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 Determinants of Clinical Trial Participation and Impact on Survival Outcomes Among Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5833-5833
Author(s):  
Gabriella C Malave ◽  
Prashant Kapoor ◽  
Angela Dispenzieri ◽  
Morie A. Gertz ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Research Funding ◽  
Trial Participation ◽  
Newly Diagnosed ◽  
Clinical Trial Participation ◽  
Advisory Committees ◽  
Baseline Characteristics

Background: The overall participation of cancer patients in interventional clinical trials in the United States remains very low, with ~5% of patients being enrolled in clinical trials nationwide. The outcomes of patients with MM have improved significantly over the past decade, but available data suggest that the participation rates for patients with MM is comparable to other cancers. The drivers of participation and the potential impact of clinical trial participation have not been systematically studied in MM. Patients and Methods: We identified 228 patients who were enrolled into clinical trials for initial therapy of newly diagnosed MM between 2004 and 2018, and 4 controls for each of these patients. Controls were patients with NDMM, who were diagnosed closest in time to the index patients and did not participate in an interventional treatment trial. Various baseline characteristics as well as overall survival were compared between the two groups. Results: The baseline characteristics of the two groups are as shown in the Table. Patients who entered clinical trials were more likely to be female, resided closer to the clinic, and were more likely to have a prior history of MGUS. They were more likely to have higher ISS Stage, and a higher serum LDH, but there was no difference in the FISH risk status. Other indices of disease burden such as lower hemoglobin and platelets, higher serum creatinine were all seen more often in the control group, but may have been influenced by the trial entry criteria. Looking at the outcomes, the overall survival was longer among those enrolled into clinical trials compared to those who did not [median 103 (95% CI; 86, 136) vs. 63 (95% CI; 53, 69) months, p<0.001 (Figure). Conclusions: The current study provides important clues regarding demographic determinants of trial participation and disease biology related features that reflect likelihood of trial participation. Overall survival was significantly longer among the trial participants, which likely represent a mix of reasons including baseline status of patients, intensity of monitoring and efficacy of novel treatment approaches. Table Disclosures Kapoor: Janssen: Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding; Takeda: Honoraria, Research Funding. Dispenzieri:Alnylam: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Akcea: Consultancy; Intellia: Consultancy. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Spectrum: Honoraria, Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy. Leung:Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees. Russell:Imanis: Equity Ownership. Kumar:Takeda: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

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

The Ki67/CD138 Ratio Independently Predicts Overall Survival in the Upfront Treatment of Newly Diagnosed Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2016-2016
Author(s):  
Tomer M Mark ◽  
Peter Forsberg ◽  
Ihsane Ouansafi ◽  
Adriana C Rossi ◽  
Roger N Pearse ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Newly Diagnosed ◽  
First Line ◽  
Advisory Committees ◽  
Line Therapy

Abstract Background: Assessment of malignant plasma cell cycling via plasma cell labeling index (PCLI) has been a validated prognostic tool in multiple myeloma (MM) but the test requires specialized technical expertise and is not widely available. Ki67 is a well-known protein marker of cellular proliferation on immunohistochemical (IHC) staining with prognostic utility in other malignancies. In an effort to develop a simpler system to provide analogous information to PCLI, we used a novel IHC co-staining technique for CD138 and Ki67 to quantify plasma cells in active cycling. We then performed a retrospective analysis of the ratio of Ki67/CD138 (Ki67%) in newly diagnosed patients with multiple myeloma receiving 1st-line therapy to correlate with clinical outcomes. Methods: A retrospective cohort study of patients (pts) with treated symptomatic MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital. For inclusion in the analysis, subjects must have started first-line treatment in the period of 2005-2010, and had available bone marrow biopsies. Double-staining with Ki67 and CD138 was performed by IHC. The Ki67% was calculated as the percent of plasma cells expressing CD138 that were also found to express Ki67. Treatment outcomes were stratified and compared based on %Ki67. Response was determined by monthly serum protein electrophoresis / immunofixation (IFX) with free light chain analysis according to International Multiple Myeloma Working Group (IMWG) guidelines. Pts who were IFX negative but had no subsequent bone marrow biopsy were classified as being in unconfirmed complete remission. Results: We identified 151 patients with newly diagnosed MM and available %Ki67 expression who received first-line therapy over the period of 2005-2010. Patient were subdivided into two groups based on %Ki67: Low: %ki67 <= 5%, n = 87; and High: %Ki67 >5, n=64, to allow for comparison of treatment response and survival analysis. Specific therapeutic agent exposure history did not differ significantly between patients. Both groups had similar depth of response rates (ORR) to front-line therapy, Table 1. Median progression-free survival for the high versus low %Ki67 groups approached statistical significance at 54 months (95% CI 30.8,67.4) versus 26.9 months (95% CI 21.6,40.2), respectively (P = 0.083). At data cut-off, there were 30 deaths in the low %Ki67 group (1-yr OS 93%, 5-yr OS 71%) and 36 deaths in the high %Ki67 group (1-yr OS 94%, 5-yr OS 62%). Median overall survival (OS) was not reached for Ki67% <= 5% (95% CI 97.3,NR) vs. 78.9 months (95% CI 55.9,93.1) for Ki67% > 5%, (P = 0.0434), Figure 1. Multivariate cox regression for factors with influence on OS showed that only high-risk cytogenetics (HR 2.05, 95% CI 1.17, 2.92, P = 0.027), ISS (HR 1.835, 95% CI 1.33, 3.60, P = 0.000), and %Ki67 group status had an independent effect on survival outcome. Low (<=5%) versus high (>5%) %Ki67 influenced overall survival with a hazard ratio of 1.76 (CI 1.07,2.92, P = 0.027). Survival after ASCT was significantly longer in the low %Ki67 group with median OS not reached (95%CI, 97.3, NR) versus 86.9 months (95% CI 43.9, NR) for high %Ki67 group (P = 0.04). Discussion: The ratio of IHC double positive Ki67 and CD138 of > 5% is an independent prognostic marker for overall survival in newly diagnosed MM undergoing 1st line therapy. The %Ki67 serves as a simpler and widely available analog to PCLI that can be presently performed in most hematopathology laboratories. Table 1: First Line Treatment and Best Response (modified IMWG Criteria) Ki67% <= 5(N = 87)n (%) Ki67% > 5(N = 64)n (%) P Treatment Exposure* Lenalidomide 59 (67.8) 48 (75) 0.34 Thalidomide 30 (34.5) 14 (21.9) 0.09 Bortezomib 25 (28.7) 14 (21.9) 0.34 Alkylating agent 11 (12.6) 4 (6.3) 0.19 ASCT 27 (31) 22 (34.4) 0.66 Best Response Overall Response (>= Partial response) 77 (88.4) 57 (89.1) 0.41 Complete response 15 (17.2) 22 (34.4) Unconfirmed complete response** 14 (16.1) 8 (12.5) Very good partial response 23 (26.4) 15 (23.4) Partial response 25 (28.7) 12 (18.8) Stable disease 9 (10.3) 5 (7.8) Progressive disease 1 (1.2) 2 (3.1) * Percentages do not add to 100% due to instances of concurrent therapy use ** Unconfirmed complete response: immunofixation negative, but no confirmatory bone marrow biopsy available Figure 1 Overall Survival by %Ki67 Figure 1. Overall Survival by %Ki67 Disclosures Mark: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Pekle:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:Celgene: Speakers Bureau. Coleman:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Honoraria. Niesvizky:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

