Postremission Therapy in Adult Acute Myeloid Leukemia (AML): A Randomized Comparison of Intensified Consolidation Therapy without Maintenance Therapy Against Conventional Consolidation with Maintenance Therapy -JALSG AML-97 Trial-.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 868-868 ◽  
Author(s):  
Shuichi Miyawaki ◽  
Hisashi Sakamaki ◽  
Shigeki Ohtake ◽  
Fumiharu Yagasaki ◽  
Kinuko Mitani ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Induction Therapy ◽  
Risk Group ◽  
Randomized Study ◽  
Risk Groups ◽  
Consolidation Therapy ◽  
Poor Risk ◽  
Short Course ◽  
To Receive ◽  
Good Risk

Abstract Between 1997 and 2001, JALSG conducted a randomized study to assess the optimal post remission therapy for adult AML in the first CR. The JALSG AML97 enrolled 809 previously untreated AML patients (pts) aged 15–64 yrs. Induction therapy consisted of cytarabine (100mg/m2 day1–7) and idarubicin (IDR 12mg/m2 day1– 3). If the patients did not achieve remission after the first induction therapy, the same therapy was given once more. Pts were categorized into good, intermediate or poor risk groups by risk factors based on the previous JALSG AML studies. All CR pts were randomized to receive either the intensified short course post remission regimen (arm A) or the conventional JALSG’s post remission regimen for AML including maintenance therapy (arm B). Arm A: 1) AraC 200mg/m2 day1–5+ Mitoxantrone (MTZ) 7mg/m2 day1–3, 2) AraC 200mg/m2 day1–5+Daunorubicin (DNR) 50mg/m2 day1–3, 3) AraC 200mg/ m2 day1–5+ Aclacinomycin (ACR) 20mg/m2 day1–5, 4) AraC 200mg/m2 day1–5+ Etoposide (ETP) 100mg/m2 day1–5 + Vincristine (VCR) 0.8mg/m2 day 8 + Vindesine (VDS) 2 mg/m2 day10. Arm B: 1) AraC 200mg/m2 day1–5 + MTZ 7mg/m2 day1–3, 2) Behenoyl AraC (BHAC) 200mg/m2 day1–7 + ETP 100mg/m2 day1–5 + DNR 50mg/m2 day1–3 + 6 mercptopurine (6MP) day1–7, 3) BHAC 200mg/m2 day1–7 + ACR 14mg/m2 day1–7, and then 6 courses maintenance therapy: 1) BHAC 170mg/m2 day1–5 + DNR 50mg/m2 day1,4+6MP day1–7, 2) BHAC 170mg/m2 day1–5 + MTZ 5mg/m2 day1–3, 3) BHAC 170mg/m2day1–5 + ETP 80mg/m2 day1,5,7 + VDS 2mg/m2 day1,8, 4) BHAC 170mg/m2 day1–5 + ACR 14mg/m2 day1–4 + 6MP day1–7, 5) BHAC 170mg/m2 day1–5 + DNR 50mg/m2 day1–4 + 6MP day1–7, 6) BHAC 170mg/m2 day1–5 + ETP 80mg/m2 day1,5,7 + VDS 2mg/m2 day1,8. Result: Of the 809 pts registered, 789 pts (median age: 45 years) were evaluable. 621 pts (78.7%) achieved CR after one or two courses of induction therapy. The 5-year OS rate of arm A was 45.6% and of arm B 53.2% (p=0.3259). The 5-year DFS rate of CR patients was 34.8% in arm A and 28.9% in arm B (p=0.4978). Among the good risk group, the 5-year OS rate of arm A was 62.1% and of arm B 70.2% (p=0.5068), and the 5-year DFS rate of arm A was 53.4% and of arm B 42.0% (p=0.3719). Among the intermediate risk group, the 5-year OS rate of arm A was 35.6% and of arm B 45.5% (p=0.4776), and the 5-year DFS rate of arm A was 26.0% and of arm B 26.1% (p=0.9653). Among the poor risk group, the 5-year OS rate of arm A was 29.7% and of arm B was 33.4% (p=0.6523), and the 5-year DFS rate of arm A was 20.4% and of arm B was 13.5% (p=0.6339). In conclusion: JALSG’s conventional post remission therapy consisting of 3 courses of consolidation and 6 courses of maintenance therapy could be replaced by a shorter duration of intensified consolidation therapy.

Postremission Therapy in Adult Acute Myeloid Leukemia (AML): A Randomized Comparison between High Dose Ara-C Therapy and Conventional Consolidation Therapy (JALSG AML 201 Study).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2005-2005 ◽  
Author(s):  
Shuichi Miyawaki ◽  
Shigeki Ohtake ◽  
Shin Fujisawa ◽  
Hitoshi Kiyoi ◽  
Katsuji Shinagawa ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Risk Group ◽  
Randomized Study ◽  
Risk Groups ◽  
Young Group ◽  
High Dose ◽  
Poor Risk ◽  
Leukemia Group ◽  
Good Risk

