Therapeutic Manipulation of Cancer Cell Metabolism with the Mitochondrial Metabolism Inhibitor Cpi-613 in Addition to Chemotherapy Abrogates the Adverse Prognostic Effect of Age in Relapsed and Refractory AML

Abstract Background: Acute myeloid leukemia is an aggressive malignancy with poor outcomes especially in patients 60 years of age or older. This thought to be in part from increased resistance to chemotherapy in AML cells arising in an older host. One of the nine recognized biological hallmarks of aging is a decline in mitochondrial quality. The effect of exploiting this age-related metabolic vulnerability in relapsed AML has not been previously established. CPI-613 is a first-in-class agent that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, effectively impairing the TCA cycle. We have combined CPI-613 with high dose cytarabine and mitoxantrone in phase I and II clinical trials in over 100 patients with relapsed or refractory AML. Methods: To determine the effect of the addition of CPI-613 in older patients, the phase I and II datasets were combined and outcomes by age were analyzed and compared to age related outcomes in a historical dataset of patients treated with a high dose cytarabine, mitoxantrone and L-asparaginase but without CPI-613. In both trials, patients were given CPI-613 as a 2-hour infusion on days 1 through 5. Cytarabine was dosed at 3,000 mg/m² (if younger than 60) or at 1,500 mg/m² (if 60 years of age or older), given every 12 hours for 5 doses, starting on day 3 following the CPI-613 infusion. The mitoxantrone was dosed at 6 mg/m² and is given once daily following the first, third and fifth cytarabine doses. At day 14, nadir marrow was evaluated, and patients with residual disease could be re-treated as above or with an abbreviated 3-day cycle. Responding patients were eligible to receive up to 2 abbreviated 3-day consolidation cycles. The historical cohort was treated identically without CPI-613, except L-Asparaginase was given at a dose of 6,000 units/m2 following the last dose of cytarabine. Results: Patient characteristics are summarized in Table 1. In the historical dataset younger patients had a highly significant increase in median overall survival when compared to patients ≥60 years of age (figure 1A). In contrast, older and younger patients treated with CPI-613 in addition to the chemotherapy had no significant difference in median survival (figure 1B). Additionally, when outcome by dose of CPI-613 was analyzed, older but not younger patients had a significant improvement in survival when given a dose of 2,000 mg/m2 compared to those given 1,500 mg/m2 (figure 1C+D). Patients 60 years of age or older had a response rate of 55% and a median overall survival of 12.4 months when treated with a dose of CPI-613 of 2,000 mg/m2. Conclusions: Targeting mitochondrial metabolism exploits an age-related metabolic vulnerability in AML arising in older patients. These results have led to a randomized phase III trial of CPI-613 at 2,000 mg/m2 in combination with high dose cytarabine and mitoxantrone compared to high dose cytarabine and mitoxantrone alone in relapsed or refractory AML patients 60 years of age or older. Disclosures Pardee: Amgen: Speakers Bureau; Karyopharm: Research Funding; Celgene: Speakers Bureau; Rafael Pharmaceuticals: Employment; Novartis: Speakers Bureau. Ellis:Alexion: Speakers Bureau. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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Multicentre, Open Label, Randomized Phase III Study of Cpi-613® (devimistat) in Combination with High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) in Older Patients (≥ 60 years) with Relapsed / Refractory Acute Myeloid Leukemia (AML) - Armada 2000 (AML003) Trial

Blood ◽

10.1182/blood-2019-129377 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2658-2658 ◽

Cited By ~ 1

Author(s):

Timothy S. Pardee ◽

Sanjeev Luther ◽

Marc E. Buyse ◽

Bayard L Powell ◽

Jorge E. Cortes

Keyword(s):

