A New Prognostic Disease Specific Model To Predict Survival after Intensive Antileukemic Treatment for Young Patients with Poor-Risk MDS and AML: Results of the CRIANT and AML-10 Studies Conducted by the EORTC/GIMEMA/SAKK/HOVON/EBMT Groups.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2020-2020
Author(s):  
M. Oosterveld ◽  
S. Suciu ◽  
P. Muus ◽  
M. Delforge ◽  
A. Belhabri ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Prognostic Value ◽  
De Novo ◽  
Survival Rates ◽  
White Blood Count ◽  
Poor Risk ◽  
Prognostic Importance ◽  
De Novo Aml ◽  
Disease Specific

Abstract The use of intensive antileukemic treatment is less widely accepted in high-risk MDS pts compared to de novo AML, due to the reported inferior results. It is questionable whether the poorer outcome reflects an intrinsic property of the involved stem cell or a higher frequency of poor prognostic factors. The purpose of this analysis is to identify disease-specific prognostic factors for outcome of young (aged <56 years) MDS and AML pts. This analysis combines the data of 591 pts in the AML-10 study and 203 pts with high-risk MDS or secondary AML (sAML) in the CRIANT study. Both groups received identical remission-induction therapy (idarubicin, cytarabine and etoposide), followed by one consolidation course with intermediate dose of cytarabine and idarubicin (IDIA). In both studies post-consolidation therapy consisted of alloSCT if an HLA-identical sibling donor was available. The remaining pts received autoSCT (ASCT) in AML-10 or were randomized between ASCT and a 2nd consolidation course in CRIANT. The CR rate was 68% (AML-10) vs. 59% (CRIANT) (p=0.02). The 4-year survival rates were 35% vs. 33% (p=0.80). DFS at 4 years was 43% (AML-10) vs. 35% (CRIANT) (p=0.18). For overall survival (OS) in both studies, study was not of importance (HR=1.09, p=0.45), but the following variables showed independent prognostic value: cytogenetic risk group (the HR for poor vs intermediate risk was 1.68, 95% CI 1.24–2.27, p=0.0008), white blood count (WBC) ≥ 100 x 109/l (HR=2.02, 95% CI 1.53–2.68, p<0.0001), age 46–55 yrs (HR=1.39, 95% CI 1.16–1.67, p=0.0004) and performance status (PS) (HR=1.32, 95% CI 1.17–1.49, p <0.0001). For DFS, the following factors were of an independent prognostic importance: cytogenetics (p<0.0001), age 46–55 (HR=1.23, p=0.05), WBC >100 (HR=1.67, p=0.02) and donor availability (HR=0.77, p=0.04). Some variables were of prognostic value for OS in only one of the studies: in the CRIANT study number of cytopenias (3 vs 0–2) and AHD >6 months appeared of prognostic importance for OS, wherease FAB subtype M2/M4 and cytogenetics inv(16)/t(8;21) were prognostic in AML-10. Therefore a specific prognostic score for OS was established for each study, AML-10 (based on cytogenetics, PS, FAB, WBC and age) and CRIANT (based on cytogenetics, nr of cytopenias, age, AHD and WBC). The AML-10 study distinguished 5 groups with an estimated 4-year survival rate of 69%, 40%, 45%, 26% and 17%, resp. The prognostic value of this score has been validated on patients treated in the AML-10 study with mitoxantrone instead of idarubicin: the 4-year survival were 76%, 46%, 41%, 33% and 18%, resp. The CRIANT study distinguished 5 groups with a 4-year survival rates of 72%, 44%, 39%, 12% and 0%, resp. In conclusion: the prognostic scores identify a group of 26% AML and 42% MDS pts, with a 4-year survival less than 20%. Apparently current treatment modalities are unsatisfactory for these poor-risk pts and novel treatment strategies should be offered to these pts in the context of clinical trials. Our finding that different variables are of prognostic importance in MDS/sAML and de novo AML pts supports the hypothesis that these are intrinsically different disorders. The CRIANT-derived score is a valuable alternative for the IPSS in intensively treated high-risk MDS pts.

Cloretazine is an effective induction therapy in elderly patients (pts) with poor-risk de novo AML

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6512-6512 ◽  
Author(s):  
J. E. Karp ◽  
D. Rizzieri ◽  
N. Vey ◽  
G. Mufti ◽  
R. Geller ◽  
...  
Keyword(s):  
High Risk ◽  
De Novo ◽  
Performance Status ◽  
Single Agent ◽  
Early Death ◽  
Hematologic Malignancies ◽  
Hematologic Toxicity ◽  
Nccn Guidelines ◽  
Poor Risk ◽  
De Novo Aml

