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.

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.

Bortezomib, Doxorubicin and Dexamethasone (PAD) Combination Therapy Followed by Thalidomide and Dexamethasone (TD) as a Salvage Treatment for Relapsed Multiple Myeloma (MM): Preliminary Analysis of Efficacy and Safety.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2731-2731 ◽  
Author(s):  
Sung Sook Lee ◽  
Cheolwon Suh ◽  
Bong-Seog Kim ◽  
Jooseop Chung ◽  
Young-Don Joo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Univariate Analysis ◽  
Dose Intensity ◽  
Cross Resistance ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Therapy Regimen ◽  
Overall Response ◽  
Effective Regimen ◽  
Grade 3

Abstract Introduction: PAD was reported to be highly effective regimen as an induction therapy before high dose therapy. TD is an another effective regimen with no cross resistance. We conducted a phase II study with PAD followed by TD in relapsed MM to test effectiveness of this combination. Method: Patients were planned to receive 6 cycles of PAD, (bortezomib 1.3 mg/m2 days 1, 4, 8 and 11, doxorubicin 4.5 mg/m2 days 1–4, dexamethasone 40 mg days 1–4, every 21 days). Responders following 6 cylces of PAD received 12 cycles of TD (thalidomide 100 mg days 1–28 and dexamethasone 40 mg days 1–4, every 28 days). In patients with progression during PAD therapy, regimen was changed to 12 cycles of thalidomide 200 mg days 1–28 and dexamethasone 40 mg days 1–4, every 28 days. Result: This study aimed to enroll 40 patients till Oct 2007 and we are reporting preliminary result with 35 patients. Efficacy could be assessed in 29 patients. After two cycles of PAD, 29 patients showed response with 5 CR. Overall response rate to 6 cylces of PAD was 96.4% with 39.3% CR. Six of total 13 patients with TD showed further improvement of response status with 5 additional CR. Overall response to PAD followed by TD was 92.8%: CR 57.1%, nCR 10.7%, VGPR 7.1%, PR 17.9%, SD 3.6%, PD 3.6%. There was no prognostic factor for CR+nCR achieving in the univariate analysis. The median follow-up was 8.4 months with 1 year PFS 66.8% and 1 year OS 59.4%. One hundred fourty-six PAD cycles (median 5, range 1–6) in 35 patients were assessable for safety. The most common hematologic toxicity was thrombocytopenia, with grade 3/4 in 37.1%. Grade 3/4 neutropenia was observed in 5.8%. Sensory neuropathy occurred with grade 2 in 31.4% and grade 3 in 8.6%. The median dose intensity was 1.44 mg/m2/week for bortezomib and 5.25 mg/m2/week for doxorubicin, which correspond 83.2% and 87.5% of the planned dose intensities, respectively. A total of 112 TD treatment cycles (median 0, range 0–12 cycles) was administered. Two patients developed grade 3 neutropenia. One patient die by the pneumonia. Conclusion: PAD followed by TD in patients with relapsed multiple myeloma is very active and tolerable. Updated results will be presented at the meeting. *Protocol Number: KMM55-NCT00319865

Impact of Five Prophylactic Filgrastim Schedules on Hematologic Toxicity in Early Breast Cancer Patients Treated With Epirubicin and Cyclophosphamide

2005 ◽  
Vol 23 (28) ◽  
pp. 6908-6918 ◽  
Author(s):  
Paola Papaldo ◽  
Massimo Lopez ◽  
Paolo Marolla ◽  
Enrico Cortesi ◽  
Mauro Antimi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Early Breast Cancer ◽  
Dose Intensity ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Breast Cancer Patients ◽  
Nonrandomized Trial ◽  
Grade 3 ◽  
To Receive