A Phase 1/2 Study of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1068-1068 ◽  
Author(s):  
Anna B. Halpern ◽  
Megan Othus ◽  
Emily M Huebner ◽  
Kaysey F. Orlowski ◽  
Bart L. Scott ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Phase 1 ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3 ◽  
Dose Levels

Abstract Introduction:"7+3" with standard doses of cytarabine and an anthracycline has remained the mainstay of induction chemotherapy for newly diagnosed AML. Since some studies have shown improved outcomes with high-dose cytarabine, cladribine, or escalated doses of anthracyclines, we conducted a phase 1/2 study (NCT02044796) of G-CLAM using escalated doses of mitoxantrone for newly diagnosed AML or high-risk MDS (>10% blasts). Methods: Patients≥18 years were eligible if they had treatment-related mortality (TRM) scores of ≤6.9 (corresponding to a predicted risk of early death with standard induction chemotherapy of ≤6.9%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5 times upper limit of normal). Excluded were patients with uncontrolled infection or concomitant illness with expected survival <1 year. In phase 1, cohorts of 6-12 patients were assigned to 1 of 4 total dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day, days 1-3, compared to 10 mg/m2/day used in standard dose G-CLAM previously established in relapsed/refractory AML). Other drug doses were G-CSF 300 or 480 μg/day (for weight </≥76 kg; days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). In phase 2, patients were treated at the maximum tolerated dose (MTD) of mitoxantrone. A second identical course of G-CLAM was given if complete remission (CR) was not achieved with cycle 1. Up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed if CR or CR with incomplete platelet or blood count recovery (CRp/i) was achieved with 1-2 cycles of induction therapy. Dose-limiting toxicities (DLTs) were: 1) grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7-day delay of the subsequent treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding febrile neutropenia, infection or constitutional symptoms. Results: Among 33 patients (median age of 57.3 [range: 26-77], median TRM score 2.31 [0.16-5.90]) treated in phase 1, one DLT occurred at dose levels 3 and 4 (respiratory failure in both cases), establishing G-CLAM with mitoxantrone at 18 mg/m2/day as the MTD. Sixty-two patients, including 6 treated in phase 1, received G-CLAM at MTD. Patient characteristics were as follows: median age 58 (21-81) years, median TRM score 2.85 (0.06-6.73), with AML (n=52) or high-risk MDS (n=10). Cytogenetics were favorable in 6, intermediate in 44, and adverse in 12 (MRC criteria); 11 patients had NPM1 and 6 had FLT3 mutations. Fifty-two patients (83.9%, 95% confidence interval: 72.3-92.0%) achieved a CR (n=48 [77.4%: 65.0-87.1%]), or CRp/i (n=4 [6.5%: 1.8-15.7%]) with 1-2 cycles of therapy. Only 3 patients required 2 cycles to best response. Among the 48 CR patients, 43 (89.6%) were negative for measurable residual disease (MRDneg) by flow cytometry. Four patients had morphologic leukemia free state, 1 patient with myeloid sarcoma had a partial remission, 4 had resistant disease, and 1 died from indeterminate cause. One patient died within 28 days of treatment initiation (septic shock). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 26 and 23 days. Besides infections and neutropenic fever, maculopapular rash, and hypoxia (fluid overload/infection-related) were the most common grade ≥3 adverse events. In addition to the phase 1/2 MTD cohort, there were 15 patients treated in an expansion cohort and 3 eligible patients treated off protocol with mitoxantrone at 18 mg/m2. For these 80 patients combined treated at MTD, the CR and CR/CRp/i rates were 76.3% and 81.2%. After multivariable adjustment, compared to 300 patients treated with 7+3 on the SWOG S0106 trial, G-CLAM with mitoxantrone 18mg/ m2 was associated with an increased probability of CR (odds ratio [OR]= 3.08, p=.02), CR/CRp/i (OR=2.96, p=.03), a trend towards improved MRDnegCR (OR= 3.70, p=.06), and a trend towards improved overall survival ([OS]; hazard ratio=0.34, p=.07). For the entire study cohort, the 6 and 12-month relapse-free survival were 73% (64-83%) and 62% (42-74%) and the 6 and 12-month OS were 89% (82- 96%) and 77% (67-88%). Conclusions: G-CLAM with mitoxantrone up to 18 mg/m2/day is well tolerated and has potent anti-leukemia activity. This regimen may warrant further randomized comparison with 7+3. We also plan to examine the addition of sorafenib to G-CLAM in newly diagnosed AML patients regardless of FLT3 status. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding. Erba:Ariad: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding.

