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

Blood ◽  
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.

Effective Remission Induction for AML Using Two Days of Chemotherapy: Older Patients Tolerate and Respond Equally Well

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4004-4004
Author(s):  
Neel B. Shah ◽  
Melissa L. Larson ◽  
Nitin Goyal ◽  
Ann M. Thomas ◽  
Jamile M. Shammo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Older Patients ◽  
Response Rates ◽  
Remission Induction ◽  
High Dose ◽  
Refractory Disease ◽  
Toxicity Profile ◽  
Induction Regimen ◽  
High Dose Cytarabine

Abstract Background: The remission induction regimen used for treatment of adult AML has traditionally been the “7+3” regimen, which has not changed significantly since 1981. CR rates have been in the 55–60% range, historically. We present a single institution, retrospective analysis of a regimen consisting of two pulses of chemotherapy 96 hours apart with high-dose cytarabine and mitoxantrone. It is based on the concept of timed sequential therapy where the first pulse of chemotherapy recruits leukemic cells into the cell cycle and is followed by the second pulse at the time of peak cell recruitment. Cytarabine is a cell cycle-specific drug, and mitoxantrone was chosen because of its resistance to the effects of the gene MDR1, which is commonly expressed in adult leukemia, as well as its favorable cardiac toxicity profile. Patients and Methods: One hundred four patients with AML were treated with timed sequential chemotherapy from April 1997 to April 2008. Each pulse of chemotherapy consisted of 2 doses of cytarabine 2gm/m2 given 12 hours apart (at t=0 and t=12) followed by one dose of mitoxantrone 30 mg/m2 administered after the second cytarabine dose (t=15) given on days 1 and 5. Bone marrow biopsies were performed to assess for leukemia free-state (day 14) and subsequently for remission documentation. Responses were defined per the Revised IWG Recommendations (Cheson, J Clin Onc21: 4642, 2003). Toxicities, response rates, relapse rates, and preexisting conditions were also recorded. Results: Median age of the 104 patients was 57 y [range 17–79]. There were 47 males and 57 females. Forty-two patients (40%) were 60 years of age or older with 17 (16%) of them older than 70 years. Forty patients (38%) had preexisting MDS. Five patients (4.8%) had favorable cytogenetics, 61 (58.7%) had intermediate cytogenetics, and 38 (36.5%) had unfavorable cytogenetics. Seventy-four patients (71%) achieved a leukemia free state based on the day 14 bone marrow biopsy. At the time of the remission documentation bone marrow biopsy, the IWG-defined responses seen are the following: 56 CR (53.8%), 9 CRi (8.6%), and 10 CRp (9.6%). Three additional patients (2.9%) had a return to MDS (RMDS). Twenty patients (19.2%) had refractory disease. Overall, 78 patients had a response, (ORR=75%). The 30-day mortality rate was 2.8% (3/104). In the 62 patients under 60 years of age, 51 (82%) responded to chemotherapy. In the 42 patients age 60 and older, 27 had a response (64%). Thirteen of the seventeen patients age 70 and older had a response (10 CR, 2 CRp, 1 CRi) for an ORR of 76.4%. The remaining 4 patients in this age group had refractory disease. Conclusion: This remission induction regimen of high dose cytarabine and mitoxantrone produces very high response rates, even in the older AML patients. The response rates in both younger patients and older patients compare favorably with the rates historically seen with the standard 7 + 3 regimen. The 30-day mortality rate of less than 3% is less than that previously reported with the 7 + 3 regimen. This may be attributable to improvements in supportive care; although, this could also represent the favorable toxicity profile of this effective, novel regimen.

Tolerability of An Effective Two Day Induction Regimen for Newly Diagnosed AML

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4035-4035
Author(s):  
Melissa L. Larson ◽  
Nitin Goyal ◽  
Ann M. Thomas ◽  
Jamile M. Shammo ◽  
John J. Maciejewski ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Induction Therapy ◽  
Dose Intensity ◽  
Remission Induction ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Refractory Disease ◽  
Induction Regimen ◽  
High Dose Cytarabine ◽  
Grade 3

