scholarly journals Phase 3 randomized trial of chemotherapy with or without oblimersen in older AML patients: CALGB 10201 (Alliance)

2021 ◽  
Vol 5 (13) ◽  
pp. 2775-2787
Author(s):  
Alison R. Walker ◽  
Guido Marcucci ◽  
Jun Yin ◽  
William Blum ◽  
Wendy Stock ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Phase 1 ◽  
Effective Means ◽  
Cell Leukemia ◽  
Event Free Survival ◽  
Phase 1 Study ◽  
Phase 3 ◽  
Free Survival ◽  
B Cell Leukemia ◽  
Disease Free

Abstract Overexpression of B-cell leukemia/lymphoma 2 (BCL2) renders acute myeloid leukemia (AML) cells resistant to chemotherapy and has been associated with unfavorable outcomes. Oblimersen (G3139) is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 BCL2 codons. In a phase 1 study of AML patients treated with G3139, cytarabine, and daunorubicin induction with cytarabine consolidation, no antisense-related toxicity was reported, and BCL2 downregulation occurred in patients achieving complete remission. In this phase 3 trial, untreated older AML patients were randomized to cytarabine (100 mg/m2 per day on days 4-10) and daunorubicin (60 mg/m2 per day on days 4-6) followed by cytarabine consolidation (2000 mg/m2 per day on days 4-8) with (arm A) or without (arm B) G3139 (7 mg/m2 per day on days 1-10 [induction] or days 1-8 [consolidation]). A total of 506 patients were enrolled. No differences in toxicity were observed between arms. Estimated overall survival (OS) at 1 year was 43% for arm A and 40% for arm B (1-sided log rank P = .13), with no differences in disease-free (DFS; P = .26) or event-free survival (P = .80). Subgroup analyses showed patients age <70 years in arm A had improved OS by 1 month vs those in arm B (P = .04), and patients with secondary AML in arm A had better DFS vs those in arm B (P = .04). We conclude that addition of G3139 to chemotherapy failed to improve outcomes of older AML patients. However, more effective means of inhibiting BCL2 are showing promising results in combination with chemotherapy in AML. This trial was registered at www.clinicaltrials.gov as #NCT00085124.

Results of a Phase 1 Study of Quizartinib (AC220) As Maintenance Therapy in Subjects with Acute Myeloid Leukemia in Remission Following Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 428-428 ◽  
Author(s):  
Brenda M. Sandmaier ◽  
Samer K Khaled ◽  
Betul Oran ◽  
Guy Gammon ◽  
Denise Trone ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Dose Level ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Phase 3 ◽  
Equity Ownership ◽  
Grade 3

Abstract FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Hematopoietic cell transplantation (HCT) is a recommended treatment for patients with FLT3-ITD(+) AML. However, a high rate of relapse after a HCT is observed when compared to FLT3-ITD(-) patients with the 2 year relapse rate of 30% vs. 16% in FLT3-ITD(+) and FLT3-ITD(-) patients, respectively (Brunet, J. Clin. Oncol. 2012). Quizartinib (AC220) is an oral FLT3 receptor tyrosine kinase inhibitor that has shown a high level of single agent activity in nearly 500 patients with FLT3(+) relapsed or refractory AML and is currently in a Phase 3 study. This Phase 1 study examined maintenance therapy with quizartinib in AML patients (aged 18 years or older) in remission after receipt of an allogeneic HCT. Dose escalation was conducted using a modified 3+3 design, where 6 subjects were enrolled at each dose level. Two dose levels were tested; dose level 1 (DL1) at 40 mg and dose level 2 (DL2) at 60 mg given daily in continuous 28 day cycles. Dose limiting toxicities (DLTs) were assessed for the first 2 cycles and subjects were allowed to continue up to a maximum of 24 cycles. Thirteen subjects were recruited and enrollment was completed in June 2013. The median age was 43 (range 23 to 61) years. All subjects had received an HLA-matched allogeneic HCT (3 related and 10 unrelated) a median of 56 (range 41 – 70) days before study enrollment. All subjects were positive for the FLT3-ITD mutation by local testing at the time of diagnosis. Seven subjects were enrolled at DL1, including one who relapsed after 22 days on study and was replaced per protocol as deemed not evaluable for DLTs. There was 1 DLT of Grade 3 gastric hemorrhage which resolved and the subject was able to continue on a reduced dose (30 mg) of quizartinib. Six subjects were enrolled at DL2, including one subject who experienced 1 DLT of Grade 3 anemia but was able to continue on a reduced dose (30 mg). Of the 13 total subjects, 10 (77%) received quizartinib for more than a year. Six (45%) subjects are continuing to receive quizartinib currently (15, 16, 18, 18, 23, and 23 cycles) and 2 (15%) subjects have completed 24 cycles. Three subjects (23%) discontinued due to AE: Grade 4 neutropenia (Cycle 4), Grade 2 corneal epithelium defect (Cycle 9), and Grade 3 autoimmune hemolysis (Cycle 15); 1(8%) discontinued for disease relapse (Cycle 1) and 1 (8%) for protocol non-compliance (Cycle 13). The most common (≥20%) treatment-related adverse events (AEs) were diarrhea (38%; 5 subjects), neutropenia (31%; 4 subjects), nausea (23%; 3 subjects) and leukopenia (23%; 3 subjects). This is the first study conducted to determine whether or not quizartinib can be safely administered as post-transplant maintenance therapy in patients with AML. The data from this study support the use of post-transplant maintenance therapy with quizartinib and show early evidence indicating a reduced relapse rate with only 1 relapse reported out of 13 subjects, which compares favorably to historical reference data. No MTD was identified but 60 mg daily was selected as the highest dose for continuous daily administration based on Phase 2 study data in relapsed or refractory subjects (J Cortes, Blood (ASH Annual Meeting Abstracts) 2013 [Abstract]). Quizartinib maintenance has been included in the current Phase 3 QUANTUM-R study comparing quizartinib vs. salvage chemotherapy in relapsed or refractory FLT3-ITD(+) AML. Disclosures Sandmaier: Astellas Pharma, Inc: Research Funding; Ambit Bioscience Corporation: Research Funding. Khaled:Ambit Bioscience Corporation: Research Funding; Astellas Pharma, Inc: Research Funding. Oran:Astellas Pharma, Inc: Research Funding; Ambit Bioscience Corporation: Research Funding. Gammon:Ambit Bioscience Corporation: Employment, Equity Ownership. Trone:Ambit Bioscience Corporation: Employment, Equity Ownership. Frankfurt:Astellas Pharma, Inc: Research Funding; Ambit Bioscience Corporation: Research Funding.

