High Dose Cytarabine and Clofarabine (HiDAC → CLOF) in Relapsed or Refractory Acute Myeloid Leukemia, a Phase 2 Trial.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1936-1936 ◽  
Author(s):  
Bayard Powell ◽  
Ralph D’Agostino ◽  
Denise Levitan ◽  
Leslie Renee Ellis ◽  
Susan Lyerly ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Single Agent ◽  
High Dose ◽  
Phase 2 ◽  
High Dose Cytarabine ◽  
First Relapse ◽  
Acute Myeloid ◽  
Refractory Aml

Abstract High dose cytarabine (HiDAC) is the most effective single agent studied to date for the treatment of acute myeloid leukemia (AML); clofarabine (CLOF) is also an active single agent in AML. Preclinical data suggest synergy between cytarabine and clofarabine. Based on the results of a limited phase 1 trial (Blood2006; 108: 221b), we conducted a phase 2 study of HiDAC (2g/m2 over 3 hours) followed immediately by CLOF (40 mg/m2 infused over 2 hours), given daily for 5 days, in 39 adults with AML in first relapse (n = 27), second relapse (n = 3), or refractory to initial induction chemotherapy (n = 9). Prophylactic intravenous hydrocortisone was incorporated to decrease the occurrence of skin toxicity. Patients with persistent leukemia on day 12–14 (n = 12) received a second course of HiDAC → CLOF for 3 days. The mean age was 53.4 years (range 18.4 – 79.0). Accrual began March 2006 and was completed in July 2008. Thirtyseven of 39 patients are evaluable for response (two patients were treated recently and are not included in this analysis): 14/37 achieved a complete remission (CR), 2/37 a CR with incomplete blood count recovery (CRi) for an overall response (CR or CRi) in 16/37 (43%; 95% CI 27 – 59%). Twelve of 37 (32%) patients had resistant disease, 3/37 (8%) died of complications during marrow aplasia, 5/37 (14%) died of complications of their AML with unknown bone marrow status, and 1/37 (3%) refused further evaluation or treatment. CR or CRi was achieved in 11/25 patients in first relapse, 2/3 in second relapse, and 3/9 with refractory AML. Twelve patients received a second induction – 2/12 (17%) achieved a CR and 1/12 (8%) a CRi. Toxicity data are complete in 36 patients; the most frequent grade 3/4 non-hematologic toxicities were transient elevations of AST/ALT observed in 23/36 (64%) patients, hyperbilirubinemia in 8/36 (22%), infection in 16/36 (44%), and rash in 8/36 (22%). Patients who achieved CR or CRi received up to 3 additional courses of HiDAC → CLOF each daily for 5 days. Twenty-seven of 39 (69%) patients have died with a median survival of 119 days (95% CI 71 – 322 days). In summary, HiDAC → CLOF is a very active combination in adults with relapsed and refractory AML, a group in whom CR/CRi rates of 30–35% are achieved with many salvage regimens. Toxicities are comparable to other salvage regimens with transient elevations in transaminases identified as the most frequent toxicity.

scholarly journals A phase 1 study of azacitidine with high-dose cytarabine and mitoxantrone in high-risk acute myeloid leukemia

2020 ◽  
Vol 4 (4) ◽  
pp. 599-606 ◽  
Author(s):  
Kirk E. Cahill ◽  
Yasmin H. Karimi ◽  
Theodore G. Karrison ◽  
Nitin Jain ◽  
Margaret Green ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
High Dose ◽  
Phase 2 ◽  
Phase 1 Study ◽  
High Dose Cytarabine ◽  
Acute Myeloid

Abstract In this phase 1 study, azacitidine (AZA) was given before high-dose cytarabine (HiDAC) and mitoxantrone (mito) based on the hypothesis that epigenetic priming with a hypomethylating agent before cytotoxic chemotherapy would improve response rates in patients with high-risk acute myeloid leukemia (AML), including relapsed/refractory disease. The primary objective was to establish the recommended phase 2 dose of AZA given before standard HiDAC/mito. In a dose escalation scheme, 46 patients (median age, 66 years) received AZA at 37.5, 50, or 75 mg/m2 subcutaneously or IV once daily on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10 (the HiDAC/mito dose was reduced 33% in elderly subjects). Two dose-limiting toxicities occurred (both in the same patient): acute liver failure and kidney injury at the 50 mg/m2 dose. The 30-day induction death rate was 2.2% (1 of 46). The overall response rate, including complete remission and complete remission with incomplete count recovery, was 61% (28 of 46). Previously untreated patients aged ≥60 years with therapy-related AML and de novo AML were more likely to respond than untreated patients with AML progressing from an antecedent hematologic disorder (myelodysplastic syndrome and chronic myelomonocytic leukemia). Patients with favorable European Leukemia Network risk (P = .008), NPM1 mutations (P = .007), or IDH2 mutations (P = .03) were more likely to respond, and those with TP53 mutations (P = .03) were less likely to respond. The recommended phase 2 dose of AZA is 75 mg/m2 per day on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10. This trial was registered at www.clinicaltrials.gov as #NCT01839240.