Abstract Between 2001 and 2005, JALSG conducted a randomized study to assess the optimal post remission therapy for adult AML in the first CR. JALSG AML201 enrolled 1064 previously untreated AML patients (pts) aged 15–64 yrs. The induction therapy consisted of cytarabine (Ara-C 100mg/m2 day1–7) and idarubicin (IDR 12mg/m2 day1– 3) (arm A) or cytarabine (100mg/m2 day1–7) and daunorubicin (DNR 50mg/m2 day1– 5) (arm B). If the patients did not achieve remission after the first induction therapy, then the same therapy was given once more. Pts were categorized into good, intermediate or poor risk groups by risk factors based on the criteria established in previous JALSG AML studies. All CR pts were stratified according to the induction, the number of courses of induction, age and karyotype and were randomly assigned to the high dose Ara-C (HDAC) post remission regimen (arm C) or the conventional JALSG post remission regimen (arm D). Arm C: the three courses of HDAC which consisted of Ara-C 2.0g/m2 q12h day1–5, arm D: the first course consisted of Ara-C 200mg/m2 day1–5+ mitoxantrone (MIT) 7mg/m2 day1–3, 2) Ara-C 200mg/m2 day1–5+ DNR 50mg/m2 day1–3, 3) Ara-C 200mg/m2 day1–5+ aclarubicin (ACR) 20mg/m2 day1–5, 4) Ara-C 200mg/m2 day1–5+ etoposide (ETP) 100mg/m2 day1–5 + vincristine (VCR) 0.8mg/m2 day 8 + vindesine (VDS) 2 mg/m2 day10. Results: Of the 1064 pts registered, 1057 pts (median age: 47 years) were evaluable. 825 pts (78%) achieved CR after one or two courses of induction therapy. Of the 825 pts in CR, 781 pts were assigned to arm C or arm D. The 4-year OS rate of arm C was 61.6% while that of arm D was 62.8% (p=0.58). The 4-year RFS rate of the CR patients was 42.8% in arm C and 40.8% in arm D (p=0.65). Among the good risk group, the 4-year OS rate of arm C was 77.0% while that of arm D was 75.8 % (p=0.40), and the 4-year RFS rate of arm C was 54.6% while that of arm D was 53.1% (p=0.71). Among the intermediate risk group, the 4-year OS rate of arm C was 63.2% while that of arm D was 65.7% (p=0.78), and the 4-year RFS rate of arm C was 38.7% while that of arm D was 42.2% (p=0.63). Among the poor risk group, the 4-year OS rate of arm C was 36.3% while that of arm D was 34.1% (p=0.71), and the 4-year RFS rate of arm C was 25.9% while that of arm D was 6.6% (p=0.17). In the CBF leukemia group, the 4-year OS rate of arm C was 79.4% while that of arm D was 66.5% (p=0.09), and the 4-year RFS rate of arm C was 57.7% while that of arm D was 43.7% (p=0.14). Among the young group (<50yrs), the 4-year OS rate of arm C was 66.5% while that of arm D was 66.2% (p=0.37), and the 4-year RFS rate of arm C was 43.9% while that of arm D was 45.6% (p=0.32). Among the old group (>=50 yrs), the 4-year OS rate of arm C was 53.4% while that of arm D was 57.7% (p=0.90), and the 4-year RFS rate of arm C was 39.1% while that of arm D was 33.8% (p=0.67). Conclusion: The conventional post remission therapeutic regimen established by JALSG consisting of 4 courses of consolidation was thus found to be as effective as the three courses of HDAC therapy. To further confirm these results, a longer follow-up is therefore needed.

Long-Term Follow-up of the Randomized JALSG AML 201 Study Comparing High Dose Ara-C Therapy with Conventional Consolidation Therapy in Adult Acute Myeloid Leukemia (AML)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 135-135
Author(s):  
Shuichi Miyawaki ◽  
Shigeki Ohtake ◽  
Shin Fujisawa ◽  
Hitoshi Kiyoi ◽  
Katsuji Shinagawa ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Risk Group ◽  
Randomized Study ◽  
Risk Groups ◽  
Young Group ◽  
High Dose ◽  
Poor Risk ◽  
Wbc Count ◽  
Leukemia Group

