Prospective Randomized Comparison of High Dose AraC and AutoPBSCT as Late Consolidation for Patients ≤60 Years with Standard Risk AML: Final Results of the AML SHG-Hannover 01/99 Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 607-607
Author(s):  
Arnold Ganser ◽  
Jürgen Krauter ◽  
Dieter Hoelzer ◽  
Oliver G. Ottmann ◽  
Hans Martin ◽  
...  
Keyword(s):  
De Novo ◽  
Standard Dose ◽  
Normal Karyotype ◽  
High Dose ◽  
Free Survival ◽  
Matched Sibling ◽  
Related Donor ◽  
To Receive ◽  
Standard Risk ◽  
Better Than

Abstract We treated 520 patients ≤60 years with de novo (n=414) or secondary (n=106) AML. Patients with CBF-leukemias [t(8;21) or inv(16)] or normal karyotype and good response (GR) to induction I (≤5% blasts in d15 BM) were considered standard risk (SR), all others as high risk (HR). Patients with t(15;17) were excluded. Induction I consisted of standard dose araC, idarubicine and etoposide (IVA-I). Patients with GR to IVA-I continued with IVA–II on d21. In patients with bad response (>5% BM blasts on d15), the second cycle consisted of either IVA–II or FlAG/Ida. Induction was followed by early consolidation with intermediate dose araC. As late consolidation, SR patients with normal karyotype and an HLA-matched sibling received matched related donor (MRD) transplantation. The remaining SR patients were randomized between high dose (HD) araC (12 x 3g/m2)/daunorubicine (3 x 45mg/m2) or an autologous peripheral blood stem cell transplantation (autoPBCSCT) with PBSC mobilized after early consolidation. 90% of the 262 SR patients achieved CR in contrast to only 59% of the 249 HR patients (overall CR rate 74%). After 75 months, overall survival (OS) and relapse free survival (RFS) was significantly better for SR than for HR patients. Within the SR group, OS for patients with CBF leukemia (n=62) at 56 months was significantly better than for patients with normal karyotype (n=200). RFS was similar for both groups. 57 SR patients (14 with CBF leukemia) were randomized to receive HD araC and 62 (16 with CBF leukemia) to undergo autoPBSCT. At 70 months, OS and RFS was not different for the patients treated with autoPBSCT and for those receiving HD araC. This was true for patients with normal karyotype as well as CBF leukemias. Median duration of neutropenia (<500/μl) was 9 days for autoPBSCT and 19 days for HD araC (p<0.01) with a significantly higher rate of septicemia (21% vs. 11%) and pneumonia (14% vs. 3%) after HD araC. Duration of thrombocytopenia was 21 days for HD araC and 11 days for autoPBSCT (p<0.01). In SR patients with normal karyotype, OS and RFS after MRD transplantation did not significantly differ from HD araC or autoPBSCT. However, when looking at the FLT3 status in patients with normal karyotype (n=49), chemoconsolidation resulted in an inferior survival (17%) in patients with mutated FLT3 as compared to autotransplantation (67%). In conclusion, outcome is similar in SR AML patients after autoPBSCT, HD araC or MRD transplantation. In SR patients without an HLA-identical sibling donor, autoPBSCT instead of HD araC as used in our study is recommended for late consolidation due to the reduced treatment related toxicity and should be studied prospectively in patients with mutated FLT3.

Late Consolidation for Patients with Standard Risk AML up to 60 Years: Results of a Prospective Randomized Comparison of High Dose AraC and Autologous PBSCT.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 145-145 ◽  
Author(s):  
Arnold Ganser ◽  
Jürgen Krauter ◽  
Dieter Hoelzer ◽  
Oliver Ottmann ◽  
Hans Martin ◽  
...  
Keyword(s):  
Overall Survival ◽  
De Novo ◽  
Standard Dose ◽  
Normal Karyotype ◽  
High Dose ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Significant Difference ◽  
Autologous Pbsct ◽  
Standard Risk

