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

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.

Valproic Acid (VPA) Achieves High Response Rates in Patients with Low-Risk Myelodysplastic Syndromes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 789-789 ◽  
Author(s):  
Andrea Kuendgen ◽  
Mathias Schmid ◽  
Sabine Knipp ◽  
Akos Czibere ◽  
Barbara Hildebrandt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Valproic Acid ◽  
High Risk ◽  
Response Rate ◽  
Response Duration ◽  
Risk Groups ◽  
Low Risk ◽  
Bone Marrow Blast ◽  
Median Response ◽  
Blast Count

Abstract Valproic acid shows in-vitro activity against AML blasts and synergizes with ATRA in differentiation induction. We reported in-vivo activity of VPA and VPA+ATRA in patients with MDS and AML. Here we present follow-up data on 119 patients treated between February, 2002, and July, 2005. 87 patients were started on VPA monotherapy. Addition of ATRA was planned for patients who did not respond or relapsed after an initial response. 32 patients were treated with VPA +ATRA from the start. VPA was targeted to reach serum concentrations of 50–110 μg/ml. Median treatment duration was 4 months (&lt;1–42) for VPA and 3 months (&lt;1–35) for ATRA. 25 patients (21%) achieved responses according to International Working Group (IWG) criteria for MDS. The response rate was 28% in MDS (n=58) and 15% in AML (n=61). One patient achieved CR, and another patient achieved PR. 23 patients showed hematologic improvement. The median response duration was 4 months (2–33). 45 patients (38%) had stable disease, and 49 (41%) showed progressive disease. Among the 25 responders, 17 relapsed. 10 of these subsequently received ATRA, which resulted in a second remission in 4. Median response duration of the second responses (20 months, n=4) was significantly longer than the first response (4 months, n= 25, p=0,008). Of 94 nonresponders, 25 received additional ATRA without response. The response rate among the 87 patients on VPA monotherapy was higher than among the 32 patients receiving VPA+ATRA from the start (24% vs. 13%). We found a response rate of 42% in MDS with a normal blast count (PSA, RSA, RCMD, RSCMD; n=36), 6% in RAEB (RAEB I+II; n=18), 15% in AML (n=61), and 0% in CMML (n=4). The difference in response rate was significant when RSA, RCMD, and RSCMD were taken together and compared with all other disease types (p = 0.001). Treatment responses were correlated with risk assessment according to the International Prognostic Scoring System. Patients with low-risk MDS (IPSS low + int-1) had a significantly higher response rate than all other risk groups (p = 0.049). The response rate was 44% in low-risk (n=16), 29% in intermediate-1 (n=28), 10% in intermediate-2 (n=10), and 0% in high-risk MDS (n=4). We compared response duration in patients with PSA, RSA, RCMD, and RSCMD, and patients with RAEB I+II and AML, using the Kaplan-Meyer method. We found a significantly longer response duration in good-risk patients (3 months (2–26) vs. median not reached (2–33); p=0,043). Bone marrow blast count was predictive of response (p = 0.004). For cytogenetic risk groups, there was a trend of lower responses in patients with a high-risk karyotype (11%), compared to an intermediate (17%) or low-risk karyotype (28%). 72 patients had a bone marrow blast count &gt;5%. In 3 of these patients, the blast count normalized, 4 achieved a reduction by more than 50%, and 3 had a complete peripheral blast clearance. We conclude that VPA has a high response rate in low-risk MDS. In patients responding to VPA monotherapy, subsequent combination with ATRA may lead to prolonged responses. For patients with high-risk MDS, combination regimens including inhibitors of signal transduction, or demethylating agents should be investigated.