6512 Background: The incidence of AML increases with age with a median of 68 years in the US. The treatment of elderly pts (≥60 years) with AML poses challenges related to pt characteristics (age, performance status (PS), comorbidities) and adverse biological features. The majority of elderly pts are not considered for standard induction therapies that incorporate araC + anthracycline, and complete remission rates (CR+CRp), leukemia-free (LFS) and overall survival (OS) are significantly lower than in younger pts. As a result, NCCN guidelines recommend investigational therapy for this population. Cloretazine (C) is a novel DNA alkylating agent that selectively targets the O-6 position in guanine and has been developed in AML, based on phase I data demonstrating activity in refractory hematologic malignancies with acceptable toxicity. Methods: A multi-center trial in elderly pts with untreated poor-risk AML and high risk MDS was performed. Pts received C (600 mg/m2) as a single 30–60 minute infusion. Retreatment for induction was permitted for pts who showed improvement. A consolidation course of C at 400 mg/m2 was an option for pts who achieved a CR. Results: 105 pts were treated, of whom 45 pts (median age 72, range 60–84) had de novo AML, 44 had secondary AML, and 16 had high-risk MDS. Considering only de novo AML pts, pt characteristics are the following: M/F=25/20; favorable/intermediate/poor/NA cytogenetics =0/28(62%)/15(33%)/2; and PS 0/1/2=8(18%)/21(47%)/16(36%). The CR rate was 49% (N=22). CR was 50% for pts with intermediate cytogenetics and 53% for pts with poor risk cytogenetics. CR remained consistent despite increasing PS (PS0=50%, PS1=48%, PS2=50%). For responders, the median time for ANC≥1000 cells/dl was 31 days (range 27–44) and for plt≥20,000/dl was 22 days (range 14–29). There was no significant non-hematologic toxicity; the early death rate was 20%. Of the 22 pts who achieved CR, 8 remain alive and disease-free at a median of 337 days (range 137–546). At one year, the LFS is 27% and the OS is 22%. Conclusion: C is very well tolerated and has demonstrated impressive response results as a single agent in an elderly pt population with poor risk AML. [Table: see text]

Prognostic significance of surface marker expression on blasts of patients with de novo acute myeloblastic leukemia.

1990 ◽  
Vol 8 (3) ◽  
pp. 423-430 ◽  
Author(s):  
I Schwarzinger ◽  
P Valent ◽  
U Köller ◽  
C Marosi ◽  
B Schneider ◽  
...  
Keyword(s):  
Complete Remission ◽  
De Novo ◽  
Surface Membrane ◽  
Survival Rates ◽  
Prognostic Significance ◽  
Acute Myeloblastic Leukemia ◽  
Probability Of Survival ◽  
Surface Marker Expression ◽  
Median Period ◽  
De Novo Aml

The prognostic significance of the expression of surface membrane antigens on the blasts of 123 consecutive patients with de novo acute myeloblastic leukemia (AML) was evaluated. For this purpose, reactivity of monoclonal antibodies (mAbs) CLB-ERY3 (antiblood-group H antigen), VIM-D5 (CD15), WT1 (CD7), MY7 (CD13), MY9 (CD33), VID-1 (antihuman leukocyte antigen locus DR [anti-HLA DR]), VIM-2 (CDw65L), VIM-13 (CD14), 63D3 (CD14) and anti-TdT with leukemic blast cell populations was prospectively analyzed with respect to the rates of complete remission (CR), continuous complete remission (CCR), and survival. The overall rate of CR was 65%, the 6-year rates of overall CCR and survival were 23% and 13%, respectively (median period of patient observation, 30 months). Of all Abs tested, four (CLB-ERY3, MY7, anti-TdT, and VIM-D5) were found to be of prognostic value. Reactivity of CLB-ERY3, MY7, and anti-TdT was predictive for CR (CLB-ERY3+, 43% v CLB-ERY3-, 73%, P less than .02; MY7+, 59% v MY7-, 91%, P less than .003; TdT+, 28% v TdT-, 71%, P less than .001, respectively) and probability of survival (significantly lower survival rates: CLB-ERY3+, P less than .02; MY7+, P less than .03; and TdT+ cases, P less than .001, respectively). Reactivity of VIM-D5 was significantly associated with a higher probability of CCR (P less than .01). Our results confirm earlier reports on the prognostic significance of expression of CD13 and TdT in AML and indicate CLB-ERY3 (antiblood-group H antibody) and VIM-D5 (CD15) as further markers predictive for the clinical outcome in patients with de novo AML.

scholarly journals The preoperative prognostic value of the radiomics nomogram based on CT combined with machine learning in patients with intrahepatic cholangiocarcinoma

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Youyin Tang ◽  
Tao Zhang ◽  
Xianghong Zhou ◽  
Yunuo Zhao ◽  
Hanyue Xu ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Intrahepatic Cholangiocarcinoma ◽  
Prognostic Value ◽  
Survival Rates ◽  
Low Risk ◽  
Liver Carcinoma ◽  
Incidence And Mortality ◽  
Significant Difference ◽  
Prognostic Prediction