Abstract A randomized study had been performed between December 2001 and December 2005 to assess the optimal post remission therapy for adult AML in the first CR. The updated results are here presented, after a median follow-up of 48 months. JALSG AML201 enrolled 1064 previously untreated AML patients (pts) aged 15–64 yrs. The induction therapy consisted of cytarabine (Ara-C 100 mg/m2 day1–7) and idarubicin (IDR 12 mg/m2 day1–3) (arm A) or cytarabine (100 mg/m2 day1–7) and daunorubicin (DNR 50 mg/m2 day1–5) (arm B). If the patients did not achieve remission after the first induction therapy, then the same therapy was given once more. Pts were categorized into good, intermediate or poor risk groups by risk factors based on the criteria established in previous JALSG AML studies (Miyawaki et al. Cancer 2005). All CR pts were stratified according to the induction, the number of courses of induction, age and karyotype and were randomly assigned to the high dose Ara-C (HDAC) post remission regimen (arm C) or the conventional JALSG post remission regimen (arm D). Arm C: the three courses of HDAC which consisted of Ara-C 2.0 g/m2 q12h day1–5, arm D: the first course consisted of Ara-C 200 mg/m2 day1–5+ mitoxantrone (MIT) 7 mg/m2 day1–3, 2) Ara-C 200 mg/m2 day1–5+ DNR 50 mg/m2 day1–3, 3) Ara-C 200 mg/m2 day1–5+ aclarubicin (ACR) 20 mg/m2 day15, 4) Ara-C 200 mg/m2 day1–5+ etoposide (ETP) 100 mg/m2 day1–5 + vincristine (VCR) 0.8 mg/m2 day 8 + vindesine (VDS) 2 mg/m2 day10. Results: Of the 1064 pts registered, 1057 pts (median age: 47 years) were evaluable. 823 pts (78%) achieved CR after one or two courses of induction therapy. Of the 823 pts in CR, 781 pts were assigned to arm C (n=389) or arm D (n=392). The 5-year OS rate of arm C was 57.8% while that of arm D was 55.9% (p=0.96). The 5-year RFS rate of the CR pts was 42.7% in arm C and 38.9% in arm D (p=0.73). Among the good risk group (n=155), the 5-year OS rate of arm C was 69.9% while that of arm D was 80.5 % (p=0.11), and the 5-year RFS rate of arm C was 54.5% while that of arm D was 55.7% (p=0.53). Among the intermediate risk group (n=439), the 5-year OS rate of arm C was 50.9% while that of arm D was 48.5% (p=0.59), and the 5-year RFS rate of arm C was 41.5% while that of arm D was 36.5% (p=0.50). Among the poor risk group (n=49), the 5-year OS rate of arm C was 12.9% while that of arm D was 17.2% (p=0.58), and the 5-year RFS rate of arm C was 14.3% while that of arm D was 15.5% (p=0.78). In the CBF leukemia group (n=218), the 5-year OS rate of arm C was 75.0% while that of arm D was 65.8% (p=0.17), and the 5-year RFS rate of arm C was 56.5% while that of arm D was 38.7% (p=0.05). Among the young group (&lt;50yrs) (n=467), the 5-year OS rate of arm C was 62.1% while that of arm D was 66.4% (p=0.23), and the 5-year RFS rate of arm C was 44.6% while that of arm D was 45.6% (p=0.59). Among the old group (&gt;=50 yrs) (n=314), the 5-year OS rate of arm C was 51.3% while that of arm D was 40.1% (p=0.16), and the 5-year RFS rate of arm C was 40.0% while that of arm D was 28.1% (p=0.23). After all of consolidation, the lowest WBC count and the duration of neutropenia in arm C were significantly lower and longer than those in arm D. There was a higher rate of documented infection in arm C (20.9%) than in arm D (14.5%) (p&lt; 0.001). Conclusion: The conventional post remission therapeutic regimen established by JALSG consisting of 4 courses of consolidation was found to be as effective as the three courses of HDAC therapy. HDAC therapy produced a slightly positive effect on RFS in only the CBF leukemia group.

Postremission Treatment with Chemotherapy or Allogeneic Stem Cell Transplantation (Allo-SCT) in Adults with Acute Myeloid Leukemia (AML) -JALSG AML-97 Trial-.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2298-2298
Author(s):  
Hisashi Sakamaki ◽  
Shuichi Miyawaki ◽  
Shigeki Ohtake ◽  
Fumiharu Yagasaki ◽  
Kinuko Mitani ◽  
...  
Keyword(s):  
Survival Rate ◽  
Induction Therapy ◽  
Disease Free Survival ◽  
Risk Groups ◽  
Free Survival ◽  
Intention To Treat ◽  
Poor Risk ◽  
Short Course ◽  
Matched Sibling ◽  
Disease Free Survival Rate

Abstract The aim of this study was to investigate the efficacy of allo-SCT as a postremission treatment in patients (pts) with intermediate/poor risk AML in first CR. Previously untreated pts aged15–64 years were eligible. Pts received standard induction therapy consisting of cytarabine (100 mg/m2 d1–7) and idarubicin (12 mg/m2 d1- 3). If the pts did not achieve remission after the first induction therapy, the same induction therapy was given once more. The pts who achieved CR were randomized into an intensified short-course postremission regimen group (arm A) and conventional JALSG postremission regimen group (arm B). Pts were also categorized into good, intermediate or poor risk groups by risk factors based on previous JALSG AML trials using univariate and multivariate analyses. The intermediate or poor risk pts <=50 years old with an HLA-matched sibling were assigned to the allo-SCT group. The overall survival rate (OS) and the disease-free survival rate (DFS) of the pts of this group were compared with those of intermediate or poor risk pts <=50 years old without an HLA-matched donor (non-transplant group), to adhere to the intention-to-treat principle. Result: 809 pts were registered between December 1997 and July 2001. 789 pts were evaluable (median age: 45 years). 621 pts achieved CR (78.7%) after one or two courses of induction therapy. Os of 789 evaluable pts at five years and DFS of CR pts at five years were 40.8% and 35.5%, respectively. Of the 75 pts who were assigned to the allo-SCT group, 56 pts underwent allo-SCT (38 during CR1 and 18 after relapse). For the allo-SCT group, OS and DFS at 5 years were 51.8% and 43.1%, respectively. For the non-transplant group (n=95), OS and DSF at 5 years were 32.2% and 18.3%, respectively. DFS was significantly better in the allo-SCT group compared to the non-transplant group (p=0.005). OS was marginally better in the allo-SCT group (p=0.06). In conclusion, our study showed that allo-SCT for pts with intermediate or poor risk is effective as a postremission treatment in adult AML.

