High Dose (HD-AraC) Vs Standard Dose Cytosine Arabinoside (SDAraC) during Induction and Value of IL-2 during Maintenance in Acute Myelogenous Leukemia (AML): Impact of AraC Dose on Complete Remission Rate and Toxicity (Results on the first 1700 randomized patients of the AML-12 trial of EORTC and GIMEMA Leukemia Groups)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 134-134 ◽  
Author(s):  
Roelof Willemze ◽  
Stefan Suciu ◽  
Franco Mandelli ◽  
Boris Labar ◽  
Jean-Pierre Marie ◽  
...  
Keyword(s):  
Complete Remission ◽  
Remission Rate ◽  
Myelogenous Leukemia ◽  
Phase Iii ◽  
Remission Induction ◽  
Induction Treatment ◽  
High Dose ◽  
Sufficient Information ◽  
Treatment Groups

Abstract The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) with the same drugs. Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization was performed after CR in pts without a donor: auto-SCT followed or not by low dose IL-2. The trial was powered to detect an 8% difference in the 5-yr survival rate; secondary endpoints were response to induction, DFS, toxicity. Randomization was performed centrally; the 1st randomization was stratified for age, performance status, WBC and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 previously untreated AML pts (APL excluded), age<61 years, (891 by EORTCLG and 1114 by GIMEMA) were randomized. Currently for 1700 pts (857 in SD-AraC vs 843 in HD-AraC arm) sufficient information on remission induction response is available. The median follow up is 3 years. After 1 or 2 courses of induction, CR was achieved in 631 (73.6%) pts (SD-AraC group) vs 680 (80.7%) pts (HD-AraC group): p=0.001. Partial remission or resistance was documented in 161 (18.8%) vs 114 (13.5%) pts, and death in induction in 65 (7.6%) vs 49 (5.8%). Induction toxicity profile and grade was similar in the 2 arms except for conjunctivitis grade 3: 0.1% (SD-AraC) vs 4.4% (HD-AraC). Currently in 909 pts cytogenetic information is not yet available and in 791 pts cytogenetic information is known. Comparison of SD-AraC vs HD-AraC according to cytogenetic subgroups is shown in the Table. No cytogenetics Good Intermediate Bad Very bad No pts 448 vs 461 55 vs 50 215 vs 200 89 vs 90 50 vs 42 CR (%) 71.2 vs 82.4 90.9 vs 84.0 78.6 vs 82.5 68.5 vs 77.8 64.0 vs 54.8 PR/Resistance (%) 20.3 vs 12.6 0 vs 6.0 15.3 vs 10.5 27.0 vs 16.7 26.0 vs 40.5 Induction death (%) 8.5 vs 5.0 9.1 vs 10.0 6.0 vs 7.0 4.5 vs 5.6 10.0 vs 4.8 In pts who reached CR, the DFS was similar in the 2 treatment groups: the 3-yr DFS rate was 43.4% (SD-Ara-C) vs 44.6% (HD-Ara-C), hazard ratio (HR)=0.96 (p=0.66). A total of 291 vs 313 DFS-events were reported in the 2 treatment groups: 230 (36.5%) vs 236 (34.7%) relapsed and 61 (9.7%) vs 77 (11.3%) died in CR. Among pts who reached CR, 451 pts had an HLA identical sibling and 860 did not or have not been typed. In the first group, 120/200 (60.0%) SD-AraC vs 134/251 (53.4%) HD-AraC pts underwent an allo-SCT. In the 2nd one, 211/431 (49.0%) SD AraC pts vs 211/429 (49.2%) HD AraC pts underwent an auto-SCT. In pts with a donor, the 3-yr DFS rate was 51.8% (SD-Ara-C) vs 47.6% (HD-Ara-C), HR=1.13, p=0.41, whereas in those without a donor the 3-yr DFS rate was 39.6% (SD-Ara-C) vs 42.9% (HD-Ara-C), HR=0.91, p=0.31. Evaluation of the first 1700 patients of the EORTC-GIMEMA AML-12 trial shows that, with a median follow-up of 3 years, HD-AraC in the induction treatment leads to a significantly higher CR rate than SD-Ara-C without improving the DFS.