Complete Remission ◽

Phase I ◽

Phase Ii ◽

Older Patients ◽

Research Funding ◽

Phase Iii ◽

High Dose ◽

Open Label ◽

High Dose Cytarabine ◽

Refractory Aml

Background: Despite recent advances, outcome of patients with AML, particularly the older ones, remains poor. This is in part because of adverse features more frequently associated with AML in this patient population. Older patients with AML have high mortality (>90%). This is driven by the fact that over 50% of patients will experience a relapse, and most relapsed patients will die from AML within a year. There is no consensus standard treatment for relapsed or refractory disease, highlighting the high unmet need for these patients. Devimistat is a novel lipoic acid analogue that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase. This inhibits mitochondrial respiration and cause hyper-phosphorylation of PDH and activation of adenosine monophosphate activated kinase (AMPK) in AML cells. The ARMADA 2000 trial seeks to leverage the unique mechanism of action of this agent to improve the outcomes for older patients suffering from relapsed or refractory AML. To date devimistat has been given to more than 108 relapsed or refractory AML patients in multiple clinical trials (phase I and phase II). These studies suggest that devimistat can be safely combined with high dose cytarabine and mitoxantrone in relapsed or refractory AML patients. The possible beneficial effect in older patients was demonstrated by the dose response relationship seen in older but not younger patients. The combined efficacy result from 23 treated patients (≥ 60 years) on either of phase I or phase II studies of devimistat and high dose cytarabine and mitoxantrone (CHAM) showed complete remission (CR) rate of 48%, CR + CRi of 52% and median overall survival (OS) of 12.4 months [interim result of this study was presented at EHA Annual Meeting 2018, for further details please refer: Analysis of phase I and pilot phase II data reveal 2,000 mg/m2 as the optimal dose of CPI-613 in combination with cytarabine and mitoxantrone for elderly patients with relapsed or refractory AML]. Given the favorable safety profile of CHAM with the promising response results achieved in these trials, further evaluation of devimistat in AML is warranted. The current study evaluates devimistat in combination with high dose cytarabine and mitoxantrone (CHAM) in older patients with relapsed or refractory AML. Method: This is a multicentre, open label, randomized phase III study of devimistat in combination with high dose cytarabine and mitoxantrone (CHAM) compared to high dose cytarabine and mitoxantrone (HAM) in older patients with relapsed/refractory AML. Eligible patients are male and female individuals who are 60 years and older with histologically documented AML that is relapsed from, or refractory to, prior standard therapies that include standard dose cytarabine or high dose cytarabine based induction cycle or no response after at least 3 cycles of a hypomethylating agent with or without venetoclax. Other key inclusion criteria include ECOG performance status 0-2 and expected survival >3 months. A total of 500 patients will be randomized in a 1:1 fashion between arms. Following completion of all planned induction and/ or consolidation therapy cycles, patients in remission on the CHAM arm will continue to receive devimistat during maintenance cycle(s) until disease recurrence, availability of stem cell transplant, the advent of intolerable side effects, or patient withdrawal of consent. Primary endpoint of the study is complete remission (CR) of CHAM compared to HAM. Secondary endpoints include overall survival (OS), complete remission with partial hematologic recovery (CRh) and safety. Exploratory analysis will examine the expression of a gene signature from baseline marrow samples found to be predictive of response in the phase I study. Additional analysis will correlate the expression of several key proteins including PDH, KGDH, PDK1-4, SOD2 and CD79a in baseline marrow samples with response. Statistical analysis plan for this trial is summarized in Table 1 and Table 2. This study was initiated in November 2018 and planned at approximately 87 sites in more than 13 countries, recruiting 500 patients. The interim analysis of the study is expected to be completed as early as Q3 2020. Clinical trial information: NCT03504410 Disclosures Pardee: Rafael Pharmaceuticals: Consultancy, Research Funding; Karyopharm: Research Funding; Pharmacyclics/Janssen: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; CBM Bipharma: Membership on an entity's Board of Directors or advisory committees; Spherix Intellectual Property: Research Funding. Luther:Rafael Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Buyse:Rafael Pharmaceuticals: Consultancy. Powell:Rafael Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Janssen: Research Funding. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; BiolineRx: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Devimistat is not approved by the FDA for any indication and the clinical trial describes its use in AML.

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Favorable Outcome In Patients with Poor Prognosis Acute Myeloid Leukemia (AML) Using a 2-Day Induction Regimen Incorporating High Dose Cytarabine and Mitoxantrone.

Blood ◽

10.1182/blood.v116.21.1069.1069 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1069-1069

Author(s):

Melissa L Larson ◽

Sheena Sahota ◽

Margaret C Keller ◽

Bharathi Muthusamy ◽

Allison Zindell ◽

...

Keyword(s):

