- Email: [email protected]
P138 Valproic acid at therapeutic plasma levels may increase 5-azacitidine efficacy in higher risk myelodysplastic syndromes
5. Therapy survival (EFS) of the whole group were 51% and 48%, respectively (Figure 1) at ten years of follow up. WHO classification was predictive for both OS and EFS. None of the following variables significantly influenced OS or EFS: blast percentage and ferritin levels at the time of alloSCT, age, conditioning regimen (MC vs. RIC) (50−48% for OS and 46−42% for EFS for MC vs. RIC, respectively) although patients receiving RIC were significantly older (42 vs. 55 years). When only high risk patients (RAEB-1, RAEB-2, AML and MDS/MPD) were considered, disease status at transplant significantly influenced the outcome with better results being observed for patients in CR or No-ch (Figure 2). Summary: In summary, a significant percentage of patients with MDS, including high-risk patients, remain alive more than ten years after transplantation showing that this approach remains the only curative one for these patients. The WHO classification and the state of disease at transplantation in the high risk group are the most powerful predictors for survival. P137 Supporting MDS patients in a regional hospital setting T. Chimonas, P. Mylona ° , A. Panoutsopoulos, G. Penesis, V. Voudoukis, M. Pavlaki, F. Pozi, G. Mavras, G. Andrianopoulos. Argos General Hospital, Argos, Greece *E-mail: [email protected] Background: The myelodysplastic syndromes are characterized by ineffective hematopoiesis, leading to pancytopenia. Refractory anemia is often the dominant manifestation, requiring frequent hospitalizations for blood transfusions. Not all patients have access to specialized hematologic units, and many are supported by smaller, regional general hospitals. The purpose of this study is to examine the characteristics and the disease course of patients treated in this setting. Methods and Materials: This was a retrospective study of 12 patients with MDS who were hospitalized during the period 2007–2008 for blood transfusions. Their medical history and treatment, transfusion needs, complications and disease course were recorded. Results: During this period, 8 men and 4 women (overall mean age 79.1±4.7) were admitted regularly for blood transfusions. The mean duration of their follow-up was 272.7±213.5 days. Their mean hospitalization rate was 13.8±8.6 admissions per year (range 3−30). Their mean hematocrit was 25.2±2.5% and they required transfusions of 2.4±1.2 units of packed red blood cells per month. Among the patients, 7 developed moderate to severe neutropenia (<1000 cells/mm3 ) and 4 moderate to severe thrombocytopenia (<50.000 cells/mm3 ) at some point during their follow-up. Two of the patients presented with severe infections, requiring hospitalization. In three of the patients, transformation to acute myeloid leukemia
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was observed. Three suffered from severe hemorrhagic complications, of which 2 were fatal (epistaxis and pulmonary hemorrhage). The overall mortality rate was therefore 17%. Among the patients, 8 were treated with erythropoietin, 2 with granulocyte-colony stimulating factors and 2 with antineoplasmatic drugs. Conclusions: Patients with myelodysplastic syndrome supported with blood transfusions in our hospital were more elderly than the age range reported in the literature. It is possible younger patients tend to be treated in specialized hematological centers. Our patients suffered from advanced disease, with a high hospitalization rate (more than once a month) and required a significant number of transfusions. The most important complications in this cohort were hemorrhages, which could be fatal. As life expectancy is progressively getting longer, there will be many physicians in the future who will be called to treat MDS patients. We hope our clinical experience will be helpful to them. P138 Valproic acid at therapeutic plasma levels may increase 5-azacitidine efficacy in higher risk myelodysplastic syndromes M. Voso1 ° , V. Santini2 , C. Finelli3 , P. Musto4 , E. Pogliani5 , A. Di Tucci6 , G. Alimena7 , F. Buccisano8 , A. Cortellezi9 , M. Petti10 , G. Zini11 , E. Fabiani11 , P. Fazi12 , A. Piciocchi12 , G. Leone11 . 