Value of Low Dose IL-2 as Maintenance Following Consolidation Treatment or Autologous Transplantation in Acute Myelogenous Leukemia (AML) Patients Aged 15-60 Years Who Reached CR After High Dose (HD-AraC) Vs Standard Dose (SD-AraC) Cytosine Arabinoside During Induction: Results of the AML-12 Trial of EORTC and GIMEMA Leukemia Groups.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 791-791 ◽  
Author(s):  
Roelof Willemze ◽  
Stefan Suciu ◽  
Franco Mandelli ◽  
Stijn J.M. Halkes ◽  
Jean-Pierre Marie ◽  
...  
Keyword(s):  
Overall Survival ◽  
Low Dose ◽  
Hazard Ratio ◽  
Myelogenous Leukemia ◽  
Phase Iii ◽  
Medical Decision ◽  
Induction Treatment ◽  
High Dose ◽  
Observation Period

Abstract Abstract 791 The AML-12 randomized phase III trial of the EORTC and GIMEMA Leukemia Groups assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) combined with the same drugs. Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin (50 mg/sqm for 3 days). Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability, cytogenetics and age. A 2nd randomization was performed after consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2 (4-8 × 106 IU s.c. for 5 days per month) during one year. A total of 577 patients were required to be randomized for the 2nd question in order to reach 255 events (relapses or deaths) which would allow to detect a 11.5% increase in the 3-year disease-free survival (DFS) from 50% to 61.5% corresponding to hazard ratio (HR) = 0.70 (2-sided alpha=5%, statistical power=80%). Randomization was performed centrally; the 2nd randomization was stratified for induction treatment, cytogenetic/molecular genetic group, number of courses to reach CR, auto-SCT planned (No/Yes) and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 previously untreated AML pts (APL excluded), age<61 years, were randomized (891 by EORTC-LG and 1114 by GIMEMA) and 104 (GIMEMA) were registered to receive SD-AraC (+etoposide+daunorubicine) in induction. After 1 or 2 courses of induction, CR was achieved in 1377 patients. Between 4/2000 and 5/2008 550 (230 EORTC, 320 GIMEMA) were randomized for the IL-2 question: 276 in IL-2, 274 Observation (Obs) arm; the remaining patients were not randomized due to prolonged hypoplasia after consolidation or after auto-SCT, or refusal of the patient or a planned allo-SCT. The 2 groups were well balanced with respect to the stratification factors, age, sex, WBC counts and history of the disease. Currently, maintenance/observation period has been documented for 144 IL-2 and 144 Obs patients. The patients received a median of 30 s.c. injections (range 3-60) of IL-2. In more than 75% of patients, the mean dose was 6 × 106 IU per injection. Grade 3-4 toxicity was more frequent in the IL-2 compared to Obs arm and consisted of hypersensitivity (4.2% vs 0%), fatigue (9% vs 1.4%), rigor/chills (4.2% vs 0%), arthralgia/myalgia (3.5% vs 0%). A total of 32 patients (22.2%) out of 144 stopped IL-2 prematurely based on patient refusal or medical decision due to toxicity. In the Obs arm, 4 (2.8%) patients out of 144 went off study due to toxicity. Maintenance/observation period has not yet been documented for 132 IL-2 and 130 Obs patients. Among them 28 (21.2%) vs 13 (10%) respectively went off-study due to toxicity of the previous treatment (autoSCT or consolidation), 41 vs 45 due to early relapse, 9 vs 11 due to protocol violation, 9 vs 5 due to other reason. For the total of 550 patients, the median follow-up from the 2nd randomization was 3.6 years. As of July 2009, a total of 269 DFS events were reported: 132 (IL-2 arm) vs 137 (Obs arm); among them 242 relapses (121 vs 121) and 27 deaths without relapses (11 vs 16). The DFS from 2nd randomization was similar in the 2 groups: the 3-yr DFS rate was 44.1% (IL-2) vs 42.0% (Obs), hazard ratio (HR)=0.93 (95% CI 0.74-1.19), p=0.57. A total of 106 patients died in each treatment group. The 3-yr overall survival rate was 54.1% (IL-2) vs 55.9% (Obs), HR=1.01 (95% CI 0.77-1.32), p=0.94. The initial treatment received/randomized did not impact the treatment outcome after the 2nd randomization. This evaluation of the second randomization (IL-2 vs Obs) of the EORTC-GIMEMA AML-12 trial shows that, with a median follow-up of 3.6 years, low dose IL-2 maintenance does not lead to a higher DFS and overall survival. Disclosures: Muus: Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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.