Abstract Background Intrahepatic cholangiocarcinoma is an aggressive liver carcinoma with increasing incidence and mortality. A good auxiliary prognostic prediction tool is desperately needed for the development of treatment strategies. The purpose of this study was to explore the prognostic value of the radiomics nomogram based on enhanced CT in intrahepatic cholangiocarcinoma. Methods In this retrospective study, 101 patients with pathological confirmation of intrahepatic cholangiocarcinoma were recruited. A radiomics nomogram was developed by radiomics score and independent clinical risk factors selecting from multivariate Cox regression. All patients were stratified as high risk and low risk by a nomogram. Model performance and clinical usefulness were assessed by calibration curve, ROC curve, and survival curve. Results A total of 101patients (mean age, 58.2 years old; range 36–79 years old) were included in the study. The 1-year, 3-year, and 5-year overall survival rates were 49.5%, 26.6%, and 14.4%, respectively, with a median survival time of 12.2 months in the whole set. The least absolute shrinkage and selection operator (LASSO) method selected 3 features. Multivariate Cox analysis found three independent prognostic factors. The radiomics nomogram showed a significant prognosis value with overall survival. There was a significant difference in the 1-year and 3-year survival rates of stratified high-risk and low-risk patients in the whole set (30.4% vs. 56.4% and 13.0% vs. 30.6%, respectively, p = 0.018). Conclusions This radiomics nomogram has potential application value in the preoperative prognostic prediction of intrahepatic cholangiocarcinoma and may facilitate in clinical decision-making.

Reduced Intensity Conditioned Allogeneic Stem Cell Transplantation Is as Effective in Poor Risk as Standard Risk Acute Myeloid Leukaemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2901-2901
Author(s):  
Wendy Ingram ◽  
Ziyi Lim ◽  
Antonio Pagliuca ◽  
Stephen Devereux ◽  
Aloysius Ho ◽  
...  
Keyword(s):  
Stem Cell ◽  
De Novo ◽  
Chronic Gvhd ◽  
Mixed Chimerism ◽  
Poor Risk ◽  
Grade Ii ◽  
De Novo Aml ◽  
Standard Risk ◽  
Good Risk ◽  
Reduced Intensity

Abstract Poor risk cytogenetics and multi-lineage dysplasia are commonly found in older patients with acute myeloid leukaemia (AML) and despite intensive chemotherapy prognosis remains grim. We compared the outcome of standard risk to poor risk AML (both according to cytogenetic risk group and presence of underlying dysplasia) following reduced intensity conditioned (RIC) allogeneic haematopoietic stem cell transplantation (allo-HSCT) in 65 patients (32 males, 33 females) with a median age of 53years (range 22–65years). Conditioning regimen incorporated fludarabine(150mg), Alemtuzumab(100mg) and busulphan(8mg–16mg). 35/65 had a background of multi-lineage dysplasia (MLD-AML), 30/65 de-novo AML. According to cytogenetics, 48 were standard risk, 15 poor risk and 2 good risk (both good risk cases were in second remission). Median number of chemotherapy regimens administered prior to RIC HSCT was 3 (range 1–8), with 33/65 receiving FLAG chemotherapy and 2/65 a previous autologous HSCT. 57/65 were in complete remission (CR) at time of HSCT, 6/65 partial remission (PR) and 2/65 refractory disease. 51/65 were in first remission, 14/65 second remission. Sibling donor was used in 25/65, volunteer unrelated donor (VUD) in 40/65 (1 antigen mismatch 13/40, 2 antigen mismatch 3/40). Bone marrow (BM) was administered to 17/65 and peripheral blood stem cell (PBSC) to 48/65. Median follow-up was 389days (range 36–1731) for all patients and for those alive 633days (range 71–1731). Failure to engraft occurred in 1 patient and late graft rejection in 3 patients. The day+100 transplant related mortality for all patients was 11%. The overall survival (OS) at 1year for siblings versus VUD was 77% v 58% (p=0.46) and the disease free survival (DFS) 50% versus 53% (p=0.98). The OS for de-novo AML versus TLD-AML at 1year 73% versus 59% (p=0.34) and DFS 59% versus 46% (p=0.06). Comparison of the OS at 1year for the standard versus poor risk cytogenetic groups was 63% versus 72% (p=0.33), and DFS 50% versus 57% (p=0.68) respectively. 15/65 developed acute GvHD grade II–III. The cumulative incidence of chronic GvHD was 19% in those surviving after day+100. 46% of patients achieved full donor engraftment on lineage specific chimerism at day+100. Incremental donor leukocyte infusions (DLI) were administered to 25 patients. 16/25 received DLI for mixed chimerism, 9/16 reverted to 100% donor, 4/16 continued with stable mixed chimerism and 3/16 developed relapsed disease. 9/25 received DLI for disease relapse resulting in complete remission in 3/9 cases. 10/23 patients administered DLI developed GvHD grade II–III. In summary, RIC allo-HSCT incorporating Alemtuzumab was equally well tolerated in both sibling and VUD allografts, with a low incidence of acute and chronic GvHD. The results show favourable outcome in a poor risk cohort of patients with AML, with comparable OS compared to standard risk/de-novo AML. DFS was not affected by cytogenetic risk however comparison of de-novo AML to MLD-AML did show a trend (p=0.06) in favour of de-novo AML.