scholarly journals Physical and Psychological Impairments As Practical Frailty Markers in Elderly AML Fit for Intensive Chemotherapy; Interim Data of a Prospective Cohort Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3831-3831
Author(s):  
GI June MIN ◽  
Byung Sik Cho ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
Young-Woo Jeon ◽  
...  
Keyword(s):  
Cohort Study ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Prospective Cohort ◽  
Research Funding ◽  
Handgrip Strength ◽  
Intensive Chemotherapy ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Elderly Aml

Background The comprehensive geriatric assessment (CGA) typically refers to a multidimensional assessment designed to evaluate an older person's functional ability, physical health, cognition, psychological health, nutritional status, and social support. There is a significant heterogeneity in terms of their underlying health and resilience to the burden of disease and treatments in elderly AML (eAML). To date, a few have evaluated the predictive value of CGA among newly diagnosed eAML. The purpose of this study is to investigate the potential clinical value of CGA as a screening test for frailty in eAML. We designed a comprehensive CGA battery with measures which previously validated, standardized, and widely used. This study is a single-center prospective observational cohort study focused on discriminating between those older patients who are fit for intensive therapies and those who are vulnerable and may experience excess toxicity. Patients and method This prospective cohort study is to investigate the predictive values of each domain of CGA to discriminate vulnerable patients in eAML fit for intensive chemotherapy. Between November 2016 and July 2019, we enrolled newly diagnosed eAML patients aged ≥60 years considered fit for intensive chemotherapy, who had adequate performances and organ functions. All the enrolled patients were administered various questionnaires for an initial CGA and functional evaluation divided into 3 categories; (1) Social and Nutritional support (OARS and MNA), (2) Psychological (MMSE-KC, SGDS-K, PHQ-9, NCCN distress thermometer, MADRS, and KNU-DESC), and (3) Physical function (ECOG, KIADL, SPPB, Handgrip strength, and PTA by professional ENT evaluation). Results Seventy-seven patients were enrolled, in whom the median age of 64 years (range, 60-74), 58.4% were males, and 93.5% and 77.9% of patients had on ECOG score of 0~1 and HCT-CI score of 0~2, respectively. All enrolled patients were treated with intensive chemotherapy, and 62.3% achieved the first complete remission. Three patients experienced early death within 60 days (3.9%). During induction chemotherapy, the median recovery period for neutrophil and platelet counts was 26 (range, 24-29) and 30 (range, 27-33) days, respectively. The median hospitalization days for induction chemotherapy were 32 days (range, 21-104), and infection and GI complications (NCI-CTC-AE based any grade 79.2% and 67.5% respectively) were the most common complications primarily affecting tolerance to the initial chemotherapy. The grade III to IV infection, GI complications, hepatopathy, and acute kidney injury developed in 67.5%, 42.9%, 37.7%, and 16.9% of patients, respectively. Physical impairments were significantly associated with a higher incidence of infection (intact vs. any impairments; 46.4% vs. 79.6%, p=0.003), of which handgrip strength was most accurate tool to predict infection risk (p =0.032), and a trend of more GI complications (intact vs. any impairments; 28.6% vs. 51.0%, p=0.056), resulting in prolonged hospitalization (intact vs. any impairments; 32.2±1.7 days vs. 37.5±2.1 days, p=0.088) for the period of induction chemotherapy. Psychological impairment (intact vs. any impairments; 30.9±1.3 days vs. 38.2±2.1 days, p=0.005), particularly cognitive dysfunction measured by MMSE-KC (p=0.033), was also significantly associated with prolonged hospitalization. Conclusions This data demonstrates that a significant proportion of eAML fit for intensive chemotherapy based on performance status and comorbidity had social, nutritional, physical, psychological impairments by initial CGA assessments. These interim data focusing on early events suggest that impaired physical and/or psychological functions would be useful to identify eAML with intolerance to intensive chemotherapy. This ongoing exploratory prospective study will enroll more eAML patients (targets number=100) and further follow up currently enrolled patients, which will give us invaluable data to develop practical frailty marker and a new model for fitness for intensive chemotherapy. Disclosures Kim: Takeda: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Il-Yang co.: Research Funding. Lee:Achillion: Research Funding; Alexion: Consultancy, Honoraria, Research Funding. Kim:Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding.