Abstract Background: The standard remission induction regimen for treating Acute Myeloid Leukemia consists of seven days of continuous infusion cytarabine and three days of an anthracycline, the “7 + 3” regimen. We present a single institution, retrospective analysis of toxicity associated with a regimen that requires only two days of chemotherapy using high dose cytarabine and mitoxantrone. The regimen is based on the timed sequential therapy concept where two pulses of chemotherapy are given. The first pulse recruits cells into the cell cycle, while the second pulse is given at the time of peak recruitment. Methods: One hundred four patients with AML were treated with two days of chemotherapy given 96 hours apart from April 1997 to April 2008. Each day of chemotherapy consisted of two doses of cytarabine 2gm/m2 (at t=0 and t=12) followed by one dose of mitoxantrone 30 mg/m2 administered after the second cytarabine dose (t=15). Each patient’s chart and electronic record were thoroughly reviewed, and toxicities associated with induction therapy were analyzed and graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events v3.0. Responses were defined per the Revised IWG Recommendations (Cheson, J Clin Onc21: 4642, 2003). Results: One hundred four patients were eligible for toxicity evaluation. Hematologic toxicities were the most common toxicities seen with this induction therapy. Overall, all patients experienced hematologic toxicity of some grade with 98% of patients having one or more Grade 3/4 hematologic toxicity. The incidences of grade 3/4 hematologic toxicities are the following: Hemoglobin 65.3% (Gr 3 59.6%, Gr 4 5.7%), thrombocytopenia 93.2% (Gr 3 9.6%, Gr 4 83.6%), and neutropenia 89.4% (Gr 3 1.9%, Gr 4 87.5%). Febrile neutropenia occurred in 64% of the patients, and grade 3 and 4 infections occurred in 25%. Common non-hematologic toxicities included fatigue, nausea, vomiting, diarrhea, and electrolyte abnormalities. The vast majority of non-hematologic toxicities were grade 1 and 2. Three patients (2.9%) died within the first 30 days of induction therapy. One patient died before completing therapy due to massive hemoptysis. One died from complications of refractory disease, and the third patient died from disseminated fungal infection. An additional 10 patients (6 TF-RD, 1 TF-aplasia, 1 CR, 1 CRi, 1 CRp) died within the first 60 days. Of the 6 patients with refractory disease, 4 received re-induction therapy to which 3 did not have a response and the fourth died of sepsis while aplastic. Two patients had intracerebral hemorrhage (TF-aplasia and CRp). One patient died suddenly in CR of unknown causes and one patient (CRi) died from complications of pneumonia/ARDS. Conclusion: Although this regimen incorporating high dose cytarabine into remission induction presents a significantly higher dose intensity of cytarabine and mitoxantrone compared to that of the “7+3” regimen, the toxicity profile and 30-day mortality rate compare favorably to the “7 + 3” regimen. This regimen has been shown to produce a CR rate comparable to that of the “7+3” regimen with equal efficacy and better tolerance in elderly patients with AML. We conclude that this regimen effectively administers a high yet apt dosage of chemotherapy, and it can even be used for remission induction in elderly patients. This induction regimen could serve as a platform for future studies of maintenance and biologic therapies in the elderly AML patients.

scholarly journals Intensive chemotherapy is the treatment of choice for elderly patients with acute myelogenous leukemia

Blood ◽  
1981 ◽  
Vol 58 (3) ◽  
pp. 467-470 ◽  
Author(s):  
KA Foon ◽  
J Zighelboim ◽  
C Yale ◽  
RP Gale
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Older Patients ◽  
Myelogenous Leukemia ◽  
Remission Induction ◽  
High Dose ◽  
Intensive Chemotherapy ◽  
Younger Patients ◽  
Remission Rates ◽  
Induction Regimen ◽  
Acute Myelogenous

Abstract One-hundred and seven patients with acute myelogenous leukemia (AML) ranging in age from 15 to 82 yr who were previously untreated, received a 70 day high-dose remission induction regimen consisting of daunorubicin, cytarabine, and thioguanine (TAD). Identical complete remission rates of 65% were observed for 33 patients 60 yr of age and older and for 74 patients age 15–59 yr. Median remission duration and survival were 14 mo and 22 mo for patients 60 yr and older, and 16 mo and 22 mo for patients 15–59 yr. These differences are not significant. These data indicate that older patients respond to intensive chemotherapy in a similar manner to younger patients with this disease.

scholarly journals Intensive chemotherapy is the treatment of choice for elderly patients with acute myelogenous leukemia