Mortality Rate ◽

Induction Therapy ◽

Older Patients ◽

Overall Response Rate ◽

Response Rate ◽

Remission Induction ◽

High Dose ◽

Younger Patients ◽

Induction Regimen ◽

High Dose Cytarabine

Abstract Abstract 1069 Background: Cytogenetic data plays an important role in assessing prognosis and determining choice of therapy for AML. Traditionally, patients with AML are treated with infusional cytarabine and an anthracycline. CR rates with this regimen have been reported at 50–60%. Evaluation of novel treatment regimens for AML should include determination of the impact of the regimen on intermediate and unfavorable cytogenetics. We present a retrospective analysis of a 2-day remission induction regimen, based on the concept of timed sequential therapy. The regimen combines high dose cytarabine, which has been shown to improve remission rates when used in induction therapy, and dose intensified anthracycline therapy, which has been shown to improve outcome in younger patients. The cycling cells are eradicated during an initial pulse of therapy, then, previously quiescent cells are targeted during the second pulse of therapy. Here we present the analysis of the study regimen and the response rates of patients with intermediate and unfavorable cytogenetic profiles. Patients and Methods: One hundred fifty five patients categorized as having intermediate or unfavorable cytogenetics were treated with timed sequential chemotherapy from 1998–2009. The treatment regimen consisted of two doses of cytarabine 2 gm/m2 IVPB given over 3 hours, administered 12 hours apart. This was followed by one dose of mitoxantrone 30 mg/m2 IVPB over 1 hour on days 1 and 5. Pre-therapy cytogenetic data was collected for each patient. Responses to therapy were determined based on IWG response criteria for AML. Results: One hundred fifty five patients with intermediate and unfavorable karyotypes received high dose cytarabine and mitoxantrone for remission induction therapy. Median age of patients was 55 years (ranged from 17–85). Sixty patients were 60 years or older. Eighty three patients (53.5%) had intermediate and 72 (46.5%) had unfavorable karyotypes. The younger patients (under 60 years of age) with intermediate cytogenetics achieved the following responses: 34 CR, 6 CRi, and 2 CRp. The overall response rate (ORR) was 80.8% for these younger patients, while the ORR for the older patients (over 60 years of age) with intermediate cytogenetics was 77.4% (15 CR, 4 CRi, 5 CRp). In the unfavorable cytogenetic category, the ORR of the younger patients (under 60 years of age) was 60.5% with 13CR, 8 CRi, and 5 CRp, while an ORR of 44.8% was shown in the older patients (over 60 years of age) with 9 CR, 1 CRi, and 3 CRp. Overall, twenty two out of seventy two (30.5%) had CR in the unfavorable group, 9 (12.5%) had CRi, and 8 (11%) had CRp for an overall response rate of 54%. The 30 day mortality rate was 3.8% (6/155). The 60 day mortality rate was 11.6%. The most common adverse events were Grade 3/4 hematologic toxicities. Conclusion: This convenient, 2-day induction regimen leads to high response rates with low treatment-related mortality in older patients and patients with unfavorable cytogenetic characteristics. Based on the tolerability and effectiveness, this regimen could potentially be useful in high risk transplant-eligible patients for remission induction. It appears that this regimen would also be appropriate for initial cytoreduction in elderly patients with AML prior to introduction of novel therapeutic strategies, such as hypomethylating agents or oral clofarabine for consolidation and maintenance. Disclosures: No relevant conflicts of interest to declare.

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Impact Of Dialysis-Dependent Renal Failure At Time Of Myeloma Diagnosis On Overall Survival - a 15-Year Single Centre Analysis

Blood ◽

10.1182/blood.v122.21.3230.3230 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3230-3230

Author(s):

Philip T Murphy ◽

Cherisse Baldeo ◽

Patrick O'Kelly ◽

Jeremy Sargant ◽

Patrick Thornton ◽

...

Keyword(s):

Overall Survival ◽

Renal Impairment ◽

Patient Population ◽

Older Patients ◽

Conflicts Of Interest ◽

Wilcoxon Test ◽

High Dose ◽

Term Survival ◽

Old Patients ◽

Younger Patients

Abstract In myeloma, the use of autologous stem cell transplantation in younger patients as well as the introduction of thalidomide, lenalidomide and bortezomib has resulted in improvement in long-term survival of both younger and older patients. Bortezomid and high dose dexamethasone is currently recommended to treat newly diagnosed myeloma patients presenting with renal impairment and may lead to varying degrees of improvement in renal function. We have assessed not only survival trends for all patients diagnosed at our centre over the past 18 years but also the survival of the subset of patients with severe renal impairment who required dialysis at diagnosis. All patients diagnosed with myeloma at our centre between January 1995 and December 2012 were included. We constructed Kaplan-Meier curves and used the Breslow generalised Wilcoxon test to evaluate overall survival (OS) patterns (diagnosed in three calendar periods: 1995-2000; 2001-2006; 2007-2012) for our total patient population as well as the subset of patients who required dialysis within 4 weeks of diagnostic bone marrow test. 262 patients (60.3% males) were diagnosed between 1995 and 2012. For all patients, median OS significantly increased from 13.2 months in period 1995-2000 to 27 months in period 2001-2006 with median OS not yet reached in period 2007-2012 (p=0.0001). In patients 70 years old or less, median OS significantly increased from 25.4 months in period 1995-2000 to 46.7 months in period 2001-2006 with median OS not yet reached in period 2007-2012 (p=0.0482). Improved median OS was also seen in patients > 70 years old: 4.4 months in period 1995-2000, 17.4 months in period 2001-2006 and 25.1 months in period 2007-2012 (p<0.0001). In contrast, patients requiring dialysis at diagnosis (n = 44) had much worse outcomes: median OS in the period 1995-2000 was 2.8 months and although there was a slight improvement in median OS in the period 2001-2006 (p=0.0318), there has been no further improvement in median OS in the period 2007-2012. In our overall myeloma patient population, median OS has continued to increase over the time periods 1995-2000, 2001-2006 and 2007-2012, both for younger patients 70 years old or less and older patients >70 years old. Patients requiring dialysis at diagnosis, however, continue to have much poorer median OS, despite the use of bortezomib and dexamethasone containing regimens in recent years. The possible benefit of improved supportive measures and the early use of other emerging novel agents in this poor prognostic subgroup should be explored in the clinical trial setting. Disclosures: No relevant conflicts of interest to declare.