scholarly journals Blockade of IL-15 Utilizing Bnz-1, a Selective γ-Chain Inhibiting Peptide, Is Safe and Has Clinical Activity in Patients with T-Cell Large Granular Lymphocytic Leukemia (T-LGLL): Results of a Phase I/II Multi-Center Clinical Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2835-2835 ◽  
Author(s):  
Jonathan E. Brammer ◽  
Lubomir Sokol ◽  
Yutaka Tagaya ◽  
Kerry Rogers ◽  
Anjali Mishra ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Phase I ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Weekly Dose ◽  
Advisory Committees ◽  
Large Granular Lymphocytic Leukemia

T-cell large granular lymphocytic leukemia (T-LGLL) is an incurable, and likely under-diagnosed leukemia characterized by abnormal clonal proliferation of CD8+ memory T-cells. The clonal outgrowth of T-LGLL cells can lead to the development of profound neutropenia and anemia which results in frequent infections, transfusion dependence, and impairment in quality of life and lifespan. There have been few prospective clinical trials in this disease, and no drugs have been FDA approved for its treatment. The primary driver of leukemogenesis in T-LGLL is known to be interleukin-15 (IL-15), a gamma-chain cytokine that induces proliferation of T-LGLL cells. BNZ-1 is a novel pegylated peptide antagonist that inhibits IL-15 by binding to the common γ-chain receptor for cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Studies utilizing BNZ-1 in vitro on T-LGLL cell lines, and ex vivo on clinical patient samples demonstrated significant inhibition of downstream signaling and increased LGLL cell apoptosis (Wang et al., Leukemia 2018). Given these results, we conducted a phase I/II dose escalation study to evaluate the safety, maximum tolerated dose (MTD), and preliminary efficacy of BNZ-1 in T-LGLL (NCT03239393). Patients with T-LGLL were eligible if they had one or more of the following: absolute neutrophil count (ANC) <500 cells/m3, neutropenia with recurrent infections, or symptomatic or transfusion-dependent anemia. Diagnosis of T-LGLL required: >400/mm3 CD3+CD57+ cells or >650 mm3 CD8+ cells, with a clonal T-cell receptor rearrangement. No prior therapy within 30 days or 5 half-lives was permitted. MTD was evaluated using a standard 3+3 design; with a dose escalation strategy using four doses of BNZ-1: 0.5 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg. BNZ-1 was administered by infusion on Days 1, 8, 15, and 22 of a 4-week cycle. Patients then had the option to enter the 3-month extension period, at the same weekly dose. Efficacy was determined utilizing criteria from the ECOG5998 study in T-LGLL. CR was defined as complete normalization of blood counts. Partial response (PR) in neutropenic patients was determined by 4 weeks or greater response with ANC >500 cells/mm3 if >/=50% improvement from baseline. For transfusion-dependent anemia patients, a >/=50% decrease in monthly transfusions for at least 2 months was required for a PR. For patients with symptomatic anemia, improvement in hemoglobin >/=1 g/dL with improvement in symptoms constituted a PR. Patients with a response were permitted to remain on a long-term extension (LTE). Eighteen patients, at 3 US centers were enrolled on study including: 3 patients at 0.5 mg/kg, 4 at 1 mg/kg, 5 at 2 mg/kg, and 6 at 4 mg/kg. 10 patients were enrolled for neutropenia, 4 for transfusion dependent anemia, 2 for symptomatic anemia, and 2 with anemia and neutropenia. 15 patients (83%) completed all 16 weeks of treatment, 2 patients declined to enter the extension phase, and one patient on the 2 mg/kg dosage was taken off study at 4 weeks due to neutropenia <100 thought secondary to T-LGLL. One patient developed grade 2 hyperbilirubinemia, which was thought possibly due to study drug though was grade 1 at baseline.The MTD was not reached. Four patients attained a PR: 3 patients with transfusion-dependent anemia became transfusion independent, while one patient with neutropenia had significant resolution of her neutropenia (Table). These three patients remain on the LTE, though one patient is under observation. Correlative studies demonstrated apoptosis of T-LGLL cells on flow cytometry utilizing CD3 T-cell gating within 24 hours of the first dosage of BNZ-1 (a representative example is shown in the Figure), confirming in patients that inhibition of IL-15 induces apoptosis of T-LGLL cells. In this Phase I/II clinical trial, IL-15 blockade utilizing BNZ-1 demonstrated increased apoptosis in patients with T-LGLL, with early evidence of clinical response, particularly amongst patients with transfusion-dependent anemia. Remarkably, these patients remained transfusion-independent while on BNZ-1. The MTD was not reached in this cohort of patients, and there were minimal AEs associated with BNZ-1. Further analysis of responding patients is underway to determine the most effective approach utilizing BNZ-1 in this rare disease. Table Disclosures Brammer: Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Sokol:EUSA: Consultancy. Tagaya:Bioniz: Membership on an entity's Board of Directors or advisory committees; Bioniz: Research Funding. Rogers:AbbVie: Research Funding; Acerta Pharma: Consultancy; Genentech: Research Funding; Janssen: Research Funding. Waldmann:Bioniz: Membership on an entity's Board of Directors or advisory committees. Azimi:Bioniz: Employment. Frohna:Bioniz: Employment. Ratnayake:Bioniz: Employment. Loughran:Bioniz: Membership on an entity's Board of Directors or advisory committees; Keystone Nano: Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Multicenter, Open-Label Feasibility Study of Daratumumab with Dose-Adjusted EPOCH in Newly Diagnosed Plasmablastic Lymphoma: AIDS Malignancy Consortium 105

