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.

Severe Toxicities During Pediatric Acute Myeloid Leukemia Chemotherapy: A Report From the Children's Oncology Group.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1071-1071 ◽  
Author(s):  
Lillian Sung ◽  
Richard Aplenc ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Soheil Meshinchi ◽  
...  
Keyword(s):  
Supportive Care ◽  
De Novo ◽  
Fungal Infections ◽  
High Dose ◽  
High Dose Cytarabine ◽  
Sterile Site ◽  
De Novo Aml ◽  
Grade 3 ◽  
Severe Hyperbilirubinemia ◽  
Severe Grade

Abstract Abstract 1071 Background: Treatment of children with acute myeloid leukemia (AML) is associated with considerable toxicity. Children's Oncology Group (COG) AAML0531 trial adopted a modified AML Medical Research Council backbone and reviewed adverse event reports in real time to maximize accurate toxicity data. As of March 31, 2010, AAML0531 had randomized 968 patients with de novo AML to gemtuzumab ozogamicin (GMTZ) versus no GMTZ. Accurate description of toxicities with the backbone regimen as well as increment toxicities of new agents is important to optimize supportive care. Objectives were to describe hepatic, cardiac and infectious toxicities and duration of neutropenia in all patients, and to compare toxicities between treatment arms. Methods: AAML0531 included those ≥ 1 month to ≤ 30 years with de novo AML and used a 5 cycle chemotherapy regimen: Induction (Ind) I and II: cytarabine, daunorubicin, and etoposide (ADE 10+3+5 and 8+3+5); Intensification (Int) I: cytarabine and etoposide; Int II: mitoxantrone and high-dose cytarabine; and Int III: high-dose cytarabine and L'asparaginase. Subjects were randomized to receive or not receive GMTZ 3 mg/m2 during Ind I and Int II. Common Terminology Criteria for Adverse Events v3.0 toxicities were collected prospectively. Hepatic (ALT, bilirubin and veno-occlusive disease (VOD)), cardiac (left ventricular systolic dysfunction (LVSD)) and infection (sterile site bacterial and fungal) toxicities were targeted. All grades of cardiac and VOD toxicities were captured; all other severe (≥ grade 3) toxicities were recorded. Cumulative incidence (CI) of toxicities was calculated only during protocol chemotherapy. Duration of neutropenia was reported from beginning of cycle to absolute neutrophil recovery ≥ 500/uL for patients alive during the cycle. Results: Table describes the prevalence of severe (≥ grade 3) toxicities and illustrates that severe high ALT occurred in 3–10%, high bilirubin was less common and VOD was reported in ≤ 1% of cycles. Severe LVSD also was rare although compliance with suggested cardiac monitoring ranged from 50–80% per course of treatment. In terms of grade 1 or 2 LSVD there were no differences in any course except for Int II where grade 1 or 2 LVSD was higher with GMTZ (8.0% versus 2.4%; P<.05). Severe sterile bacterial infections were very common occurring in about 30% during Ind I and II, 45% during Int I and 60% during Int II and III. The eight month CI of severe high ALT was 19±4%, hyperbilirubinemia was 10±3%, and VOD was 1±1%. CI of severe elevations in ALT were near significantly more common with GMTZ (22±5% versus 16±5%, P=0.053). Severe LVSD CI was 4±2%, sterile site bacterial infection CI was 82±4% and sterile site microbiologically documented fungal infections CI was 14±3%. CI of severe hyperbilirubinemia, VOD, LVSD and infections were not significantly different with GMTZ. The median (range) duration of neutropenia of Ind I and II in the no GMTZ arm were 30 (3-75) and 28 (1-61) days while for Int I, II and III were 27 (1-53), 37 (6-92) and 39 (16-91) days respectively. Administration of GMTZ did not significantly prolong neutropenia. There was no difference in toxic mortality by GMTZ during Ind I or across all courses of chemotherapy. Conclusions: The COG AML0531 backbone regimen is associated with significant toxicities: 19% of patients have severe elevations in ALT and 10% have severe hyperbilirubinemia. VOD is rare and occurs in 1%. Sterile site invasive infections are very common, particularly during high dose cytarabine. Sterile site microbiologically documented fungal infections occurs in 14% in spite of current supportive care practices. GMTZ contributes to increased high ALT and more grade 1 or 2 LVSD, both of which are of questionable clinical significance. Understanding these toxicities is important as this backbone will be carried into future studies of AML. Decreasing both bacterial and fungal infections will be important supportive care initiatives. Disclosures: Smith: Pfizer, Inc: Member, Medical Advisory Committee (for bosutinib, not GO).