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High Dose Cytarabine Is Superior to Intermediate Dose Cytarabine As Post-Remission Therapy for Younger Patients with Favorable Risk Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v128.22.4032.4032 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4032-4032

Author(s):

Nurul Aidah Abdul Halim ◽

Gee Chuan Wong ◽

Ho YL Aloysius ◽

William YK Hwang ◽

Yeh Ching Linn ◽

...

Keyword(s):

Overall Survival ◽

Myeloid Leukemia ◽

Risk Group ◽

High Dose ◽

Free Survival ◽

Younger Patients ◽

High Dose Cytarabine ◽

Acute Myeloid ◽

Intermediate Dose

Abstract In the initial CALGB study and the retrospective analysis that followed 4 years later, high dose cytarabine, used as postremission chemotherapy in patients with acute myeloid leukemia (AML), resulted in significantly better overall survival and sustained remission when compared to lower doses of cytarabine, especially in young patients with core binding factor mutations (CBF). However, the toxicity seen with high dose cytarabine (HiDAC) prompted several studies to evaluate the role of intermediate dose cytarabine (MidAc). These studies concluded that MidAc produced similar overall survival and leukemia free survival to HiDAC while achieving a better side effect profile. Following these later findings, the consolidation protocol for AML patients 60 years or younger treated in the Singapore General Hospital was changed to 3 - 4 cycles of cytarabine 1.5g/m2 q12 D1, 3, and 5 (MidAc) from 3g/m2 q12 D1, 3, and 5 (HiDAC) in 2011. Cytarabine dose for older patients remain unchanged at 1g/m2 q12 D1, 3, and 5. A five year landmark analysis was performed to assess the difference in outcomes between these two regimens. Patients with non-M3 AML treated between 2004 and 2015 who received a cytarabine consolidation after achieving complete morphologic remission post standard 3+7 induction procotol (idarubicin 12mg/m2 D1-3 and cytarabine 100mg/m2 as a continuous infusion from D1-7) were included in the analysis. Patients who received an autologous or allogeneic hematopoietic stem cell transplant at first complete remission were excluded. 92 patients were identified for analysis with median age of 47 (range 16-76). The majority of patients belonged to the ELN favorable risk group (62 out of 92). 77 patients were aged 60 years or younger amongst which 48 patients received HiDAC and 29 patients received MidAc after a change in protocol. The median follow up for patients receiving HiDAC and MidAc was 104 and 39 months respectively. The 5-year overall survival (OS) between patients who had HiDAC and MidAc was 66.7% and 45.7% (p=0.16); and the 5-year leukemia free survival (LFS) was 51.9% and 41.6% (p=0.23). For comparison, the 5-year OS for patients above the age of 60 treated before and after 2011 was 16.7% and 46.7% (p = 0.3) and LFS was 16.7% and 55.6% (p= 0.35) respectively. Amongst 55 patients aged 60 or younger with favorable ELN risk, the survival outcomes were significantly better in the cohort receiving HiDAC compared with MidAc. 5 year OS were 86.1% vs. 44.5%, median OS not reached vs. 45 mths (p= 0.004). 5 year LFS were 63.9 vs. 36.8%, median LFS not reached vs. 20mths (p= 0.03). The cumulative incidence of relapse at 5 years was 33.4% in HiDAC and 61.1% in MidAc (p=0.04). No survival differences between the HiDAC and MidAc cohort were seen in the non-favorable risk group; 5 year OS was 26.7% vs 36.7% (p = 0.22), 5 year LFS was 26.7% vs 33.3%(p = 0.78) respectively. 13 (23.7%) favorable risk patients aged 60 or younger died during the follow up period. 5 patients died of complications of treatment, 4 (8%) in the HiDAC cohort and 1(3%) in the MidAc group (p= 0.4). Most deaths (4 out of 5) were attributable to neutropenic sepsis. Median age of patients who died during treatment was 54 years (range: 36 to 58) compared to 45 years (range: 15 to 60), (p = 0.23) amongst those who did not die from treatment related complications. In conclusion, in our cohort of patients consolidated with cytarabine monotherapy, HiDAC offers a better OS and LFS outcomes compared with MidAc in younger patients with favorable risk profile, albeit with a non-significant trend to an increase in treatment related mortality. Further studies looking into the interaction of cytarabine dose with specific genetic and cytogenetic AML sub-groups are warranted. OS of patients aged 60 or younger with ELN favorable risk AML (p= 0.01) Cumulative Incidence of Relapse of patients aged 60 or younger with ELN favorable risk AML (p= 0.04) Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Hwang: Roche: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support; Pfizer: Honoraria, Other: Travel support; Sanofi: Honoraria, Other: Travel support; Janssen: Honoraria, Other: Travel support; MSD: Honoraria, Other: Travel support; Novartis: Honoraria, Other: Travel support; BMS: Honoraria, Other: Travel support.