Bortezomib+Chemotherapy Based Salvage Combinations in Refractory AML, Preliminary Results

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4000-4000
Author(s):  
Miklos Udvardy ◽  
Attila Kiss ◽  
Bela Telek ◽  
Robert Szasz ◽  
Peter Batar ◽  
...  
Keyword(s):  
Cell Lines ◽  
De Novo ◽  
Case Reports ◽  
Fatal Outcome ◽  
Normal Karyotype ◽  
Secondary Aml ◽  
Poor Risk ◽  
Group 2 ◽  
De Novo Aml ◽  
Group 1

Abstract Bortezomib (Velcade) proved to be the standard element of refractory myeloma 2nd and 3rd line treatment, while many studies are suggesting excellent results in 1st line. Proteasome inhibition, the block of angiogenesis, modification of the NF-kappa-B system seems to be a challenging target in other malignant diseases, including refractory acute myeloid leukemia (AML), as well. In vitro data clearly support, that bortezomib exerts antiproliferative and pro-apoptotic effects in different AML cell-lines, along with human AML cell cultures, and moreover bortezomib was able to restore, or at least improve anthracyclin and possibly ARA-C sensitivity in different cell-lines (including AML). More recently, a Phase I trial showed bortezomib monotherapy efficient (only in few percents) in childhood refractory acute leukemia. Some case reports were shown at ASH 2007. We have tried bortezomib containing first or second line combinations in 27 (14 female, 13 male, mean age 57.6 years) patients with refractory or poor risk AML, in a small retrospective survey. The combinations were as follows: HAM or Flag-Ida, combined with bortezomib 1,3 mg pro sqm, day O and seven). The following groups were considered as refractory or poor risk AML: De novo AML, 2nd line: No response/remission to first line standard treatment (“3+7”), n=2 (Velcade- Flag-Ida treatment) De novo AML 1st line: bilineal or biphenotypic (flow-cytometry) n=2 (Velcade-Flag- Ida treatment) De novo AML with complex (numerical or more than 3 abnormalities) karyotype or normal karyotype with flt-3 TKD mutation, n=9, 1st line (Velcade-Flag-Ida n=6, Velcade- HAM protocol, n=3) Secondary AML or AML with evidence of previous more than 6 mo duration high grade MDS, n=14, 1st line: (Velcade-Flag-Ida n=9, Velcade-HAM n=5) RESULTS: Complete remission (CR) 12/27, partial remission (PR) 9/27, no remission 5/27, progression during treatment: 1/27.Best responses were seen in de novo cases. CR had been achieved in all patients of group 1 (two standard risk patients not responding to 3+7 protocol), and group 2 (biphenotypic, bilineal). The CR rate was quite appreciable in group 3, i.e. 6/9 (complex karyotype or normal karyotype with FLt-3 mutation – the response rate was excellent with flt-3 mutated cases). In group 4. (MDS, secondary AML) the results were less impressive. There were no major differences according to protocol (Flag-Ida or HAM) Allogeneous stem cell transplantation could have been performed in 1st CR in two patients (one from group 1. and another from group 2.). One of them died due to relapse, the other one is in CR since then. The combinations seem to be relatively safe. Induction related death rate was low (1 elderly patient acute thrombocytopenic bleeding with refractory MDS-AML). 5 other patients had severe neutropenic sepsis (2 with fatal outcome). Pulmonary syndrome, which may follow Velcade+ARA-C had not been documented. Other adverse events did not differ from the pattern observed with standard induction therapies.

A Retrospective Comparison of Matched Elderly Patients Treated with Laromustine (Cloretazine®) or Best Supportive Care or Low Dose Ara-C in the LRF AML14 Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2960-2960 ◽  
Author(s):  
Robert Hills ◽  
Susan O’Brien ◽  
Verena Karsten ◽  
Alan K. Burnett ◽  
Francis Giles
Keyword(s):  
High Risk ◽  
Supportive Care ◽  
Low Dose ◽  
De Novo ◽  
Performance Status ◽  
Single Agent ◽  
Best Supportive Care ◽  
Cell Counts ◽  
Retrospective Comparison ◽  
De Novo Aml