A Study of the Toxicity of Gemtuzumab Ozogamicin in Primary and Relapsed AML, Administered Alone or Simultaneously with Intensive Chemotherapy.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4512-4512
Author(s):  
Thomas Stauffer Larsen ◽  
Kai G. Schmidt
Keyword(s):  
Response Pattern ◽  
Gemtuzumab Ozogamicin ◽  
Infectious Complications ◽  
Late Relapse ◽  
High Dose ◽  
Intensive Chemotherapy ◽  
Hepatic Toxicity ◽  
Allogeneic Transplant ◽  
High Dose Cytarabine ◽  
Grade 3

Abstract Introduction: Gemtuzumab Ozogamicin (Mylotarg®) is a humanized anti CD33 antibody linked to the cytotoxic drug calicheamicin, which has shown considerable antileukaemic effect in the treatment of relapsed AML. With special regard to its toxicity, we present our preliminary results of Mylotarg treatment when administered on compassionate basis as consolidating monotherapy, or combined with intensive chemotherapy. Patients and methods: A total of 86 doses, corresponding to 65 courses were administered to 49 patients. Indications for Mylotarg treatment ( mono ~ monotherapy; comb ~ combination therapy. No.of courses are shown in parentheses): Primary AML: Reinduction ( mono:1; comb:3). Cytogenetic reinduction ( mono:3; comb:1). Consolidation ( mono:24; comb:2). Relapsed AML: Induction ( mono:4; comb:11). Reinduction ( mono:1; comb:2). Cytogenetic reinduction ( mono:1). Consolidation ( mono:10; comb:2). Results: Up-front consolidation with Mylotarg as monotherapy ( 30 doses; 24 patients; mean Mylotarg dose 5.7 mg/m2). Fever: 51% of doses. Focal infections: 17%. Bacteremia 7%. Biochemical findings: Platelet nadir at day 10 ( < 20 bill./l: 25% doses). Neutrophil nadir at day 11 ( mean count = 0.12 bill./l). Hepatic toxicity ( grade 1; % of doses): Alkaline phosphatase 7%; ALAT: 13%; Bilirubin 0. A similar pattern was seen in the 10 relapsed patients consolidated with Mylotarg as monotherapy. One patient receiving an allogeneic transplant 3 months after Mylotarg treatment developed fatal VOD. Three other patients who undervent allogeneic stem cell transplantation 2, 2 and 3 months, respectively, after the administration of Mylotarg did not experience severe hepatic complications. We compared twelve courses of Mylotarg combined with DaunoXome and high dose cytarabine with ( n=10) or without ( n=2) added fludarabine and etoposide, administered to10 patients in 1st relapse with 8 similar courses but without Mylotarg, administered to 7 patients with similar characteristics regarding age, CR1 duration and cytogenetics ( mean Mylotarg dose 4.4 mg/m2). More cases of grade 3 diarrhea ( 33% vs 13%) and bacteremia ( 67% vs 38%) were seen in the Mylotarg group, in which three patients suffered hypoplastic deaths. One of these patients developed intestinal perforation following postremission treatment. The two other patients, with an early refractory relapse, and a late relapse with high risk chromosomal aberation, respectively, died from infectious complications following 20 and 36 days of profound neutropenia. These 3 patients recieved 5.9, 8.3 and 5.0 mg/m2 respectively, compared to the average Mylotarg dose of 4.4 mg/m2. Conclusion: Mylotarg seems to increase toxicity when added to intensive chemotherapy in relapsed AML. The feasibility of this approach must await further studies evaluating toxicity, appropriate dosing and response pattern. When administered as consolidating monotherapy toxicity is modest.