1 Hematology, Universita Cattolica, Rome, Italy; 2 University of Florence, Italy; 3 University of Bologna, Italy; 4 Hematology-Rionero in Vulture, Italy; 5 Universita Milano-Bicocca, Italy; 6 Centro Oncologico Businco, Cagliari, Italy; 7 Universita La Sapienza, Roma, Italy; 8 Universita Tor Vergata, Roma, Italy; 9 IRCCS Regina Elena, Milano, Italy; 10 Istituto Oncologico Regina Elena, Rome, Italy; 11 Hematology, Universita Cattolica, Rome, Italy; 12 Gimema Data Center, Rome, Italy *E-mail: [email protected] Epigenetic changes have been shown to play a role and to cooperate with genetic alterations in the pathogenesis of myelodysplastic syndromes (MDS). The potential reversibility of DNA and chromatin modifications makes chromatin remodelling enzymes attractive targets for therapeutic intervention in this disease. We conducted a phase II study on the combination of the DNA-methyltransferase inhibitor (DNMTi) 5-azacitidine (5-AZA), the histone deacetylase inhibitor (HDACi) valproic acid (VPA), and the differentiating agent all-trans retinoic acid (ATRA) in patients with intermediate-2/high-risk MDS, according to International Prognostic Scoring System (IPSS). Bone marrow morphology was centrally reviewed before enrolment. VPA was initially given at 600–1500 mg daily to reach a final plasma concentration above 50 microg/ml, then 5-AZA was added at a standard dose of 75 mg/sqm daily, subcutaneously, 7 days for 8 monthly cycles. In case of minor response, stable disease or failure after 4 cycles, ATRA was added at 30 mg/sqm orally daily, on
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days 8−27 for 4 monthly cycles. Treatment was continued in responding patients until response persisted. The protocol included 62 patients (43 males, 19 females, median age 70 years, range 53−83 yrs). Diagnosis was RAEB for 39 patients (62.90%), RAEB-t for 19 (30.65%), and CMML for 4 patients (6.45%). The IPSS score was int-2 (1.5) for 42 patients and High (2) for 20 patients. A valproic acid concentration between 45 and 55 microg/ml was reached in a median of 7 days (range 2−28 days). The median overall survival was 14.4 months. At a median follow-up of 12 months (range: 0.7−21.0), the disease progressed in 20 patients, with 21% cumulative incidence of progression. Of 26 patients who completed 8 cycles, 30.7% obtained complete or partial remission, 15.4% major hematological improvement, while 38.5% showed a stable disease. ATRA was added in 11 patients on cycle 5, without significant clinical benefit. Drug-related toxicity was mild. Favourable prognostic factors for survival were IPSS Int-2 and plasma VPA 50 mg/ml (Log-Rank=0.013 and 0.007, respectively). Analysis of polymorphisms important for metabolism of the drugs used in the trial, showed that carriers of the CYP2C19*2 variant of cytochrome P450 required higher valproic acid dose to achieve the target VPA plasma concentration of 50 mg/ml on day 1 of 5-AZA (p = 0.0021). Other enzymatic polymorphisms, including CYP2C19*3, CYP3A4-A290G, GSTP1-Ile105 Val, cytidine deaminase (CDA-92A>G, CDA-451C>T and −897C>A), did not play a role as predictors of toxicity or response. These data may indicate that the association of valproic acid may indeed improve response to azacitidine and that including pharmacogenetic analyses into future trials on epigenetic treatment may help to define patient-tailored approaches.