Implications of NRAS mutations in AML: a study of 2502 patients

Blood ◽  
2006 ◽  
Vol 107 (10) ◽  
pp. 3847-3853 ◽  
Author(s):  
Ulrike Bacher ◽  
Torsten Haferlach ◽  
Claudia Schoch ◽  
Wolfgang Kern ◽  
Susanne Schnittger
Keyword(s):  
Molecular Markers ◽  
Hot Spots ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Prognostic Impact ◽  
Event Free Survival ◽  
Free Survival ◽  
Total Cohort ◽  
History Of ◽  
Disease Free

We analyzed 2502 patients with acute myeloid leukemia at diagnosis for NRAS mutations around the hot spots at codons 12, 13, and 61 and correlated the results to cytomorphology, cytogenetics, other molecular markers, and prognostic relevance of these mutations. Two hundred fifty-seven (10.3%) of 2502 patients had NRAS mutations (NRASmut). Most mutations (112 of 257; 43.6%) were found at codon 12, mostly resulting in changes from glycine to asparagine. The history of AML did not differ significantly in association with NRAS mutations. The subgroups with inv(16)/t(16;16) and inv(3)/t(3;3) showed a significantly higher frequency of NRASmut (50 of 133, 37.6% [P < .001], and 11 of 41, 26.8% [P = .004], respectively) than the total cohort. In addition, in these 2 subgroups, mutations of codon 61 were significantly overrepresented (both P < .001). In contrast, NRAS mutations were significantly underrepresented in t(15;17) (2 of 102; 2%; P = .005) in the subgroup with MLL/11q23 rearrangements (3 of 77; 3.9%; P = .061) and in the complex aberrant karyotype (4 of 258; 1.6%; P < .001). Overall, we did not find a significant prognostic impact of NRASmut for overall survival, event-free survival, and disease-free survival. However, there was a trend to better survival in most subgroups, especially when other molecular markers (FLT3-LM, MLL-PTD, and NPM) were taken into account.

Addition of Androgens Improves Survival in Elderly Patients With Acute Myeloid Leukemia: A GOELAMS Study

2017 ◽  
Vol 35 (4) ◽  
pp. 387-393 ◽  
Author(s):  
Arnaud Pigneux ◽  
Marie C. Béné ◽  
Philippe Guardiola ◽  
Christian Recher ◽  
Jean-Francois Hamel ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Event Free Survival ◽  
Free Survival ◽  
Disease Free ◽  
Acute Myeloid