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BST-236, a Novel Cytarabine Pro-Drug, Enables Safe and Effective Administration of High Dose Cytarabine to Older or Unfit Patients with Acute Leukemia. Results of a Phase I/II Study

Blood ◽

10.1182/blood.v130.suppl_1.893.893 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 893-893

Author(s):

Tsila Zuckerman ◽

Ron Ram ◽

Maya Koren-Michowitz ◽

Luiza Akria ◽

Ron Hoffman ◽

...

Keyword(s):

Acute Leukemia ◽

Phase I ◽

De Novo ◽

High Dose ◽

Newly Diagnosed ◽

Standard Chemotherapy ◽

High Dose Cytarabine ◽

Unfit Patients ◽

Refractory Aml

Abstract Introduction: First line therapy of AML has not changed significantly since the 1970s and still relies on cytarabine as its backbone. Older patients or patients with comorbidities have low tolerability to intensive cytarabine treatment due to increased morbidity and mortality related to its toxicity, such as cerebellar toxicity, bone marrow suppression, gastrointestinal toxicity and infections. Hence, currently available intensive cytarabine treatment is unjustified in this population due to its poor risk/benefit ratio, and therefore, older and unfit AML patients are usually treated with reduced intensity therapy with poor outcomes. BST-236 is a new compound of cytarabine covalently bound to asparagine. It acts as a pro-drug of cytarabine, enabling delivery of high cytarabine doses to leukemia cells with lower systemic exposure to the free drug and relative sparing of normal tissues. As such, BST-236 may serve as an ideal therapy for leukemia, particularly for delivering high doses of cytarabine to medically unfit or older adults. The aim of this Phase I/II study was to evaluate the safety and optimal dose of BST-236 in refractory/relapsed or newly-diagnosed acute leukemia patients unfit for standard induction therapy. Methods: Acute leukemia patients, either relapsed/refractory, or older or unfit newly-diagnosed, were enrolled to a prospective open label single arm study. The study included 6 dose-escalating cohorts of patients treated with 6 daily doses of BST-236 administered as a 1-hour intravenous infusion. Cohorts 1-4 enrolled patients age ≥18 years, dosed with 0.5 g/m2, 1.5 g/m2, 3 g/m2 or 4.5 g/m2, respectively, with a 50% dose reduction in each cohort for patients age >50 years. Cohorts 5 and 6 enrolled patients ≥70 years of age, dosed with 4.5 g/m2 or 6 g/m2, respectively (Table 1). Results: Twenty-six (26) patients received at least 2 daily doses of BST-236, twenty-three (23) of them (14 males and 9 females) completed at least one 6-day treatment course, including 2 patients who received 2 courses. Out of the 23 patients who completed at least one treatment course, median age 77 (range 27-90), 6 had relapsed/refractory AML following standard chemotherapy, median age 64 years (range 27-81), 15 were newly-diagnosed AML patients unfit for standard chemotherapy, median age 78 years (range 70-89), including 11 patients (73%) with AML secondary to myelodysplastic disorder (MDS) or myeloproliferative neoplasms, median age 77 years (range 70-89), and 2 patients with de novo ALL, age 79 and 90. BST-236 treatment was well-tolerated and MTD was not reached in this study. Notably, the maximal dose of 6 g/m2/d BST-236 is the molar equivalent of 4 g/m2/d of cytarabine. Moreover, adverse events were mainly hematological "on-target" events, and no neurological events or >grade 2 events such as mucositis, diarrhea, or alopecia were reported in any of the cohorts during treatment or within 30 days of follow up. Assessment of the outcome of cohort 6 is still ongoing and will be available in the coming weeks. The majority of the newly diagnosed AML patients in cohorts 1-5 responded to BST-236 (Figure 1). The overall response and Complete Remission (CR) rates, of the newly-diagnosed AML patients (de novo and secondary to MDS) was 71% and 43%, respectively. Follow up of the Overall Survival (OS) of these patients is still ongoing, and is currently 6.9 months (active) for all responders, 9.2 months (active) for CR patients, and 0.6 months for the non-responders (Figure 2). Notably, 67% of the responding patients had secondary AML, refractory to hypomethylating agents (HMA). No CR was reached in the 6 patients suffering from relapse or refractory AML, and their median OS was 2.3 months (Figure 2). Conclusions: This Phase I/II study demonstrates that BST-236, a cytarabine pro-drug, is able to safely deliver high-dose cytarabine to older and unfit patients (median age 78) with no significant typical cytarabine toxicities other than "on-target" hematological events. Moreover, the general wellbeing of the patients during and after administration, as noted by the treating physicians, was exceptionally improved compared to intensive therapy. The good safety profile, accompanied by the high response rates and significantly prolonged survival of the older and unfit newly-diagnosed population, most of them refractory to HMA, is highly encouraging. A phase II study is planned to confirm these results. Disclosures Zuckerman: BioSight Ltd.: Consultancy. Gengrinovitch: Biosight: Employment. Flaishon: BioSight: Employment. Ben Yakar: Biosight: Employment.