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1595-1595 ◽  
Author(s):  
Carlyn Rose Tan ◽  
Stefan K. Barta ◽  
Shelly Y. Lensing ◽  
Ariela Noy
Keyword(s):  
Clinical Trial ◽  
B Cell ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hiv Positive ◽  
Newly Diagnosed ◽  
Advisory Committees

Background: Plasmablastic lymphoma (PBL) is an aggressive large B-cell lymphoma commonly associated with HIV, immunosuppression, old age, and autoimmune disorders, but can be seen in immunocompetent patients. Intensive regimens, including EPOCH, have only a median overall survival between 9 to 15 months. Complete response rates are 40% to 65%. Patients with refractory or relapsed disease typically have a dismal prognosis. Little progress has been made in treating PBL without a single dedicated clinical trial to date. PBL has morphologic and immunophenotypic characteristics overlapping high-grade B-cell lymphoma and multiple myeloma. It is CD20 negative and positive for plasma cell markers, including CD38, CD138, and MUM-1/IRF-4, with a proliferation index typically > 90%. Daratumumab (DARA) is a human IgG1k anti-CD38 monoclonal antibody (mAb). CD38 is a transmembrane receptor with enzymatic activity highly expressed on the surface of plasma cells and plasmablasts. DARA induces directed cell killing of CD38 expressing cells including complement dependent cytotoxicity and antibody-dependent cell cytotoxicity (ADCC). DARA has significant activity as a single agent and part of combination therapy in myeloma. In non-Hodgkin lymphoma (NHL), DARA resulted in synergistic reduction of tumor growth when combined with rituximab and CHOP (R-CHOP) in follicular lymphoma systemic xenograft models and induced dose-dependent ADCC on mantle cell and follicular lymphoma cells lines in the presence of peripheral blood mononuclear cells in vitro (Pérez-Galán P, et al. Hematol Oncol. 2017). In addition, in vivo models using DLBCL (SU-DHL-6) cells injected in SCID mice showed superiority of DARA in combination with CHOP vs DARA alone (63% vs 55%, p <0.01). In a patient-derived DLBCL model with high CD38 expression, DARA with CHOP or R-CHOP showed tumor regression, and tumors did not regrow when treatment with DARA was stopped after 3 doses. (Doshi P, et al. Haematologica. 2014). We designed an innovative approach to treat PBL using a combination of chemotherapy and directed immunotherapy with a mAb. We hypothesize that adding the potent CD38-directed mAb DARA to DA-EPOCH is safe and feasible and results in improved outcomes in PBL similar to the benefit seen with adding rituximab to a CHOP or EPOCH backbone in other DLBCL subtypes. This will be the first clinical trial dedicated to patients with PBL. Study Design and Methods: This is a non-randomized, multicenter study conducted by the AIDS Malignancy Consortium. Both HIV negative and HIV positive PBL patients ≥ 18 years old with Stage II to IV PBL or Stage I with elevated LDH and/or bulky tumor, who have measurable disease and adequate organ function are eligible. HIV positive patients must have CD4 ≥ 100 cells/μL and be on concurrent combination antiretroviral therapy (cART) or agree to start cART. Key exclusion criteria include receiving ≥ 1 prior cycle of combination chemotherapy, hepatitis B seropositivity, and active CNS involvement. DARA will be given in conjunction with DA-EPOCH every 21 days for 6 cycles. DARA 16 mg/kg will be administered intravenously weekly for the first 3 cycles on days 1, 8, and 15, then on day 1 for cycles 4-6. The primary aim is to determine the percentage of newly diagnosed PBL patients who complete ≥ 3 cycles of DARA with DA-EPOCH irrespective of HIV status. We expect that 85% of patients will complete ≥ 5 cycles of DA-EPOCH alone based on the CALGB 50303 study (Bartlett NL, et al. JCO. 2019). Allowing for a lower proportion completing with the addition of DARA, we hypothesize that > 75% of patients will complete ≥ 3 cycles of protocol treatment. An early stopping rule for completing <3 cycles will be employed. The planned enrollment is 15 patients. Correlations with clinical outcomes will include immunohistochemistry on tumor specimens and peripheral blood to study EBV clearance and identify predictive biomarkers. We will study non-invasive monitoring by circulating tumor DNA using plasma DNA mutation panels and clonal immunoglobulin. Disclosures Tan: Merck: Research Funding; Bayer: Research Funding; Takeda: Research Funding; Janssen: Research Funding. Barta:Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Seattle Genetics: Honoraria, Research Funding; Celgene: Research Funding; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Mundipharma: Honoraria; Bayer: Consultancy, Research Funding. Noy:NIH: Research Funding; Pharamcyclics: Research Funding; Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; Raphael Pharma: Research Funding. OffLabel Disclosure: Daratumumab is being used off-label on this clinical trial.