Abstract 421 patients (pts.) up to 60 years with de novo (n=328) or secondary (n=93) AML were treated with risk-adapted therapy. Pts. with CBF-leukemias [t(8;21) or inv(16)] or normal karyotype and good response (GR) to induction I (up to 5% blasts in day 15 BM) were considered standard risk (SR), all others as high risk (HR). Induction I consisted of standard dose araC, idarubicine and VP16 (IVA-I). Pts. with GR to IVA-I continued with IVA-II on day 21. In pts. with bad response, the second cycle consisted of either IVA-II or FlAG/Ida. Double induction was followed by early consolidation with intermediate dose araC. As late consolidation, SR patients were randomized between high dose (HD) araC (12 x 3g/m2)/daunorubicine (3 x 45mg/m2) or an autologous PBSCT with PBSC mobilized after early consolidation except SR pts. with normal karyotype and an HLA-matched sibling who were allotransplanted. 214 pts. were classified as SR and 199 as HR. 91% of the SR and 59% of the HR pts. achieved CR (overall CR rate 75%) and 1% of the SR pts. died during induction. After 55 months, overall survival was significantly better for SR (49%) than for HR pts. (25%). Within the SR group, relapse free survival at 46 months was 63% for 21 pts. with inv(16), 58% for 25 pts. with t(8;21), and 37% for 148 pts. with normal karyotype (p = 0.13). Overall survival at 48 months was significantly better (p=0.014) for pts. with inv(16) (93%) than for those with t(8;21) (60%) or normal karyotype (44%). 48 SR pts. (12 with CBF leukemia) were randomized to receive HDaraC and 53 (14 with CBF leukemia) to undergo autoPBSCT. At 55 months, the overall survival was 52% for the autotransplanted pts. and 65% for those receiving HDaraC (p=0.71, intent-to-treat analysis). Median duration of neutropenia (<500/ μl) was 8 days for autoPBSCT and 19 days for HDaraC. Eleven pts. died in the HDaraC group (4 in CR and 7 from relapse) and 12 autotransplanted pts. died (1 in CR and 11 from relaspe). In pts. with normal karyotype, overall survival at 55 months for the allotransplanted SR pts. (n = 29) was 58% with no significant difference to HDaraC (62%) or autoPBSCT (43%). Relapse free survival for SR pts. with normal karyotype was 56% after allotransplantation, and 36% after autoPBSCT and HDaraC respectively (p = n.s.). In conclusion, overall survival is similar in SR AML pts. after autoPBSCT, HDaraC or allotransplantation. In SR pts. without an HLA-identical sibling donor, the reduced treatment related toxicity recommends autoPBSCT as late consolidation. In standard risk pts. with normal karyotype, allotransplantation from an HLA-identical sibling seems to have the highest antileukemic activity.

Updated Results of JALSG AML201 Study Comparing Intensified Daunorubicin with Idarubicin in Patients with De Novo Acute Myeloid Leukemia: Effect of Hematopoietic Stem Cell Transplantation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2171-2171 ◽  
Author(s):  
Shigeki Ohtake ◽  
Shuichi Miyawaki ◽  
Hiroyuki Fujita ◽  
Hitoshi Kiyoi ◽  
Katsuji Shinagawa ◽  
...  
Keyword(s):  
Overall Survival ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Standard Dose ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Related Donor ◽  
To Receive