Safety and activity of venetoclax in combination with high-dose cytarabine in children with relapsed or refractory acute myeloid leukemia.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 10004-10004 ◽  
Author(s):  
Seth E Karol ◽  
Thomas Alexander ◽  
Soumyasri Das Gupta ◽  
Stanley B. Pounds ◽  
Kristin Canavera ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Level ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Phase 1 ◽  
High Dose ◽  
Phase 2 ◽  
High Dose Cytarabine ◽  
Grade 3 ◽  
Acute Myeloid

10004 Background: Venetoclax is an orally available BCL-2 antagonist with demonstrated activity in adults with newly diagnosed or relapsed acute myeloid leukemia (AML). Here, we describe the first use of venetoclax 1) in combination with high-dose cytarabine and idarubicin 2) in patients 2-22 years old with relapsed AML. Methods: Patients with relapsed AML or AML refractory to at least two courses of induction therapy were enrolled in this Phase 1 study with a rolling-six design. All patients received venetoclax (240 or 360 mg/m2) on days 1-28 and low-dose (LD: 100 mg/m2 every 12 hours x 20 doses) or high-dose (HD: 1000 mg/m2 every 12 hours x 8 doses) cytarabine beginning on day 8 (Table). Patients who had previously received < 270 mg/m2 of doxorubicin equivalents also received idarubicin 12 mg/m2 on day 8 in dose level 4; other patients were enrolled on the expansion cohort at dose level 3. Non-hematologic CTCAE grade 3 or higher toxicities were intensity limiting (ILT), excluding those anticipated with HD cytarabine. Results: Among 18 evaluable patients, a single ILT (prolonged hematological suppression beyond day 50) was observed (Table). Toxicities were consistent with the underlying cytotoxic chemotherapy, with 14 patients experiencing a total of 40 grade 3 toxicities including 6 documented infections and 23 episodes of febrile neutropenia. There was 1 grade 4 fungal sepsis. The recommended phase 2 dose of venetoclax was 360 mg/m2 (max 600 mg) when combined with HD cytarabine or HD cytarabine/idarubicin. Of the 12 patients with > 50% reduction in blasts following the 7-day venetoclax window therapy, end-of-cycle marrow responses included 7 CR/CRi and 3 PR. Minimal residual disease negative remissions occurred in 4 patients. BH3 profiling of samples and a phase 2 expansion of both dose levels 3 and 4 to further characterize the promising activity of these combinations are underway. Conclusions: Venetoclax combined with cytarabine or cytarabine/idarubicin is active and well tolerated in pediatric patients with relapsed/ refractory AML. Clinical trial information: NCT03194932. [Table: see text]

scholarly journals A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia

Blood ◽  
2017 ◽  
Vol 129 (24) ◽  
pp. 3165-3174 ◽  
Author(s):  
Ramiro Garzon ◽  
Michael Savona ◽  
Rachid Baz ◽  
Michael Andreeff ◽  
Nashat Gabrail ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nuclear Export ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Nuclear Accumulation ◽  
Phase 2 ◽  
Safety And Efficacy ◽  
Acute Myeloid

