reached for OT, p=0.61), however post-transplant therapy was predictive of PFS (median PFS 23 months for NM vs 34 months for LM vs 28 months for BM vs 76 months for OT, p=0.01). High risk cytogenetics was associated with a worse OS but not PFS when compared to patients with standard risk (median OS: not reached for standard risk vs 60 months for HRA, p=0.0006; median PFS: 27 months for standard risk vs 22 months for HRA, p=0.70). In patients that did not receive maintenance therapy presence of HRA was a strong predictor of OS and PFS (median OS: not reached for standard risk vs 36 months for HRA, p<0.0001; median PFS: 24 months for standard risk vs 7 months for HRA, p<0.0001). Patients receiving maintenance therapy appeared to have a similar PFS and OS irrespective of cytogenetics (median OS: not reached for standard risk vs 62 months for HRA, p=0.14; median PFS: 35 months for standard risk vs 34 months for HRA, p=0.79).On multivariable analysis ISS stage III and achieving CR/stringent CR predicted PFS whilst the only independent predictors of OS were presence of HRA and achieving CR/stringent CR. The combination of bortezomib, lenalidomide and dexamethasone followed by ASCT is a highly effective regimen producing deep and durable responses in many patients. Maintenance therapy in this cohort may overcome the poor prognostic impact of high risk cytogenetic abnormalities. Table Table. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gertz:Abbvie: Consultancy; Apellis: Consultancy; annexon: Consultancy; Medscape: Consultancy; celgene: Consultancy; Prothena: Honoraria; spectrum: Consultancy, Honoraria; Amgen: Consultancy; janssen: Consultancy; Ionis: Honoraria; Teva: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Physicians Education Resource: Consultancy.

scholarly journals Inotuzumab Ozogamicin (Ino) May Overcome the Impact of Philadelphia Chromosome (Ph)-like Phenotype in Adult Patients (pts) with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1641-1641 ◽  
Author(s):  
Elias Jabbour ◽  
Kathryn G. Roberts ◽  
Koji Sasaki ◽  
Yaqi Zhao ◽  
Chunxu Qu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
The Impact

Background: Ino showed significant activity in phase II trials in pts with R/R ALL, that was subsequently confirmed in Phase III trial where Ino demonstrated higher response rates and superior overall survival vs standard of care chemotherapy (SOC) in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R ALL).Ph-like or BCR-ABL1-like ALL possesses a gene expression profile similar to that of BCR-ABL1 ALL but lacks the BCR-ABL1 fusion protein. It is characterized by increased expression of hematopoietic stem-cell genes, deletion of B-cell lineage genes and kinase-activating alterations. Ph-like ALL is associated with refractoriness to standard induction/consolidation chemotherapy and poor prognosis. Aim: To evaluate the outcomes of pts with R/R Ph-like ALL treated in phase II trial with Ino monotherapy. Methods: We performed an integrated analysis of whole genome sequencing (to identify sequence mutations, structural variations and DNA copy number alterations), and transcriptome sequencing (RNAseq; to quantify gene expression, determine Ph-like gene expression profile and identify fusions) on 53 patients' samples treated with Ino between June 2010 and September 2012. Results: Fifty-three evaluable pts with R/R ALL with stored baseline samples were analyzed. Pts characteristics are summarized in Table 1. Median age was 50 years. Ino was given as Salvage 1, Salvage 2, and Salvage 3 and beyond in 20 (38%), 18 (34%), and 15 (28%) pts, respectively. Figure 1 reflects the different genomic subgroups identified among 53 evaluable pts. Ph-like gene signature was found in 12 pts (22.6%). Among these 12 pts, 6 had IGH-CRLF2, 2 IGH-EPOR, 1 SNX2-ABL1, and 3 had no fusions identified. The overall response rates (ORR) were 54% [complete remission (CR) 20%, CR with partial hematologic recovery (CRh) 32%, and marrow CR (CRi) 2%]. Among pts with morphologic remission, 46% and 82% achieved minimal residual disease (MRD) negativity at CR and at any time, respectively. The ORR for pts with Ph-like ALL, Ph-positive ALL, ALL with KMT2A, and others were 58% (CR=25%; CRh=33%), 42% (CR=8%; CRh=33%), 57% (CR=14%; CRh=29%; CRi=14%), and 56% (CR=26%; CRh=30%), respectively. The respective overall MRD negativity rates were 71%, 100%, 75%, and 83% (Table 1). The median follow-up was 60 months. The median event-free (EFS) and overall survival (OS) were 3.3 and 5.4 months, respectively. There was no difference in EFS and OS between the subgroups analyzed (P=0.464; P=0.824). The median EFS and OS were 4.5 and 4.5 months for pts with Ph-like, 3.1 and 7.2 months for those with Ph-positive ALL, 2.8 and 4.4 months for those with KMT2A, and 2.2 and 4.6 months for others (Table 1). 21 (40%) pts had subsequent allogeneic stem cell transplant; 6 (50%), 3 (25%), 4 (57%), and 8 (36%) in each subgroup, respectively. The rate of VOD was 3 (6%) with no difference among different subgroups. Conclusion: The current analysis suggest that Ino therapy may overcome the impact of Ph-like phenotype in pts with ALL. Confirmation of these findings in a larger cohort and in frontline ALL patients is needed. Disclosures Jabbour: Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Jain:Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Konopleva:Cellectis: Research Funding; Agios: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Eli Lilly: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Ablynx: Research Funding; Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding. Mullighan:Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; AbbVie: Research Funding; Loxo Oncology: Research Funding; Amgen: Honoraria, Other: speaker, sponsored travel. Kantarjian:Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria.