Cladribine in Combination with Standard Daunorubicine and Cytarabine (DAC) as a Remission Induction Treatment Improves the Overall Survival in Untreated Adults with AML Aged < 60 y Contrary to Combination Including Fludarabine (DAF): A Multicenter, Randomized, Phase III PALG AML 1/2004 DAC/DAF/DA Study in 673 Patients-A Final Update.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2055-2055
Author(s):  
Jerzy Holowiecki ◽  
Sebastian Grosicki ◽  
Slawomira Kyrcz-Krzemien ◽  
Kazimierz Kuliczkowski ◽  
Aleksander B Skotnicki ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Remission Rate ◽  
Randomized Study ◽  
Phase Iii ◽  
Remission Induction ◽  
Induction Treatment ◽  
P Value ◽  
Who Grade ◽  
Free Survival

Abstract Abstract 2055 Poster Board II-32 This trial is a continuation of earlier Polish Adult Leukemia Group (PALG) studies on the use of purine analogues for therapy of AML patients (Leukemia 2004,18:989–97, updated at 7 y: ASH 2006, Abstr.N#2003, Ann Hematol. 2008, 87:361–7). The goal of the present study was to evaluate the efficacy of combination including fludarabine – DAF (daunorubicine 60 mg/m2/d iv, d 1–3; cytarabine (AraC) 200 mg/m2/d ci, d 1–7, and fludarabine 25 mg/m2 iv d 1–5) in untreated adult patients with AML, based on head to head comparison with DAC (DNR, AraC, Cladribine), and standard DA regimens (preliminary results: ASH 2008, abstr.#133). Primary end-points were: complete remission rate (CR) and overall survival (OS); secondary objectives were: toxicity and leukemia-free survival (LFS). Patients achieving CR received two courses of subsequent intensive consolidation: HAM (HD AraC, mitoxantrone) and HD AraC. Reduction of consolidation was accepted in patients treated with early alloBMT. In case of partial remission (PR) after the first induction course the same regimen was repeated. Patients with no remission (NR) or with PR after 2 induction courses were withdrawn from the study. Between 09.2004 and 05.2008, 673 adult untreated AML patients aged 18–60 y, median 47 y, sex: male 49,5%, female 50,5%, treated in 18 co-operating PALG centers were centrally randomized to either DAF (n=225), DAC (n=224) or DA (n=224) arm (1:1:1). PML/RAR alfa positive - FAB M3 cases were excluded. The study groups were well balanced in respect of age, sex, FAB subtype, and WBC. The results are summarized in the table. Outcome DAC (n = 223) DAF (n = 219) DA (n = 210) P Value (DAC vs DA) P Value (DAC vs DAF) CR 68 59 56 .013 .08 CR after 1 cycle 62 55 50,5 .017 16 3-yr OS 46 30 31 02 .02 2-yr LFS 47 40 39 NS NS Both, the entire CR rate and the CR rate after a single induction course were significantly superior in the DAC arm if compared with DA and DAF subgroups. With a median follow-up of 34 months (the longest observation time 5y) the OS rate equaled 46% for the DAC treated subgroup and was higher in comparison to the standard DA arm and the DAF arm. There were no significant differences in the leukemia free survival rates. The early death rates of 8,5–11%. were similar in the studied treatment subgroups. All patients developed WHO grade IV thrombocytopenia and agranulocytosis. The frequency and severity of infections, mucositis, vomiting, diarrhoea, alopecia, polyneuropathy as well as of cardiac, liver or kidney dysfunctions were comparable in particular arms. In conclusion, this updated results of randomized study prove that the incorporation of cladribine to the standard DA induction regimen (DAC) improves CR rate and the overall survival in adults with AML aged up to 60 y, without additional toxicity. This beneficial effect was not observed in patients treated using the DAF protocol with fludarabine added to the standard “DA 3+7” schedule. Disclosures: Robak: Celgene: Consultancy; Roche: Honoraria, Research Funding; Genmab: Research Funding; Cambridge Antibody Technology: Research Funding; GlaxoSmithKline: Honoraria. Warzocha:BMS: Consultancy, Honoraria; Celgene: Consultancy; Roche: Honoraria; Pfizer: Honoraria; Amgen: Honoraria.