Purpose To evaluate the comparative efficacy of varying intensity schedules of recombinant human granulocyte colony-stimulating factor (G-CSF; filgrastim) support in preventing febrile neutropenia in early breast cancer patients treated with relatively high-dose epirubicin plus cyclophosphamide (EC). Patients and Methods From October 1991 to April 1994, 506 stage I and II breast cancer patients were randomly assigned to receive, in a factorial 2 × 2 design, epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 intravenously on day 1 every 21 days for 4 cycles ± lonidamine ± G-CSF. The following five consecutive G-CSF schedules were tested every 100 randomly assigned patients: (1) 480 μg/d subcutaneously days 8 to 14; (2) 480 μg/d days 8, 10, 12, and 14; (3) 300 μg/d days 8 to 14; (4) 300 μg/d days 8, 10, 12, and 14; and (5) 300 μg/d days 8 and 12. Results All of the G-CSF schedules covered the neutrophil nadir time. Schedule 5 was equivalent to the daily schedules (schedules 1 and 3) and to the alternate day schedules (schedules 2 and 4) with respect to incidence of grade 3 and 4 neutropenia (P = .79 and P = .89, respectively), rate of fever episodes (P = .84 and P = .77, respectively), incidence of neutropenic fever (P = .74 and P = .56, respectively), need of antibiotics (P = .77 and P = .88, respectively), and percentage of delayed cycles (P = .43 and P = .42, respectively). G-CSF had no significant impact on the delivered dose-intensity compared with the non–G-CSF arms. Conclusion In the adjuvant setting, the frequency of prophylactic G-CSF administration during EC could be curtailed to only two administrations (days 8 and 12) without altering outcome. This nonrandomized trial design provides support for evaluating alternative, less intense G-CSF schedules for women with early breast cancer.

Bortezomib, Doxorubicin and Dexamethasone (PAD) Combination Therapy Followed by Thalidomide and Dexamethasone (TD) as a Salvage Treatment for Relapsed Multiple Myeloma (MM): Analysis of Efficacy and Safety

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5187-5187
Author(s):  
Jae Hoon Lee ◽  
Cheolwon Suh ◽  
Sung Sook Lee
Keyword(s):  
Multiple Myeloma ◽  
Univariate Analysis ◽  
Dose Intensity ◽  
Cross Resistance ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Therapy Regimen ◽  
Overall Response ◽  
Effective Regimen ◽  
Grade 3

Abstract Introduction: PAD was reported to be highly effective regimen as an induction therapy before high dose therapy. TD is an another effective regimen with no cross resistance. We conducted a phase II study with PAD followed by TD in relapsed MM to test effectiveness of this combination. Method: Patients were planned to receive 6 cycles of PAD, (bortezomib 1.3 mg/m2 days 1, 4, 8 and 11, doxorubicin 4.5 mg/m2 days 1–4, dexamethasone 40 mg days 1–4, every 21 days). Responders following 6 cylces of PAD received 12 cycles of TD (thalidomide 100 mg days 1–28 and dexamethasone 40 mg days 1–4, every 28 days). In patients with progression during PAD therapy, regimen was changed to 12 cycles of thalidomide 200 mg days 1–28 and dexamethasone 40 mg days 1–4, every 28 days. Response was assessed by EBMT criteria, with additional categories of nCR and VGPR. Adverse events were graded by the NCI-CTC, Version 3.0. Result: This study aimed to enroll 40 patients till Oct 2007 and we are reporting the result with 40 patients. Efficacy could be assessed in 34 patients. After two cycles of PAD, 34 patients showed response with 6 CR. Overall response rate to 6 cylces of PAD was 90.9% with 36.4% CR. Seven of total 24 patients with TD showed further improvement of response status with 7 additional CR. Overall response to PAD followed by TD was 94%: CR 57.6%, nCR 15.2%, VGPR 6%, PR 15.2%, SD 3%, PD 3%. There was no prognostic factor for CR+nCR achieving in the univariate analysis. The median follow-up was 16.2 months with 2 year OS 54.5%. The median PFS time from study treatment was 18 mon (95% CI, 11.0~24.9 mon), median OS was not reached. The median OS time from first diagnosis was 112.9 mon (95% CI, 24.6~201.1 mon). One hundred seventy-eight PAD cycles (median 6, range 1–6) in 38 patients were assessable for safety. The most common hematologic toxicity was thrombocytopenia, with grade 3/4 in 39.5%. Grade 3/4 neutropenia was observed in 10.5%. Sensory neuropathy occurred with grade 2 in 26.3% and grade 3 in 13.2%. The median dose intensity was 1.35 mg/m2/week for bortezomib and 5.21 mg/m2/week for doxorubicin, which correspond 78% and 86.8% of the planned dose intensities, respectively. A total of 185 TD treatment cycles (median 2, range 0–12 cycles) was administered. One patient die by the pneumonia. Conclusion: PAD followed by TD in patients with relapsed multiple myeloma is very active and tolerable.