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High Efficacy and Significantly Shortened Neutropenia Of Dose-Dense S-HAM As Compared To Standard Double Induction: First Results Of a Prospective Randomized Trial (AML-CG 2008)

Blood ◽

10.1182/blood.v122.21.619.619 ◽

2013 ◽

Vol 122 (21) ◽

pp. 619-619 ◽

Cited By ~ 4

Author(s):

Jan Braess ◽

Karl-Anton Kreuzer ◽

Karsten Spiekermann ◽

Hans Walter Lindemann ◽

Eva Lengfelder ◽

...

Keyword(s):

Overall Survival ◽

Primary Endpoint ◽

De Novo ◽

Standard Dose ◽

Haematological Toxicity ◽

Induction Treatment ◽

High Dose ◽

Younger Patients ◽

High Dose Cytarabine ◽

Dose Dense

Abstract Background For curative treatment of younger patients with acute myeloid leukemia (AML) double induction with two cycles of intensive cytarabine/ anthracycline based chemotherapy 21 days apart is the current standard of care. In the prospective randomized AML-CG 2008 trial we asked question whether current results could be improved on by a dose-dense regimen (S-HAM – Sequential High-dose cytArabine and Mitoxantrone) in which the interval between cycles was minimized to 3 days. A prior large one-armed study (AML-CG 2004) had demonstrated a high antileukemic efficacy and shortened neutropenia of the S-HAM regimen as compared to a historical control of standard double induction treatment. The first clinical results of the randomized comparison are presented here. Methods All patients with first diagnosis of a de-novo or secondary AML (excluding APL) that were deemed fit for intensive induction chemotherapy by their treating physician were eligible for this study. Younger patients in the standard arm were treated with one cycle of TAD-9 (standard dose cytarabine and daunorubicine 60mg/m2 for 3 days) and a mandatory second cycle of HAM (high dose cytarabine and mitoxantrone) starting at day 21. Elderly patients were treated with one cycle of HAM followed by a second cycle of HAM only in case of residual leukemia in the day 16 bone marrow aspirate. Patients in the experimental arm all received S-HAM (two sequential cycles of high-dose cytarabine on days 1+2, mitoxantrone days 3+4) with a 3 days interval. Patients in the age cohort 60 – 69 could be allocated to the “younger” or “elderly” cohort according to their biological fitness at the discretion of the treating physician. However high-dose cytarabine dosages were allocated according to chronological age with patients <60 years receiving 3g/m2 cytarabine per dose and patients 60+ years receiving 1g/m2. The primary endpoint was the overall response rate (i.e. CR + CRirate), secondary endpoints were duration of critical neutropenia, overall survival amongst others. Postremission treatment consisted of recommended early allogeneic transplantation in high risk patients and conventional postremission treatment according to the AML-CG standard (one cycle of TAD-9 consolidation followed by up to 3 years of maintenance treatment) in patients with low risk disease. Results 396 patients were randomized into the study with an age range of 18 to 86 years (median 58). The 387 evaluable patients (184 standard, 203 experimental) were well balanced according to their clinical characteristics, cytogenetics, molecular genetics and overall risk profile. For the primary endpoint a higher ORR of 77% for S-HAM could be found as compared to 72% in the standard arm which was however not significant because a 15% difference had been postulated for the study. Non-hematological toxicities did not show any significant differences. However this was in clear contrast to hematological toxicities: Importantly the duration of critical neutropenia was highly significantly reduced by more than 2 weeks from 45 days (standard) to 29 days (S-HAM) counted from day 1 of treatment. Similarly critical thrombocytopenia was reduced by 13 days from 46 days to 33 days. The early death (ED) rate between both arms was identical between both arms. However a subgroup analysis demonstrated a significantly reduced ED rate in patients receiving 1g/m2 S-HAM as compared to all other treatment groups. The respective ED rates for the various time intervals (always counted from day d1 of treatment) for the 1g/m2S-HAM group were as follows: Interval d1-14 1%, d1-30 3%, d1-60 5%, d1-90 10%. Data for overall survival will be available in November 2013. Conclusion The dose-dense induction regimen S-HAM was highly feasible in patients up to the 8th age decade. The antileukemic efficacy was high with an ORR of 77% for the whole group of unselected patients. As compared to standard double induction dose-dense S-HAM reduced critical neutropenia by more than two weeks. Moreover the subgroup of patients receiving the 1g/m2 S-HAM regimen experienced the lowest ED rate ever reported in the AML-CG trials. This underlines that in contrast to our general expectations the concept of dose-density is able to combine high antileukemic efficacy with significantly reduced haematological toxicity in AML, characterising this approach as first candidate for the next standard arm for future trials of the study group. Disclosures: Lengfelder: TEVA/ Cephalon: Research Funding.