High Dose (HD-AraC) Vs Standard Dose Cytosine Arabinoside (SD-AraC) During Induction and IL-2 Vs Observation After Consolidation/Autologous Stem Cell Transplantation in Patients with Acute Myelogenous Leukemia (AML): Final Report of the AML-12 Trial of EORTC and GIMEMA Leukemia Groups on the Value of High Dose AraC

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 257-257 ◽  
Author(s):  
Roelof Willemze ◽  
Stefan Suciu ◽  
Franco Mandelli ◽  
Giovanna Meloni ◽  
Boris Labar ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Myelogenous Leukemia ◽  
Phase Iii ◽  
High Dose ◽  
Treatment Difference

Abstract Abstract 257 The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/sqm/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm/d for 3 days) and etoposide (50 mg/sqm/d for 5 days) vs SD-AraC (100 mg/sqm/d for 10 days) with the same drugs, in previously untreated AML < 61 year old patients (APL excluded). Patients (pts) in complete remission (CR) had to receive consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization had to be done after evaluation of consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2. The aim of the trial was to detect an 8% treatment difference (from 35% to 43%) in the 5-yr overall survival (OS) rate, corresponding to a hazard ratio (HR) of 0.80 (alpha=5%, power=95%); secondary endpoints were response to induction, toxicity, disease-free survival (DFS) from CR. Randomization was performed centrally; the 1st randomization was stratified for age (<46 vs > 45 yrs), performance status, WBC and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 pts from 68 centers were randomized. Due to insufficient reporting, 3 centers, who recruited 63 patients, have been excluded from the analysis. The remaining 1942 pts (872 pts entered by EORTC-LG and 1070 by GIMEMA) 969 were randomized in SD-AraC and 973 in HD-AraC arm; among them 25 and 28, respectively, were ineligible, but kept in the analysis. Both arms were comparable with respect to gender, age (median=45 yrs), disease history, initial leukocyte count, PS, FAB and cytogenetics. At a median follow up of 6 yrs, 1114 pts had died. Results: After 1 or 2 courses of induction, CR was achieved in 1430 pts (73.6%); 684 (71.9%) pts (SD-AraC group) vrs 746 (78.7%) pts (HD-AraC group): p=0.002. Resistance was documented in 173 (18.2%) vrs 123 (13%), and death during induction in 85 (8.9%) vrs 71 (7.5%) pts, respectively. Induction toxicity profile and grade was similar in the 2 arms except for conjunctivitis grade 3: HD-AraC>SD-AraC. CR rates for pts<46 yrs were 74.7% (SD-AraC) and 81.4% (HD-AraC) and for pts>45 yrs 66.4% (SD-AraC) and 71.8% (HD-AraC). 634 pts (SD-AraC and 686 (HD-AraC) received a consolidation cycle. Among 765 CR-pts<46 yrs 284 pts had an HLA identical sibling (<46D) and 481 did not or had not been typed (<46NoD). Among 665 CR-pts>45 yrs 225 pts had an HLA identical sibling (>45D) and 440 did not or had not been typed (>45NoD). In the <46D group 211 underwent an allo-SCT and 11 an auto-SCT. In the <46NoD group 274 underwent an auto-SCT and 29 a MUD-SCT; in the >45D group 147 underwent an allo-SCT and 14 an auto-SCT. In the >45NoD group 244 underwent an auto-SCT and 12 a MUD-SCT. Comparisons of treatments arm regarding OS from randomization, DFS and Survival (S) from CR are indicated in the Table. The impact of age on the treatment difference regarding OS was almost significant (p=0.06). In pts >45 who reached CR, the decrease in the relapse rate in the HD-Ara-C arm vrs SD-Ara-C arm (45.5% vs 49.4%) was counterbalanced by an increase in the death in CR rate (18.4% vs 13.2%). Conclusion: The final evaluation of the EORTC-GIMEMA AML-12 trial shows that, with a median follow-up of 6 years, HD-AraC in the induction treatment leads to a significantly higher CR rate than SD-Ara-C and results in improvement in overall survival but only in pts under the age of 46 years. Disclosures: Muus: Amgen: Membership on an entity's Board of Directors or advisory committees. Beksac:Janssen Cilag: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau.