Prognosis of Acute Myeloid Leukemia with Translocation (8;21): A Survey of 142 Cases Investigated in the JALSG AML97 Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4511-4511
Author(s):  
Nahoko Hatsumi ◽  
Shuichi Miyawaki ◽  
Hisashi Sakamaki ◽  
Shigeki Ohtake ◽  
Fumiharu Yagaski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Maintenance Therapy ◽  
Induction Therapy ◽  
Risk Group ◽  
Standard Dose ◽  
Significant Prognostic Factor ◽  
Female Ratio ◽  
Poor Risk ◽  
Two Factors ◽  
Wbc Count

Abstract Background: Translocation (8;21) is one of the most common structural aberrations found in AMLand good response rates and a better DFS have been described in pts possessing it. Especially, the DFS rate may exceed 60–70% in younger pts given repetitive courses of HDAra-C. However, it was recently reported that a subtype of AML with t(8;21) showed a poor prognosis and this case also had the KIT mutation. As a result, we retrospectively analyzed the prognosis of AML pts with t(8;21) prospectively enrolled in the JALSG AML97 study. Patients and Methods: Between 1997 and 2001, JALSG AML97 enrolled 809 pts previously untreated for AML and pts with M3 were excluded. From the 789 eligible pts, we selected the subjects with t(8;21) for this study. Induction therapy consisted of cytarabine and idarubicin. All CR pts were randomized to receive either four courses of standard dose consolidation therapy without maintenance therapy or three courses of standard dose consolidation with 6 courses of maintenance therapy. HDAra-C was not administered in the JALSG AML97 study. Peripheral blood and bone marrow smears and karyotypes were reevaluated by the central review committees. Any patients who underwent SCT were censored at the date of SCT. The Kaplan-Meier method was used to estimate OS and DFS. For comparisons of OS or DFS, the log rank test was used. Result: Cytogenetic studies were performed in 783 patients (99.2%) and only 15 studies resulted in failure. One hundred forty-two (18.5%) of those pts showed t(8;21). The median age was 43 yrs (15–64). The male: female ratio was 95: 47. The distribution of FAB types was as follows: AMLM2, 130; M4, 6; M1, 5; and M5, 1. A total of 69 (48.6%) pts had a sole t(8;21), 46 (32.4%) had a loss of a sex chromosome, and 27 (19.0%) had other cytogenetic abnormalities. The CR rate was 90.0%. Thirty-two pts underwent two courses of induction therapy. The early death (< one month) rate was 1.4% (2/142). Only a high WBC count (>=10x109/L) was found to be a marginally significant prognostic factor (p=0.0517). The estimated OS rate at 5yrs was 53.6%, and the DFS of the CR pts was 41.2%. We found no relationship between OS or DFS and the following factors: age, gender, karyotypic abnormality, performance status, the percentage of MPO positive blasts, the presence or absence of Auer rods, the platelet count, the number of induction therapies for CR and the type of postremisson therapy. However, two factors, the WBC count and the percentage of blasts in bone marrow were found to be strongly predictive factors for the outcome. For the pts with a WBC count >=10x109/L, the DFS rate at 5yrs was 30.8%, while for the pts with less than 10x109/L, it was 48.8% (p=0.0215). For the pts with blast >=50% and less than 50%, the DFS rates at 5yrs were 32.2% and 56.7% (p=0.0087), respectively. According to these two factors, a poor risk group (N=30, 21.0%) was thus identified. They had a WBC count >=10x109/L and blast >=50%. The DFS rate at 5yrs was only 22.3 % in the poor risk group while that of the other pts was 48.9% (P=0.0003). Conclusion: This study confirmed that all AML pts with t(8;21) shows a high response rate and a good prognosis, thus indicating that this favorable AML group includes a poor risk group which can be identified based on the WBC count and the blast percent in the bone marrow.

Induction Therapy with “3+7” Chemotherapy Plus ATRA Followed by Consolidations with Three Courses of Idarubicin Alone and Maintenance Therapy with ATRA in Newly Diagnosed Acute Promyelocytic Leukemia (APL) Has An Excellent Leukemia-Free Survival but Minimal Toxicity in Low and Intermediate Risk Groups.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2072-2072
Author(s):  
Moon-Young Choi ◽  
Yeung-Chul Mun ◽  
Se Hoon Park ◽  
Eun Kyung Cho ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
Relapse Rate ◽  
Induction Therapy ◽  
Risk Group ◽  
Risk Groups ◽  
High Risk Group ◽  
Low Risk ◽  
Intermediate Risk ◽  
Newly Diagnosed