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Devimistat in combination with high dose cytarabine and mitoxantrone compared with high dose cytarabine and mitoxantrone in older patients with relapsed/refractory acute myeloid leukemia: ARMADA 2000 Phase III study

Future Oncology ◽

10.2217/fon-2019-0201 ◽

2019 ◽

Vol 15 (28) ◽

pp. 3197-3208 ◽

Cited By ~ 4

Author(s):

Timothy S Pardee ◽

Sanjeev Luther ◽

Marc Buyse ◽

Bayard L Powell ◽

Jorge Cortes

Keyword(s):

Clinical Trial ◽

Complete Remission ◽

Older Patients ◽

Myeloid Leukemia ◽

Tca Cycle ◽

Phase Iii ◽

High Dose ◽

High Dose Cytarabine ◽

Acute Myeloid ◽

Refractory Aml

Devimistat (CPI-613®) is an intravenously administered, novel lipoate analog that inhibits two key tricarboxcylic acid (TCA) cycle enzymes, pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes (KGDH). These complexes control TCA cycle entry of glucose and glutamine-derived carbons, respectively. Acute myeloid leukemia (AML) cells upregulate the TCA cycle in response to DNA damaging agents and treatment with devimistat increases sensitivity to them. A Phase I study of devimistat in combination with cytarabine and mitoxantrone produced a complete remission rate of 50% in patients with relapsed or refractory AML. In the combined Phase I/II experience, older patients with R/R AML treated with 2000 mg/m2 of devimistat had a 52% complete remission/complete remission with incomplete hematologic recovery rate and a median survival of 12.4 months. This report outlines the rationale and design of the ARMADA 2000 study, a Phase III clinical trial of devimistat in combination with high dose cytarabine and mitoxantrone compared with high dose cytarabine and mitoxantrone alone for older patients (≥60 years of age) with relapsed or refractory AML. Clinical trial registration: NCT#03504410

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Autologous Stem Cell Transplantation for Multiple Myeloma in Patients over 70 Years: A Matched Comparison with Patients under 65 Years.

Blood ◽

10.1182/blood.v106.11.1173.1173 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1173-1173

Author(s):

Shaji Kumar ◽

Martha Lacy ◽

Angela Dispenzieri ◽

Suzzane Hayman ◽

William Hogan ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Older Patients ◽

Control Group ◽

High Dose ◽

High Dose Therapy ◽

Younger Patients ◽

Dose Therapy

Abstract Background: High dose therapy with autologous stem cell rescue has been shown to prolong survival in patients with multiple myeloma in randomized controlled trials. However, most of the prospective studies have included younger patients, usually 65 or less. It is important to have a better understanding of the outcome of transplantation in the older patients given the median age of onset of myeloma of 65 years. We retrospectively reviewed our institutions experience with high dose therapy for patients over 70 years. Methods: We identified 35 patients with multiple myeloma, from the transplant database, who were at or over the age of 70 at the time of their high dose therapy. We matched these patients to 70 patients (two matches for each patient), based on stage at transplant (primary refractory, plateau phase, relapse off therapy, or relapse on therapy), Durie Salmon stage, high or low labeling index, conventional cytogenetics (abnormal vs normal), presence or absence of circulating plasma cells at time of transplant, and whether cyclophosphamide was used as part of mobilization in that order of priority. Results: The median age of the two groups were 55.3 (Range 37.3–64.8) and 71.7 (Range 70–75.8) years at the time of transplant. The median time to transplant from diagnosis was similar (6.4 for the older patients compared to 6.9 months for the other, P = NS). Ten of the 35 older patients received reduced dose melphalan (140 mg/2)) compared to 3 patients in the control group; P < 0.01. The median follow up from transplant was 10.1 months for the older patients compared to 18 months for the control group. The overall response rate was similar for the two groups (97.1% for the older patients compared to 95.5 for the control group). Eleven (31%) of the older patients and 17 (24%) of the control patients achieved a CR (P = NS). The post transplant progression free survival estimate at 1 year post transplant was 65.3% for the older patients compared to 66% for the control group (P = 0.3)The two year estimated overall survival from transplant was similar in the two groups; 58% for the older patients compared to 67% for the control group. The overall survival from diagnosis was similar for the two groups (P = 0.6). The median number of days hospitalized was 9 days for the older population compared to 5 days for the control group (P = 0.37). Four patients died within the first one hundred days, one (3%) among the older patient group and 3 (4.3%) in the control group. Conclusions: High dose therapy and autologous stem cell transplantation is feasible in selected patients with multiple myeloma over 70 years. It is likely that these older patients were selected based on their overall performance status, a factor that is difficult to analyze in this retrospective review. Nearly 70% of the elderly patients received full dose melphalan for conditioning (200 mg/m2). The toxicity of transplant as well as the outcome appears to be very similar to the younger patients. Patients with multiple myeloma should not be excluded from high dose therapy solely on the basis of their chronological age.