Dramatic Improvement in CR Rate and CR Duration with Imatinib in Adult and Elderly Ph+ ALL Patients: Results of the GIMEMA Prospective Study LAL0201.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2739-2739 ◽  
Author(s):  
Marco Vignetti ◽  
Paola Fazi ◽  
Giovanna Meloni ◽  
Annalisa Chiarenza ◽  
Michele Malagola ◽  
...  
Keyword(s):  
Complete Remission ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Induction Treatment ◽  
High Dose ◽  
Dramatic Improvement ◽  
Strong Activity ◽  
Free Survival ◽  
Entire Treatment

Abstract In 2001, the GIMEMA Group started a phase II study to evaluate Imatinib both in adult (study A, 18–60 years) and elderly (Study B, &gt;61 years) patients with Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL). In study A, adult patients with Ph+ ALL received the standard GIMEMA induction (VCR, DNR, PDN, L-ASP) and consolidation (MTZ and high-dose Ara-C) treatments, without imatinib. All patients in hematological complete remission (HCR) after the consolidation, either with or withouth a donor, received imatinib p.o. at the dosage of 800 mg/day for 6 months. After completing the 6-months therapy, in the absence of safety concerns, if the investigator considered the patient eligible for treatment, the therapy with imatinib was continued. A total of 22 patients have been enrolled [7 in molecular complete remission (MCR) and 15 still BCR/ABL+]: 18 are still in HCR after a median follow up of 20 months (2 – 26). In particular, all the 7 patients PCR- when started imatinib are still in HCR (6 PCR- and 1 becoming PCR+), after a median follow-up of 19 months (7.6 – 24) and eleven of the 15 PCR+ patients are in CHR after a median follow-up of 19 months (1.2 – 26). Of the remaining 4 PCR+ patients, 1 died in CR after an alloSCT and 3 patients relapsed at 4, 9 and 11 months, respectively. The probability of disease-free survival at 2 years is 79% (C.I. 95%: 58,4 – 100,3). Figure Figure In study B, planned for elderly patients usually not eligible for intensive treatments, the induction therapy consisted of imatinib 800 mg/day p.o. associated to prednisone 40 mg/sqm/day for 30 days, withouth any other chemotherapy. Up to date only 12 patients have been enrolled. Median age was 67.5 yrs (61–78), 9 were females. Eleven (92%) obtained a CR with the prednisone-Imatinib association induction treatment, 1 patient discontinued the treatment for toxicity. The post-remissional treatment mainly consisted of imatinib alone: 8 patients are still in CR, after a median follow up of 7 months (4 – 15), 2 relapsed at 4 and 4 months and 1 died in CR due to a 2nd neoplasia. In conclusion, these studies, planned 3 years ago to verify the feasibility and toxicity of imatinib in adult and elderly Ph+ ALL patients, clearly suggest a strong activity of Imatinib also in this disease, not only giving the possibility of inducing a CR as monotherapy, but even of maintaining long-lasting hematological and molecular CR withouth allogeneic stem cell transplantation. Further studies are mandatory to finally identify the best way to integrate imatinib in the entire treatment strategy of this disease.

Rituximab Plus Hypercvad (R-HCVAD) Alternating with Rituximab Plus High-Dose Methotrexate-Cytarabine (R-M/A) in Untreated Mantle Cell Lymphoma (MCL): Prolonged Follow-Up Confirms High Rates of Failure-Free Survival (FFS) and Overall Survival (OS).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 128-128 ◽  
Author(s):  
Jorge Enrique Romaguera ◽  
Luis Fayad ◽  
Maria A. Rodriguez ◽  
Fredrick B. Hagemeister ◽  
Barbara Pro ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Complete Remission ◽  
Stem Cell Transplant ◽  
Pulmonary Hemorrhage ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Cell Transplant