Blood ◽  
1981 ◽  
Vol 58 (3) ◽  
pp. 467-470 ◽  
Author(s):  
KA Foon ◽  
J Zighelboim ◽  
C Yale ◽  
RP Gale
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Older Patients ◽  
Myelogenous Leukemia ◽  
Remission Induction ◽  
High Dose ◽  
Intensive Chemotherapy ◽  
Younger Patients ◽  
Remission Rates ◽  
Induction Regimen ◽  
Acute Myelogenous

One-hundred and seven patients with acute myelogenous leukemia (AML) ranging in age from 15 to 82 yr who were previously untreated, received a 70 day high-dose remission induction regimen consisting of daunorubicin, cytarabine, and thioguanine (TAD). Identical complete remission rates of 65% were observed for 33 patients 60 yr of age and older and for 74 patients age 15–59 yr. Median remission duration and survival were 14 mo and 22 mo for patients 60 yr and older, and 16 mo and 22 mo for patients 15–59 yr. These differences are not significant. These data indicate that older patients respond to intensive chemotherapy in a similar manner to younger patients with this disease.

Timed Sequential Induction Therapy with Cytarabine and Mitoxantrone In Acute Myeloid Leukemia (AML): A Well-Tolerated Regimen with High Response Rates In Older Patients and Transformed AML.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1068-1068
Author(s):  
Sheena Sahota ◽  
Melissa L Larson ◽  
Margaret C Keller ◽  
Jamile M. Shammo ◽  
Allison Zindell ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Older Patients ◽  
De Novo ◽  
Response Rates ◽  
High Response ◽  
Remission Induction ◽  
High Dose ◽  
Remission Duration ◽  
Induction Regimen ◽  
De Novo Aml

Abstract Abstract 1068 Background: Patients with AML who are eligible for chemotherapy are traditionally treated with infusional cytarabine and an anthracycline. CR rates with this combination have been approximately 50–60% with an induction mortality of 10–25%. However, this treatment is less effective in older patients in terms of CR attainment, remission duration, and overall survival. We present a retrospective analysis of an induction regimen that was designed based on the concept of timed sequential therapy. An initial pulse of chemotherapy is administered to eradicate cells in S phase. This is followed by a rest period during which previously quiescent cells that enter the cell cycle can be targeted by a second pulse of chemotherapy. The regimen incorporates high dose cytarabine, which has been shown to improve remission duration when used in induction, and dose-intensified anthracycline therapy, which has been shown to improve outcomes in younger patients. This report highlights the responses and tolerability of the study regimen, particularly in elderly patients and patients with prior myelodysplastic syndrome (MDS). Patients and Methods: One hundred sixty six patients were treated with timed sequential chemotherapy from 1998–2009. The treatment consisted of two doses of cytarabine 2 gm/m2 IVPB over 3 hours administered 12 hours apart followed by one dose of mitoxantrone 30 mg/m2 IVPB over 1 hour on days 1 and 5. Data on pre-therapy cytogenetics and MDS was collected for each patient. Remission status was assigned per the IWG response criteria for AML. Results: Median age of the patients was 54.5 years (range 17–85). There were eighty males and eighty-six females. Out of 166 patients, 11 (6.6%) patients had favorable, 83 (50%) had intermediate, and 72 (43.4%) had unfavorable karyotypes. One-third of the patients (57 pts) had AML transformed from MDS. The overall response rate (ORR: CR+CRi+CRp) for all patients was 69.9%. In patients who had de novo AML, the ORR was 79.8%, regardless of age. Patients over age 60 with de novo AML had an ORR of 74%. For those patients under the age of 60, the ORR was 82%. The ORR for patients with transformed AML was 52.6% (53% in pts over age 60, 52% in pts less than 60). The 30 day mortality rate was 3.4% (6/166). Five of the six patients who died had an unfavorable karyotype with 2 patients having therapy-related AML. The 30 day mortality for patients older than 60 was 3.3% (2/61) and for all patients was 3.6% (6/166). The 60 day mortality rate in all patients was 10.8% (18/166). Of the additional 12 patients, seven died from progressive disease and only 3 died of suspected therapy-related complications. Grade 3/4 hematologic toxicities were the most common adverse events seen. Conclusion: This is a convenient, 2-day induction regimen that is well-tolerated with comparatively low 30 and 60 day mortality and high response rates in older patients and those patients with AML transformed from MDS. This would be an excellent initial regimen for remission induction in a select population of patients in whom novel consolidation or maintenance therapies can be incorporated to further improve outcome. Disclosures: No relevant conflicts of interest to declare.