Abstract We conducted a randomized study to determine whether the intensified daunorubicin (DNR) induction chemotherapy would be as effective as idarubicin (IDR) in adult acute myeloid leukemia (AML). From December 2001 to December 2005, 1064 newly diagnosed patients with de novo AML were registered and 1057 were eligible. Median age was 47 years old (range 15 to 64). The patients with AML excluding FAB-M3 were randomized to receive either increased dose of DNR (50 mg/m2 daily for 5 days) or standard dose of IDR (12 mg/m2 daily for 3 days), with cytarabine 100 mg/m2 daily for 7 days by continuous intravenous infusion for induction chemotherapy. Complete remission (CR) was achieved in 407 patients (77.5%; 95% CI, 73.9% – 81.1%) in DNR group and 416 patients (78.2%; 74.7% – 81.7%) in IDR group (p = 0.79). After a median follow up of 48 months there was also no significant difference between the groups in the longer-time measures of efficacy: estimated overall survival at 5 years was 48.0% (95% CI: 43.3% – 52.8%) for DNR and 47.6% (42.8% – 52.4%) for IDR (p = 0.54); estimated relapse free survival at 5 years from CR was 40.7% (35.4% – 45.4%) for DNR and 40.6% (35.6% – 45.6%) for IDR (p = 0.97). The second purpose of this study was to evaluate the efficacy of allogeneic hematopoietic stem cell transplantation (allo-SCT) during the first CR in patients with intermediate or poor risk. If the patients other than CBF leukemia were in CR and had an HLA identical related donor, we recommended them to receive allo-SCT. Of the 823 patients that achieved CR, 132 (16.0%, madeian age, 37 years old; range, 15 – 61) received allo-SCT during the first CR: 72 patients, allo-SCT from a related donor and 60, from an unrelated donor. We examined the efficacy of SCT by comparing these patients with those who did not receive SCT using a matched-pair analysis method. We were able to select 95 pairs of patients by matching karyotype (MRC category), prognostic category established by JALSG, number and type (DNR or IDR) of induction therapy, post-remission therapy and age, that received (SCT pts) and did not receive SCT (non-SCT pts) during the first CR. Variables such as initial WBC count, diagnosis by FAB classification and myeloperoxidase positivity of blasts were comparable between the two groups. Estimated relapse free survival at 5 years from CR was 62.9% (52.5% – 73.3%) for SCT pts and 28.2% (20.6% – 35.8%) for non-SCT pts (p &lt; 0.0001), and estimated overall survival at 5 years was 62.7% (51.5% – 73.8%) for SCT pts and 49.3% (40.6% – 58.1%) for non-SCT pts (p = 0.016). Estimated overall survival at 5 years was 47.0% (39.5% – 54.5%) in patients that received their first allo-SCT after relapse. It is noteworthy that many patients who suffered from relapse were also rescued by allo-SCT. We conclude that the long-term efficacy of the induction chemotherapy with increased dose of DNR and that with standard dose of IDR were comparable demonstrating high remission rate and fair overall survival. They are equally effective for the treatment of AML patients up to 64 years old. It is suggested that SCT during the first CR is recommended for patients that are categorized into the intermediate or poor risk group if a suitable donor is available.

scholarly journals A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study

Blood ◽  
1996 ◽  
Vol 88 (8) ◽  
pp. 2841-2851 ◽  
Author(s):  
JK Weick ◽  
KJ Kopecky ◽  
FR Appelbaum ◽  
DR Head ◽  
LL Kingsbury ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
High Dose ◽  
Consolidation Therapy ◽  
Oncology Group ◽  
Free Survival ◽  
Southwest Oncology Group ◽  
To Receive ◽  
Acute Myeloid