Abstract Selinexor is a novel, first-in-class, selective inhibitor of nuclear export compound, which blocks exportin 1 (XPO1) function, leads to nuclear accumulation of tumor suppressor proteins, and induces cancer cell death. A phase 1 dose-escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8, or 10 doses of selinexor in a 21- or 28-day cycle. The most frequently reported adverse events (AEs) in patients with AML were grade 1 or 2 constitutional and gastrointestinal toxicities, which were generally manageable with supportive care. The only nonhematological grade 3/4 AE, occurring in &gt;5% of the patient population, was fatigue (14%). There were no reported dose-limiting toxicities or evidence of cumulative toxicity. The recommended phase 2 dose was established at 60 mg (∼35 mg/m2) given twice weekly in a 4-week cycle based on the totality of safety and efficacy data. Overall, 14% of the 81 evaluable patients achieved an objective response (OR) and 31% percent showed ≥50% decrease in bone marrow blasts from baseline. Patients achieving an OR had a significant improvement in median progression-free survival (PFS) (5.1 vs 1.3 months; P = .008; hazard ratio [HR], 3.1) and overall survival (9.7 vs 2.7 months; P = .01; HR, 3.1) compared with nonresponders. These findings suggest that selinexor is safe as a monotherapy in patients with relapsed or refractory AML and have informed subsequent phase 2 clinical development. This trial was registered at www.clinicaltrials.gov as #NCT01607892.

scholarly journals Outcomes of Six-Dose High-Dose Cytarabine as a Salvage Regimen for Patients with Relapsed/Refractory Acute Myeloid Leukemia

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Brandi Anders ◽  
Lauren Veltri ◽  
Abraham S. Kanate ◽  
Alexandra Shillingburg ◽  
Nilay Shah ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Disease Free Survival ◽  
High Dose ◽  
Free Survival ◽  
High Dose Cytarabine ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Relapsed/refractory acute myeloid leukemia (RR-AML) is associated with poor prognosis and long-term disease-free survival requires allogeneic hematopoietic cell transplantation (allo-HCT). Limited data exists, regarding the optimal regimen to obtain remission prior to allo-HCT. Single agent high-dose cytarabine (10–12 doses administered every 12 hours) has been previously used as induction therapy. Six-dose high-dose cytarabine (HiDAC-6), commonly used as a consolidation regimen, has never been evaluated as induction therapy. We present a retrospective review of 26 consecutive patients with RR-AML receiving single agent cytarabine 3 g/m2intravenously every 12 hours on days 1, 3, and 5 for a total of six doses (HiDAC-6). Median follow-up for surviving patients was 10.4 months (range 1.6–112.2 months). Complete remission was obtained in 62% (54% CR and 8% CRi) of the patients. The median relapse-free survival (RFS) was 22.3 months (range 0.7–112 months), event-free survival (EFS) was 4.7 months (range 0.5–112 months), and the overall survival (OS) was 9.6 months (range 1–112 months). Thirty-five percent of patients were able to subsequently proceed to allo-HCT. Treatment-related toxicities included neutropenic fever (38%), infection (35%), neurotoxicity (8%), and skin toxicity (8%). This is the first study to demonstrate HiDAC-6 as an active treatment option for younger patients with RR-AML which can effectively serve as a bridge to allo-HCT without significant toxicity.

Treatment of relapsed acute myeloid leukemia with idarubicin and intermediate-dose cytarabine.

1989 ◽  
Vol 7 (1) ◽  
pp. 45-49 ◽  
Author(s):  
J L Harousseau ◽  
J Reiffers ◽  
P Hurteloup ◽  
N Milpied ◽  
H Guy ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Skin Toxicity ◽  
High Dose ◽  
Optimal Dosage ◽  
Consolidation Therapy ◽  
High Dose Cytarabine ◽  
First Relapse ◽  
Relapsed Acute Myeloid Leukemia ◽  
Acute Myeloid

High-dose cytarabine (HDARA-C) is an effective but toxic treatment for acute myeloid leukemia (AML). In order to reduce the incidence of severe complications noted with HDARA-C-containing regimens, we used a combination of intravenous (IV) idarubicin (IDARUB) at optimal dosage and cytarabine (ARA-C) at intermediate dosage. Thirty-five patients aged 23 to 78 years (median, 56) with AML in first relapse received IDARUB, 8 mg/m2/d for five days, and ARA-C, 1 g/m2 every 12 hours for six doses. Of the 35 patients, 21 achieved a complete remission (CR), four had a partial remission (PR), four died in aplasia, and six were nonresponders. The only factor influencing the CR rate was the duration of the first CR (35% for patients relapsing before 16 months v 83% for patients relapsing after 16 months, P = .003). Mucositis was the most significant extrahematologic side effect. Diarrhea, skin toxicity, and hepatic disturbances were rare and mild. There was no cerebellar toxicity, even in 25 patients greater than 50 years of age. This regimen is effective and well tolerated even in elderly patients, and could be used either as induction or consolidation therapy for the treatment of AML.