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.

Efficacy and Feasibility of High-Dose Cytarabine Plus Idarubicin and Amifostine As Induction Schedule: A Prospective Observational Study of 100 AML Elderly Fit Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3621-3621
Author(s):  
Debora Capelli ◽  
Martina Chiarucci ◽  
Francesco Saraceni ◽  
Antonella Poloni ◽  
Mauro Montanari ◽  
...  
Keyword(s):  
Prospective Observational Study ◽  
Low Dose ◽  
De Novo ◽  
High Dose ◽  
Allogeneic Transplant ◽  
Free Survival ◽  
Induction Regimen ◽  
High Dose Cytarabine ◽  
De Novo Aml ◽  
Grade 3

Abstract Abstract 3621 Acute myeloid leukemia (AML) has a dismal prognosis in elderly population because of intrinsic chemoresistance and frailty of patients. High-dose Cytarabine (HiDAC) in induction therapy did not improve the CR in younger AML patients and recent guidelines discourage this approach in elderly because of high extrahematological toxicity. Amifostine showed to selectively protect normal Hemopoietic progenitors from chemotherapy and we previously successfully tested the feasibility of an induction schedule including HiDAC (3 g/m2 days 1,2,3,4,5), Idarubicin 40mg/m2 on day 3 preceeded by Amifostine (740 mg/m2). We designed a prospective observational study including the same induction schedule, aimed to evaluate the outcome (CR rate, OS and EFS) of a larger population of fit AML elderly patients. Fit patients, selected according the Multidimensional Geriatric Assessment, received 1–2 courses and underwent PBSC mobilization after consolidation. Patients who collected ≥3×10e6CD34+/kg received ASCT, while poor mobilizers were considered for alternative regimen including Allogeneic transplantation from an HLA-matched sibling, chemotherapy (CHT) or Gemtuzumab-Ozogamicin (GO). We registered 156 consecutive patients, aged >59 yrs; 56 were unfit for intensive induction chemotherapy and received only palliative care; 100 (64%) fulfilled the inclusion criteria of our protocol: 91 received the scheduled induction regimen, while 9 received a Fludarabine regimen because of reduced cardiac function. These patients were not included in the response evaluation, but were considered for the outcome (according to the ITT criteria). Patients' characteristics are shown in table 1. CR was achieved in 73.6% of patients; multivariate analysis showed secondary disease as predictive of poor response, with a 65% CR rate (RR = 2.54; 95% CI: 1–6.45; p= 0.05) vs 83% in primary disease. Induction death rate was 5% and not influenced by any prognostic factors. The median time to achieve neutrophil>500× 106/L and platelet>20,000×106/L, were 17 and 19 days (ranges of 9–29 and 3–47 respectively). The main extrahematological toxicity were grade 3–4 mucositis (13%) and hepatic toxicity (9%). We also observed 66 grade III-IV febrile neutropenia/infectious episodes. Overall 65 patients received a first consolidation course and mobilization for PBSC harvest; we observed 6 TRD, a 3% of grade 3–4 hepatic and neurological toxicity and 6% of grade 3–4 cardiac toxicity; in 4 patients we observed rapid early leukemia relapse; overall 55 patients were eligible for post-consolidation therapy. Only 24 patients achieved a succesfull PBSC mobilization and ASCT was performed in 21 (2 relapsed and died before ASCT and 1 received Allogeneic Transplant). Thirty-one patients were poor mobilizers: 3 received Allogeneic Transplant, 3 CHT, 5 stopped treatment because of persistent aplasia and 20 received low-dose GO (3 mg/m2 monthly for 3 times and every 3 months after; median: 3, range 3–6 courses). With a median follow-up of 70 months (range 24–124) 21 patients are alive (19 in continuous CR), 6 after ASCT, 13 after GO, 1 after CHT. The 8 yrs Overall Survival (OS), Disease Free Survival (DFS) and Event Free Survival (EFS) are respectively 20.4% (median: 11.4 months), 24,3% (median 8.8 months) and 17,7% (median: 8.8 months). Secondary AML and hyperleukocytosis are factors predictive of OS at the multivariate analysis. Patients with secondary disease have a 1.59 RR to die with a 9.9% 8 yrs OS vs 27.1% of patients with primary AML. Patients with WBC ≥50,000/mcl had a 2.2 RR to die with a 0% OS at 33 months vs 23.2% 8 yrs OS in patients with WBC<50,000/mcl. In conclusion our novel intensive induction regimen for fit AML patients is safe and effective both in term of CR rate and outcome. The ASCT feasibility was confirmed to be poor in this setting (21%) while GO low-dose seems to be feasible and promising. Finally our prospective study in 156 elderly AML patients describes the real-life outcome of this setting, suggesting that two thirds of AML elderly patients are fit for intensive treatment and that long term OS can be achieved in a relevant proportion of patient with de novo AML. Table 1: Patients' characteristics N (%) Gender: Male 58 Female 42 Karyotype: Favorable 5 (5.7) Intermediate 49 (56.3) Unfavorable 33 (38) De novo AML 61 Secondary AML 39 Age: <70 yrs 55 >69 yrs 45 WBC count: <50,000/mcl 89 ≥50,000/mcl 11 PS: 0–2 96 3 4 FDI 0 60 >0 40 Sorror 0–2 62 (74.7) >2 21 (25.3) Disclosures: No relevant conflicts of interest to declare.