Outcomes in CCG-2961, a Children’s Cancer Group Phase III Trial for Untreated Acute Myeloid Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 169-169 ◽  
Author(s):  
Beverly J. Lange ◽  
Franklin O. Smith ◽  
Patricia A. Dinndorf ◽  
Carola A.S. Arndt ◽  
Dorothy R. Barnard ◽  
...  
Keyword(s):  
De Novo ◽  
Interleukin 2 ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Remission Induction ◽  
High Dose ◽  
Free Survival ◽  
Cancer Group ◽  
De Novo Aml

Abstract CCG-2961 tested an intensively timed induction therapy consisting of cytarabine (AC), etoposide, thioguanine, dexamethasone, idarubicin and daunorubicin. Patients in remission after induction were randomized to a second induction course (Arm A) or a 3-drug combination of fludarabine, AC, and idarubicin (Arm B). Course 3 for patients with related donors was bone marrow transplantation (BMT); for those without donors, high dose AC/l-asparaginase. After Course 3 patients without donors were randomized to 14 infusions of Interleukin 2 (IL2) over 18 days or follow-up. CNS prophylaxis was intrathecal AC. Eligibility included all subtypes of de novo AML except acute promyelocytic leukemia and AML in patients with Down syndrome. CCG-2961 opened in Oct.1996 and closed in Dec. 2002. The DSMC suspended the study between Oct. 1999 and May 2000 while the 2961 Committee developed supportive care policies to reduce treatment-related mortality (TRM). CCG-2961 enrolled 900 de novo patients aged 3 days to 21 years, with 495 and 405 patients accruing pre-and post suspension respectively. Remission induction rate is 88.5%. With median follow-up of 3.6 years (range: 0 – 8.1 years), event-free survival (EFS) at 3 years is 44±3% and survival (OS) 57±3%. Disease-free survival (DFS) following Course 2 Arms A and B are not different, although relapse is significantly higher in Arm A (7.3% .vs. 3.1% P=0.018) and TRM more common in Arm B (7.9% vs.4.2% P=0.059), despite 7 less days of neutropenia in Arm B (P&lt;0.001). DFS is 65±9% for patients with a donor versus 50±5% for patients without a donor (P=0.005); respective OS, 74±8% and 66±5% (P=0.221). However, among 98 patients in CR1 with t(8;21) or inv(16) cytogenetics, outcomes in those without and with a donor were no different: DFS (61±12% vs. 72±18%, P = 0.49) and OS (78±10% vs. 77±17%, l P= 0.85). DFS with and without IL2 is 55±9% and 60±8%(P=0.606). Outcomes improved progressively over time. EFS pre- and post-suspension are 41±4% and 47±5%(P=0.038); OS, 52±5% and 63±5%(P=0.005); TRM is 17±3% pre- and 12±3% post-suspension (P=0.039). Factors predictive of inferior EFS are age &gt;17 years, Afro-American and Hispanic ethnicity, body mass index &lt;10th or &gt;95th percentile for age, absence of related marrow donor, WBC &gt; 50,000/mm3, karyotype with −7/7q, −5/5q- or &gt; cytogenetic 5 abnormalities, FLT3/ITD, &gt;15 % morphologic blasts on day 14 or &gt;0.5% immunologically detectable blasts at the end of induction. CCG-2961 confirms the efficacy and high TRM of intensively timed therapy. Neither fludarabine nor IL2 increases DFS or OS, and availability of a donor does not improve outcomes in those with favorable cytogenetics.