Abstract Background : A substantial proportion of older patients with AML are considered unlikely to benefit from an intensive treatment approach. They often receive either best supportive care (BSC), low dose treatment such as Low Dose Ara-C (LDAC), or clinical trials of novel agents. In one of the few randomised studies where patients were prospectively considered likely to be unfit for intensive therapy, LDAC was superior to BSC with 18% v 1% patients achieving CR. No patients with high risk cytogenetics (Grimwade 1998), achieved CR (Burnett 2007). Laromustine (Cloretazine®) is a novel sulfonylhydrazine alkylating agent which preferentially targets the O6 position of guanine resulting in DNA cross-links. Laromustine has previously shown clinical activity in patients with de novo AML and high risk MDS (Giles et al. JCO 2007). A confirmatory phase II study of single agent laromustine was conducted in previously untreated patients ≥ 60 years old with de novo AML, prospectively considered likely to be unfit for intensive chemotherapy. Patients had at least one poor risk factor, defined by age ≥70, performance status 2, unfavorable cytogenetics, or cardiac, pulmonary or hepatic dysfunction. Eighty-five patients received induction therapy with 600 mg/m2 laromustine. Second induction cycles were administered in 14 patients after partial response or hematologic improvement. Eighteen patients received at least one consolidation cycle of cytarabine 400 mg/m2/day CIV for 5 days. Methods: A retrospective non-randomised comparison was performed between the 85 patients treated with laromustine, and 121 patients satisfying the same entry criteria, treated in the AML 14 trial with either BSC or LDAC. Outcomes were compared using Mantel-Haenszel and logrank methods for unadjusted comparisons, and regression methods for adjusted analyses. Results : Patients in AML14 were slightly older than those treated with laromustine (median age 75 v 73), and tended to have higher white blood cell counts; by contrast, there were significantly fewer cardiac or respiratory comorbidities reported in the AML14 population. Other important risk factors such as performance status and cytogenetics were similar between the groups. Responses overall (CR/CRp) were seen in 33% (28/85) of patients treated with laromustine, compared with 2% (1/60) and 23% (14/61) in patients treated with BSC and LDAC (p&lt;0.0001, p=0.2, respectively). In particular, 1 patient with −5/del(5q), and 3 patients with −7/del(7q) cytogenetics experienced a CR with laromustine; patients in AML 14 with adverse cytogenetics saw no remissions. Survival was significantly improved in the laromustine group compared to BSC (1 year survival 20% v 8%, unadjusted HR 0.58 [0.40–0.84] p=0.004), and roughly comparable to that of LDAC (1 year survival 20% v 25%, HR 1.04 [0.73–1.49] p=0.8). Analyses adjusted for differences in baseline demographics, and using propensity scores gave consistent figures. Conclusions: Retrospective comparison of unrandomised data has significant limitations even though care has been taken to match for factors known to be predictive for survival. Laromustine was able to achieve a higher CR rate than LDAC or BSC, and produced remissions in groups where no remissions have previously been seen with LDAC or BSC. Laromustine gave significantly better survival than BSC, and demonstrated similar survival to LDAC.

Epigenetic Therapy with 5-Azacitidine, Valproic Acid, and ATRA in Patients with High-Risk AML or MDS: Results of the French VIVEDEP Phase II Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 763-763 ◽  
Author(s):  
Emmanuel Raffoux ◽  
Adrienne de Labarthe ◽  
Audrey Cras ◽  
Christian Recher ◽  
Pascal Turlure ◽  
...  
Keyword(s):  
Valproic Acid ◽  
High Risk ◽  
Response Rate ◽  
De Novo ◽  
Expression Profiles ◽  
Intensive Therapy ◽  
Epigenetic Therapy ◽  
Median Response ◽  
Secondary Aml ◽  
De Novo Aml

Abstract Introduction: Promising results have been reported last year with a combination of 5-azacitidine (AZA), valproic acid (VPA), and all-trans retinoic acid (ATRA) in patients with AML/MDS treated at MDACC in a Phase I/II study (Soriano et al. Blood 2007). We report here on a similar study conducted in 9 centers between 7/2006 and 8/2007. Methods: Patients with high-risk AML (AML in patients aged 70y+ unsuitable for intensive chemotherapy or early relapsing/refractory AML) or MDS (int-2/high IPSS without possibility of allogeneic SCT) were eligible. Treatment consisted of 6 cycles with AZA 75 mg/m2/d SC (d1-7), VPA 35 to 50 mg/kg/d PO (d1-7), and ATRA 45 mg/m2/d PO (d8-28). Cycle 1 was initiated at the hospital but cycles 2–6 were planned monthly in out-patients. Response was assessed after cycle 1, 3, and 6 (IWG AML criteria). VPA was started at 35 mg/kg/d and then increased at 50 mg/kg/d if well tolerated. Sixty-three patients were enrolled and 51 are evaluable. Results: Patients characteristics were: M/F, 27/24; median age, 73y (50–87); median WBC, 2.3 × 109/L; PS 0-1/2, 45/6 patients; median follow-up, 13 months. Forty-two patients had AML (31 de novo, 9 therapy-related, 2 post-MDS/MPD) and 9 had MDS. Only 6 patients had received prior intensive therapy. Cytogenetics was available in 46 patients with high-risk features in 26 of them (complex, -7). Twenty-nine patients stopped the treatment after 1–5 cycles: 13 due to disease progression, 11 due to toxic events (mostly infection), and 5 due to physician decision despite stable disease. VPA was associated with notable CNS toxicity at 50 mg/kg, but not at the 35 mg/kg dose level. ATRA-related symptoms (headaches, mucosal dryness) were noted. In the 22 patients who received the 6 cycles, re-hospitalization rate was 27, 41, 23, 18, 20, and 14% after cycle 1 to 6, respectively. Among these patients, 11 reached CR (6 after cycle 3) and 5 reached PR (4 after cycle 3). The CR/PR rate was thus 31%, reaching 35% in the 46 patients who did not interrupt the treatment in the absence of progression or toxic event. Table 1 gives CR/PR rate according to various patient subsets. In patients with de novo AML, CR/PR rate was 45%. Advanced age and high-risk cytogenetics did not influence the response rate. In multivariate analysis, cytogenetics but not age remained, however, a poor risk factor for OS (PS, WBC, and MDS/secondary AML being other significant factors). Ten of the 16 responders relapsed after a median response duration of 10.6 months. Median OS was 12 months (not reached in the responders). Results of sequential DNA methylation and gene expression profiles monitoring (#17 patients) will be presented. Conclusion: This study confirms that epigenetic therapy with AZA, VPA, and ATRA yields a 35% response rate in patients with high-risk AML/MDS. Although randomized studies are needed (AZA ± HDAC inhibitors), this combined approach appears to be a good option to treat older patients with low WBC and favorable PS, whatever their cytogenetics. Maintenance options should be investigated in responding patients. Table 1 CR/PR No CR/PR P values Age < 75y 7 (27%) 19 Age ≥ 75y 9 (45%) 11 0.23 Standard-risk cytogenetics 8 (44%) 10 High-risk cytogenetics 7 (29%) 17 0.35 De novo AML 13 (45%) 16 MDS/secondary AML 3 (18%) 14 0.11 PS 0-1 16 (40%) 24 PS 2 0 (0%) 6 0.08 WBC < 5.109/L 15 (43%) 20 WBC ≥ 5.109/L 1 (9%) 10 0.07