Treatment of patients with advanced colorectal carcinomas with fluorouracil alone, high-dose leucovorin plus fluorouracil, or sequential methotrexate, fluorouracil, and leucovorin: a randomized trial of the Northern California Oncology Group.

1989 ◽  
Vol 7 (10) ◽  
pp. 1427-1436 ◽  
Author(s):  
F H Valone ◽  
M A Friedman ◽  
P S Wittlinger ◽  
T Drakes ◽  
P D Eisenberg ◽  
...  
Keyword(s):  
Objective Response ◽  
Dose Intensity ◽  
Rank Test ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Time To Failure ◽  
Colorectal Carcinomas ◽  
Log Rank Test ◽  
Grade 3 ◽  
Sequential Methotrexate

We compared the effectiveness of fluorouracil (5-FU) alone (arm A), high-dose leucovorin plus 5-FU (arm B), and sequential methotrexate, 5-FU, and leucovorin (arm C) for treatment of patients with advanced colorectal carcinomas who had not received prior chemotherapy. Arm A consisted of infusions of 5-FU at 12 mg/kg/d intravenously (IV) for 5 days followed by weekly infusions of 5-FU at 15 mg/kg; arm B consisted of leucovorin infusions at 200 mg/m2/d IV plus infusions of 5-FU at 400 mg/m2/d IV on days 1 through 5 of a 28-day cycle; arm C consisted of methotrexate at 50 mg/m2 orally every 6 hours for five doses followed by infusions of 5-FU, 500 mg/m2 IV, and leucovorin, 10 mg/m2 orally, every 6 hours for five doses every other week. A total of 265 patients were entered into the trial, of whom 249 (94%) were fully evaluable. The objective response rate (complete [CR] plus partial [PR] responses) was 17.3% on arm A, 18.8% on arm B, and 19.8% on arm C (log-rank test, P greater than .4). The median time to failure was 138 days on arm A, 166 days on arm B, and 182 days on arm C (log-rank test, P values of arm A v B = .06; arm A v arm C = .04). Median survival was 345 days on arm A, 324 days on arm B, and 356 days on arm C (log-rank test, P greater than .4). Treatment with 5-FU alone was significantly more dose intensive and more toxic than either of the experimental combinations. The rates of grade 3 or greater nonhematologic toxicity were 42.3% on arm A, 24.3% on arm B, and 14.3% on arm C. Hematologic toxicity was milder but had the same pattern. This study indicates that these regimens of high-dose leucovorin plus 5-FU and sequential methotrexate, 5-FU, and leucovorin are not more effective than is 5-FU alone for treatment of patients with colorectal carcinomas when 5-FU is administered at high-dose intensity.

Phase 1/2 Study of Tandutinib (MLN518) Plus Standard Induction Chemotherapy in Newly Diagnosed Acute Myelogenous Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 158-158 ◽  
Author(s):  
Daniel J. DeAngelo ◽  
Philip C. Amrein ◽  
Tibor J. Kovacsovics ◽  
Rebecca B. Klisovic ◽  
Bayard L. Powell ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Induction Therapy ◽  
De Novo ◽  