Purpose Elderly patients with acute myeloid leukemia (AML) have a poor prognosis, and innovative maintenance therapy could improve their outcomes. Androgens, used in the treatment of aplastic anemia, have been reported to block proliferation of and initiate differentiation in AML cells. We report the results of a multicenter, phase III, randomized open-label trial exploring the benefit of adding androgens to maintenance therapy in patients 60 years of age or older. Patients and Methods A total of 330 patients with AML de novo or secondary to chemotherapy or radiotherapy were enrolled in the study. Induction therapy included idarubicin 8 mg/m2 on days 1 to 5, cytarabine 100 mg/m2 on days 1 to 7, and lomustine 200 mg/m2 on day 1. Patients in complete remission or partial remission received six reinduction courses, alternating idarubicin 8 mg/m2 on day 1, cytarabine 100 mg/m2 on days 1 to 5, and a regimen of methotrexate and mercaptopurine. Patients were randomly assigned to receive norethandrolone 10 or 20 mg/day, according to body weight, or no norethandrolone for a 2-year maintenance therapy regimen. The primary end point was disease-free survival by intention to treat. Secondary end points were event-free survival, overall survival, and safety. This trial was registered at www.ClinicalTrials.gov identifier NCT00700544. Results Random assignment allotted 165 patients to each arm; arm A received norethandrolone, and arm B did not receive norethandrolone. Complete remission or partial remission was achieved in 247 patients (76%). The Schoenfeld time-dependent model showed that norethandrolone significantly improved survival for patients still in remission at 1 year after induction. In arms A and B, respectively, 5-year disease-free survival was 31.2% and 16.2%, event-free survival was 21.5% and 12.9%, and overall survival was 26.3% and 17.2%. Norethandrolone improved outcomes irrelevant to all prognosis factors. Only patients with baseline leukocytes > 30 × 109/L did not benefit from norethandrolone. Conclusion This study demonstrates that maintenance therapy with norethandrolone significantly improves survival in elderly patients with AML without increasing toxicity.

scholarly journals Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1224-1232 ◽  
Author(s):  
Maria R. Baer ◽  
Stephen L. George ◽  
Richard K. Dodge ◽  
Kieran L. O'Loughlin ◽  
Hans Minderman ◽  
...  
Keyword(s):  
Older Patients ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Phase 3 ◽  
Free Survival ◽  
Psc 833 ◽  
Group B ◽  
Leukemia Group ◽  
Disease Free ◽  
Acute Myeloid

The Cancer and Leukemia Group B conducted a phase 3 trial of the P-glycoprotein modulator PSC-833 in untreated acute myeloid leukemia patients aged 60 years and older. Patients were randomized to 1 of 2 regimens, with doses determined in a prior phase 1 study, consisting of cytarabine 100 mg/m2/d by 7-day infusion, with daunorubicin 60 mg/m2 and etoposide 100 mg/m2 daily for 3 days (ADE), or daunorubicin 40 mg/m2 and etoposide 60 mg/m2 for 3 days with PSC-833, 2.8 mg/kg over 2 hours, and then 10 mg/kg/d by 3-day infusion (ADEP). The ADEP arm was closed after randomization of 120 patients (61 to ADE and 59 to ADEP) because of excessive early mortality. Rates of complete remission, nonresponse, and death were 46%, 34%, and 20% for ADE, versus 39%, 17%, and 44% for ADEP (P = .008). Nevertheless, disease-free survival (median 7 vs 8 months; P = .38) and overall survival (approximately 33% alive at 1 year) did not differ and were similar to historical results. Although the number of patients was limited, ADE patients whose pretreatment cells exhibited PSC-833–modulated dye efflux in vitro (n = 22) had worse outcomes than those without efflux (n = 11) (complete remission, nonresponse, and death rates of 41%, 41%, and 18%, compared with 91%, 9%, and 0%; P = .03), but with ADEP outcomes were nearly identical. Moreover, for patients with PSC-833–modulated efflux, median disease-free survival was 5 months with ADE and 14 months with ADEP (P = .07). Further modulation trials in older patients must await the design of less-toxic regimens.

scholarly journals Selinexor in combination with decitabine in patients with acute myeloid leukemia: results from a phase 1 study

2019 ◽  
Vol 61 (2) ◽  
pp. 387-396 ◽  
Author(s):  
Bhavana Bhatnagar ◽  
Qiuhong Zhao ◽  
Alice S. Mims ◽  
Sumithira Vasu ◽  
Gregory K. Behbehani ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Acute Myeloid

First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 391-391
Author(s):  
Dean F. Bajorin ◽  
Johannes Alfred Witjes ◽  
Jürgen Gschwend ◽  
Michael Schenker ◽  
Begoña P. Valderrama ◽  
...  
Keyword(s):  
High Risk ◽  
Residual Disease ◽  
Radical Surgery ◽  
Unmet Need ◽  
Disease Free Survival ◽  
Phase 3 ◽  
Double Blind ◽  
Meaningful Improvement ◽  
Free Survival ◽  
Disease Free