Is Longer MDS Duration Prior to Non-Intensive AML Treatment a Favorable Prognostic Factor? Results of the 00331 Multicenter Phase II Decitabine Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2185-2185
Author(s):  
Michael Lubbert ◽  
Claudia Schmoor ◽  
Björn Rüter ◽  
Mathias Schmid ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Research Funding ◽  
Disease Duration ◽  
Cox Regression ◽  
De Novo ◽  
Performance Status ◽  
Treatment Modalities ◽  
White Blood Count ◽  
Large Trial ◽  
Comorbidity Index

Abstract Abstract 2185 Background: Secondary (s)AML from MDS is more frequent in older AML patients, and associated with an overall worse outcome with standard chemotherapy than de novo AML, particularly after MDS of longer duration (1). The azanucleoside hypomethylating agents 5-azacytidine (Vidaza) and 5-aza-2′-deoxycytidine (Decitabine, DAC) are active in MDS and, as recently shown, also AML. Compared to other predictors of response to these drugs, MDS duration prior to treatment thus far has received only limited attention, with two recent publications reporting conflicting results (2, 3). To independently validate our finding that shorter duration of MDS prior to DAC treatment may be a novel predictor of poor outcome (2, 4), we now applied this parameter to a large trial of low-dose DAC in AML pts (aged >60 years and judged ineligible for standard induction chemotherapy), about half of them with sAML from MDS with variable disease duration. Patients and Methods: Comparisons of response rate (RR, i.e. CR or PR) and overall survival (OS) from start of treatment according to MDS duration (pre-specified categorization according to quartiles) were performed post-hoc in 109 patients (pts) with previously untreated sAML (median age 72 years) treated with DAC (given over 72 hours, every 6 weeks, for up to 4 courses, followed by “maintenance” with 3 daily 1-hour infusions of DAC 20 mg/m2 every 4–6-weeks). Median WBC prior to treatment was 5.200/μl, median serum LDH 279U/l, 31.2% of pts had adverse cytogenetics, 82.6% had a performance status > 1, and 80.7% had a comorbidity index (HCT-CI) >=1. Comparisons by logistic regression and Cox regression (univariate and multivariate, adjusted for other prognostic factors showing an effect in this population of sAML pts) were performed. Results: Of the 227 AML patients treated within the 00331 trial, 109 (48%) had prior MDS with known MDS duration, with a median duration of 8 (25% quartile 3, 75% quartile 25, range 1–101) mths. The overall RR in these pts was 26/109 (24%), the overall 1 yr OS rate was 31% (94 deaths). A comparison of RR according to MDS duration revealed a trend to an increase in RR with longer duration of MDS [<3: 4/25 (16%), 3–8: 5/29 (17%), 8–25: 7/27 (26%), >=25 mths: 10/28 (36%), test for heterogeneity p=0.29, test for trend p=0.06]. Similarly, when OS from start of DAC was analyzed according to this parameter, for pts with previous MDS of longer duration there was a trend to better outcome [<3: 1 yr OS rate 23%, 3–8: 28%, 8–25: 26%, >=25 mths: 46%, test for heterogeneity p=0.17, test for trend p=0.16]. When these analyses were adjusted for other prognostic factors showing an effect in this population of sAML pts (comorbidity index, sLDH with respect to RR, and performance status, comorbidity index, and white blood count with respect to OS), the results were similar (effect of MDS duration with respect to RR: test for heterogeneity p=0.35, test for trend p=0.06, and effect of MDS duration with respect to OS: test for heterogeneity p=0.04, test for trend p=0.11). Conclusion: In this large cohort of uniformly treated pts with sAML, MDS of longer duration appeared to be associated with a better outcome, even after adjusting for important other prognostic factors. These results are supported by a similar analysis of MDS pts randomized in the 06011 EORTC intergroup trial (which compares DAC to Best Supportive Care), where MDS patients with longer (>=3 mths) disease duration prior to treatment also had better outcome (4). They warrant application of this discriminator in the evaluation also of other non-intensive AML treatment modalities. References 1. Estey et al., Blood 90:2969-77, 1997 2. Wijermans et al., Ann. Hematol. 84 Suppl 1:9-14, 2005 3. Kantarjian et al., Cancer 109:265-73, 2007 4. Lübbert, Suciu et al., Abstract submitted, ASH 2010 Disclosures: Off Label Use: decitabine is FDA-approved for treatment of MDS and AML with up to 30% blasts. In the present study, patients with AML and higher blast percentage were treated. Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Döhner: Pfizer: Research Funding.