NPM-1, but Not FLT3-ITD Mutations Predict Early Blast Cell Clearance and CR Rate in Patients with Normal Karyotype AML or High-Risk Myelodysplastic Syndrome (MDS).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 805-805 ◽  
Author(s):  
Karsten Spiekermann ◽  
Annika Dufour ◽  
Gudrun Mellert ◽  
Evelin Zellmeier ◽  
Jan Braess ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Factors ◽  
De Novo ◽  
Blast Cell ◽  
High Dose ◽  
Bone Marrow Blast ◽  
Npm1 Mutation ◽  
Free Survival ◽  
Cell Clearance ◽  
High Dose Cytarabine

Abstract Background: Mutations in the NPM1 gene represent the most frequent alterations in patients with AML and are associated with a favourable clinical outcome. Patients and Methods: We analyzed 803 patients that were treated in the AMLCG2000 study. Patients with de novo or secondary AML or high-risk myelodysplastic syndrome (MDS) were randomly assigned upfront for induction therapy containing one course with standard dose and one course with high-dose cytarabine, or two courses with high-dose cytarabine, and in the same step received postremission prolonged maintenance or busulfan/cyclophosphamide chemotherapy with autologous stem-cell transplantation. At diagnosis mutations in the NPM1 and FLT3 gene were analyzed by routine molecular techniques. Results: The median age of all patients was 60 years and the median observation time 23 months. Results of the mutations status of FLT3 (FLT3-ITD) and NPM1 were available in 761/803 (94,8 %) and 690/803 (85,9 %) patients, respectively. NPM1 and FLT3-ITD mutation were found in 352 (51,1%) and 199 (28,9%), respectively. On the basis of these two molecular markers, patients were grouped in 4 subgroups: 1. NPM1+/FLT3−, N=214 (31%), 2. NPM1+/FLT3+, N=138 (20%); 3. NPM1−/FLT3−, N=276 (40%); NPM1−/FLT3+ (9%). The CR-rates were significantly higher in NPM1+ (74,4%) than in NPM1− (55,9%) patients, but were unaffected by the FLT3-ITD status. Overall survival (OS), event-free survival (EFS) and relapse free survival (RFS) was significantly higher in NPM1 positive and FLT3-ITD negative patients. In a multivariate analysis age, WBC, the presence of the NPM1 mutation and de novo AML were independent prognostic factors for the CR-rate. The NPM1− and FLT3 mutation status, age and LDH were identified as independent prognostic factors for RFS. To further characterize the biological effects of NPM1 and FLT3 mutations, we analyzed the in vivo blast cell clearance measured by the residual bone marrow blast cells one week after the end of the first induction cycle (d+16 blasts). The percentage of patients with adequate blast cell reduction (residual bone marrow blast &lt;10%) was significantly higher in NPM1+ patients (87,3%) compared to NPM1− (65,7%) patients. The presence of a FLT3-ITD mutation had no effect on early blast cell clearance. Conclusions: The presence of a NPM1 mutation represents an independent positive prognostic factor for the CR-rate and RFS/OS. In contrast, FLT3-ITD mutations do not affect the CR-rate, but have a negative prognostic impact on RFS and OS. The higher sensitivity of NPM1-positive blasts towards the induction therapy point to a central role of NPM1 in the regulation of apoptotic cell death in AML.

Autologous Transplantation in De Novo Non-Promyelocytic Acute Myeloid Leukemia (AML) Patients in First Complete Remission (CR1) with Peripheral Blood Stem Cell (PBSC) Collection Following Consolidation with High-Dose Cytarabine and Etoposide: A Single Institution Experience

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4461-4461
Author(s):  
Eugene Choi ◽  
Lingyi Chen ◽  
Srikanth Nagalla ◽  
Vamshi Kaveti ◽  
Regina Mullaney ◽  
...  
Keyword(s):  
De Novo ◽  
Disease Free Survival ◽  
High Dose ◽  
Free Survival ◽  
Kaplan Meier ◽  
Cd34 Cells ◽  
High Dose Cytarabine ◽  
Lost To Follow Up ◽  
Disease Free