Interest in high-dose cytarabine (HDAC) for both induction and postremission therapy for acute myeloid leukemia (AML) prompted the Southwest Oncology Group (SWOG) to initiate a randomized trial comparing HDAC with standard-dose cytarabine (SDAC) for remission induction of previously untreated AML and to compare high-dose treatment versus conventional doses for consolidation therapy. Patients less than 65 years of age with de novo or secondary AML were randomized for induction between SDAC 200 mg/ m2/d for 7 days by continuous infusion or HDAC at 2 g/ m2 intravenously every 12 hours for 12 doses; both groups received daunorubicin (DNR) at 45 mg/m2/d intravenously for 3 days. Complete responders to SDAC were randomized to receive either two additional courses of SDAC plus DNR or one course of HDAC plus DNR. Complete responders to HDAC were nonrandomly assigned to receive one additional course of HDAC plus DNR. Of patients randomized between SDAC (n = 493) and HDAC (n = 172) induction, 361 achieved complete remission (CR). The CR rate was slightly poorer with HDAC: 55% versus 58% with SDAC for patients aged less than 50, and 45% (HDAC) versus 53% (SDAC) for patients aged 50 to 64 (age-adjusted one-tailed P = .96). With a median follow-up time of 51 months, survival was not significantly better with HDAC (P = .41); the estimated survival rate at 4 years was 32% (HDAC) versus 22% (SDAC) for those aged less than 50, and 13% (HDAC) versus 11% (SDAC) for those aged 50 to 64. However, relapse-free survival was somewhat better following HDAC Induction (P = .049): 33% (HDAC) versus 21% (SDAC) at 4 years for those aged less than 50, and 21% (HDAC) versus 9% (SDAC) for those aged 50 to 64. Induction with HDAC was associated with a significantly increased risk of fatal (P = .0033) and neurologic (P < .0001) toxicity. Among patients who achieved CR with SDAC, survival and disease-free survival (DFS) following consolidation randomization were not significantly better with HDAC compared with SDAC (P = .77 and .46, respectively). Patients who received both HDAC induction and consolidation had the best postremission outcomes; however, the proportion of CR patients who did not go on to protocol consolidation therapy was more than twice as high after HDAC induction compared with SDAC. Induction therapy with HDAC plus DNR was associated with greater toxicity than SDAC plus DNR, but with no improvement in CR rate or survival. Following CR induction with SDAC, consolidation with HDAC increased toxicity but not survival or DFS. In a nonrandomized comparison, patients who received both HDAC induction and consolidation had superior survival and DFS compared with those who received SDAC induction with either SDAC or HDAC consolidation.

Role of Consolidation Therapy in the Treatment of Patients up to 60 Years with High Risk AML.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 172-172 ◽  
Author(s):  
Jürgen Krauter ◽  
Gerhard Heil ◽  
Dieter Hoelzer ◽  
Oliver Ottmann ◽  
Hans Martin ◽  
...  
Keyword(s):  
High Risk ◽  
De Novo ◽  
Standard Dose ◽  
Normal Karyotype ◽  
Allogeneic Transplantation ◽  
Unrelated Donor ◽  
Secondary Aml ◽  
Autologous Pbsct ◽  
Matched Sibling ◽  
Family Donor

Abstract In the prospective multicenter AML 01/99 trial, 484 patients with acute myeloid leukemia up to 60 years (385 with de novo and 99 with secondary AML) were treated with risk-adapted therapy. Patients with CBF-leukemias [t(8;21) or inv(16)] or normal karyotype and good response (GR) to induction I (≤5% blasts in day 15 BM) were considered standard risk (SR), all other patients as high risk (HR). Patients with t(15;17) were excluded. Induction course I consisted of standard dose araC, idarubicine and etoposide (IVA-I). Patients with GR to IVA-I continued with IVA-II on day 21 as double induction. In patients with bad response (&gt;5% bone marrow blasts on day 15), the second cycle consisted of FlAG/Ida. Double induction was followed by an early consolidation with intermediate dose araC. As late consolidation, HR patients with an HLA-matched sibling were scheduled for a matched related donor (MRD) transplantation whereas patients without a family donor should undergo autologous peripheral blood stem cell transplantation (autoPBSCT). PBSC were mobilized after early consolidation. A pilot study within the 01/99 trial showed superior results for matched unrelated donor (MUD) transplantation compared to patients who had undergone autoPBSCT. Therefore, since 2003 all HR patients without a sibling donor were scheduled for MUD transplantation. 234 patients were classified as HR, of whom 137 (58%) achieved complete remission. 31 (13%) of the HR patients died during induction. After 70 months, overall survival (OS) was significantly worse for HR patients (28%) than for SR patients (51%). For HR patients, there was no difference in OS and relapse-free survival (RFS) between those patients classified as HR because of bad response to IVA-1 (n = 76), unfavourable karyotype (n = 83) or both characteristics (n = 75). Moreover, RFS was neither different between HR patients with de novo or secondary AML nor between HR patients with normal karyotype, complex karyotype or other high risk cytogenetics. Regarding the different regimens for late consolidation, the “as treated” analysis of the HR patients revealed that OS and RFS was significantly better after an MRD transplantation (n=34, OS 68%, RFS 65%) than after autoPBSCT (n=26, OS 23%, RFS 7%). OS and RFS for the 29 patients who received MUD transplantation was also significantly better than after autoPBSCT with 56% and 52% respectively. In conclusion, HR patients as defined in our study do not benefit from an autologous PBSCT even after intensive double induction and early consolidation. Therefore, an allogeneic transplantation from a related or unrelated donor should be performed.