Single Agent ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Background: Tandutinib is an orally bioavailable small molecule inhibitor of FLT3, c-KIT, and PDGFR with a single-agent MTD of 525 mg b.i.d. Tandutinib demonstrated single agent anti-leukemic activity in patients with relapsed/refractory AML with FLT3 ITD mutations, with ≥50% decreases in bone marrow and peripheral blast counts in 12/25 patients and 1 CR without platelet normalization. Since tandutinib is synergistic with cytarabine and daunorubicin in vitro, we sought to determine the MTD of tandutinib in combination with standard induction chemotherapy in patients with newly diagnosed AML, with or without FLT3 ITD mutations. Methods: A starting dose of Tandutinib 200 mg b.i.d was administered during induction and consolidation therapy, and for an additional 6 months. Induction therapy consists of cytarabine 200mg/m2/day IVCI, days 1–7, plus daunorubicin 60mg/m2/day, days 1–3. Consolidation therapy is given as 2–4 cycles of standard (3000mg/m2 IV every 12h, days 1, 3, 5) or in older patients modified (2000mg/m2/day IV, days 1–5) high-dose cytarabine. DLT is defined as failure to recover marrow function (ANC ≥500/μL; platelets ≥20,000/μL), or grade 3/4 non-hematologic toxicity not resolved to grade 2 (except anorexia, alopecia, fatigue) by day 42 of induction therapy, or any unexpected grade 3/4 non-hematologic toxicities. Results: 29 patients have been enrolled: median age 60y (range 26–83); 13M, 16F; 23 de novo, 6 secondary AML; 9 with unfavorable cytogenetics; 5 with FLT3 ITD mutations. Cohort 1 consisted of 7 patients treated with continuous daily dosing of tandutinib 200 mg b.i.d. Due to GI intolerance, the protocol was amended so that tandutinib was administered only on days 1–14 of induction therapy and each cycle of consolidation. Under the amended schedule 8 patients were treated with tandutinib 200 mg b.i.d. (Cohort 2) and 14 patients have been treated with tandutinib 500 mg b.i.d. (Cohort 3). Full safety and efficacy data are available for the 15 patients in cohorts 1 and 2. Diarrhea, nausea and vomiting have been the most common drug-related AEs, and were more frequent with continuous daily dosing of tandutinib. GI tolerance in Cohort 2 has been acceptable, with no patients requiring termination or reduction in tandutinib for GI toxicity. Although continuous dosing was not feasible, no DLTs were seen in Cohorts 1 or 2; one DLT consisting of obtundation not clearly related to tandutinib during induction occurred in Cohort 3, One patient in Cohort 3 experienced non-dose limiting generalized muscle weakness, which reversed within 24 hours after discontinuation of tandutinib. Tandutinib was restarted at a reduced dose in this patient without recurrence. 5/7 patients in Cohort 1 and 6/8 patients in Cohort 2 achieved a CR. PK data have been collected for all 15 patients in Cohorts 1 and 2; median steady state tandutinib concentration was 195 ng/mL (range: 52–486). Conclusions: Tandutinib 200 and 500 mg b.i.d. in combination with standard therapy for newly diagnosed AML appears well tolerated using the amended dosing schedule (days 1–14). Updated results from Cohort 3 (tandutinib 500 mg b.i.d) will be presented.