Twice Daily Fludarabine and Cytarabine Combination (BID-FA) Is Effective in Pts with De Novo Acute Myeloid Leukemia (AML), Relapsed/Refractory (R/R) AML, High-Risk Myelodysplastic Syndromes (MDS), and Blast Phase Chronic Myeloid Leukemia (CML-BP)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4939-4939
Author(s):  
Hady Ghanem ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
High Dose ◽  
Platelet Recovery ◽  
De Novo Aml ◽  
To Receive

Abstract Abstract 4939 Background: High dose cytarabine containing regimens are still considered standard options for pts (pts) with AML relapsing after a first complete remission (CR1) lasting more than 12 months. No standard options exist for pts relapsing after shorter remission duration or with primary refractory disease. We conducted a phase II study assessing the efficacy and safety of twice daily fludarabine and cytarabine (BID FA) in pts with R/R AML, high-risk MDS and CML-BP. Pts and Methods: 147 pts with de Novo AML, R/R AML, intermediate-2 and high-risk MDS, and CML-BP, with a performance status of 3 or less, as well as normal organ functions were eligible. Pts were scheduled to receive fludarabine 15 mg/m2 intravenously (IV) q12 hrs on days 1 to 5 as well as cytarabine at the dose of 0. 5 g/m2IV over 2 hrs q12 hrs on days 1 to 5. GO was administered at the dose of 3 mg/m2 IV on day 1 for the first 70 pts enrolled. Courses were repeated every 4 to 6 weeks for a maximum of 7 courses. Pts with CML-BP were allowed to receive concomitant tyrosine kinase inhibitors. Four pts with AML who had FLT3 mutation were allowed to receive BID FA and sorafenib. Results: A total of 147 pts were treated. The median age was 63 years (range, 20 to 85 years). 131 (89%) had AML, 7 (5%) had high-risk MDS, and 9 (6%) had CML-BP. Of the 131 AML pts, 17 (12%) were de novo AML, 50 (38%) were in first salvage: first CR duration (CRD1) of less than 12 months in 39 pts (29%), and more than 12 months in 11 (9%) pts. Cytogenetic studies showed diploid karyotype in 52 pts (35%) and unfavorable chromosomal abnormalities involving chromosomes 5 and 7 in 30 pts (20%). 128 pts (87%) had a PS ≥1. Sixty-four pts (44%) had failed previous intensive chemotherapy, while 21 (14%) had failed targeted and hypomethylating agents. Forty-three (29%) pts had failed both. Overall, 34 pts (23%) achieved a complete remission (CR) and 8 (6%) achieved a CR without platelet recovery (CRp), for an overall response rate (ORR) of 29%. 6 pts received reinduction therapy, of which 3 achieved a CR. The CR rates for AML pts with frontline therapy, with relapsed AML with CRD1 ≥12 months, relapsed AML with CRD1< 12 months, and R/R AML beyond first salvage were 47%, 64%, 21%, and 14%, respectively. In CML-BP, 2 (22%) of 9 pts had objective responses (1 CR, 1 CRp). 1 of the 7 pts with MDS responded (Table 1). The treatment was well tolerated with only 7 of the pts experiencing grade 3 and 4 toxicities including mainly skin rash and increased liver enzymes. The overall 4-week mortality rate was 13%. With a median follow-up of 24 months (range, 10 to 33), 20 patients (14%) remained alive. The overall 6-month survival rate was 44%. The median overall survival (OS) and event free survival (EFS) were 5 months (range, 0. 1 to 33) and 1 month (range, 0. 1 to 33), respectively. The median CR/CRp duration was 12 months. Median OS for pts with de novo AML, a CRD1≥12 months, pts with CRD1<12 months and pts receiving second salvage and beyond were 8, 12, 5, and 4 months respectively. Median EFS for pts with de novo AML, a CRD1≥12 months, pts with CRD1<12 months and pts receiving second salvage and beyond were 3, 7, 1 and 1 month respectively. Conclusion: BID FA appears to be active with an ORR of 29% in a heavily pre-treated population. This combination is safe with a low rate of 4-week-mortality of 13%. Disclosures: No relevant conflicts of interest to declare.