Abstract Abstract 2072 Poster Board II-49 Backgrounds Currently, there are many efforts to design risk-adapted strategies in newly diagnosed acute promyelocytic leukemia (APL) by modulating treatment intensity and those seem to be an efficient approach to minimize treatment-related morbidity and mortality (TRM) while maintain the potential in cure for each relapse-risk group. We had postulated that maintaining of Ara-C during induction therapy might have acceptable toxicities yet obtaining good CR in newly diagnosed APL, and idarubicin alone during consolidation periods might have excellent LFS and OS with low relapse rate. Patients and Methods Eighty six patients with newly diagnosed APL were enrolled in the “multicenter AML-2000 trial” after informed consents were obtained during the period of January 2000 to July 2007. For remission induction therapy, patients received oral ATRA (45mg/m2/d, maintained until CR) combined with idarubicin (12mg/m2/d, D1-D3) plus Ara-C (100mg/m2/d, D1-D7). After CR achievement, patients received 3 monthly consolidation courses consisting of idarubicin (12mg/m2/d, D1-D3) alone and maintenance therapy with ATRA (45mg/m2/d, D1-D15, every 2 month) alone had continued for 2 years. Total patients were divided into low-risk, intermediate-risk and high-risk groups according to a predictive model for relapse risk (Sanz score) based on pretreatment WBC and platelet count and the treatment outcomes were compared in the different risk groups. Results The median age of our cohort was 40 years old (range; 6-80) and median follow-up was 27 months (range; 1-90). The distribution of patients in the 3 risk groups was as follows ; 28 (32.6%) patients in low-risk, 40 (46.5%) in intermediate-risk and 18 (20.9%) in high-risk. Overall, CR was achieved in 78 (90.7%) of 86 patients. The CR rate according risk groups was 96.4% in low-risk, 87.5% in intermediate-risk, and 88.9% in high-risk group and there was no significant statistical difference among the different risk groups. During induction therapy, 48 (55.8%) patients experienced grade 3-4 treatment-related toxicity (TRT), mostly fever and infection (38.8% of all patients) and 6 (7.0%) patients died of treatment-related complications. During 3 consolidation courses, 25 (29.1%) of 78 patients experienced grade 3-4 TRT in 1st course, 27 (36.0%) of 75 patients in 2nd course, and 14 (28.0%) of 50 patients in 3rd course. Overall, 3 (3.5%) patients died of treatment-related complications in CR. The incidence of TRT and treatment-related mortality (TRM) during induction or consolidation therapy showed no significant statistical difference among the different risk groups. The relapse occurred in 6 (7.0%) patients; 2 cases in intermediate-risk and 4 cases in high-risk. However, none had relapsed in low risk group, 5 patients of relapsed patients relapsed during consolidation courses and only one patient, however, relapsed during maintenance therapy. The overall survival (OS) and leukemia-free survival (LFS) rate at 7 years in all of patients was 76.7% and 83.5%, respectively. The OS rate at 7 years was 92.9% in low-risk, 78.6% in intermediate-risk and 53.6% in high-risk group (P:0.04) and the LFS rate at 7 years was 96.4%, 83.4% and 62.2% respectively, showing the significant difference between 3 different risk groups (P:0.046). Conclusions This study indicates that our protocol composed of induction therapy with “3+7” chemotherapy plus ATRA followed by consolidations with three courses of idarubicin alone and maintenance therapy with ATRA alone yields a high CR rate and low relapse rate but minimal acceptable toxicities. Despite of adding Ara-C during induction therapy, we did not find much significant toxicities but having good CR rates, and despite of not adding any additional low/intermediate dose chemotherapies(ie, 6MP), we were able to observe significantly high relapse rate in low and intermediate risk group with excellent LFS and OS. Meanwhile, in high-risk group, the relapse rate was significantly higher than other risk groups and most of the relapses occurred in the middle of consolidation courses. This data suggests that our consolidation therapy composed of anthracycline alone may be not enough to minimize risk of relapse in high-risk group in contrast with the low and intermediate-risk groups. More intensive consolidation therapy combined with other effective, but get tolerable chemotherapies or hematopoietic stem cell transplantation in first CR or the combination of arsenic trioxide or others in front-line therapy should be considered in the patients with high-risk of relapse. Disclosures: No relevant conflicts of interest to declare.

A Prospective, Multicenter, Randomized, Trial of Bortezomib/Melphalan/Prednisone (VMP) Versus Bortezomib/Thalidomide/Prednisone (VTP) as Induction Therapy Followed by Maintenance Treatment with Bortezomib/Thalidomide (VT) Versus Bortezomib/Prednisone (VP) in Elderly Untreated Patients with Multiple Myeloma Older Than 65 Years.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3-3 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Albert Oriol ◽  
Joaquin Martinez ◽  
M Teresa Cibeira ◽  
Norma C. Gutiérrez ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Risk Group ◽  
High Risk Group ◽  
Cardiac Events ◽  
Advisory Committees ◽  
To Receive ◽  
Standard Risk