Treatment of Patients up to 60 Years with High Risk AML: Final Results of the AML SHG-Hannover 01/99 Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 433-433 ◽  
Author(s):  
Jürgen Krauter ◽  
Gerhard Heil ◽  
Dieter Hoelzer ◽  
Oliver G. Ottmann ◽  
Hans Martin ◽  
...  
Keyword(s):  
High Risk ◽  
De Novo ◽  
Standard Dose ◽  
Normal Karyotype ◽  
Multicenter Trial ◽  
Unrelated Donor ◽  
Secondary Aml ◽  
Autologous Pbsct ◽  
Matched Sibling ◽  
Family Donor

Abstract In this prospective multicenter trial, we treated 520 patients with AML ≤60 years (414 with de novo and 106 with secondary AML). Patients with CBF-leukemias [t(8;21) or inv(16)] or normal karyotype and good response (GR) to induction I (≤5% blasts in day 15 BM) were considered standard risk (SR), all other patients as high risk (HR). Patients with t(15;17) were excluded. Induction course I consisted of standard dose araC, idarubicine and etoposide (IVA-I). Patients with GR to IVA-I continued with IVA-II on day 21. In patients with bad response (BR; &gt;5% BM blasts on day 15), the second cycle consisted of either IVA-II or FlAG/Ida. Double induction was followed by early consolidation with intermediate dose araC. As late consolidation, HR patients with an HLA-matched sibling were scheduled for a matched related donor (MRD) transplantation; patients without a family donor should undergo autologous peripheral blood stem cell transplantation (autoPBSCT). PBSC were mobilized after early consolidation. An interim analysis showed superior results for allogeneic transplants compared to patients who had undergone autoPBSCT. Therefore, since 2003 all HR patients without a sibling donor were scheduled for matched unrelated donor (MUD) transplantation. 147 of 249 HR patients (59%) achieved complete remission. 33 (13%) of the HR patients died during induction. After 75 months, overall survival (OS) was significantly worse for HR patients (24%) than for SR patients (53%). For HR patients, there was no difference in OS and relapse-free survival (RFS) between patients classified as HR because of BR to IVA-1 (n = 83), unfavourable karyotype (n = 87) or both characteristics (n = 79). RFS was neither different between HR patients with de novo or secondary AML nor between HR patients with normal karyotype, complex karyotype or other high risk cytogenetics. Regarding late consolidation, the “as treated” analysis revealed that OS and RFS was significantly better after an MRD transplantation (n=41, OS 67%, RFS 62%) than after autoPBSCT (n=27, OS 14%, RFS 7%). Patients who received a MUD transplantation (n=32) showed a significantly better RFS (52%) than after autoPBSCT. RFS and OS after MUD transplantation did not differ significantly from MRD transplants. OS of patients after autoPBSCT was not significantly different from patients who received no transplant at all after entering CR. Of the 69 HR patients who did not enter CR after induction, 44 received an MRD or MUD transplantation. 15 of these patients (35%) are alive in CR. In conclusion, HR patients as defined in our study do not benefit from an autologous PBSCT and an allogeneic MRD or MUD transplantation should be performed. Moreover, allogeneic transplants are a viable salvage option for HR patients not entering CR.