391 Background: The standard of care (SOC) for patients (pts) with MIUC is radical surgery ± cisplatin-based neoadjuvant chemotherapy (chemo), but many pts are cisplatin-ineligible. There is no conclusive evidence supporting adjuvant chemo in pts who did not receive neoadjuvant chemo and in those with residual disease after neoadjuvant cisplatin. This phase 3 trial of adjuvant nivolumab (NIVO) vs placebo (PBO) in pts with MIUC after radical surgery ± neoadjuvant cisplatin (CheckMate 274) aims to address an unmet need in these pts. We report the initial results. Methods: This is a phase 3, randomized, double-blind, multicenter trial of NIVO vs PBO in pts with high-risk MIUC (bladder, ureter, or renal pelvis) after radical surgery. Pts were randomized 1:1 to NIVO 240 mg Q2W or PBO for ≤ 1 year of adjuvant treatment. Pts had radical surgery within 120 days ± neoadjuvant cisplatin or were ineligible/declined cisplatin-based chemo, evidence of UC at high risk of recurrence per pathologic staging, were disease-free by imaging, and ECOG PS ≤ 1. Primary endpoints: disease-free survival (DFS) in all randomized pts (ITT population) and in pts with tumor PD-L1 expression ≥ 1%. DFS was stratified by nodal status, prior neoadjuvant cisplatin, and PD-L1 status. Non–urothelial tract recurrence-free survival (NUTRFS) in ITT pts and in pts with PD-L ≥ 1% is a secondary endpoint. Safety is an exploratory endpoint. Results: In total, 353 pts were randomized to NIVO (PD-L1 ≥ 1%, n = 140) and 356 pts to PBO (PD-L1 ≥ 1%, n = 142). The primary endpoint of DFS was met in ITT pts (median follow-up, 20.9 mo for NIVO; 19.5 mo for PBO) and in pts with PD-L1 ≥ 1%. DFS and NUTRFS were improved with NIVO vs PBO in both populations (Table). DFS improvement with NIVO was generally consistent across subgroups. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 17.9% and 7.2% of pts in the NIVO and PBO arms, respectively. Conclusions: NIVO demonstrated a statistically significant and clinically meaningful improvement in DFS vs PBO for MIUC after radical surgery, both in ITT pts and pts with PD-L1 ≥ 1%. AEs were manageable and consistent with previous reports. These results support adjuvant NIVO as a new SOC for pts with MIUC with high risk for recurrence despite neoadjuvant chemo or those ineligible for and/or declining cisplatin-based chemo. Clinical trial information: NCT02632409 . Research Sponsor: Bristol Myers Squibb[Table: see text]

Allogeneic Stem-Cell Transplantation Using a Reduced-Intensity Conditioning Regimen Has the Capacity to Produce Durable Remissions and Long-Term Disease-Free Survival in Patients With High-Risk Acute Myeloid Leukemia and Myelodysplasia

2005 ◽  
Vol 23 (36) ◽  
pp. 9387-9393 ◽  
Author(s):  
Sudhir Tauro ◽  
Charles Craddock ◽  
Karl Peggs ◽  
Gulnaz Begum ◽  
Premini Mahendra ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Allogeneic Transplantation ◽  
Disease Relapse ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Disease Free ◽  
Reduced Intensity

Purpose The toxicity of allogeneic stem-cell transplantation can be substantially reduced using a reduced-intensity conditioning (RIC) regimen. This has increased the proportion of patients with myeloid malignancies eligible for allogeneic transplantation. However, the capacity of RIC allografts to produce durable remissions in patients with acute myeloid leukemia (AML) and myelodysplasia (MDS) has not yet been defined, and consequently, the role of RIC allografts in the management of these diseases remains conjectural. Patients and Methods Seventy-six patients with high-risk AML or MDS received an allograft using a fludarabine/melphalan RIC regimen incorporating alemtuzumab. The median age of the cohort was 52 years (range, 18 to 71 years). Results The 100-day transplantation-related mortality rate was 9%, and no patient developed greater than grade 2 graft-versus-host disease. With a median follow-up of 36 months (range, 13 to 70 months), 27 patients were alive and in remission, with 3-year actuarial overall survival (OS) and disease-free survival (DFS) rates of 41% and 37%, respectively. The 3-year OS and DFS rates of patients with AML in complete remission at the time of transplantation were 48% and 42%, respectively. Disease relapse was the most common cause of treatment failure and occurred at a median time of 6 months after transplantation. All but one patient destined to relapse did so within 24 months of transplantation. Conclusion The extended follow-up in this series identifies a high risk of early disease relapse but provides evidence that RIC allografts can produce sustained DFS in a significant number of patients with AML who would be ineligible for allogeneic transplantation with myeloablative conditioning.

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