scholarly journals Presence of Extrachromosomal DNA (ecDNA) Impacts Both Progression Free and Overall Survival and Is an Independent Poor Prognostic Marker in Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 461-461
Author(s):  
Parth Shah ◽  
Anil Aktas-Samur ◽  
Mariateresa Fulciniti ◽  
Raphael Szalat ◽  
Masood A. Shammas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Board Of Directors ◽  
Copy Number ◽  
Research Funding ◽  
P Value ◽  
Newly Diagnosed ◽  
Extrachromosomal Dna ◽  
Publicly Traded ◽  
Advisory Committees

Abstract Background Focal amplifications and rearrangements drive tumor growth and evolution in cancer. Focally amplified regions often involve the juxtaposition of rearranged segments of DNA from distinct chromosomal loci into a single amplified region and nearly half of these regions can be explained by circular, extrachromosomal DNA (ecDNA) formation. Cancer-associated ecDNA shows a unique circular placing ecDNA at the interface of cancer genomics and epigenetics. As formation of ecDNA represents a manifestation of genomic instability, we have investigated presence and prognostic impact of ecDNA in multiple myeloma (MM). Methods Whole genome (WGS) and transcriptome (RNAseq) sequencing data from CD138 purified MM cells from 191 uniformly-treated newly diagnosed MM patients were used for this analysis. Copy number variants (CNV), single nucleotide variants (SNV) and structural variants (SV) were identified on all WGS samples using Facets, Mutect2 and Manta. Seed data from these CNV results was passed to the AmpliconArchitect tool to determine presence of focally amplified and rearranged segments of DNA. Seed CNV thresholds were set for a minimum CNV size of 100kb and a copy number of equal or greater to 5. Extrachromosomal calls were then annotated using the Amplicon Classifier to determine the presence of ecDNA. Multivariate survival analysis was performed after segregating samples into the conventional myeloma risk classifications including translocations, copy number alterations, ISS, age and mutations associated with risk. Differential expression analysis was performed on transcriptomic data using DEseq2. Results We identified 6.8% of the newly diagnosed patients with ecDNA, 12.5% with complex non-cyclic DNA amplifications and 10.1% with linear amplifications. ecDNA and complex events were targeting MM dependent genes, including MYC/PVT1, IRF4 as well as known driver genes such as CDYL and TRAF2. We further evaluated association between ecDNA, complex rearrangements, linear amplification and patients with none of these amplification types and found that patients with ecDNA had significantly poor PFS (median PFS 22 months vs. 41 months) and OS (median OS 41 months vs. 105 months). Patients having ecDNA in their MM cells did not show any significant enrichment for known translocations, double hit or TP53 mutations. In a multivariate model including ecDNA and all other known MM risk features, ecDNA was found to be an independent predictor of progression free survival.(HR 2.6, CI: 1.26 -5.6, p=0.0082) and overall survival (HR 7.94 CI:3.5-17.9 p &lt; 0.0001). Patients with ecDNA have higher mutational load probability(8798 vs 6982, effect size = 0.64 , probability is 91.1). However, this was not reflected in heterogeneity by using MATH score. We found that patients with ecDNA are likely to have BRAF mutations (OR= 25.07 [2.57 - 330 95% CI], p value = 0.002), however overall RAS/RAF pathway mutations were similar to other patients. Patients with ecDNA showed fragile DNA with more breaks (median segments 197 vs. 125.5, p value = 0.001). Although ecDNA is defined as copy number gain with fragments having 5 or more copies, overall genomic gain between ecDNA and other patients were similar. However, overall genomic loss in patients with ecDNA were higher than others (7% vs. 4.2%, p = 0.06). By differential gene expression analysis we noted 98 differentially expressed genes in MM cells with ecDNA. The downregulated geneset involved pathways responsible for cell death as well as the RAS pathway. Interestingly, CD38 was upregulated in the ecDNA dataset suggesting greater potential for CD38 targeting therapies in these patients. Conclusions ecDNA, as an unique marker of perturbed genomic integrity, is observed in a subset of patients and is an independent prognostic marker in newly diagnosed MM patients. As patients with ecDNA are not fully captured by other risk features its incorporation in an expanded definition of a high risk group of multiple myeloma should be investigated. Future studies will endeavor to explore the biological mechanism through which ecDNA are formed and influences outcomes in myeloma. Figure 1 Figure 1. Disclosures Richardson: Sanofi: Consultancy; GlaxoSmithKline: Consultancy; Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; AbbVie: Consultancy; Oncopeptides: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy; Protocol Intelligence: Consultancy; Celgene/BMS: Consultancy, Research Funding; Secura Bio: Consultancy; Regeneron: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Perrot: Abbvie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: 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; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau: Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria. Thakurta: Oxford University: Other: Visiting Professor; BMS: Current Employment, Current equity holder in publicly-traded company. Anderson: Gilead: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: 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; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Munshi: Legend: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Adaptive Biotechnology: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Celgene: Consultancy; Pfizer: Consultancy.