Treatment of Poor Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia with a Combination of 5-Azacytidine and Valproic Acid

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3639-3639 ◽  
Author(s):  
Andrea Kuendgen ◽  
Gesine Bug ◽  
Oliver G. Ottmann ◽  
Detlef Haase ◽  
Barbara Hildebrandt ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Stable Disease ◽  
Response Rate ◽  
De Novo ◽  
Prolonged Treatment ◽  
Fish Analysis ◽  
Peripheral Cell ◽  
Median Response ◽  
Poor Risk ◽  
Cell Counts

Abstract The DNA demethylating agent 5-Azacytidine (5-Aza) is the first drug to achieve a survival benefit in patients with poor-risk MDS. In vitro, synergism with inhibitors of histone deacetylases has been described, and the clinical feasibility of combining 5-Aza with Valproic Acid (VPA) has also been demonstrated. Response rates are at least comparable to 5-Aza monotherapy and time to response appears to be significantly shortened. However, the optimal dosing schedule for this combination is still uncertain. VPA was administered orally and continuously to achieve a serum level of 80–110μg/ml. 5-Aza was given at an increased dosage of 100mg/m2/d in a 5-day schedule every 28 days, in order to avoid weekend applications. Between March and Juli, 2007, 25 patients were included; 24 received at least one complete cycle of therapy. Median age was 73 (59–87) years. Diagnoses were 7 RAEB, 3 RAEB-T, 11 AML, 3 CMML (according to FAB), or 1 RAEB I, 4 RAEB II, 6 de-novo AML, 7 secondary AML/MDS, 3 therapy-related MDS/AML, 3 CMML II (according to WHO). All MDS patients had an IPSS score of intermediate II or high. 8 patients showed a normal karyotype, 6 had intermediate-risk single aberrations and 10 had poor-risk cytogenetics. 7 patients had previously received intensive chemotherapy. Karyotype was determined by conventional cytogenetics as well as FISH analysis of circulating 34+-cells and bone marrow. Patients received a median of 5 (1–17) cycles. The response rate was 33%, including 1 CR, 1 CRi, 5 PR and one patient with hematologic improvement but 6% remaining marrow blasts. 9 patients (38%) achieved at least stable disease, 5 of these obtained marrow CR (n=3) or PR (n=2). These patients typically showed a hypoplastic marrow with significantly reduced blast cells but without regeneration of peripheral cell counts. Response rate was highest in previously untreated patients with 10–30% marrow blasts (55%), while only one of 6 patients with relapsed/refractory AML achieved CRi. Cytogenetic remissions occurred in 6 patients (4 cytogenetic CR and 2 PR). Out of 7 patients with chromosome 7 abnormalities, 4 (57 %) responded. Median number of cycles to achieve a response was 2. While it took only 1 or 2 cycles in 5 patients, three patients needed 8 or 9 cycles. Median response duration was not reached, since only 3 patients relapsed after 5, 6, and 10 treatment cycles. Median survival from start of therapy was 8 (1–17) months (see fig.). 6 patients currently remain on treatment. Most patients had transient CNS side effects leading to dose reduction or transient discontinuation in 8 and cessation of therapy in 2. In one patient Coombs-negative hemolysis occurred. It is unknown whether this AE was related to the study drugs. Two patients developed a rash after 5-Aza. Myelosuppression occurred in all patients especially during the initial cycles. Treatment had to be delayed in most of the patients during the first cycles, and dose reductions of 5-Aza were necessary in 7 cases. One patient died of pneumonia after the first cycle. Myelosuppression appeared to be more severe than with 5-Aza alone. Whether this was due to dose intensification of 5-Aza, combination with VPA, or unfavourable patient characteristics remains uncertain. In future studies we would prefer a schedule of 75mg/m2/d for 5 days, which has proven effective in recent trials. Although the combination of demethylating agents and HDAC inhibitors may achieve earlier responses in some patients, this approach does not seem to obviate the need for prolonged treatment. Patients who achieve at least stable disease should be kept on treatment as long as possible. Figure Figure

Outcome of Myelodysplastic Syndrome Treated with Intensive Chemotherapy within the AMLCG99 Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2773-2773
Author(s):  
Utz Krug ◽  
Carsten Muller-Tidow ◽  
Matthias Stelljes ◽  
Maria Cristina Sauerland ◽  
Achim Heinecke ◽  
...  
Keyword(s):  
High Risk ◽  
De Novo ◽  
Allogeneic Transplantation ◽  
Intensive Chemotherapy ◽  
Employment Equity ◽  
Term Survival ◽  
Secondary Aml ◽  
Equity Ownership ◽  
De Novo Aml