Influence of BMI on outcomes of high-dose cytarabine and mitoxantrone induction therapy for AML.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7106-7106
Author(s):  
Mansoor Burhani ◽  
Manish J. Dave ◽  
Parameswaran Venugopal ◽  
Melissa L. Larson
Keyword(s):  
Induction Therapy ◽  
Adult Population ◽  
Outcome Data ◽  
Obese Group ◽  
High Dose ◽  
Free Survival ◽  
Actual Weight ◽  
Induction Regimen ◽  
High Dose Cytarabine ◽  
Overweight Group

7106 Background: Acute Myeloid Leukemia (AML) affects thousands of Americans every year. With approximately 35.7% of the U.S. adult population being obese, it is important to understand how a patient’s BMI can affect their outcome with AML treatment. This study evaluates a high-dose cytarabine and mitoxantrone induction regimen, and the results are examined to determine the effect of BMI on outcome, in terms of induction response and survival. Methods: Eighty nine patients were treated with a High Dose Cytarabine and Mitoxantrone regimen from 2008-2012. Two doses of cytarabine 3 gm/m2 were given 12 hours apart followed by one dose of mitoxantrone 30 mg/m2on days 1 and 5. All patients were dosed based on their actual body weight. Before treatment began, the BMI for each of the patients was recorded. The outcome data was collected and analyzed. Results: Of the 89 patients, 22 patients were normal, 33 overweight, and 34 obese. The BMI readings are based on the definitions established by the WHO. The overall CR rate for all 89 patients was 65%. The CRR for normal patients was 77%, 55% for overweight patients, and 68% for obese patients. 62 (70%) patients remain alive: 73% of normal patients, 58% of overweight, and 79% of obese. 17 of patients never achieved remission, even after multiple induction courses: 2 (9%) in the normal group, 10 (30%) in the overweight group, and 5 (15%) in the obese group. Of the responders, 35% of normal patients had a relapse, 30% in the overweight group, and 21% in the obese group with median relapse free survival of 8 months, 10 months and 6 months, respectively. Conclusions: Patients with a healthier BMI were more likely to respond to induction therapy with high-dose cytarabine and mitoxantrone. However, there was no difference in relapses amongst the groups. Patients who did not respond initially were unlikely to respond to other treatments. Therefore, using actual weight to determine dosing in AML induction therapy is the appropriate strategy.

Optimization of Chemotherapy for Younger Patients With Acute Myeloid Leukemia: Results of the Medical Research Council AML15 Trial

2013 ◽  
Vol 31 (27) ◽  
pp. 3360-3368 ◽  
Author(s):  
Alan K. Burnett ◽  
Nigel H. Russell ◽  
Robert K. Hills ◽  
Ann E. Hunter ◽  
Lars Kjeldsen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Remission Induction ◽  
High Dose ◽  
Younger Patients ◽  
High Risk Patients ◽  
High Dose Cytarabine ◽  
Risk Patients ◽  
Acute Myeloid