Temsirolimus, An mTOR Inhibitor, In Combination with Low-Dose Clofarabine in Older Patients with Advanced Acute Myeloid Leukemia: Results of a Phase 2 GIMEMA Study (AML-1107)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 510-510
Author(s):  
Sergio Amadori ◽  
Adriano Venditti ◽  
Emanuele Ammatuna ◽  
Alberto M. Martelli ◽  
Giovanna Meloni ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Disease Free Survival ◽  
Phase 2 ◽  
Mtor Inhibition ◽  
First Relapse ◽  
Acute Myeloid ◽  
Refractory Aml

Abstract Abstract 510 Background: Elderly patients with refractory or relapsed AML have a dismal prognosis and new treatments are needed for these patients.The PI3K/AKT signaling pathway is frequently dysregulated in AML and contributes to cell proliferation and survival through activation of the mTOR kinase and its downstream effectors. mTOR inhibition with Sirolimus or its analogs, such as Temsirolimus, has been associated with clinical responses in AML and may enhance the sensitivity of leukemic cells to cytotoxics. Clofarabine is a second-generation nucleoside analog with activity in AML. Based on this, a multicenter, phase 2, open label, two-stage study was conducted to assess the efficacy and safety of Temsirolimus in combination with low-dose Clofarabine as salvage therapy for older pts with AML. Methods: Eligible were pts older than 60 years of age with first relapse or primary refractory AML. Induction consisted of a single course of Clofarabine 20 mg/m2 iv d 1–5 and Temsirolimus 25 mg (flat dose) iv d 1, 8 and 15; a second course was allowed in pts achieving PR. Pts entering CR/CRi receive up to 12 monthly courses of maintenance with Temsirolimus (25 mg iv d 1 and 8 per course). The primary endpoint was complete remission with (CR) or without (CRi) hematopoietic recovery; secondary endpoints were overall survival, disease-free survival and toxicity. Pre and post-therapy bone marrow samples were obtained from a subset of pts to assess biomarkers. Results: Accrual began April 2009 and was completed in June 2010. To date, 52 of 54 enrolled pts are evaluable for response and toxicity (1 too early; 1 died pre-therapy): median age 70 yrs (range 60–78); 58% males; 17 pts with primary refractory AML; 35 pts with AML in first relapse (duration of CR1 < 6 mos 34%, ≥ 6 mos 66%); cytogenetics (MRC criteria): favorable in 4, intermediate in 37, adverse in 6, and unavailable in 5 pts. In all, 11 pts (21%; 95% CI 11–35%) have achieved CR (n=4) or CRi (n=7); 1 achieved PR; 7 (13%) died within 30 days of induction therapy (3 from infection, 3 from disease progression, 1 from cerebrovascular accident); 33 were resistant. CR or CRi was achieved in 9/35 pts (26%) in first relapse, and 2/17 (12%) with primary refractory disease. CR+CRi rates among: age < 70 and ≥ 70, 19% and 25%; first CR duration shorter and longer than 6 mos, 17% and 30%; favorable, intermediate, adverse and unknown cytogenetics, 50%, 22%, 0% and 20%. The median duration of remission for the 11 responders was 3.5 mos; 7 pts have relapsed to date and 4 (2 CR, 2 CRi) are currently maintaining a response at 2+, 4+, 11+ and 12+ mos from remission. With a median follow-up of 5 mos (range 0.3–14), the median overall survival for the entire population was 4.3 mos, and for responders 7.6 mos. Besides myelosuppression, most common grade 3–4 adverse events included infection (48%), febrile neutropenia (35%), transaminase elevation (11%), nausea and vomiting (8%), and fatigue (8%). Median times to recovery of neutrophils to 500/cmm and platelets to 50,000/cmm in responders were 28 and 32 days, respectively. Inhibition of phospho-S6RP, a downstream effector of mTOR, was documented in 12/21 (57%) pts analysed, and correlated with an improved rate of clinical response: 7/12 (58%) responded vs 0/9 pts with no detectable target inhibition. Conclusion: These data indicate that a regimen combining Temsirolimus with low-dose Clofarabine can be safely administered to elderly pts with advanced AML. Encouraging anti-leukemic activity was recorded in this difficult-to-treat patient population, particularly in pts showing evidence of an on-target effect on mTOR signaling. Further investigation of this novel regimen as front-line therapy in older pts with AML considered unsuitable for intensive chemotherapy is planned. Disclosures: Off Label Use: Clinical trial investigating Clofarabine and Temsirolimus in patients with acute myeloid leukemia.

Sign in / Sign up

Export Citation Format

Share Document