Abstract Abstract 2773 Introduction: For patients with high-risk myelodysplastic syndromes an epigenetic therapy with hypomethylating agents is considered standard of care. Intensive chemotherapy can be offered to a subset of patients; however, data about the long-term outcome of MDS patients receiving intensive chemotherapy are scarce. Methods: For this evaluation, 104 adult patients with IPSS intermediate-2 or high-risk MDS with at least 10% bone marrow blasts of all age groups treated within the AMLCG1999 trial were included. Patients were randomized upfront to receive 1. double induction therapy with either standard-dose containing TAD - versus high-dose containing HAM–HAM, 2. TAD consolidation therapy followed by either a monthly maintenance therapy for 3 years after achievement of CR or an autologous stem cell transplantation (patients aged ≥ 60 years were all assigned to maintenance therapy), and 3. blast priming with filgastrim starting on day -1 of chemotherapy in selected centers. Results: Fifty-four patients had IPSS Score intermediate-2 and 50 patients were IPSS high risk. Median bone marrow blast count at diagnosis was 15%. The median age was 63.5 years (range: 27–76 years), 39 patients (37.5 %) were female. Median lactate dehydrogenase (LDH) serum level was 296 U/l, median leukocyte count at diagnosis was 5,950 per μl. The cytogenetic risk groups were as follows: favorable 3, intermediate 57, unfavourable 37, missing 7. Among 38 patients with normal karyotype, NPM1/FLT3 mutational status was available for 22 with 5 patients having the combination NPM1 mutated/FLT3 wildtype. Comparison with 2051 patients with de novo AML within the same trial revealed the following significant differences: patients with MDS were older, had a higher male to female ratio, a lower LDH serum level at diagnosis, a lower leukocyte count at diagnosis and were more likely to have adverse cytogenetic risk. Compared to 636 patients with secondary AML after MDS, cytotoxic therapy or irradiation, the cohort of patients with MDS did not display any significant differences except the sex distribution. Patients with MDS displayed a CR rate of 48% (50/104 patients), which was significantly lower than de novo AML patients (67%) and not different to secondary AML patients (47%). Median overall survival in MDS patients was 320 (95% CI: 236 to 505) days with a 2-year and 5-year survival of 33.4% (95% CI: 23.6% to 43.2%) and 22.7% (95% CI: 13.5% to 31.9%), respective, which was significantly (p=0.03) lower than in patients with de novo AML (median 484, 95% CI 435 to 541 days) and comparable to patients with secondary AML (median 282, 95% CI 224 to 311 days, p=0.13). Median relapse-free survival in responding MDS patients was 536 (95% CI: 264 to 1299) days with no significant differences of RFS compared to de novo or secondary AML patients. In multivariate analyses, the diagnosis of MDS remained an independent prognostic factor for CR probability but had no independent influence on survival compared with de novo AML patients. Nine patients proceeded to allogeneic stem cell transplantation in first complete remission of whom six remain in first complete remission between 1354 and 1911 days after achievement of CR. In addition, 16 patients remained in CR for more than one year without allogeneic transplantation. Discussion: Taken together, outcome of patients with intermediate-2 or high-risk MDS after intensive chemotherapy is comparable to the outcome of patients with secondary AML. Adjustment for known risk factors such as age, cytogenetic risk and LDH revealed that inferior outcome of MDS patients compared to patients with de novo AML is attributable to the higher incidence of adverse risk factors. CR-rates appear to be higher compared to hypomethylating therapy and a fraction of MDS patients experiences long-term survival by intensive chemotherapy. Allogeneic transplantation can improve long-term survival for patients achieving remission. Disclosures: Krug: MedA Pharma: Honoraria; Novartis: Honoraria; Alexion: Honoraria; Boehringer Ingelheim: Research Funding; Sunesis: Honoraria. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