75 mg/m2 /day IV for 5 days. For course 3 patients received 75 mg/m2 /day SQ x 5 days. (See Figure 1) Beyond course 3 patients received 75 mg/m2 /day either SQ or IV x 5 days every 4 weeks based on patient preference. Intra-patient dose for route of administration comparison allowed for less variability and a more accurate comparison. Peripheral blood was collected on days 1, 3 and 5 for each course and LINE1 DNA methylation was measured using bisulfitePCR Pyrosequencing to measure global DNA methylation changes induced by azacitidine. Results: In total 17 patients were treated (3 at 25 mg, 4 at 50 mg, 4 at 75 mg, 3 at 100 mg, and 3 at 150 mg/m2 ). Diagnosis included 5 patients with MDS, 10 patients with AML (2 untreated older patients, 7 relapsed or refractory patients), 1 patient with CML (imatinib refractory), and 1 patient with non-Hodgkin’s lymphoma (relapsed disease). At the time of submission 14 patients were evaluable for response with 4 CR (1 mCr, 1 CRp), 1 PR, 6 SD and 3 PD reported. The median number of cycles given was 3 (range 1−14+). LINE1 DNA methylation decreased by 1.4, 2.3, 4.8, 1.9 and 4.0% on day 5 for the 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg/m2 dose levels respectively (Figure 2). Mean decrease in LINE1 DNA methylation with 75 mg/m2 IV was 3.7% and only 2.6% by 75 mg/m2 of azacitidine SQ (Figure 2). There was a large amount of inter-patient variability but less intra-patient variability in DNA methylation response to azacitidine. Conclusion: Azacitidine is effective at inhibiting DNA methylation at multiple dose levels for both IV and SQ routes of administration. There is a high degree of patientto-patient variability in DNA methylation changes, but 75 mg/m2 lead to the greatest mean decrease in DNA methylation by a 5 day IV regimen.
P139 A phase I biological study of azacitidine (Vidaza) to determine the optimal biological dose and route of administration
P140 Reduction in serum ferritin (SF) is associated with improvement in liver transaminase levels during treatment with deferasirox (Exjade® ) in ironoverloaded patients with myelodysplastic syndromes (MDS)
A.S. Yang, A. Mohrbacher, D. Douer, G. Gorospe, H.-M. Byun. Jane Anne Nohl Division of Hematology, University of Southern California, Los Angeles, CA, USA Background: Azacitidine (5-azacytidine, Vidaza) is a DNA methylation inhibitor that has been shown to have a survival benefit in patients with high-risk myelodysplastic syndrome and is under investigation in other cancers. The purpose of this study was to determine the optimal dose and route of administration for azacitidine to inhibit DNA methylation in patients with hematologic malignancies. Methods: Eligibility included patients with hematologic malignancy that provided informed consent. Enrollment criteria varied depending on the type of cancer. Patients were enrolled into 5 escalating dose levels for the first course of therapy (25 mg, 50 mg, 75 mg, 100 mg or 150 mg IV per m2 per day for 5 days). On day 28 all patients received
N. Gattermann1 ° , M. Schmid2 , A. Guerci-Bresler3 , M. Della Porta4 , K. Taylor5 , D. Habr6 , G. Domokos7 , B. Roubert7 , P. Fenaux8 . 1 Heinrich-Heine-University, D¨usseldorf, Germany; 2 University Hospital, Ulm, Germany; 3 CHU Brabois (Groupe Francophone des My´elodysplasies), Vandoeuvre C´edex, France; 4 University of Pavia Medical School, IRCCS Policlinico S. Matteo, Pavia, Italy; 5 Mater Hospital, Brisbane, Australia; 6 Novartis Pharmaceuticals, East Hanover, NJ, USA; 7 Novartis Pharma AG, Basel, Switzerland; 8 Hˆopital Avicenne, Bobigny, France Background: Transfusional iron overload (IO) can lead to hepatocellular injury and progression to cirrhosis;