Abstract Abstract 3 In elderly pts with newly diagnosed MM, the VISTA trial has demonstrated that the combination of bortezomib plus melphalan – prednisone (VMP) is significantly superior to MP alone. However, it remains to be elucidated which agent is the optimal partner for bortezomib: an alkylating agent or an immunomodulatory drug. In order to answer this question, Spanish Myeloma Group activated a phase III trial comparing VMP versus VTP (T for thalidomide) as induction therapy. To evaluate if the treatment regimen could be further optimized by decreasing the toxicity while maintaining efficacy, the intensity of both schedules of induction was reduced as compared with the VISTA regimen but supplemented with maintenance therapy. Between April 2005 and October 2008, 260 pts were randomized to receive 6 cycles of VMP vs VTP as induction therapy followed by maintenance with VT vs VP for up to three yrs. In the VMP arm pts received bortezomib 1.3 mg/m2 twice weekly (days 1, 4, 8, 11; 22, 25, 29 and 32) for one 6-week cycle, followed by once weekly (days 1, 8, 15 and 22) for five 5-week cycles in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1–4 of each cycle. In the VTP arm pts received the same bortezomib and prednisone, but instead of melphalan they received thalidomide at a dose of 100 mg daily. Following the 6 cycles of induction, pts moved into maintenance that consisted in a conventional cycle of bortezomib, 1.3 mg/m2 twice weekly (days 1, 4, 8, 11) administered every three months in combination with either continuous thalidomide, 50 mg daily (VT) or prednisone, 50 mg on alternate days (VP). 253 pts are evaluable for response to induction; 125 were assigned to receive VMP and 128 to VTP. Regarding baseline characteristics, both arms were well balanced. Response rate to induction therapy was similar in both arms: ≥ PR in 81 and 79% of pts treated with VMP and VTP respectively, with a CR rate of 22% vs 27% (p=NS) and CR+nCR of 36% in both arms. Only two pts progressed under induction treatment in each arm. After a median follow-up of 22m (8-40), there weren't significant differences in terms of 2-y TTP (VMP 75% vs VTP 70%), PFS (VMP 71% vs VTP 61%) and OS (VMP 81% vs VTP 84%). 178 pts were randomized to maintenance and 143 are evaluable for efficacy. Overall, maintenance therapy was able to increase the CR rate from 25% (mean obtained after induction therapy) up to 42%, with no significant differences between VT and VP arms (46 and 38%). After a median duration of maintenance of 13 m there is a trend in favour of VT in terms of 1-y TTP (84% vs 71%; p=0.05), without differences in 1-y OS (92% for VT vs 89% for VP). 27 pts presented high-risk cytogenetic abnormalities (CA) ((4;14)t, (14;16)t, del[17p]); the CR rate was similar in this high-risk group as compared with standard risk group (26% vs 25% after induction and 42% after maintenance in both groups). There aren't differences between high-risk and standard-risk pts in the 2-y TTP (74% vs 73%) and 2-y OS (77% vs 81%) from inclusion; however, there is a trend to lower 1 y-TTP from the time to randomization to maintenance for the high-risk group compared to the standard-risk (68% vs 79%) without differences in 1 y-OS (90% vs 93%). Regarding toxicity, during the induction therapy, VMP resulted in higher incidence of ≥G3 neutropenia than VTP (37 vs 21%) and this translated into more ≥G3 infections (7 vs <1%); 8,5% of pts receiving VTP developed ≥G3 cardiac events (cardiac failure (5), atrial fibrillation (2), hypotension (2), heart attack (1) and AV blockage (1)). The incidence of ≥G3 PN was 5% in VMP and 9% in VTP (p=NS). During maintenance therapy, the most relevant ≥G3 toxicities included: cardiac events in 2 pts in VT (supraventricular arritmia (1) and heart attack (1)) vs 1 in VP (cardiac failure); G-I events in 4 pts in VT vs 1 in VP; finally, only one patient in VT arm died during the maintenance therapy due to sepsis. In summary the current results indicate that: 1. both modified induction schedules (VMP and VTP) are highly effective with similar ORR and CR rates, but a clear different toxicity profile (more neutropenia, but less cardiac toxiciety and PN with VMP); 2. maintenance therapy with either VT and VP markedly improve the quality of responses with a good safety profile; and finally 3. the combination of these induction and maintenance schedules seems to overcome the poor prognosis of high-risk CA in elderly MM patients. Disclosures: Mateos: Janssen Cilag: Honoraria, Speakers Bureau; Celgene corporation: Honoraria, Speakers Bureau. Off Label Use: VTP is not approved for the treatment of untreated MM patients. Cibeira:Jansen-Cilag: Honoraria; Celgene: Honoraria. Gutiérrez:Janssen Cilag: Honoraria; Celgene: Honoraria. García-Laraña:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palomera:Janssen-Cilag: Honoraria; Celgene: Honoraria. de Arriba:Janssen-Cilag: Honoraria; Celgene: Honoraria. San-Miguel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen–Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Prognostic Significance of FLT3 and NPM1 Mutations in Adults of Age 18–60 with De Novo Acute Myeloid Leukemia (AML) on SWOG S0106 Study: A Study by FHCRC and SWOG

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2520-2520 ◽  
Author(s):  
Era L. Pogosova-Agadjanyan ◽  
Kenneth J. Kopecky ◽  
Stephen Petersdorf ◽  
Harry Paul Erba ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Induction Therapy ◽  
De Novo ◽  
Risk Group ◽  
Risk Groups ◽  
Phase Iii ◽  
Intermediate Risk ◽  
Poor Risk ◽  
Flt3 Mutations ◽  
De Novo Aml ◽  
The Impact