Sequential Intensified Conditioning Regimen Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with High-Risk AML in Complete Remission: A Survey from the ALWP of the EBMT

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3105-3105
Author(s):  
Florent Malard ◽  
Myriam Labopin ◽  
Gernot Stuhler ◽  
Johanna Tischer ◽  
Joerg Thomas Bittenbring ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Research Funding ◽  
Antithymocyte Globulin ◽  
De Novo ◽  
Conditioning Regimen ◽  
Secondary Aml ◽  
Off Label ◽  
Advisory Boards ◽  
De Novo Aml

Abstract Introduction. Allogeneic hematopoietic cell transplant (HCT) is an established treatment modality that is potentially curative for many patients with acute myeloid leukemia (AML). The development of reduced intensity conditioning (RIC) allows performing HCT in elderly and/or in heavily pretreated patients and in those with comorbidities precluding the use of standard myeloablative conditioning. Post-transplant relapse remains a challenge after RIC, particularly in patients with adverse prognosis factors.The so-called "sequential" transplant approach (e.g. FLAMSA regimen combining both intensive chemotherapy and RIC HCT within the same procedure) initially developed in patients with refractory AML, could be a promising strategy to improve disease control and decrease the risk of relapse in high-risk AML patients in complete remission (CR). Patients and methods. In the current study we analyzed transplantation outcomes in a cohort of 411 adults AML patients in CR at time of transplant, treated between 2002 and 2013. Patients received a "sequential" conditioning regimen based on Fludarabine 30 mg/m2/d, high-dose aracytine 1-2 g/m2/d, amsacrine 100 mg/m2/d for 5 days and after a 3 days rest, total body irradiation (TBI) 4Gy, cyclophosphamide 50-120 mg/kg, and antithymocyte globulin (ATG) for 2 to 3 days (TBI group, n=269 [65%]). In 142 (35%) patients, TBI was substituted by IV Busulfan 3.2 mg/kg/d for 2 days, or orally equivalent dose (Bu group). 323 patients (79%) had de-novo AML and 88 (21%) had a secondary AML (with prior myelodysplastic syndrome). At time of transplant, 300 (73%) patients were in CR1 and 111 (27%) in CR2. Cytogenetic study in de novo AML was favorable in 19 patients (6%), intermediate in 102 (32%) and poor in 41 (13%). Cytogenetic data were missing in 161 (50%). 104 (25%) patients received matched related donors (MRD) and 307 (75%) unrelated donor (URD) HCT. Majority of patients (94%) received mobilized peripheral blood stem cells graft. Results. Median follow-up of surviving patients was 28 months and median age at transplant was 54 years (18-76). ANC>500/μL was achieved at a median of 17 (range, 9-74) days after HCT. Sixteen patients (4%) failed to engraft. Two year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 22% (95%CI, 18-26%) and 22% (95%CI, 18-27%), respectively. The Kaplan-Meier estimate of overall (OS) and leukemia-free survival (LFS) at 2 years were 59% (95%CI, 54-65%) and 56% (95%CI, 50-61%), respectively. Acute GVHD (grade II-IV) occurred in 109 (28%) patients. The 2-year cumulative incidence of chronic GVHD was 31% (95%CI, 26-36), extensive in 17% (95%CI, 12-21). Two years RI, NRM, LFS and OS in TBI vs. Bu patients were 21.8% vs 21.7% (p=0.69), 29.4% vs 18.3% (p=0.008), 48.8% vs 59.6% (p=0.045) and 51.2% vs 64.0% (p=0.013), respectively. In multivariate analysis adjusted for variable with different distribution between Bu and TBI groups, the type of conditioning (TBI vs Bu) has no impact on RI, NRM, LFS and OS. Age over 55 at transplant was an independent adverse prognostic factor in multivariate analysis for NRM (hazard ratio (HR: 1.61, 95% CI: 1.00-2.61, p=0.05)), LFS (HR: 1.39, 95% CI: 1.00-1.92, p=0.05) and OS (HR: 1.55, 95% CI: 1.11-2.18, p=0.01). Being treated in an experienced center (defined as having including 10 or more transplants in the study) was associated with a significant lower RI (HR: 0.84, 95% CI: 0.75-0.93, p=0.001) and better LFS (HR: 0.91, 95% CI: 0.84-0.98, p=0.01) and OS (HR: 0.91, 95% CI: 0.84-0.98, p=0.02). Finally, transplantation from an URD was associated with a significant increase in NRM (HR: 2.11, 95% CI: 1.14-3.91, p=0.02). Of note, CR1 vs. CR2 and de novo vs. secondary AML had no impact on patients' outcome. Conclusions. These results in a rather large cohort of patients with AML suggest that a FLAMSA "sequential" regimen provided an efficient disease control in high-risk AML patients including in CR2 and secondary AML. Furthermore Busulfan and TBI based FLAMSA "sequential" regimens provide a similar outcome. These results should be confirmed in a multicenter well design randomized study. Disclosures Off Label Use: off-label drug use: antithymocyte globulin (ATG) for allo-SCT conditioning. Tischer:Sanofi-Aventis: Other: advisory board. Schmid:Neovii: Consultancy; Janssen Cilag: Other: Travel grand. Mayer:Janssen: Research Funding. Hallek:Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding.

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