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was observed. Three suffered from severe hemorrhagic complications, of which 2 were fatal (epistaxis and pulmonary hemorrhage). The overall mortality rate was therefore 17%. Among the patients, 8 were treated with erythropoietin, 2 with granulocyte-colony stimulating factors and 2 with antineoplasmatic drugs. Conclusions: Patients with myelodysplastic syndrome supported with blood transfusions in our hospital were more elderly than the age range reported in the literature. It is possible younger patients tend to be treated in specialized hematological centers. Our patients suffered from advanced disease, with a high hospitalization rate (more than once a month) and required a significant number of transfusions. The most important complications in this cohort were hemorrhages, which could be fatal. As life expectancy is progressively getting longer, there will be many physicians in the future who will be called to treat MDS patients. We hope our clinical experience will be helpful to them. P138 Valproic acid at therapeutic plasma levels may increase 5-azacitidine efficacy in higher risk myelodysplastic syndromes M. Voso1 ° , V. Santini2 , C. Finelli3 , P. Musto4 , E. Pogliani5 , A. Di Tucci6 , G. Alimena7 , F. Buccisano8 , A. Cortellezi9 , M. Petti10 , G. Zini11 , E. Fabiani11 , P. Fazi12 , A. Piciocchi12 , G. Leone11 . 1 Hematology, Universita Cattolica, Rome, Italy; 2 University of Florence, Italy; 3 University of Bologna, Italy; 4 Hematology-Rionero in Vulture, Italy; 5 Universita Milano-Bicocca, Italy; 6 Centro Oncologico Businco, Cagliari, Italy; 7 Universita La Sapienza, Roma, Italy; 8 Universita Tor Vergata, Roma, Italy; 9 IRCCS Regina Elena, Milano, Italy; 10 Istituto Oncologico Regina Elena, Rome, Italy; 11 Hematology, Universita Cattolica, Rome, Italy; 12 Gimema Data Center, Rome, Italy *E-mail: [email protected] Epigenetic changes have been shown to play a role and to cooperate with genetic alterations in the pathogenesis of myelodysplastic syndromes (MDS). The potential reversibility of DNA and chromatin modifications makes chromatin remodelling enzymes attractive targets for therapeutic intervention in this disease. We conducted a phase II study on the combination of the DNA-methyltransferase inhibitor (DNMTi) 5-azacitidine (5-AZA), the histone deacetylase inhibitor (HDACi) valproic acid (VPA), and the differentiating agent all-trans retinoic acid (ATRA) in patients with intermediate-2/high-risk MDS, according to International Prognostic Scoring System (IPSS). Bone marrow morphology was centrally reviewed before enrolment. VPA was initially given at 600–1500 mg daily to reach a final plasma concentration above 50 microg/ml, then 5-AZA was added at a standard dose of 75 mg/sqm daily, subcutaneously, 7 days for 8 monthly cycles. In case of minor response, stable disease or failure after 4 cycles, ATRA was added at 30 mg/sqm orally daily, on
S140
Posters
days 8−27 for 4 monthly cycles. Treatment was continued in responding patients until response persisted. The protocol included 62 patients (43 males, 19 females, median age 70 years, range 53−83 yrs). Diagnosis was RAEB for 39 patients (62.90%), RAEB-t for 19 (30.65%), and CMML for 4 patients (6.45%). The IPSS score was int-2 (1.5) for 42 patients and High (2) for 20 patients. A valproic acid concentration between 45 and 55 microg/ml was reached in a median of 7 days (range 2−28 days). The median overall survival was 14.4 months. At a median follow-up of 12 months (range: 0.7−21.0), the disease progressed in 20 patients, with 21% cumulative incidence of progression. Of 26 patients who completed 8 cycles, 30.7% obtained complete or partial remission, 15.4% major hematological improvement, while 38.5% showed a stable disease. ATRA was added in 11 patients on cycle 5, without significant clinical benefit. Drug-related toxicity was mild. Favourable prognostic factors for survival were IPSS Int-2 and plasma VPA 50 mg/ml (Log-Rank=0.013 and 0.007, respectively). Analysis of polymorphisms important for metabolism of the drugs used in the trial, showed that carriers of the CYP2C19*2 variant of cytochrome P450 required higher valproic acid dose to achieve the target VPA plasma concentration of 50 mg/ml on day 1 of 5-AZA (p = 0.0021). Other enzymatic polymorphisms, including CYP2C19*3, CYP3A4-A290G, GSTP1-Ile105 Val, cytidine deaminase (CDA-92A>G, CDA-451C>T and −897C>A), did not play a role as predictors of toxicity or response. These data may indicate that the association of valproic acid may indeed improve response to azacitidine and that including pharmacogenetic analyses into future trials on epigenetic treatment may help to define patient-tailored approaches.
