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 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.

Chimerism and clinical outcomes of 110 recipients of unrelated donor bone marrow transplants who underwent conditioning with low-dose, single-exposure total body irradiation and cyclophosphamide

Blood ◽  
2005 ◽  
Vol 105 (8) ◽  
pp. 3035-3041 ◽  
Author(s):  
Mark Girgis ◽  
Chris Hallemeier ◽  
William Blum ◽  
Randy Brown ◽  
Hsiu-san Lin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Low Dose ◽  
Risk Group ◽  
Unrelated Donor ◽  
Single Exposure ◽  
Organ Toxicity ◽  
Poor Risk ◽  
Total Body ◽  
Good Risk

AbstractWe hypothesized that low-dose (550-cGy), single-exposure, high dose rate (30 cGy/min) total body irradiation (TBI) with cyclophosphamide as conditioning for HLA-compatible unrelated donor (URD) bone marrow transplantation (BMT) would result in donor chimerism (DC) with a low risk for serious organ toxicity and treatment-related mortality (TRM). Twenty-six patients with good risk diagnoses (acute leukemia in first complete remission [CR] and chronic-phase chronic myelogenous leukemia [CML]) and 84 with poor risk diagnoses underwent this regimen and URD BMT. Unsorted marrow nucleated cells were assessed for chimerism using VNTR probes. All DC occurred in 78 (86%) of 91 evaluable patients at 1 or more follow-up points. Graft failure occurred in 7 (7.7%) patients. Fatal organ toxicity occurred in only 2% of patients. TRM rates through 2 years of follow-up were 19% and 42% in those with good and poor risk diagnoses, respectively. Overall and disease-free survival rates in the good risk group were 47% and 40%, respectively, and in the poor risk group they were 25% and 21%, respectively, at a median follow-up for living patients of 850 days (range, 354-1588 days). This regimen resulted in 100% DC in most patients undergoing URD BMT with a relatively low risk for fatal organ toxicity and TRM.

scholarly journals Treatment of AML with Myelodysplasia Related Changes(AML-MRC) By Sequential Therapy of Azacitidine (AZA) and Intensive Chemotherapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5288-5288
Author(s):  
Taiichi Kyo ◽  
Kouhei Kyo ◽  
Kayo Toishikawa ◽  
Ryota Imanaka ◽  
Tetsuro Ochi ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Risk Group ◽  
Sequential Therapy ◽  
Small Sample ◽  
Remission Induction ◽  
High Dose ◽  
Intensive Chemotherapy ◽  
Secondary Aml ◽  
Poor Risk ◽  
Kaplan Meier