scholarly journals Use of High Dose Cytarabine (HiDAC) for Post-Remission or Re-Induction Therapy Is Safe and Effective in Select Older AML Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4422-4422
Author(s):  
Jillian Lykon ◽  
Ellen Madarang ◽  
Nina Nguyen ◽  
Wenhui Li ◽  
Sunil G. Iyer ◽  
...  
Keyword(s):  
Older Adults ◽  
Febrile Neutropenia ◽  
Board Of Directors ◽  
Research Funding ◽  
Average Dose ◽  
Advisory Committees ◽  
Poor Risk ◽  
Risk Patients ◽  
Dose Reductions

Abstract Introduction A standard therapy for fit older adults (≥60 years) with acute myeloid leukemia (AML) being treated with curative intent consists of induction chemotherapy with cytarabine and an anthracycline followed by 1-4 cycles of shorter course post-remission therapy with cytarabine +/- anthracycline. Historically, HiDAC has been reserved for younger patients due to the high incidence of cytarabine-induced neurotoxicity, febrile neutropenia, and hospital re-admissions in older patients (Mayer et al. 1994). In select older adults (e.g., those with good-risk cytogenetic/molecular abnormalities, or requiring reinduction for persistent AML), the risk/benefit for HiDAC may favor its use. Real world evidence is lacking on the safety of full dose HiDAC (total 18 grams/cycle) in fit older adults in the 60-75 age range. Methods We performed a retrospective analysis of AML patients ≥60 years who received at least one cycle of HiDAC, defined as 3g/m2 every 12 hours for 6 doses, either days 1-3 or days 1, 3, 5, as post-remission therapy or primary re-induction (i.e., after failure of primary induction with 7+3 or CPX-351) between July 1, 2014 and May 28, 2021. AML risk was defined by European LeukemiaNet (ELN) guidelines. All patients had daily neurologic exams including prior to each dose of HiDAC and at the beginning of each nursing shift. The primary endpoint was tolerability, defined as average dose per cycle, rate of dose reductions, incidence of febrile neutropenia, cerebellar toxicity, and rate of hospital re-admissions. Secondary endpoints were overall survival (OS), composite complete remission (CCR) for patients treated with HiDAC re-induction, and duration of relapse-free survival (RFS) (from day 1 of treatment) in all patients. Results From July 2014 to May 2021, 34 patients ≥60-years-old were treated with HiDAC at our center. Median age at HiDAC administration was 64 (60-73) [Table 1]. Approximately half the patients were Hispanic and male and almost all (97%) had ECOG performance scores of 0-1. HiDAC was used as post-remission therapy (following 7+3-type induction in 80%) in 25 patients and as re-induction in 14. Eleven patients (32%) were ELN favorable risk, 8 (25%) were intermediate, and 15 (44%) were poor risk. For post-remission therapy, the average total dose of cytarabine per cycle was 16.6 gm/m2 (6-18 gm/m2) and the median number of cycles was 4 (1-4) [Table 2]; 6 patients (24%) required dose reductions, the most common reason being upcoming allogeneic stem cell transplant (n=4). No cerebellar toxicity was observed. Duration of neutropenia was on average 15 days (7-53) in the re-induction group and 7.5 days (1-29) in the post-remission group, with 23 post-remission patients (92%) receiving granulocyte colony stimulating factors (G-CSF). Eleven hospital readmissions occurred, most commonly (73%) for febrile neutropenia. Early mortality rates were low, with one patient on the post-remission arm and one patient on the re-induction arm dying within 30 and 60 days, respectively, both due to sepsis. Median OS was 15.8 months (95% CI 0-31.8) in patients who received post-remission HiDAC, with 44% of patients still alive with a median follow up of 17.2 months (95% CI 7.2-55.8). Favorable risk patients (n=11) receiving post-remission HiDAC had median OS of 15.8 months (95% CI 0-43.1), while intermediate/poor risk patients (n=14) had median OS of 11.3 months (95% CI 9.3-13.2) [p=0.53]. Median OS was 9.8 months (95% CI 2.5-17.1) in patients who received HiDAC re-induction, with 29% of patients still alive with a median follow up of 28.6 months (95% CI 16.6-39.9) [Table 3]. Five patients (36%) achieved CCR after HiDAC re-induction, all of whom went on to receive post-remission HiDAC. Median RFS was 8.5 months for re-induction and 8.8 months for post-remission patients [Table 3]. Conclusions HiDAC (18 grams) can be safely given to select patients over age 60. Critical to tolerability is rigorous screening of "fitness," limiting the upper age receiving HiDAC to 75, ensuring adequate renal function and euvolemia, and advances in supportive care. Encouraging survival outcomes were observed in older adults receiving post-remission or re-induction HiDAC, independent of ELN risk. Figure 1 Figure 1. Disclosures Bradley: AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sekeres: Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding.