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.

Treatment of Adult Patients with High Risk Acute Myeloblastic Leukemia up to 60 Years: Role of Consolidation Therapy within a Prospective Multicenter Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 618-618 ◽  
Author(s):  
Jürgen Krauter ◽  
Gerhard Heil ◽  
Dieter Hoelzer ◽  
Oliver Ottmann ◽  
Hans Martin ◽  
...  
Keyword(s):  
High Risk ◽  
De Novo ◽  
Standard Dose ◽  
Acute Myeloblastic Leukemia ◽  
Unrelated Donor ◽  
Consolidation Therapy ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Sibling Donor ◽  
Matched Sibling

Abstract In our prospective multicenter AML 01/99 trial for risk-adapted therapy of patients aged up to 60 years with acute myeloblastic leukemia, patients with CBF-leukemias [t(8;21) or inv(16)] or normal karyotype and good response (GR) to induction I (up to 5% blasts in day 15 BM) were considered standard risk (SR), all other patients as high risk (HR). Patients with acute promyelocytic leukemia were excluded. Between January 1999 and May 2004, 421 patients (328 with with de novo and 93 with secondary AML) were treated. Induction course I consisted of standard dose araC, idarubicine and etoposide (IVA-I). Patients with GR to IVA-I continued with IVA-II on day 21 as double induction. In patients with bad response (>5% bone marrow blasts on day 15), the second cycle consisted of either IVA-II or FlAG/Ida. Double induction was followed by an early consolidation with intermediate dose araC. As late consolidation, HR patients were allo- [HLA-matched sibling or matched unrelated donor (MUD)] or autotransplanted. Matched sibling allotransplantation was done in all participating centers whereas MUD transplantation was favoured by only two centers. The remaining centers performed autologous PBSCT if there was no sibling donor available. 199 patients were classified as HR, of whom 118 (59%) achieved CR, and 25 (13%) of the HR patients died during induction. After 55 months, overall survival was significantly worse for HR patients (25%) than for SR patients (49%). This was also true for the relapse-free survival (32% vs. 42%; p = 0.049). In the HR group, there was no difference in overall and relapse-free survival between those patients classified as HR because of bad response to IVA-1 (n = 65), unfavourable karyotype (n = 71) or both characteristics (n = 63). Regarding the different regimens for late consolidation, the “as treated” analysis of the HR patients revealed that overall (59% vs. 20%) and relapse-free survival (59% vs. 20%) was significantly better after an allogeneic HLA-matched sibling transplantation (n = 26) than after autoPBSCT (n=24). Overall and relapse-free survival for the 23 patients who underwent MUD transplantation were 59% and 45% respectively. In conclusion, in HR patients with an HLA-identical sibling donor an allotransplantation should be performed. The results obtained with MUD transplantation in this particular patient group are encouraging. Therefore, in HR patients without an HLA-identical sibling allografting from unrelated donors should be considered in first CR. On the other hand, HR patients as defined by our risk stratification do not seem to benefit from autografting even after intensive induction and consolidation therapy.

6-Thioguanine, Cytarabine, and Daunorubicin (TAD) and High-Dose Cytarabine and Mitoxantrone (HAM) for Induction, TAD for Consolidation, and Either Prolonged Maintenance by Reduced Monthly TAD or TAD-HAM-TAD and One Course of Intensive Consolidation by Sequential HAM in Adult Patients at All Ages With De Novo Acute Myeloid Leukemia (AML): A Randomized Trial of the German AML Cooperative Group

2003 ◽  
Vol 21 (24) ◽  
pp. 4496-4504 ◽  
Author(s):  
Thomas Büchner ◽  
Wolfgang Hiddemann ◽  
Wolfgang E. Berdel ◽  
Bernhard Wörmann ◽  
Claudia Schoch ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Lactate Dehydrogenase Level ◽  
High Dose ◽  
Free Survival ◽  
Poor Risk ◽  
De Novo Aml ◽  
To Receive ◽  
Acute Myeloid