scholarly journals A Single Center Experience of Cladribine, Cytarabine, Filgrastim and Mitoxantrone (CLAG-M regimen) in High-Risk or Relapsed/Refractory, Acute Myeloid Leukemia (AML)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4007-4007 ◽  
Author(s):  
Valérie Vidal ◽  
Laila Hamri ◽  
Alice Marceau-Renaut ◽  
Flore Sicre De Fontbrune ◽  
Virginie Eclache ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Response Rate ◽  
Intensive Therapy ◽  
Complete Response ◽  
Fish Analysis ◽  
Monosomy 7 ◽  
Secondary Aml ◽  
Subsequent Relapse ◽  
Refractory Aml

Abstract Background: High-risk (HR) AML including secondary AML (sAML) or therapy-related (tAML) are associated with significantly lower complete remission (CR) rates and poor outcome, after upfront "3+7" and post-remission chemotherapy. No standard intensive treatment approach for relapsed/refractory AML is well established, even more so, in older patients, but "bridging" such patients in CR to allogeneic stem-cell transplantation (HSCT), whenever feasible, remain the only curative strategy, as in younger patients. Addition of cladribine, a purine analog, to cytarabine is an available option. Significant clinical activity of CLAG (-M) regimens is now well established, with a response rate (RR) of 60% in relapsed/refractory AML or AML patients who failed hypomethylating agents. A prospective frontline study of an intensified CLAG-M regimen has recently confirmed its association to a high response rate, that may particularly benefit HR-AML patients, as a bridge to HSCT. As other reports in the literature remain sparse, we report here our current experience with CLAG-M in relapsed/refractory and sAML patients. Methods: From January 2015 to July 2018, 20 consecutive patients with HR-AML, were treated in our center, with one course of CLAG-M (cladribine 5 mg/m2 /day (days 2-6), cytarabine 2g/m2/day (days 2-6) and reduced to 1g/m2/day for patients 65y+, filgrastim 300mcg/daily (days 1-6), and mitoxantrone 10mg/m2/day (days 2-4)). If eligible for HSCT, a second CLAG course was to be administered to patients in CR. Extended myeloid mutation analysis was performed, using a 37-gene NGS panel. Such patients were classified according to Lindsley et al.,Blood 2015. Results: Median age was 63.5 years (33-79) with a 3:1 M/F ratio. Four sAML patients and 4 tAML patients were treated upfront (5 CR, 1 early death (ED) and 2 treatment failures). ELN cytogenetics was adverse (n=5), intermediate (n=1) or failed (n=4). Twelve patients were all treated after frontline 7+3 and intensive consolidation courses (n=10) or azacytidine (n=2). Three patients were refractory to prior intensive chemotherapy or AZA and 9 were in first or subsequent relapse, at time of CLAG-M administration. Median time from first treatment for MDS/AML to CLAG-M onset was 17 mos (3-29). Initial/relapse ELN cytogenetics was adverse (n=5), intermediate (n=5) and failed (n=2). Of these 12 patients, 7 obtained a response (6 CR, one CRi), 3 failed to obtain a response and 2 early died from sepsis. Seventeen patients could be classified, according to Lindsley et al. The 3 patients with missing NGS data, all had adverse ELN cytogenetics (inv3q/MECOM1, MLLr by FISH analysis or monosomy 7, associated with an IDH2 mutation). After one course, 5/7 patients, classified as secondary AML, obtained a CR, including one CRi, 3/4 patients classified as pan AML obtained a CR, while only 2/6 patients with mutated TP53 alleles obtained a CR (3 failed to respond). Overall, 12 of the 20 patients obtained a complete response (11 CR and 1 CRi), despite adverse genetical characteristics and 12 of them being administered CLAG-M, during the late evolution of their disease. Three patients early died due to undocumented pneumonitis (n=2) or bacterial sepsis (n=1). Otherwise, observed treatment toxicities were mild, with no unusual infections seen after CLAG-M. Median duration of neutropenia (<0.5 G/l) and thrombocytopenia (<100 G/l) was 28 (12-47) and 30 (23-40) days, respectively. Seven patients in CR received a second CLAG course before HSCT, when 3 patients, aged more than 70 years, only less intensive courses. One CR patient did not received consolidation due to severe sepsis, as also did the only patient with CRi due to persisting cytopenias. Both patients underwent HSCT. Fifteen patients were deemed eligible at entry for HSCT, based on age and performance status. Of those, 8 achieved a CR/CRi and all of them proceeded to HSCT. Four such patients are currently alive (2 mo, 2.6 y, 3y, 3.4y), 2 patients died from early relapse (4 and 6 mos) and 2 patients from HSCT toxicity. Conclusions: In this real-life small study of HR-AML patients, predominantly older than 60 years of age, CLAG-M was also used at first or subsequent relapse post-intensive therapy. Despite very unfavorable characteristics, 60 % of them obtained a complete response and 50% of those initially eligible were effectively "bridged "to HSCT, without unusually deleterious outcomes observed in this small cohort. Disclosures Peffault De Latour: Amgen Inc.: Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Braun:CELLIPSE: Research Funding.