Final Results of a Frontline Phase 1/2 Study of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone (CRd) in Multiple Myeloma (MM)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 631-631 ◽  
Author(s):  
Andrzej J Jakubowiak ◽  
Dominik Dytfeld ◽  
Sundar Jagannath ◽  
David H. Vesole ◽  
Tara B. Anderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Growth Factors ◽  
Partial Response ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Newly Diagnosed ◽  
Advisory Committees

Abstract Abstract 631 Introduction: In relapsed and/or refractory MM, the combination of carfilzomib (CFZ) with lenalidomide (Len), and low-dose dexamethasone (Dex) (CRd) has shown very promising efficacy (78% ≥partial response [PR], 40% ≥very good partial response [VGPR], and 24% CR/nCR) and good tolerability including a low rate of peripheral neuropathy (Wang et al, ASCO, 2011). In a Phase I/II study of newly diagnosed MM, the regimen was well tolerated in the Phase I portion of the study up to a maximum dose of CFZ 36 mg/m2, Len 25 mg, and Dex 40 mg, and very active with 96% ≥PR, 70% ≥VGPR, and 55% CR/nCR (Jakubowiak et al, ASH 2010). The lack of overlapping toxicities has allowed these agents to be used at full doses and for extended periods. Here we report the results for all patients (pts) enrolled in both phases of this first prospective trial of CFZ combination in new MM. Methods: In the initial eight 28-day cycles, pts were treated with CFZ at 20 mg/m2, 27 mg/m2 (Phase I), and 36 mg/m2 (Phase I and II), given IV on days 1, 2, 8, 9, 15 and 16, Len at 25 mg PO (days 1–21), and Dex at 40/20 mg PO weekly (cycles 1–4/5–8). Pts achieving ≥PR could proceed to stem cell collection (SCC) using growth factors alone (protocol recommendation) and autologous stem cell transplant (ASCT) after 4 cycles. Per protocol, ASCT candidates were offered the option to continue CRd treatment after SCC. After 8 cycles, pts received 28-day maintenance cycles of CFZ (days 1, 2, 15, 16), Len days 1–21, and Dex weekly at the doses tolerated at the end of 8 cycles. Responses were assessed by IMWG criteria with the addition of nCR. Results: Enrollment was completed (53 pts): 4 pts at CFZ 20 mg/m2, 13 at CFZ 27 mg/m2 and 36 at CFZ 36 mg/m2 (18 in Phase I and 18 in Phase II). Median age was 59 years (range 35–81; 23 pts ≥65), 60% had ISS stage II/III, and 33% (of 49 with available data) had unfavorable cytogenetics: del 13 or hypodiploidy by metaphase, or t(4;14), t (14;16), del 17p by FISH. As of June 30, 2011, toxicity data (cycles 1–8) were available for 51 pts. Hematologic toxicities were reversible and included Grade (G) 3/4: anemia (18%), neutropenia (12%), and thrombocytopenia (10%). The most common non-hematologic toxicities (all G) were hyperglycemia (76%), hypophosphatemia (61%), and infection (53%). G3/4 non-hematologic AEs included hyperglycemia (24%), DVT/PE while on ASA prophylaxis (10%), infection (6%), and mood alteration (2%). PN was limited to G1/2 sensory (24%). Forty-five pts continue treatment with 22 pts in the maintenance phase. Six pts discontinued treatment: 2 proceeded to ASCT, 1 due to toxicity, and 3 due to events unrelated to treatment or per pt wish. The majority of pts did not require dose modifications, either in the initial (31%) or in the maintenance (25%) phase. After a median of 8 cycles (range 1–20), the best responses per IMWG criteria for 49 response-evaluable pts (all pts who completed 1+ cycle) are shown in the Table. Responses were rapid with 46/49 pts achieving at least PR after 1 cycle, and improved with the duration of treatment reaching 100% ≥PR after 4 cycles and 100% ≥VGPR, 79% CR/nCR after 12 cycles. Responses were deep even at the 2 lower dose levels with the majority of pts at 36 mg/m2 still early in treatment. Responses in pts with unfavorable cytogenetics were similar to response rates in all remaining pts and included a 100% ≥PR in 6 pts with del 17p. Twenty-four pts proceeded to SCC after a median of 5 cycles of CRd (range 4–9); using growth factors only in 23 pts and cyclophosphamide and growth factors in 1 pt, with a median 6.55 × 106 CD34+ cells/kg collected (range 3.75–9.6); all resumed CRd treatment. After a median of 9.5 months of follow-up, only 1 pt has progressed, and all are alive Conclusions: CRd is highly active and well-tolerated allowing the use of full doses for an extended time in newly-diagnosed MM pts with limited need for dose modification. Responses are rapid and improve over time reaching 100% ≥VGPR and early time-to-event data are very encouraging. These results compare favorably to the best frontline regimens in MM. Disclosures: Jakubowiak: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria. Off Label Use: Use of the investigational agent carfilzomib, proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Jagannath:Millennium: Honoraria; Celgene: Honoraria; Onyx Pharmaceuticals: Honoraria; Merck: Honoraria; OrthoBiotec.Imedex: Membership on an entity's Board of Directors or advisory committees; Medicom World Wide: Membership on an entity's Board of Directors or advisory committees; Optum Health Education: Membership on an entity's Board of Directors or advisory committees; PER Group: Membership on an entity's Board of Directors or advisory committees. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Hussein:Celgene Corporation: Employment. Leveque:Onyx Pharmaceuticals: Employment. Vij:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding, Speakers Bureau; Millennium: Speakers Bureau.

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