Abstract INTRODUCTION: Autologous PBSC transplant is an important yet evolving treatment modality for patients with AML. However, the ideal mobilization regimen from which to collect PBSC remains in question. Previous reports have indicated that highdose cytarabine with etoposide is both safe and effective in terms of successful PBSC procurement, subsequent engraftment, and disease outcome. METHODS: At our institution from 1994 to 2007, 38 consecutive patients with de novo non-promyelocytic AML in first complete remission following conventional induction chemotherapy were consolidated with high-dose cytarabine (2000mg/m2 IV q12h × 8 doses, days 1–4) and etoposide (40mg/kg IV over 96h) followed by G-CSF 5 mg/kg subcutaneously starting d14 until completion of PBSC collection. Patients underwent myeloablative therapy with busulfan (1mg/kg po q6h × 16 doses, days –7 to -4) and etoposide (60 mg/kg IV over 10h, day -3) with PBSC infusion occurring on day 0 with daily G-CSF 5 mg/kg. Data regarding stem cell yield, engraftment and patient outcome was collected retrospectively. RESULTS: The average patient age was 44 years (range 19–70). Following consolidation, at least 2×106 CD34 cells/kg were isolated from all 38 patients with a median of 9.4×106 (range 2.2–43) CD34 cells/kg over a mean of 4 collections (range 1–11). Overall, 36 of 38 (95%) remained in CR and went onto PBSC transplant (one died from infectious complications during consolidation, one relapsed before transplant). The median number of stem cells infused was 8.8×106 CD 34 cells/kg (range 2.2–47). All 36 patients engrafted with the mean number of days to neutrophil recovery (ANC&gt;500) being 11 (range 8–17) and the mean number of days to platelet recovery (&gt;20,000) being 12 (range 8–19). Disease-free outcomes in patients undergoing PBSC transplant while in CR1 are presented in Figure 1. The 3y overall survival in all pts was 66%, and 56% at 5y. For good-risk cytogenetic patients, 3y OS was 78% and the 5y OS was 75%. For intermediate-risk cytogenetic patients, OS was 47% and 36% at 3y and 5y respectively. Three patients with poor cytogenetics were autulogously transplanted. One patient relapsed at day 111 and expired at day 450. The second patient remains in CR at day 246. The third patient relapsed at day 104 and expired at day 322. CONCLUSION: In patients with de novo non-promyelocytic AML in CR1, consolidation with high-dose cytarabine plus etoposide is safe and provides excellent yield of PBSCs upon growth factor accelerated hematological recovery. Subsequent engraftment after autologous transplanation is rapid. Our outcomes support the viability of this regimen in patients with good and intermediate-risk cytogenetics. Figure 1: Kaplan-Meier analysis of disease-free survival following autologous PBSC transplant. Cytogenetic analysis was unavailable in 5 patients, and 1 patient was lost to follow-up. Figure 1:. Kaplan-Meier analysis of disease-free survival following autologous PBSC transplant. Cytogenetic analysis was unavailable in 5 patients, and 1 patient was lost to follow-up.

Results in Children and Adolescents Treated According to Study AML-BFM 98: Less Toxic Deaths in the Short-Cycle Arm Than in the 6-Week Consolidation Arm.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 274-274
Author(s):  
Ursula Creutzig ◽  
Reinhardt Dirk ◽  
Joerg Ritter ◽  
Norbert Graf ◽  
Johannes Herrmann ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
De Novo ◽  
Disease Free Survival ◽  
Early Death ◽  
Initial Therapy ◽  
High Dose ◽  
Chemotherapeutic Regimen ◽  
Free Survival ◽  
Short Cycle ◽  
High Dose Cytarabine