Abstract Introduction: Aggressive MCL has a poor prognosis with a 21-40% complete remission (CR) after CHOP and a duration of response of only 10-16 months. More intense therapy could improve these statistics. Rituximab is effective in MCL and has minimal toxicity. Methods: A prospective phase II trial of R-HCVAD (considered to be one cycle) alternating every 21 days with R- M/A (considered to be another cycle) as described earlier (Ann Oncol. 13, suppl 2, 2002 #24). Prophylaxis with mesna, calcium leucovorin, prednisone eyedrops, G-CSF, antibacterial, antifungal, and antiviral therapy. CBC with differential and platelet counts X 2-3/week. Re-staging every 2 cycles including upper and lower endoscopies. Patients in complete remission (CR) after 6 courses of a planned 6-8 cycles were not offered consolidation with stem cell transplant. Post-treatment evaluation was performed every 3 months for 1 yr, every 4 months for 2 yrs, every 6 months for 2 years, then annually. Results: Of 100 patients registered, one was ineligible and two decided to not receive the treatment after registration, leaving 97 evaluable for analysis of response, survival and toxicity. An analysis of response after the first 6 cycles shows an 87% CR/CRu rate. With a median follow up of 40 months, the 3-year FFS and overall survival (OS) were 67% and 81%, respectively. Adverse factors for FFS were: Grade 4 hematologic toxicity was significant. Five patients died during treatment of sepsis (3), pulmonary hemorrhage (1), and unknown cause (1). Four patients developed myelodysplasia/acute myelogenous leukemia after treatment and while in CR and three have died, for a total of 8 deaths in the study (8%). Conclusion: R-HCVAD alternating with R-M/A without stem cell transplant is an effective regimen for treatment of aggressive untreated MCL, specially for patients ≤ 65 years old. Toxicity is as expected for an intense regimen. This encouraging data warrants continued follow-up and comparison with existing/new therapies in future trials.

Rituximab Combined to ACVBP (R-ACVBP) as a New Inductive Treatment Followed by High-Dose Consolidative Autotransplantation (HDC) for Poor Risk Diffuse Large B-Cell Lymphoma (DLBCL) in First-Line. Preliminary Results on 119 Patients of a GELA Phase II Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3049-3049 ◽  
Author(s):  
Karim Belhadj ◽  
Olivier Fitoussi ◽  
Corinne Haioun ◽  
Nicolas Mounier ◽  
Pierre Lederlin ◽  
...  
Keyword(s):  
Complete Remission ◽  
Response Rate ◽  
Bone Marrow Involvement ◽  
B Cell Lymphoma ◽  
Induction Treatment ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Induction Phase ◽  
Induction Regimen

Abstract ACVBP induction regimen followed by HDC provides a better event-free survival (EFS) and overall survival (OS) as compared to a conventional consolidative treatment in patients (pts) with aggressive non Hodgkin’s lymphoma presenting with 2 or 3 adverse age-adjusted International-Prognostic-Index (aa-IPI) who first reached complete remission. However, complete response rate (CR +CRu) after ACVBP is not superior to 65% (ASH 2005, 677a). Besides, it is established that Rituximab (R) combined with CHOP improves complete remission rate and OS in elderly pts. The objective of the study was to see if combining R (375 mg/m2) to ACVBP (Doxorubicin 75 mg/m2 d1, Cyclophosphamide 1,200 mg/m2 d1, Vindesine 2 mg/m2 and Bleomycin 10 mg d1 and d5, prednisone 60 mg/m2 d1-d5) translates into an improvement of response rate and also EFS in pts under 60y with DLBCL and aaIPI 2 or 3. Four cycles of R-ACVBP were delivered every 15 days supported by filgrastim 5 μg/kg (d6 to d13) or pegfilgrastim (6 mg at day 3). Responding pts received a consolidative BEAM and peripheral blood stem cell rescue. From 01/2004 to 12/2005, 119 DLCBL pts were enrolled. Median age was 49 years (range: 19–60), 18% with aa-IPI 3, 22% with bone marrow involvement, 96% with LDH> 1N and 88% with extranodal sites>1. 59 pts received filgrastim and 60 pegfilgrastim. Based on International Workshop Criteria, CR+CRu rate after induction treatment was 63%, PR rate 25%, stable disease 3% and progressive disease 1%. Deaths without progression occurred in 3% of the pts, and 6% of them could not be assessed (treatment was stopped because of toxic effects or major protocol violation). Hematologic toxicity was similar to that observed in previous GELA trials using ACVBP. Collection failure after the 3rd and/or 4th R-ACVBP cycle was observed in 15 pts (13%), 4 receiving filgrastim and 11 pegfilgrastim (7 of them being further collected with filgrastim). Among the 105 responding pts, 90 received HDC, 15 pts did not (physician’s decision for 4 PET-positive pts after 4 R-ACVBP, 8 collection failures, 2 pts because of a poor performance status after induction phase and one due to sudden death). Three patients died without progression during the HDC procedure. At the end of treatment, 81 pts (68%) were considered in complete remission, 14% in PR and 6% progressed. With a median follow-up of 15 months, two-year EFS was 72% ( CI 62–68%), OS was 79% ( CI 69–86%). We conclude that R-ACVBP induction regimen is feasible and safe on such high risk pts but it does not increase the CR rate. EFS seems encouraging; a longer follow-up is needed to see whether the addition of rituximab contributes to decrease the incidence of relapse.