Abstract Background Azacitidine (AZA) and intensive chemotherapy (IC) are respectively effective for MDS-MRC to some extent. However, their median overall survivals (OS) are within 1 year in the previous reports. Aims The remission induction therapy is performed with AZA for patients with the bone marrow (BM) blast of <30% and with IC for patients with the BMblast of >30% to improve CR rate. The patients who reached CR with AZA or IC, maintenance therapy by sequential AZA and IC were performed to prolong the OS. Patients and methods Sixty-six patients,who were diagnosed as AML-MRC from December, 2011 to March, 2014 in our institution were included. AZA was administered by drip infusion at a dose of 75 mg/m2 for 5 days every 26 day. As the IC, IBMP (idarubicin,behenoyl-ara-C (enocitabine), mercaptopurine, and prednisolone) was administered for 10 days. The patients ,who reached CR with AZA or IBMP, then sequential therapy of AZA for 5 days and mini-IBMP for 5 days/or BAMP (A; acularubicin) for 6 days were treated by establishing the withdrawal period for 21 to 35 days. When possible, the high-dose ara-C (HDAC) for 5 days was included. Among the patients with the BMblast of >30%, 4 patients underwent allogeneic stem cell transplantation (allo-SCT). OS was evaluated using Kaplan-Meier estimates. Results Twenty four patients, whose BM blast<30% (20 - 29%, median23%) treated with AZA as the first treatment. Six secondary AML were included. Fourteen patients were male (58%), the median age was 75-years (51-90), the IPSS cytogenetic risk was good in 5 patients (21%), intermediate in 6 (25%) and poor in 13 (54%). The median cycle of AZA was 12 (3-29). By the IWG criteria, CR was achieved by 10 patients (42%), marrow CR by 2 (8%), PR by 1 (4%), SD by 5 (21%) and PD by 6 (25%). The median number of cycle by CR was 3 (2 -10). Forty two patients, whose BM blast>30% (32-95%, median 56%) treated with the remission induction therapy by IBMP. One secondary AML was included. Thirty patients were male (73%), the median age was 73-years (36-86), the cytogenetic risk was good in 8 patients (19%), intermediate in 14 (33%) and poor in 20 (48%). CR was achieved by 34 patients (81%), PR by 4 (10%) and failure by 4 (10%). The median follow up was 13 M in the BM blast<30% group and 12 M in the BM blast>30% group. The median OS in the BM blast<30% was 23 M.The median OS in the BM blast>30% group have not reached and 1year survival was 67%, 2 years survival 51% on the basis of Kaplan-Meier estimates. In both groups, there were 51 patients with CR+PR, 9 of which were treated with AZA only after CR, and 42 (82%) of which received sequential AZA treatment and IC. HDAC was included in chemotherapy by 24 patients (57%). Thirty eight patients, other than 4 patients who underwent Allo-SCT, have not reached the median OS, and 2 years survival was 55%. As concerns cytogenetic risk, the median OS in 33 patients with poor risk was 17 M, and 33 patients with good + intermediate risk have not reached the median OS, and 2years survival was 55%. Summary/Conclusion There was only one death of chemotherapy and AZA and IC for AML-MRC is very safe and good remission induction therapy. We have not described this time, but the measures for infection by such as fungi have contributed largely. In spite of the interim analysis of small sample size as 66 patients and short observation period, the median OS is approximately 2 years, so that the sequential therapy of AZA and IC is a feasible and useful therapy which realizes prolongation of OS. Particularly, the median OS of 17 M in the cytogenetic poor risk group can be mentioned as great progress. Because before introduction of AZA, when we treated more than 200 patients with AML-MRC only by almost similar chemotherapy, the median OS in the poor risk group was only 6M. Currently, we are following up 6 patients, who stopped the treatment,alive more than 6 M without any treatments. SinceAML-MRC is a disease in elderly people, it is important to devise therapeutic methods to prolong the untreatment period with CR in many patients in the future. Disclosures No relevant conflicts of interest to declare.

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.

High Dose Daunorubicin Improves Survival in AML up to Age 60, Across All Cytogenetic Risk Groups Including Patients with Unfavorable Cytogenetic Risk, and FLT3-ITD Mutant AML: Updated Analyses from Eastern Cooperative Oncology Trial E1900

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 373-373 ◽  
Author(s):  
Marlise R. Luskin ◽  
Ju-Whei Lee ◽  
Hugo F Fernandez ◽  
Hillard M. Lazarus ◽  
Jacob M. Rowe ◽  
...  
Keyword(s):  
Overall Survival ◽  
Induction Therapy ◽  
Risk Group ◽  
Multivariable Analysis ◽  
Risk Groups ◽  
Prognostic Impact ◽  
Npm1 Mutation ◽  
Mutation Status ◽  
The Impact