Abstract Abstract 2520 INTRODUCTION. Age, cytogenetics, FLT3 and NPM1 mutations are the most significant prognostic factors (PFs) for adult AML treated with standard regimens, but the predictive significance of FLT3 and NPM1 with contemporary treatments is unknown. We examined the clinical significance of NPM1 and FLT3 mutations in adult de novo AML pts enrolled on SWOG study S0106. METHODS. S0106 was a randomized phase III clinical trial for pts of age 18–60 with de novo non-M3 AML, evaluating the effects of adding Gemtuzumab Ozogamicin (GO) to standard induction therapy (Cytosine Arabinoside and Daunomycin, AD), and of post-consolidation GO vs. no additional therapy (ASH, 2009, Abstract 790). Samples from 198 of the 600 eligible pts were evaluated. Analyses for nucleotide insertions in exon 12 of the NPM1 gene and internal tandem duplications (ITD) within exons 14–15 of FLT3 were performed using fragment analyses in diagnostic bone marrow (BM, N=190) and peripheral blood (PB, N=8) samples. Mutant/wild-type (WT) allelic ratios (AR) were computed for all mutations. Effects of mutations and other PFs on complete response (CR), resistant disease (RD), overall survival (OS) and relapse-free survival (RFS) were analyzed by logistic and Cox regression. P-values are 2-sided. RESULTS. Patient characteristics and outcomes are shown in Table 1. In univariate analyses, NPM1-Mut pts had significantly higher CR (81% vs. 58%, P=.0018) and lower RD (13% vs. 28%, P=.028) rates, better OS (64% vs. 47%, P=.045) and RFS (54% vs. 41%, P=.50). FLT3-ITD was not associated with CR or RD, but was associated with poorer OS (hazard ratio [HR] 2.28, P=.0011) and RFS (HR 2.74, P=.0009). FLT3-ITD length (range 18–366, median 46), FLT3 AR (range 0.18–8.2, median 0.98), and NPM1 AR (range 0.2–1.0, median 0.8) were not associated with CR, RD, or OS, but RFS tended to be lower with higher ITD length (P=.076). In multivariate analyses with other PFs, neither NPM1 nor FLT3 was associated with CR or RD rates, however the combined effects of FLT3 and NPM1 identified 3 mutation risk groups for OS (P=.0044, Fig 1A) and RFS (P=.0003, Fig 1B), since NPM1 did not significantly affect outcomes within the FLT3-ITD pts. These risk groups are FLT3-WT/NPM1-Mut (Good Risk: 3-yr OS 82%, RFS 69%), FLT3-WT/NPM1-WT (Intermediate Risk: OS 49%, RFS 43%), and FLT3-ITD (Poor Risk: OS 29%, RFS 14%). The impact of adding GO to induction therapy was examined within each risk group. In each risk group, CR rates were higher in the AD+GO arm, though not significantly so. Likewise, the RD rates were lower in the AD+GO arm, but this difference was significant only in the largest group: Intermediate Risk, FLT3-WT/NPM1-WT, 17% vs. 34% (P=.026). Treatment arm did not significantly affect OS and RFS in any mutation risk group. CONCLUSION. This study confirmed prognostic effects of FLT3 and NPM1 mutations in de novo AML pts treated with AD or AD+GO. Analyses of the joint impact of NPM1 and FLT3 mutations do not rule out the possibility that they act independently. With the small numbers of pts in the “good” and “poor” risk groups, there was no clear evidence that mutation status predicts clinical benefit from adding GO to therapy. We are evaluating additional samples and will update these results as data matures. Disclosures: No relevant conflicts of interest to declare.

Serum Albumin and Peripheral Blood Lymphocyte/Monocyte Ratio at Diagnosis May Provide Additional Prognostic Information in R-IPI Good Risk Diffuse Large-B-Cell Lymphoma Patients Treated with R-CHOP

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2658-2658 ◽  
Author(s):  
Branimir Spassov ◽  
Donka Vassileva ◽  
Georgi Michaylov ◽  
Gueorgui Balatzenko ◽  
Margarita Guenova
Keyword(s):  
Risk Group ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Risk Groups ◽  
Prognostic Information ◽  
Poor Risk ◽  
Risk Patients ◽  
Good Risk