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™ (VNP40101M) Is Active in Elderly Untreated Poor Risk Patients with Acute Myelogenous Leukemia (AML) or High Risk Myelodysplasia (MDS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2786-2786
Author(s):  
Francis Giles ◽  
Susan O’Brien ◽  
David Rizzieri ◽  
Judith Karp ◽  
Maureen Cooper ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Organ Dysfunction ◽  
Response Rate ◽  
Myelogenous Leukemia ◽  
Induction Treatment ◽  
Secondary Aml ◽  
Age Related ◽  
Related Risk ◽  
Elderly Aml

Abstract Background: The majority of patients (pts) with AML and high risk MDS are ≥ 60 years of age at diagnosis (median age 70), and have a poor prognosis due to age-related risk factors and disease biology. Commonly accepted risk factors in this population include age ≥ 60 yrs, ECOG PS ≥2, secondary AML, unfavorable cytogenetics, and organ dysfunction. The response rate with induction treatment for these pts is lower than that of their younger counterparts, and additional risk factors worsen prognosis. Hepatic, pulmonary, and/or cardiac compromise is likely to determine both selection and tolerance of the induction regimen, and these pts are often not considered for aggressive chemotherapy such as “3+7”. In the US, up to 70% of elderly AML/MDS pts do not receive induction treatment (Menzin, et al; Arch Int Med; 2002;162:1597). CLORETAZINE, a novel sulfonylhydrazine alkylating agent, has significant activity in AML/MDS with a favorable safety profile. In an ongoing Phase II trial, pts with AML or high risk MDS, age ≥60 years, and no prior cytotoxic treatment, receive CLORETAZINE 600mg/m2 for remission induction, re-induction, and consolidation. Methods: This elderly pt population was analyzed for the presence of risk factors and underlying organ dysfunction. Pts were assessed according to the commonly accepted risk factors described above and categorized by number of factors present. Organ dysfunction was defined as hepatic abnormalities (elevated liver function tests), moderate/severe pulmonary compromise (grade 2–4 dyspnea by NCI-CTC Version 3.0 or dependence on oxygen), and/or a history of significant cardiac disease. Data was obtained from case report forms of baseline demographics, medical history, physical exam, and concomitant medications. Results: 105 pts with age ≥60 were enrolled as of April 21, 2005. Specific risk factors were as follows: 31 pts (30%) were PS 2; 36 pts (34%) had unfavorable cytogenetics; 43 pts (41%) had secondary AML. Forty-eight pts (46%) had cardiac dysfunction; 26 pts (25%) had hepatic disease; and 19 pts (18%) had pulmonary dysfunction. The response rate (CR+CRp) for the group as a whole was 31% (N=33). Non-hematologic toxicity was minimal, and the early death rate of 18% is within the range expected for cytotoxic induction regimens in the elderly AML population. The table below describes the risk categories for all patients, early deaths, and responders: # Risk Factors N [%] # CR/CRp (%) # Early Deaths (%) Age + 0 12 (11) 7 (58) 2 Age + 1 24 (23) 9 (38) 4 Age + 2 39 (37) 8 (21) 7 Age ≥3+ 30 (29) 9 (30) 6 Total 105 33 (31) 19 (18) Conclusions: According to risk assessment on the basis of age-related risk factors, the majority of the study pt population had multiple risk factors and represents a group for whom standard AML induction therapy may not be an option. In this elderly patient population with limited therapeutic options, CLORETAZINE is tolerable and results in a response rate of 31%.