Abstract Background: Eastern Cooperative Oncology Group trial E1900 (E1900) showed that induction therapy with a high daily dose of daunorubicin (90 mg/m2) (DNR 90) improves survival in younger patients (pts) (<50 yrs) and intermediate (int) cytogenetic risk AML, but at 2 years of follow-up no benefit was seen in older pts (50-60 yrs), or in those with unfavorable cytogenetic risk or FLT3-ITD mutant AML (Fernandez et al. N Engl J Med 2009). Here we update results of E1900 with longer follow-up, focusing on the benefit of DNR 90 in cytogenetic and common molecular subgroups. Methods: Overall survival (OS) was measured from randomization for induction therapy to death from any cause (censored at last contact). Hazard ratios (HR) for death were computed using univariate and multivariable Cox proportional hazards models; multivariable Cox models were adjusted for sex, age, hemoglobin level, leukocyte count, platelet count, and cytogenetic profile. All conclusions regarding the impact of DNR 90, unless noted, are similar based on univariate and multivariable analysis. Results: Overall, 657 pts were enrolled with a median follow-up of 80.1 months. The HR for death in the DNR 90 group as compared with the standard-dose daunorubicin (45 mg/m2) (DNR 45) group was 0.74 (p=0.001). Pts <50 yrs benefited from DNR 90 (p = 0.002) while those >=50 yrs were not proven to benefit (p = 0.12). Pts with favorable (fav) and int. cytogenetic risk benefited from DNR 90 (p = 0.03 and p = 0.02, respectively). A benefit for pts with unfavorable cytogenetic risk was seen on multivariable analysis (p = 0.04). Impact of DNR 90 by mutation status: The 3 most common mutations were FLT3-ITD (24%), NPM1 (26%), and DNMT3A (24%). AML pts with any of these 3 mutations benefited from DNR 90 (p = 0.009, p = 0.002, and p = 0.02, respectively). FLT3-ITD pts who received DNR 90 had a 4-yr OS of 31%. Benefit was seen in pts age 50-60 with FLT3-ITD or NPM1 mutation (p = 0.02 and p = 0.04, respectively). No benefit of DNR 90 was seen in a small cohort of pts with MLL-PTD (p = 0.06). Benefit of DNR 90 in FLT3-ITD, NPM1, and DNMT3A mutant AML was confirmed in the int. cytogenetic risk group. Impact of DNR 90 on prognostic impact of NPM1: The presence of an NPM1 mutation conferred an improvement in OS in the DNR 90 group which was not seen in the DNR 45 group (p = 0.01 vs p = 0.3). This finding was confirmed in the int. cytogenetic risk group. Conclusion: With median follow-up of over 6 years on E1900, we confirm that DNR 90 improves outcome in pts with fav/int cytogenetic risk, DNMT3A or NPM1 mutant AML, or age < 50 (Patel et al. N Engl J Med 2012). Additionally, we now demonstrate that DNR 90 additionally benefits pts with FLT3-ITD AML, and pts with unfavorable cytogenetic risk, regardless of age. Moreover, we show that the favorable prognostic impact of the NPM1 mutation is only present when pts receive DNR 90. Given the benefit of DNR 90 across all cytogenetic risk groups as well as common molecularly defined subgroups of AML, DNR 90 should be the standard for all pts up to age 60 who are candidates for induction chemotherapy. Table HR for death by AML cohort. Subgroup N Univariate Model DNR 45 DNR 90 HR (DNR 90/DNR 45) & 95% CI Wald P All patients (n=657) Overall 330 327 0.74 (0.61, 0.89) 0.001 Age < 50 yrs³ 50 yrs 188 142 172 155 0.66 (0.50, 0.85) 0.81 (0.62, 1.06) 0.002 0.12 Cytogenetic Favorable Intermediate Unfavorable 38 232 59 51 212 63 0.51 (0.28, 0.93) 0.76 (0.61, 0.96) 0.79 (0.54, 1.16) 0.03 0.02 0.22 FLT3-ITD WT MUT 215 83 241 64 0.74 (0.59, 0.92) 0.61 (0.42, 0.89) 0.008 0.009 MLL-PTD WT MUT 290 16 296 15 0.70 (0.58, 0.86) 0.46 (0.21, 1.04) 0.0004 0.06 NPM1* WT MUT 180 65 192 65 0.70 (0.55, 0.89) 0.50 (0.32, 0.78) 0.003 0.002 DNMT3A WT MUT 177 61 194 58 0.66 (0.52, 0.85) 0.62 (0.41, 0.94) 0.001 0.02 * Statistically significant test of interaction (p<0.2) Figure 1A: Overall Survival by NPM1 Mutation Status and Treatment Arm Figure 1A:. Overall Survival by NPM1 Mutation Status and Treatment Arm Figure 1B: Overall Survival of FLT-ITD Mutant AML Patients by Treatment Arm Figure 1B:. Overall Survival of FLT-ITD Mutant AML Patients by Treatment Arm 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.

scholarly journals Standard-dose versus high-dose radiotherapy with concurrent chemotherapy in esophageal cancer: A prospective randomized study