Purpose: To examine the efficacy of prolonged maintenance chemotherapy versus intensified consolidation therapy for patients with acute myeloid leukemia (AML). Materials and Methods: Eight hundred thirty-two patients (median age, 54 years; range, 16 to 82 years) with de novo AML were randomly assigned to receive 6-thioguanine, cytarabine, and daunorubicin (TAD) plus cytarabine and mitoxantrone (HAM; cytarabine 3 g/m2 [age < 60 years] or 1 g/m2 [age ≥ 60 years] × 6) induction, TAD consolidation, and monthly modified TAD maintenance for 3 years, or TAD-HAM-TAD and one course of intensive consolidation with sequential HAM (S-HAM) with cytarabine 1 g/m2 (age < 60 years) or 0.5 g/m2 (age ≥ 60 years) × 8 instead of maintenance. Results: A total of 69.2% patients went into complete remission (CR). Median relapse-free survival (RFS) was 19 months for patients on the maintenance arm, with 31.4% of patients relapse-free at 5 years, versus 12 months for patients on the S-HAM arm, with 24.7% of patients relapse-free at 5 years (P = .0118). RFS from maintenance was superior in patients with poor risk by unfavorable karyotype, age ≥ 60 years, lactate dehydrogenase level greater than 700 U/L, or day 16 bone marrow blasts greater than 40% (P = .0061) but not in patients with good risk by complete absence of any poor risk factors. Although a survival benefit in the CR patients is not significant (P = .085), more surviving patients in the maintenance than in the S-HAM arm remain in first CR (P = .026). Conclusion: We conclude that TAD-HAM-TAD-maintenance first-line treatment has a higher curative potential than TAD-HAM-TAD-S-HAM and improves prognosis even among patients with poor prognosis.

Prospective Randomized Comparison of High Dose AraC and Autologous Peripheral Blood Stem Cell Transplantation as Late Consolidation for Patients ≤60 Years with Standard Risk AML.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 151-151
Author(s):  
Arnold Ganser ◽  
Jürgen Krauter ◽  
Dieter Hoelzer ◽  
Oliver Ottmann ◽  
Hans Martin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Peripheral Blood ◽  
De Novo ◽  
Peripheral Blood Stem Cell ◽  
Normal Karyotype ◽  
High Dose ◽  
Standard Risk ◽  
Blood Stem Cell Transplantation

Abstract 484 patients aged ≤60 years with de novo (n=385) or secondary (n=99) acute myeloid leukemia (AML) were treated with risk-adapted therapy. Patients with t(8;21), inv(16) or normal karyotype and good response (GR) to induction I (≤5% blasts in day 15 BM) were considered standard risk (SR), all others as high risk (HR). Induction I consisted of standard dose araC, idarubicine and etoposide (IVA-I). Patients with GR to IVA-I continued with IVA-II on day 21 as double induction. Patients with bad response (&gt;5% blasts in day 15 BM) received FlAG/Ida as second cycle. Double induction was followed by early consolidation with intermediate dose araC. As late consolidation, SR patients with normal karyotype and an HLA-matched sibling received matched related donor (MRD) transplantation. The remaining SR patients were randomized between high dose araC (HD-araC; 12 x 3g/m2)/daunorubicine or an autologous peripheral blood stem cell transplantation (autoPBCSCT) with PBSC mobilized after early consolidation. 90% of SR patients (n=250) achieved complete remission (CR) in contrast to 58% of HR patients (n=234) (overall CR rate 75%). 4% of the SR patients died during induction. At 70 months, overall survival (OS) was significantly better for SR (51%) than for HR patients (28%). Within the SR group, relapse free survival at 50 months was not different between patients with normal karyotype (n=165), inv(16) (n=30) or t(8;21) (n=30). 55 SR patients were randomized to receive HD-araC and 59 to autoPBSCT. Distribution of the main characteristics were well balanced (age, performance status, cytogenetics, FLT3 mutation status, de novo or secondary AML). At 63 months, OS was 62% for patients treated with autoPBSCT and 59% for those receiving HD-araC (p=0.91, intent-to-treat). Median duration of neutropenia (&lt;500/μl) was 8 days for autoPBSCT and 20 days for HD-araC (p&lt;0.05). This corresponded to a significantly higher rate of septicemia (20% vs. 10%) and pneumonia (13% vs. 3%) after HD-araC. The duration of thrombocytopenia was 22 days after HD-araC and 11 days after autoPBSCT (p&lt;0.01). 14 patients died in the HD-araC group (4 in CR and 10 from relapse) and 14 patients died after autoPBSCT (1 in CR and 13 from relapse). In patients with normal karyotype, OS at 67 months for the SR patients receiving MRD transplantation (n = 37) was 61% with no significant difference to HD-araC or autoPBSCT. In conclusion, OS is similar in SR AML patients after autoPBSCT, HD-araC or MRD transplantation. In SR patients without an HLA-identical sibling donor, autoPBSCT instead of HD-araC is recommended for late consolidation due to the reduced treatment related toxicity.