Abstract Background and Aim: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Currently, the standard of care in DLBCL patients (pts) is rituximab-CHOP immunochemotherapy (R-CHOP) and the prognostic stratification is performed by the Revised International Prognostic Index (R-IPI), identifying 3 distinct prognostic groups with a very good, good and poor outcome. A lot of new prognostic markers have been introduced into the clinical practice to perform better pts' stratification. Particular prognostic relevance has been attributed to serum albumin (SA), β2-microglobulin (B2M), peripheral blood lymphocyte/ monocyte ratio (LMR), neutrophil/lymphocyte ratio (NLR) etc. However the data of these prognostic factors across the different R-IPI prognostic groups are limited. Therefore, we decided to access whether SA, B2M, LMR and NLR were predictors of overallsurvival (OS) across the different R-IPI groups of R-CHOP treated DLBCL pts. Patients and Methods: We retrospectively reviewed the clinical outcome of 281 R-CHOP treated DLBCL pts with median age 58 years and 51.8 % male. According to the R-IPI score, the pts in very good, good and poor risk were 24.2%, 54.8% and 21%, respectively. Laboratory levels of albumin, absolute lymphocyte, monocyte and neutrophil count were recorded, and LMR and NLR - calculated. Serum B2M levels were measured by radioimmunoassay. A receiver operating characteristic (ROC) curve analysis was used to illustrate in our data set the best cut off values of SA, B2M, LMR and NLR to predict OS by Kaplan-Meier method. Univariate analysis to evaluate differences between variables was performed by the log rank. A multivariate analysis was performed by Cox proportional-hazards models. Results: The estimated 5-year OS was 87.1%, 74% and 31% for R-IPI very good, good and poor-risk patients, respectively. The median values of SA, B2M, LMR and NLR were 40.7 g/L, 2.9 mg/L, 2.95 and 2.86, respectively. Our data showed that on univariate analysis inferior OS was associated with decreased SA (≤39.4 g/L; 95% confidence interval (CI) 0.70-0.82, p=<0.001), elevated B2M (>2.6 mg/L; 95% CI 0.68-0.80, p=<0.001), reduced LMR (≤2.16; 95% CI 0.71-0.81, p=<0.001) and increased NLR (>2.61; 95% CI 0.66-0.77, p=<0.001), presented as dichotomized variables. On multivariate analysis the independent prognostic significance was confirmed only for SA and LMR, with hazard ratios of 0.23 (95% CI 0.11-0.49, p<0.001) and 0.41 (95% CI 0.21-0.81, p=0.011), respectively. Based on the dichotomized SA and LMR values a SA/LMR prognostic index (PI) was created stratifying patients into 3 risk groups: very good (SA >39.4 g/L and LMR >2.16; n=75), good (SA ≤39.4 g/L or LMR ≤2.16; n=52) and poor-risk (SA ≤39.4 g/L and LMR ≤2.16; n=41) populations. The estimated 5-year OS was 88.7% for very good, 51.7% for good, and 8.8% for poor SA/LMR PI group (p<0.001). Median OS for poor-risk patients was 1.1 years (95% CI 1.03-1.72 years) and not reached for both the very good and good-risk groups. We sought to determine whether the SA/LMR PI may provide additional prognostic information within the R-IPI risk groups. Due to low number of deaths - 4.4% (3/68), no statistics could be calculated in very good R-IPI risk group. Within the R-IPI good risk patients SA/LMR PI allowed us to discriminate 3 subgroups, characterized by significant differences in 3-year and median OS (Figure 1): a SA/LMR PI poor risk subgroup (n=18) with 10.4% 3-years OS and 1.13 years (95% CI 0.82-1.44 years) median OS; a SA/LMR PI good risk subgroup (n=32) with 59.5% 3-years OS and median not reached; and a SA/LMR PI very good risk subgroup (n=50) with not reached median OS and 91.3% 3-years OS comparable to the OS in R-IPI very good patients (p=0.229). Only SA retained its independent prognostic significance in R-IPI poor risk group. Conclusion: SA and LMR are independent prognostic markers to predict survival in DLBCL pts. Adding these variables to prognostic models such as the R-IPI score might improve their predictive ability, providing particularly relevant information within the R-IPI good risk group. A subgroup of R-IPI good risk pts with a very good SA/LMR PI was identified, comparable to the R-IPI very good risk category in terms of OS. Figure 1. Overall survival of R-CHOP treated R-IPI good risk DLBCL patients according to SA and LMR at diagnosis Figure 1. Overall survival of R-CHOP treated R-IPI good risk DLBCL patients according to SA and LMR at diagnosis Disclosures No relevant conflicts of interest to declare.

scholarly journals Thymidylate Synthase Genotype-Directed Neoadjuvant Chemoradiation for Patients With Rectal Adenocarcinoma

2011 ◽  
Vol 29 (7) ◽  
pp. 875-883 ◽  
Author(s):  
Benjamin R. Tan ◽  
Fabienne Thomas ◽  
Robert J. Myerson ◽  
Barbara Zehnbauer ◽  
Kathryn Trinkaus ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Thymidylate Synthase ◽  
Randomized Study ◽  
Locally Advanced ◽  
Rectal Adenocarcinoma ◽  
Risk Groups ◽  
Advanced Rectal Cancer ◽  
Recurrence Rates ◽  
Poor Risk ◽  
Good Risk

Purpose Downstaging (DS) of rectal cancers is achieved in approximately 45% of patients with neoadjuvant fluorouracil (FU) -based chemoradiotherapy (CRT). Polymorphisms in the thymidylate synthase gene (TYMS) had previously defined two risk groups associated with disparate tumor DS rates (60% v 22%). We conducted a prospective single-institution phase II study using TYMS genotyping to direct neoadjuvant CRT for patients with rectal cancer. Patients and Methods Patients with T3/T4, N0-2, M0-1 rectal adenocarcinoma were evaluated for germline TYMS genotyping. Patients with TYMS *2/*2, *2/*3, or *2/*4 (good risk) were treated with standard chemoradiotherapy using infusional FU at 225 mg/m2/d. Patients with TYMS *3/*3 or *3/*4 (poor risk) were treated with FU/RT plus weekly intravenous irinotecan at 50 mg/m2. The primary end point was pathologic DS. Secondary end points included complete tumor response (ypT0), toxicity, recurrence rates, and overall survival. Results Overall, 135 patients were enrolled, of whom 27.4% (37 of 135) were considered poor risk. The prespecified statistical goals were achieved, with DS and ypT0 rates reaching 64.4% and 20% for good-risk and 64.5% and 42% for poor-risk patients, respectively. Conclusion To our knowledge, this is the first study to prospectively use TYMS genotyping to direct neoadjuvant CRT in patients with rectal cancer. High rates of DS and ypT0 were achieved among both risk groups when personalized treatment was based on TYMS genotype. These results are encouraging, and further evaluation of this genotype-based strategy using a randomized study design for locally advanced rectal cancer is warranted.

Sign in / Sign up

Export Citation Format

Share Document