Abstract Study AML-BFM 98 aimed to improve prognosis by intensification and optimization of the initial therapy elements. Between 7/1998 and 6/2003, 473 children and adolescents &lt; 18 years with de novo AML entered the multicenter AML-BFM 98 trial. Treatment was based on the results of study AML-BFM 93 and was similar in standard risk (SR) and high-risk (HR) patients (definition for SR [n=192]: FABM1/M2 with Auer rods, M4eo with ≤ 5 % blasts in the day-15 bone marrow, all patients with M3; HR: all others [n=281]). Treatment: After induction with AIE (cytarabine, idarubicin and etoposide) all patients (excluding FAB M3) were treated with HAM (high-dose cytarabine 3g/m2/12h x3 days and mitoxantrone 10mg/m2/day x2 days), which, in the previous study 93, was given for HR patients only. Subsequently all patients were randomly assigned to receive either the 6-week consolidation as in the previous studies or two short therapy cycles including higher doses of cytarabine but the same cumulative dose of anthracyclines. The following therapy elements, intensification with high-dose cytarabine/etoposide and maintenance, were similar in studies 93 and 98. Allogeneic stem cell transplantation from a family donor was restricted to HR patients only. Overall results: 418 of 473 (88%) patients achieved remission. Early death rate could be reduced compared to study 93: 3.2% vs.7.4%. Five-year survival, event-free survival (EFS) and disease-free survival (DFS) were 62%±3%, 49%±3% and 57%±3%, respectively. Estimated survival improved (study 93: 58%±2%, plogrank .03), pEFS and pDFS were similar to study 93 (50%±2% and 61%±2%, n.s.). Randomization results of the 6-week consolidation arm (n=191) vs. the 2-short-cycle arm (n=199) were similar (pEFS 51%±4 and 50%±4%, n.s.). However, total treatment duration was shorter (median 15 days) and morbidity was lower in the short-cycle arm (5 vs. 9 deaths in CCR). Five-year pSurvival in HR patients (surviving &gt;.44years, median time to SCT) with or without SCT in 1. CR was similar: 69%±14% vs. 64%±4%; plogrank .35. There was no improvement of prognosis in SR patients (FAB M3 excluded) compared to the previous study 93 despite additional application of HAM (CR rate 93% vs. 89%, p(chi) .24, 5-years pEFS 62%±4% vs. 67%±4%; n.s.). Conclusion: The estimated survival is now in the range of 65%–70% for those patients who achieve remission. Results of study 98 show, that intensification of chemotherapy with HAM does not improve survival in SR patients. There is no difference in survival of HR patients receiving SCT in 1st CR compared to those with chemotherapy alone. Because improvement of prognosis can not be achieved by intensivication of therapy alone, optimizing the chemotherapeutic regimen by introducing less toxic, but similar effective therapy elements together with better supportive care strategies will reduce treatment related mortality and thereby improve survival in small steps.

Efficacy of a Two Day Induction Regimen for De Novo and Secondary AML with Intermediate and Adverse Cytogenetic Profiles

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4027-4027
Author(s):  
Melissa L. Larson ◽  
Ann M. Thomas ◽  
Nitin Goyal ◽  
Jamile M. Shammo ◽  
John J. Maciejewski ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Complete Remission ◽  
De Novo ◽  
Response Rates ◽  
High Dose ◽  
Bone Marrow Biopsies ◽  
Secondary Aml ◽  
Number Of Patients ◽  
Induction Regimen ◽  
De Novo Aml