The Reduction of Leukemic Blasts in Bone Marrow Aspirate on Day 6 of Remission Induction Treatment Is Predictive for Complete Remission Rate and Survival in Adult Acute Myeloid Leukemia; the Results of Multicenter, Prospective Polish Adult Leukemia Group Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4375-4375
Author(s):  
Jerzy Holowiecki ◽  
Sebastian Grosicki ◽  
Slawomira Kyrcz-Krzemien ◽  
Kazimierz Kuliczkowski ◽  
Marek Kielbinski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Complete Remission ◽  
Remission Rate ◽  
Prospective Trial ◽  
Complete Remission Rate ◽  
Remission Induction ◽  
Induction Treatment ◽  
Early Evaluation ◽  
Bone Marrow Specimen

Abstract The goal of this study was to prove the significance of an early evaluation of leukemic blast reduction based on cytological examination of bone marrow aspirates obtained on day 6 of remission induction treatment. Patients. 90 adult AML patients aged 18–60 (median 47) registered to the PALG prospective trial evaluating the efficacy of 3 remission induction protocols: DAF: daunorubicine (DNR) 60 mg/m2/d iv, d 1–3; cytarabine (AraC) 200 mg/m2/d ci, d 1–7, and fludarabine 25 mg/m2 2h inf. iv d 1–5), DAC (like DAF but cladribin is used at 5 mg/m2 instead of fludarabine) and the standard DA 3+7 regimen. Bone marrow aspirates were performed before the treatment and on the 6-th day of the first remission induction course, and the MGG stained marrow smears were evaluated at each centre by two experienced hematologists. Results. Based on the proportion of blasts in bone marrow specimen on day 6 patients were arranged into 2 groups: “responders”with ≤5% of blasts (n=59) and “non responders” with >5% of myeloblasts in bone marrow (n=31). The complete remission rate (CR) in the first group equalling 89% (51/59) was significantly higher in comparison to that obtained in the second group 29%(9/31), p=0,008. The probability of overall survival (OS) was also higher in the group of “responders” if compared to “non responders”; 65% versus 45% respectively, p=0,009. In multivariate analysis including bone marrow examination, cytogenetic risk group, age, leukocyte count at diagnosis and the induction arm only the persistence of leukemic blasts >5% in bone marrow specimen on 6-th day of induction was associated with higher risk of not achieving CR (HR = 52,6; p=0,00002), and with shorter OS (HR=3,13; p=0,02). Conclusion. This prospective, multicenter study demonstrates that a simple and commonly accessible evaluation of the leukemic blasts reduction in bone marrow smear on the 6-th day of remission induction treatment is a reliable and independent predictor for achieving CR and for overall survival. This offers a decision point for an early modification of the treatment strategy.

The Reduction of Leukemic Blasts In Bone Marrow Aspirate on Day 6 of Remission Induction Treatment Is Predictive for Complete Remission Rate and Survival in Adult Acute Myeloid Leukemia: The Results of Multicenter, Prospective Polish Adult Leukemia Group Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1950-1950
Author(s):  
Jerzy Holowiecki ◽  
Sebastian Grosicki ◽  
Slawomira Kyrcz-Krzemien ◽  
Kazimierz Kuliczkowski ◽  
Marek Kielbinski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Complete Remission ◽  
Remission Rate ◽  
Prospective Trial ◽  
Bone Marrow Examination ◽  
Complete Remission Rate ◽  
Remission Induction ◽  
Induction Treatment ◽  
Early Evaluation