Purpose Treatment outcomes in younger patients with acute myeloid leukemia (AML) have improved, but optimization and new combinations are needed. We assess three combinations in induction and consolidation. Patients and Methods Younger untreated patients with AML (median age, 49 years; range, 0 to 73 years) were randomly allocated to two induction courses of daunorubicin and cytarabine (DA) with or without etoposide (ADE; n = 1983) or ADE versus fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida; n = 1268), and to amsacrine, cytarabine, etoposide, and then mitoxantrone/cytarabine (MACE-MidAC) or high-dose cytarabine (n = 1,445) 3 g/m2 or 1.5 g/m2 (n = 657) in consolidation, and finally to a fifth course (cytarabine) or not (n = 227). Results Overall remission rates were similar for DA versus ADE (84% v 86%; P = .14) and ADE versus FLAG-Ida (86% v 85%; P = .7), with more course 1 remissions after FLAG-Ida (77%) reducing relapse (38% v 55%; P < .001) and improving relapse-free survival (45% v 34%; P = .01), overall and in subgroups, but with increased myelosuppression, reducing participation in the consolidation randomization. Overall outcomes were similar between MACE/MidAc and high-dose cytarabine (1.5/3.0 g/m2), but cytarabine required less supportive care. MACE/MidAc was superior for high-risk patients. A fifth course provided no benefit. The outcome for recipients of only two FLAG-Ida courses were not different from that with DA/ADE with consolidation. Conclusion FLAG-Ida is an effective remission induction treatment, with a high complete remission rate after course 1 and reduced relapse. Consolidation with MACE/MidAc is similar overall to high-dose cytarabine, but superior in high-risk patients. Cytarabine at 1.5 g/m2 is equivalent to a 3 g/m2 dose. A fifth course is unnecessary. In patients receiving FLAG-Ida (two courses) and cytarabine (two courses), 8-year survival was 63% for patients with intermediate-risk and 95% for those with favorable-risk disease.

scholarly journals 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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1355-1355 ◽  
Author(s):  
Timothy Pardee ◽  
Scott Isom ◽  
Leslie Renee Ellis ◽  
Dianna S. Howard ◽  
Rupali Bhave ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase I ◽  
Older Patients ◽  
Median Overall Survival ◽  
High Dose ◽  
Younger Patients ◽  
Age Related ◽  
High Dose Cytarabine ◽  
Refractory Aml ◽  
Phase I And Ii

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.

scholarly journals Varying intensity of postremission therapy in acute myeloid leukemia

Blood ◽  
1992 ◽  
Vol 79 (8) ◽  
pp. 1924-1930 ◽  
Author(s):  
PA Cassileth ◽  
E Lynch ◽  
JD Hines ◽  
MM Oken ◽  
JJ Mazza ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mortality Rate ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Allogeneic Bone ◽  
Consolidation Therapy ◽  
High Dose Cytarabine ◽  
Postremission Therapy ◽  
Acute Myeloid

The Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial in patients less than or equal to 65 years old (median, 44 years) to determine whether increasing the intensity of postremission therapy in acute myeloid leukemia (AML) would improve the outcome. After uniform induction therapy, patients in complete remission (CR) who were less than 41 years old and who had a histocompatible sibling underwent allogeneic bone marrow transplantation (alloBMT) (54 patients). The remainder of patients in CR were randomized to receive either 2 years of continuous outpatient maintenance therapy with cytarabine and 6- thioguanine (83 patients) or a single course of inpatient consolidation therapy consisting of 6 days of high-dose cytarabine plus 3 days of amsacrine (87 patients). The median duration of follow-up is now 4 years, and patients are included in the analyses of outcome regardless of whether they relapsed before starting the intended treatment. Four- year event-free survival (EFS) was 27% +/- 10% for consolidation therapy versus 16% +/- 8% for maintenance therapy (P = .068) and 28% +/- 11% versus 15% +/- 9% (P = .047) in patients less than 60 years old. The outcome for patients receiving alloBMT was compared with the subset of patients less than 41 years old who received consolidation therapy (N = 29) or maintenance therapy (N = 21). Four-year EFS was 42% +/- 13% for alloBMT, 30% +/- 17% for consolidation therapy, and 14% +/- 15% for maintenance therapy. AlloBMT had a significantly better EFS (P = .013) than maintenance therapy, but was not different from consolidation therapy. In patients less than 41 years old, 4-year survival after alloBMT (42% +/- 14%) did not differ from consolidation therapy (43% +/- 18%), but both were significantly better than maintenance therapy (19% +/- 17%), P = .047 and .043, respectively. The mortality rate for maintenance therapy was 0%, consolidation therapy, 21%; and alloBMT, 36%. Consolidation therapy caused an especially high mortality rate in the patients greater than or equal to 60 years old (8 of 14 or 57%). The toxicity of combined high-dose cytarabine and amsacrine is unacceptable, especially in older patients, and alternative approaches to consolidation therapy such as high-dose cytarabine alone need to be tested. In AML, a single course of consolidation therapy or alloBMT after initial CR produces better results than lengthy maintenance therapy. Although EFS and survival of alloBMT and consolidation therapy do not differ significantly, a larger number of patients need to be studied before concluding that they are equivalent.

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