Abstract Background: Cytogenetic data remains one of the most powerful prognostic factors for predicting response and survival in adult AML patients. The relationship between cytogenetics and induction response to the standard “7+3” regimen has been analyzed in the past. In a CALGB study, patients with favorable cytogenetics achieved a complete remission (CR) rate of 88%, those with intermediate cytogenetics achieved a 67% CR rate and those with adverse cytogenetics had a 32% CR rate (Byrd et al. Blood100: 4325, 2002). We present a retrospective analysis of the correlation between the hierarchical cytogenetic groups and complete remission rate following induction of AML using a novel induction regimen. This regimen was developed based on the concept of timed sequential therapy. The first pulse of chemotherapy recruits leukemic cells into the cell cycle while the second pulse is given at a time of peak cell recruitment. It utilizes two highly active anti-leukemic drugs: cytarabine, a cell cycle-specific drug, and mitoxantrone, which has a favorable cardiac toxicity profile. Patients and 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 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). Bone marrow biopsies were performed for assessment of leukemia-free state (day 14) and to document remission response. Cytogenetic results were classified into favorable, intermediate, and unfavorable categories based on CALGB data. Responses were defined per the Revised IWG Recommendations (Cheson et al, J Clin Onc21: 4642, 2003). Results: Median age of the 104 patients was 57 years [range 17–79]. There were 47 males and 57 females. Forty-two patients (40%) were 60 years of age and older, and the remaining 62 patients (60%) were younger than 60. Sixty-four patients (61.5%) had de novo AML. Five patients had favorable cytogenetics with 100% of them achieving CR. All of the patients with favorable cytogenetics were less than 60 years of age. For the 61 patients with intermediate cytogenetics, the ORR was 83.6% with a CR of 61%. In patients younger than 60, the ORR was 83.8%% (26 CR, 3 CRi, 2 CRp) with CR of 70%. For patients 60 years and older, the ORR was 83.3% (11 CR, 3 CRi, 5 CRp, 1 RMDS). In the 38 patients with unfavorable cytogenetics, the ORR was 57.9% with CR of 37%. For patients younger than 60 and 60 years and older, the overall responses were 75% and 38.8%, respectively. Of the 40 patients with secondary AML due to pre-existing MDS, the ORR was 65% with CR of 27.5%. In patients with de novo AML, the ORR was 81% with CR of 70%. Patients with prior MDS were more likely to have CRi (20% vs 1.5%), TF due to refractory disease (25% vs 15.6%) or aplasia (7.5% vs 1.5%) as compared to patients without MDS. The rates of CRp (10% vs 9%) were similar for both groups. MDS patients with intermediate cytogenetics had an ORR of 77.7% as compared to 54.5% in those with unfavorable cytogenetics. De novo patients with intermediate cytogenetics had ORR of 86% and those with unfavorable cytogenetics had ORR of 62.5%. Conclusion: Our data reflects the overall effectiveness of high dose cytarabine and mitoxantrone for induction therapy of AML. In the favorable cytogenetic group, the CR rate was higher than previously reported response rates; however, the number of patients was small. In the intermediate and unfavorable cytogenetic groups, the response rates for de novo AML compare favorably to historic controls. Patients with secondary AML respond equally well as compared to those with de novo AML; though, the influence of cytogenetics was similar to that seen in de novo AML. This regimen is very effective in producing a high response rates across cytogenetic categories.

Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study.

1997 ◽  
Vol 15 (2) ◽  
pp. 808-815 ◽  
Author(s):  
A de Gramont ◽  
J F Bosset ◽  
C Milan ◽  
P Rougier ◽  
O Bouché ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Continuous Infusion ◽  
Low Dose ◽  
Advanced Colorectal Cancer ◽  
Progression Free Survival ◽  
High Dose ◽  
Survival Times ◽  
Free Survival ◽  
Therapeutic Ratio ◽  
Grade 3

PURPOSE This multicenter study compared the therapeutic ratio of a monthly schedule of low-dose leucovorin (LV) and fluorouracil (5-FU) bolus with a bimonthly schedule of high-dose LV and 5-FU bolus plus continuous infusion in patients with advanced colorectal cancer. PATIENTS AND METHODS Of the 448 patients randomly assigned to treatment, 433 were assessable. Treatment A was a monthly regimen of intravenous (IV) LV 20 mg/m2 plus bolus 5-FU 425 mg/m2 for 5 days every 4 weeks. Treatment B was a bimonthly regimen of IV LV 200 mg/m2 as a 2-hour infusion followed by bolus 5-FU 400 mg/m2 and 22-hour infusion 5-FU 600 mg/m2 for 2 consecutive days every 2 weeks. Therapy was continued until disease progression. Second-line chemotherapy, which included 5-FU continuous infusion, was allowed in both arms. RESULTS The response rates in 348 patients with measurable lesions were 14.4% (monthly regimen) and 32.6% (bimonthly regimen) (P = .0004). The median progression-free survival times were 22 weeks (monthly regimen) and 27.6 weeks (bimonthly regimen) (P = .0012). The median survival times were 56.8 weeks (monthly regimen) and 62 weeks (bimonthly regimen) (P = .067). Grade 3-4 toxicities occurred in 23.9% of patients in the monthly arm compared with 11.1% of those in the bimonthly arm (P = .0004). Patients in arm A more frequently experienced severe granulocytopenia (7.3% v 1.9%), diarrhea (7.3% v 2.9%), and mucositis (7.3% v 1.9%) than patients in arm B. CONCLUSION The bimonthly regimen was more effective and less toxic than the monthly regimen and definitely increased the therapeutic ratio. However, there was no evidence of increased survival.