Interim Anaiysis of Intention To Treat Analysis, “Multicenter AML-2000 Trial” Based on Cytogenetics Risk Factors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4618-4618
Author(s):  
Yeung-Chul Mun ◽  
S.M. Lee ◽  
S.M. Bang ◽  
S.H. Park ◽  
E.K. Cho ◽  
...  
Keyword(s):  
De Novo ◽  
Risk Groups ◽  
Good Prognosis ◽  
Remission Induction ◽  
Secondary Aml ◽  
Intention To Treat ◽  
Prognostic Groups ◽  
Prognosis Group ◽  
De Novo Aml ◽  
Treat Analysis

Abstract The result of cytogenetics is one of the most important prognostic factors on the prognosis of AML. HDAC, auto PBPCT and allogeneic BMT after 1 or 2 times of post remission therapy based on 4 prognostic groups(APL: Acute promyelocytic leukemia, GPG: Good prognosis group, IPG: Intermediate prognosis group, PPG: Poor prognosis group by MRC definition) were underwent based on cytogenetics data. We studied CR, relapse, toxic death, DFS and OS. Inclusion criteria were age<65, PS<3 with reasonable organ functions in de novo AML, secondary AML and RAEB-T. The aims of this prospective intention to treat analysis was to compare the CR, recovery kinetics, DFS and OS by giving different therapies of intensity in the different prognostic groups based on cytogentics data. Three plus seven(Idarubicin 12mg/m2(D1–D3), Ara-C 100mg/m2(D1–D7)) were given to de novo AML, secondary AML and RAEB-T. Intermediate dose(8gm/m2) of Ara-C was given followed by HDAC or auto PBPCT to the patients with GPG(t(8:21) & inv(16)). Three times of post remission therapy including HDAC, or auto PBPCT were given to the patients with IPG or PPG(−5, −7, del 5q, complex). If HLA-identical sibling was available, then allo BMT was underwent after 1st post-remission therapy. In cases of APL, three times of post-remission therapy with idarubicin alone were given. ATRA was given to APL group during remission induction therapy and after post-remission maintenance period for 2 years. Up to Mar., 2005, 422 patients(18 centers) were enrolled. Median follow-up was 48months. Among them, 92.3% was de novo AML, and APL, GPG, IPG and PPG were 10.0%, 21.6%, 51.4%, and 14.7% respectively. Overall CR after 1st induction(3+7) were 69.9%(APL: 87.2%, GPG: 84.7%, IPG: 63.8%, PPG: 55.66%, P<0.01). Relapse rate was 12.8%(APL), 40.5%(GPG), 40.5%(IPG) and 45.6%(PPG) respectively(P<0.01). Toxicities profiles including mucositis, hepatic, cardiac and bleeding episodes were similar on 3 different therapy modalities(HDAC, auto PBPCT and allo BMT). In conclusions, this trial seems to be tolerable in terms of toxicities after induction and during post remission therapies. Among GPG, there were no significant statistical differences on OS and LFS in all the therapy modalities(ie, HDAC, Auto, Allo). In IPG, auto arm had a tendency of superior OS and LFS comparing to HDA & allo arm. In PPG, there was significant surperior LFS in allo arm. There were no statistical differences on OS in all the therapy modalities in PPG. This intention to treattrial, which had started in Jan, 2000, has been going on until now. Through this risk based trial using cytogenetics, we might be able to find optimal post-remission therapies for different risk groups with less toxicities.

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.

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