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Elderly Multiple Myeloma (MM) Patients (≥70 years) Can Safely Undergo Autologous Stem Cell Transplantation (ASCT) but Have Shorter Overall Survival Than Younger Patients (<70 years).

Blood ◽

10.1182/blood.v114.22.3409.3409 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3409-3409

Author(s):

Carla Borgono ◽

Young Trieu ◽

Wei Xu ◽

Donna E. Reece ◽

Suzanne Trudel ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Renal Disease ◽

Older Patients ◽

Elevated Serum ◽

Progression Free Survival ◽

The Elderly ◽

High Dose ◽

Younger Patients ◽

Disease Characteristics

Abstract Abstract 3409 Poster Board III-297 Introduction: MM is a disease of the elderly with a median age at diagnosis of 65 years. For younger patients (<65 years), melphalan-based ASCT is standard therapy. However, limited data are available on the efficacy of ASCT in elderly patients (pts) over age 70, with concerns of excess toxicity and transplant-related mortality (TRM). Methods: From October 2000-August 2006, 548 MM pts were transplanted at our institution, 33 of whom (6%) were ≥70 years in age. Baseline demographics, disease characteristics, transplant and survival outcomes, including toxicities were collected retrospectively on all 548 patients and differences between the older patients (≥70 years) vs the younger pts (<70 years) were analyzed. Patients receiving a second salvage or tandem transplant were excluded. As per institutional transplant standard, all patients received 3-6 cycles of high-dose dexamethasone (DEX)-based induction therapy, underwent peripheral blood stem cell mobilization with cyclophosphamide 2.5g/m2 and GCSF 10mg/kg/day, and received melphalan 200mg/m2 for conditioning (no routine dose reductions for age). Ciprofloxacin prophylaxis and GCSF use (from day 7) were used routinely during the transplant process. Results: A total of 548 MM pts were studied: 33 pts ≥70 yrs of age (median 71 yrs; range 70-74); 515 pts <70 years of age (median 59 yrs; range 29-69). Patient and disease characteristics: MM subtypes for all pts included: IgG (59%), IgA (19%), biphenotypic (2%), IgD and IgM (<1%), light chain only (5%), other (10%) (no differences between the 2 groups). For the ≥70 yrs pts at baseline: median Hb was 98g/L (range 73-141), 22% of pts were hypercalcemic at diagnosis (median 2.38 mmol/L; range 2.09-4.24), 48% had significant renal dysfunction with serum creatinine >177 umol/L at diagnosis (median creatinine 94 umol/L; range 60-450), and 79% had elevated serum beta-2 microglobulin at diagnosis (median 269 nmol/L, range 5.8-505). No differences in baseline lab values were noted between the elderly and younger groups. Comorbid disorders in the elderly pts were common: 36% cardiac conditions (hypertension, coronary artery disease, heart failure, arrthythmias), 18% prior or pre-existing malignancy (solid tumours, lymphoma, leukemia), 12% diabetes, 12% gastrointestinal (ulcers, diverticular disease, colitis), 21% prior major infection (sepsis, pneumonia, TB), 6% renal disease (chronic renal failure, cystic disease), 6% CNS (stroke, seizures). Both renal disease and prior major infections were more common in the ≥70 group (renal 6 vs 1%, p=0.04 and infections 21 vs 5%, p=0.0003. Transplant outcomes: Although a standard stem cell mobilizing procedure was utilized for all pts, fewer stem cells (CD34+ cells) were collected in the ≥70 age group in comparison to the younger pts (median 12.3 vs. 9.1 × 106/kg; p=0.004). This did not, however, translate into significant differences in days to neutrophil or platelet engraftment, nor in days of hospitalization. For the ≥70 group, 76% achieved a PR (9% VGPR/CR) as assessed 3 months post-transplant, similar to the <70 group (p=0.08). Median progression-free survival from transplant was similar between groups (23.7 vs 21.8 mos, p=0.65) but median overall survival of the elderly pts was significantly shorter than that of younger patients (46.3 vs 80.4 mos, p = 0.03). Causes of death are unknown. Toxicities: Older patients exhibited cardiac toxicities (primarily arrhythmias) more frequently than younger patients during the transplant period (grade 1/2 - 3% vs 6%, grade 3/4 – 0 vs. 2%; p<0.0001). Treatment-related deaths, however, were uncommon in both groups [none in ≥70 pts vs 1.3% in <70 pts (p=0.27)]. Conclusions: Disclosures: Reece: Ortho Biotech: Honoraria, Research Funding.

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