Abstract The goal of this study was to pr ove the significance of an early evaluation of leukemic blast reduction based on cytological examination of bone marrow aspirates obtained on day 6 of remission induction treatment. Patients: 152 adult AML patients aged 18–60 (median 47) registered to the PALG prospective trial evaluating the efficacy of 3 remission induction protocols: DAF: daunorubicine (DNR) 60 mg/m2/d iv, d 1–3; cytarabine (AraC) 200 mg/m2/d ci, d 1–7, and fludarabine 25 mg/m2 2h inf. iv d 1–5) DAC (like DAF but cladribin is used at 5 mg/m2 instead of fludarabine) and the standard DA 3+7 regimen. Patients achieving CR received two courses of subsequent intensive consolidation: HAM (HD AraC, mitoxantrone) HD AraC. In case of partial remission (PR) after the first induction course the same regimen was repeated. Patients with no remission (NR) or with PR after 2 induction courses were withdrawn from the study. Bone marrow aspirates were performed before the treatment and on the 6-th day of the first remission induction course, and the MGG stained marrow smears were evaluated at each centre by two experienced hematologists. Results: Based on the proportion of blasts in bone marrow specimen on day 6 patients were arranged into 2 groups: “responders” with &lt;5 % of blasts (n=59) and “non responders” with &gt;5% of blastic cells in bone marrow (n=31). The complete remission rate (CR) in the “responders” group equaling 86% (82/95) was significantly higher in comparison to that found in the “non responders” group 33%(19/57), p=&lt;0,00001. The probability of overall survival (OS) was also higher in the group of “responders” if compared to “non responders” one; 63% versus 33% respectively, p=0,0009. In multivariate analysis including bone marrow examination, cytogenetic risk group, age, leukocyte count at diagnosis and the induction arm, only the persistence of leukemic blasts &gt;5% in bone marrow specimens on 6-th day of induction was associated with higher risk of not achieving CR (HR = 51,1; p=0,00002), and with shorter OS (HR=2,9; p=0,004). Conclusion: This prospective, multicenter study demonstrates that a simple and commonly accessible evaluation of the leukemic blasts reduction in bone marrow smear on the 6-th day of remission induction treatment is a reliable and independent predictor for achieving CR and for overall survival. This offers a decision point for an early modification of the treatment strategy.

scholarly journals Alternating v repeated postremission treatment in adult acute myelogenous leukemia: a randomized phase III study (AML6) of the EORTC Leukemia Cooperative Group

Blood ◽  
1989 ◽  
Vol 73 (4) ◽  
pp. 896-906 ◽  
Author(s):  
R Zittoun ◽  
U Jehn ◽  
D Fiere ◽  
C Haanen ◽  
B Lowenberg ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Phase Iii ◽  
Induction Treatment ◽  
High Dose ◽  
Repeated Treatment ◽  
Free Survival ◽  
Allogeneic Bmt ◽  
Acute Myelogenous

The value of a postremission treatment in acute myelogenous leukemia (AML), with alternating combinations of non-cross-resistant drugs, has been prospectively assessed. Of 515 evaluable patients, 347 (67.4%) entered into complete remission (CR), following induction treatment with daunorubicin (DNR), vincristine (VCR), and cytosine arabinoside (ara-C). After one consolidation course, 248 patients were randomized for six courses of intensive maintenance: either repeated treatment with DNR-VCR-ara-C, or alternating treatment where amsacrine (AMSA) was combined with high dose ara-C on cycle 1,3, and 5 and with 5- azacytidine on cycle 2, 4, and 6. Ninety-nine patients were not randomized: 57 were introduced in a bone marrow transplantation (BMT) program, and 42 went off study, mainly for treatment toxicity or refusal. The main prognostic factors for achievement of CR were performance status, cytogenetics, and age, and for the disease-free survival (DFS): age and number of courses to CR. The rate of second remission was fairly high (64%) for patients relapsing off therapy. The DFS appeared identical (median, 53 weeks), in the two randomized arms, the alternating treatment not showing superiority to the repeated one, in spite of an increased toxicity. The median overall survival for patients achieving a CR was 90 weeks. The reason for the failure of alternating maintenance treatment to improve the DFS is probably related to an insufficient dose intensity: five patients who relapsed during maintenance arm B achieved a second CR with a more intensive combination of high-dose ara-C and AMSA. In addition, 60 patients underwent a BMT (43 allogeneic and 17 autologous). The DFS of patients treated with allogeneic BMT tended to be superior to the one obtained with the chemotherapy program. However the overall survival, as well as the event-free survival, seemed equivalent, including patients who relapsed before the planned BMT. Comparisons between allogeneic BMT, autologous BMT, and intensive consolidation during first CR deserve further prospective studies in AML.

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