Intensification of Chemotherapy Does Not Improve Prognosis of Standard Risk Patients Undergoing Therapy for Acute Myelogenous Leukemia: Results of the Pediatric Clinical Trial AML-BFM 98.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1793-1793
Author(s):  
Ursula Creutzig ◽  
Dirk Reinhardt ◽  
Joerg Ritter ◽  
Guenter Henze ◽  
Johannes Hermann ◽  
...  
Keyword(s):  
Clinical Trial ◽  
De Novo ◽  
Disease Free Survival ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Free Survival ◽  
High Dose Cytarabine ◽  
Standard Risk ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract In order to further improve survival of children undergoing therapy for acute myeloid leukemia (AML), the multicenter clinical trial AML-BFM 98 intensified chemotherapy for standard risk (SR) patients (pts.). In addition, this randomized trial prospectively evaluated whether 2 short cycles of chemotherapy resulted in better prognosis than a 6-week consolidation. Patients and Methods: Between July 1998 and June 2003, 461 pts. < 18 years with de novo AML were enrolled in the trial AML-BFM 98. The SR group consisted of 170 (37%) pts. (FABM1/M2 with Auer rods or M4eo with ≤ 5 % blasts in the day 15 bone marrow; all pts. with FAB M3). All other pts. (n=291) were considered as high-risk (HR) pts.. In contrast to trial AML-BFM 93, a 2nd induction (HAM) was included in the treatment strategy for SR pts. (excluding FAB M3) which consisted of high-dose cytarabine (3g/m/12h x3 days) and mitoxantrone (10mg/m/d x2 days). Both SR and HR pts. were then randomly assigned to receive a 6-week consolidation or two short cycles of therapy. Compared to the 6-week consolidation, the short cycles contained higher doses of cytarabine, but the same cumulative dose of anthracylines. All other therapy elements [first induction (AIE; cytarabine, idarubicin and etoposide), intensification (HAE; high dose cytarabine, etoposide), and maintenance therapy] were identical in studies 93 and 98. Results: Overall, 407 out of 461 (88%) pts. achieved remission (CR). Five-year survival, event-free survival (EFS) and disease-free survival (DFS) were 59%±3%, 49%±3% and 55%±3%, respectively. Estimated survival and pEFS were similar to those of study 93 (58%±2% and 50%±2%, p logrank .09 and .80). Analysis of SR pts. (FAB M3 excluded) showed that the additional application of HAM did not improve the prognosis of SR pts. compared to AML-BFM 93 [CR rate 92% vs. 91%, p(chi)=.78; 5-year pEFS 58%±5% vs. 66%±4%; p logrank =.24]. However, when comparing HAM in study 98 and the 2nd chemotherapy cycle in study 93, significantly more severe infections (grade 3/4) occurred with HAM. Overall treatment related mortality in CR was 4% in both HR and SR pts., which was similar to trial AML-BFM 93. In addition, the outcome of pts. randomized for the 6-week consolidation was similar to that of the short cycles (p logrank .81). However, morbidity was lower in the short cycle arm (6 vs. 11 deaths in CCR, 2 vs. 4 in SR pts.). Conclusion: Our results indicate that in SR pts. with AML, a more intensive chemotherapy consisting of HAM does not result in improved survival. Therefore, new treatment options should be considered in this patient group. At the same time, optimizing treatment using the less toxic therapy with short cycles and improvement of supportive care strategies might help to reduce treatment related mortality and improve outcome in children with AML.

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.

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