Dose Definition for Intravenous Cyclophosphamide in Combination with Bortezomib/Dexamethasone for Remission Induction in Patients with Newly Diagnosed Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3599-3599 ◽  
Author(s):  
Martin Kropff ◽  
Peter Liebisch ◽  
Hannes Wand ◽  
Katja Weisel ◽  
Claudia-Nanette Gann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Dose Level ◽  
Remission Induction ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Intravenous Cyclophosphamide ◽  
Grade 3

Abstract This study was designed to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and efficacy of intravenous cyclophosphamide (CY) in combination with the proteasome inhibitor bortezomib and high-dose dexamethasone (DEX) for remission induction in younger patients with newly diagnosed multiple myeloma (MM). Patients ≤ 60 years were enrolled to receive three 3-week treatment cycles with bortezomib 1.3 mg/m2/dose on days 1, 4, 8, and 11 in combination with DEX 40 mg/day orally on the day of bortezomib injection and the day thereafter. In addition, patients received CY intravenously on day 1 at either 600, 900, 1200, or 1500 mg/m2 - the optimal dose had to be defined. Recommended concomitant medication included bisphosphonates, antacids, prophylactic antiviral treatment, prophylaxis against pneumocystis pneumonia, and oral non-absorbable antifungal medication. In addition, antiemetics, cytokines, and intravenous immunoglobulins were allowed. DLT was defined using the National Cancer Institute common terminology criteria for adverse events, version 3.0 as grade 4 hematologic toxicity, ≥ grade 3 non-hematologic toxicity (except emesis, vomiting, and alopecia), ≥ grade 3 peripheral neuropathy, and ≥ grade 2 peripheral neuropathy with pain. MTD was defined as the highest dose studied for which the incidence of DLT was ≤ 33%. Thirty patients completed 78 treatment cycles. Twenty seven patients were evaluable for CY dose definition. Start dose level for CY was 1200 mg/m2. Since no patient experienced a DLT the dose level was increased to 1500 mg/m2. On this dose level a DLT occurred in 2/3 patients (67%). Therefore the dose level was decreased again to 1200 mg/m2 with 4/12 (33%) of patients experiencing DLT. On the next lower dose level a DLT was observed in 8% (1/12). Thus, the MTD for CY in combination with bortezomib and DEX based on cycle 1 was defined as 900mg/m2. Dose-limiting toxicities included leukopenia (n=5), neutropenia (n=1), and pneumonia (n=1). No patient died. Other adverse events not reaching dose-limiting intensity included thrombocytopenia, gastrointestinal irritations, fatigue, neuropathy and one patient with herpes zoster. Median time to best response was 63 days. The overall response rate (EBMT criteria) to up to three cycles of this combination was 87%, with 3 complete responses, 20 partial responses and 3 minor responses. No patient experienced progressive disease. Bortezomib combined with DEX and CY is a highly effective treatment for newly diagnosed MM. Recommended phase II/III dose of CY in this combination is 900 mg/m2. This schedule is currently being evaluated as pretransplant induction in newly diagnosed MM in a prospective trial of the Deutsche Studiengruppe Multiples Myelom (DSMM).

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