2018 ◽  
Vol 07 (01) ◽  
pp. 27-30 ◽  
Author(s):  
Navin Nayan ◽  
M. Bhattacharyya ◽  
Vikas K. Jagtap ◽  
A. K. Kalita ◽  
R. Sunku ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Total Dose ◽  
Standard Dose ◽  
Randomized Study ◽  
Complete Response ◽  
Concurrent Chemotherapy ◽  
Prospective Randomized Study ◽  
High Dose ◽  
Large Sample Size

Abstract Objective: The objective of this study is comparision of local and distant control rates with high-dose versus standard-dose radiotherapy along with concurrent chemotherapy in esophageal cancer – a prospective randomized study. Materials and Methods: Histologically proven Stage I–III patients with carcinoma esophagus were randomized into two groups. One group has been treated with standard-dose radiotherapy, i.e., a total dose of 50.4 Gy (1.8 Gy/day, 28#, 5 days/week). The other group (study arm) has received high-dose radiotherapy, i.e. a total dose of 64.8 Gy (1.8 Gy/day, 36#, 5 days/week). Both groups have received 2 cycles of 3 weekly concurrent chemotherapy (cisplatin 75 mg/m[2] on day 1 and 5-fluorouracil 750 mg/m[2] continuous intravenous infusion over 24 h on day 1–4). Follow-up response evaluation was done by both endoscopy and computed tomography scan after 6–8 weeks and after 2 months thereafter. Results: Out of a total of 28 patients, 68% showed a complete response, 14% showed partial response, and 18% patients developed progressive disease at first and subsequent follow up (median follow-up of 21 months). Among the complete response patients, rates were higher in high-dose group compared to standard-dose radiotherapy group (71% vs. 64%, P = 0.38). Treatment-related toxicities were acceptable in both groups. Conclusion: High-dose radiotherapy with concurrent chemotherapy seems to be more effective with acceptable toxicity in our study. However, further follow-up and large sample size may be required to validate the current study conclusion.

scholarly journals Comparing the Efficacy and Safety of Induction Therapies for the Treatment of Patients with Proliferative Lupus Nephritis in South Africa

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Phelisa Sogayise ◽  
Udeme Ekrikpo ◽  
Ayanda Gcelu ◽  
Bianca Davidson ◽  
Nicola Wearne ◽  
...  
Keyword(s):  
South Africa ◽  
Lupus Nephritis ◽  
Induction Therapy ◽  
Randomized Study ◽  
Induction Treatment ◽  
Limited Data ◽  
Proliferative Lupus Nephritis ◽  
Significant Difference ◽  
Kidney Replacement Therapy

Background. Lupus nephritis (LN) can be complicated with requirement for kidney replacement therapy and death. Efficacy of induction therapies using mycophenolate mofetil (MMF) or intravenous cyclophosphamide (IVCYC) has been reported from studies, but there is limited data in Africans comparing both treatments in patients with proliferative LN. Methods. This was a retrospective study of patients with biopsy-proven proliferative LN diagnosed and treated with either MMF or IVCYC in a single centre in Cape Town, South Africa, over a 5-year period. The primary outcome was attaining complete remission after completion of induction therapy. Results. Of the 84 patients included, mean age was 29.6 ± 10.4 years and there was a female preponderance (88.1%). At baseline, there were significant differences in estimated glomerular filtration rate (eGFR) and presence of glomerular crescents between both groups ( p ≤ 0.05 ). After completion of induction therapy, there was no significant difference in remission status (76.0% versus 87.5%; p = 0.33 ) or relapse status (8.1% versus 10.3%; p = 0.22 ) for the IVCYC and MMF groups, respectively. Mortality rate for the IVCYC group was 5.5 per 10,000 person-days of follow-up compared to 1.5 per 10,000 person-days of follow-up for the MMF group ( p = 0.11 ), and there was no significant difference in infection-related adverse events between both groups. Estimated GFR at baseline was the only predictor of death (OR: 1.0 [0.9–1.0]; p = 0.001 ). Conclusion. This study shows similar outcomes following induction treatment with MMF or IVCYC in patients with biopsy-proven proliferative LN in South Africa. However, a prospective and randomized study is needed to adequately assess these outcomes.

Sign in / Sign up

Export Citation Format

Share Document