75 mg/m2 /day IV for 5 days. For course 3 patients received 75 mg/m2 /day SQ x 5 days. (See Figure 1) Beyond course 3 patients received 75 mg/m2 /day either SQ or IV x 5 days every 4 weeks based on patient preference. Intra-patient dose for route of administration comparison allowed for less variability and a more accurate comparison. Peripheral blood was collected on days 1, 3 and 5 for each course and LINE1 DNA methylation was measured using bisulfitePCR Pyrosequencing to measure global DNA methylation changes induced by azacitidine. Results: In total 17 patients were treated (3 at 25 mg, 4 at 50 mg, 4 at 75 mg, 3 at 100 mg, and 3 at 150 mg/m2 ). Diagnosis included 5 patients with MDS, 10 patients with AML (2 untreated older patients, 7 relapsed or refractory patients), 1 patient with CML (imatinib refractory), and 1 patient with non-Hodgkin’s lymphoma (relapsed disease). At the time of submission 14 patients were evaluable for response with 4 CR (1 mCr, 1 CRp), 1 PR, 6 SD and 3 PD reported. The median number of cycles given was 3 (range 1−14+). LINE1 DNA methylation decreased by 1.4, 2.3, 4.8, 1.9 and 4.0% on day 5 for the 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg/m2 dose levels respectively (Figure 2). Mean decrease in LINE1 DNA methylation with 75 mg/m2 IV was 3.7% and only 2.6% by 75 mg/m2 of azacitidine SQ (Figure 2). There was a large amount of inter-patient variability but less intra-patient variability in DNA methylation response to azacitidine. Conclusion: Azacitidine is effective at inhibiting DNA methylation at multiple dose levels for both IV and SQ routes of administration. There is a high degree of patientto-patient variability in DNA methylation changes, but 75 mg/m2 lead to the greatest mean decrease in DNA methylation by a 5 day IV regimen.
P139 A phase I biological study of azacitidine (Vidaza) to determine the optimal biological dose and route of administration
P140 Reduction in serum ferritin (SF) is associated with improvement in liver transaminase levels during treatment with deferasirox (Exjade® ) in ironoverloaded patients with myelodysplastic syndromes (MDS)
A.S. Yang, A. Mohrbacher, D. Douer, G. Gorospe, H.-M. Byun. Jane Anne Nohl Division of Hematology, University of Southern California, Los Angeles, CA, USA Background: Azacitidine (5-azacytidine, Vidaza) is a DNA methylation inhibitor that has been shown to have a survival benefit in patients with high-risk myelodysplastic syndrome and is under investigation in other cancers. The purpose of this study was to determine the optimal dose and route of administration for azacitidine to inhibit DNA methylation in patients with hematologic malignancies. Methods: Eligibility included patients with hematologic malignancy that provided informed consent. Enrollment criteria varied depending on the type of cancer. Patients were enrolled into 5 escalating dose levels for the first course of therapy (25 mg, 50 mg, 75 mg, 100 mg or 150 mg IV per m2 per day for 5 days). On day 28 all patients received
N. Gattermann1 ° , M. Schmid2 , A. Guerci-Bresler3 , M. Della Porta4 , K. Taylor5 , D. Habr6 , G. Domokos7 , B. Roubert7 , P. Fenaux8 . 1 Heinrich-Heine-University, D¨usseldorf, Germany; 2 University Hospital, Ulm, Germany; 3 CHU Brabois (Groupe Francophone des My´elodysplasies), Vandoeuvre C´edex, France; 4 University of Pavia Medical School, IRCCS Policlinico S. Matteo, Pavia, Italy; 5 Mater Hospital, Brisbane, Australia; 6 Novartis Pharmaceuticals, East Hanover, NJ, USA; 7 Novartis Pharma AG, Basel, Switzerland; 8 Hˆopital Avicenne, Bobigny, France Background: Transfusional iron overload (IO) can lead to hepatocellular injury and progression to cirrhosis;