Intensification of Induction by High-Dose AraC and Outcome in Older Patients with De-Novo Acute Myeloid Leukemia (AML) and Subsets.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1978-1978
Author(s):  
Thomas Buchner ◽  
Wolfgang E. Berdel ◽  
Claudia Schoch ◽  
Torsten Haferlach ◽  
Joelle Tchinda ◽  
...  
Keyword(s):  
Older Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Standard Dose ◽  
Induction Treatment ◽  
High Dose ◽  
Similar Response ◽  
Duration Of Treatment ◽  
Free Survival ◽  
De Novo Aml

Abstract As recently reported modifications, dose or duration of treatment had no impact on outcome of AML in older patients (Burnett et al. Blood 106: 162a, 2005). We therefore evaluated 764 patients 60 years of age or older and their various prognostic subgroups in the 1992 and 1999 mulitcenter randomized trials by the German AMLCG where patients received uniform postremission consolidation by one course of TAD (standard dose thioguanine, araC, daunorubicin) and maintenance by monthly 5 day courses of reduced TAD. For maximum homogeneity this analysis was restricted to de-novo AML and to patients with known karyotype. Before treatment started, patients were assigned to induction treatment by either TAD followed by HAM (HAM, high-dose araC 1g/m2x6 / mitoxantrone 10mg/m2x3), or to induction by two courses of HAM. The second induction course (HAM) was given to only patients with 5% or more residual bone marrow blasts. Therapy administered to the two randomized groups differed by a factor 2 in their araC dose. Despite this difference in treatment intensity patients in the two arms show similar response rate, overall survival (OS), ongoing CR, and relapse-free survival (see table). The same similarity in outcome as for de-novo AML overall is true for established prognostic subgroups as listed below. Conclusion: Intensification of induction therapy by high-dose araC has no effect on outcome in older age de-novo AML. Since potential influences other than the randomized treatment were minimized, present results do not support a risk adapted intensification strategy. TAD-HAM HAM-HAM P TAD-HAM HAM-HAM P OS 4y % OS 4y % CR 4y % CR 4y % Total 18 13 .28 22 22 .53 Favorable Karyotype 17 16 .48 41 33 .82 Intermediate Karyotype 24 18 .31 24 26 .38 Unfavorable Karyotype 4 - .81 - - .37 LDH ≤ 700U/L 21 13 .86 23 24 .47 LDH > 700U/L 12 10 .07 - 16 .27 WBC ≤ 20x103/ccm 21 11 .91 22 21 .81 WBC > 20x103/ccm 15 16 .08 22 26 .19 Day 16 Blasts < 10% 26 16 .87 23 22 .81 Day 16 Blasts ≥ 10% 14 8 .28 18 19 .26

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