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 Safety and Efficacy of Combination Maintenance Therapy with Ixazomib and Lenalidomide in Post-Transplant Myeloma Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4774-4774
Author(s):  
Krina K. Patel ◽  
Jatin J. Shah ◽  
Lei Feng ◽  
Hans C. Lee ◽  
Elisabet E. Manasanch ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Clinical Trials ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Cell Carcinoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Proteasome Inhibitors ◽  
Advisory Board ◽  
Advisory Committees

Abstract Backrground: Several randomized controlled clinical trials have demonstrated improved outcomes for newly diagnosed multiple myeloma (NDMM) patients who were treated with lenalidomide as maintenance therapy after autologous stem cell transplant (ASCT). Proteasome inhibitors have demonstrated clinical benefit in myeloma patients when used as part of induction and maintenance regimens, and the combination of proteasome inhibitors and lenalidomide in induction regimens has produced strong clinical responses. In this study, the addition of ixazomib to lenalidomide maintenance post-ASCT in NDMM patients was evaluated. Methods: Patients (n=64) were started on maintenance therapy with lenalidomide and ixazomib within 60-180 days of stem cell infusion. Each cycle was defined as 28 days with lenalidomide starting at 10 mg/day orally for 28 days with the option to increase the dose to 15 mg after 3 cycles. Ixazomib was provided at 3 mg (n=48 patients) or 4 mg (n=16 patients) orally on days 1, 8, and 15 of each 28-day cycle. However, ixazomib dose was reduced to 3 mg in all patients based on toxicity observed in other clinical trials of ixazomib at that time. The primary endpoint measured was progression-free survival (PFS), which was defined as the time between ASCT and disease progression or death, whichever occurred first. Results: A total of 64 patients were enrolled on this study between December 4, 2012, and May 13, 2015. Of these patients, 41 (64.06%) were 60 years of age or older and 42 (65.63%) were male. Fourteen patients had high-risk cytogenetic features (+1q21, Del17p, t(14:16), t(4:14)), 50 patients had standard cytogenetic risk features (t(11:14), t(6:14), hyperdiploidy, normal) and 9 patients had International Staging System stage 3 disease. Median PFS (mPFS) for all patients was 73.3 months and has not been reached for those with ISS stage 1 disease. mPFS for ISS Stage 3 disease and high-risk cytogenetic subgroups was 33.8 and 25.4 months, respectively. Twenty-two patients had progressive disease, while 21 patients continue to receive dual maintenance. Response rates deepened over time from baseline post-ASCT for 39 patients. The complete response (CR)/stringent CR rate was 42.9% and median overall survival was not reached with a median follow-up of 62 months (range 25.4 - 82.1 months). Thirty-one patients (48%) had improvement from their baseline response after maintenance therapy: 6 patients improved from PR to VGPR; 7 from PR to stringent CR (sCR)/CR; 16 from VGPR to sCR/CR; 1 from SD to CR; and 1 patient improved from SD to VGPR. The median time to response in the 31 patients with improved response to maintenance therapy was 10.9 months (range, 0.9 to 51.3 months). Minimal residual disease (MRD) was evaluated by multicolor flow cytometry (10^-5) in 21 patients by bone marrow biopsy; 8 patients were MRD-positive. The most common grade 3/4 adverse events (AEs) included neutropenia (46.9%), leukopenia (20.3%), thrombocytopenia (15.6%), lung infections (26.6%), diarrhea and maculopapular rash (12.5% each). Secondary primary malignancies occurred in 9 patients; these included squamous cell carcinoma of the skin (n=4), basal cell carcinoma of the skin (n=1), squamous cell carcinoma and basal cell carcinoma of the skin (n=1), hepatocellular carcinoma (n=1), melanoma (n=1) and leukemia (n=1). AEs led to dose reductions in ixazomib and lenalidomide in 20 and 31 patients, respectively. Discontinuation of ixazomib due to AEs occurred in 4 patients. Grade 1/2 neuropathy occurred in 22 patients and led to reduction or discontinuation of ixazomib in 2 patients. Conclusion: Addition of ixazomib to lenalidomide maintenance in myeloma patients demonstrated a better than expected PFS compared with what has been reported in studies of lenalidomide alone, and was both safe and tolerable. These results indicate a significant clinical benefit, especially for standard risk patients. Figure 1 Figure 1. Disclosures Patel: Oncopeptides: Consultancy; Pfizer: Consultancy; Janssen: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Lee: GlaxoSmithKline: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Regeneron: Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Oncopetides: Consultancy; Amgen: Consultancy, Research Funding; Karyopharm: Consultancy; Legend Biotech: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Research Funding; Genentech: Consultancy. Thomas: BeiGene: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Ascentage Pharma: Research Funding; X4 Pharma: Research Funding; Genentech: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Qazilbash: NexImmune: Research Funding; Angiocrine: Research Funding; Amgen: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; Oncopeptides: Other: Advisory Board; Janssen: Research Funding; Biolline: Research Funding. Orlowski: Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees.

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