(E3) Has survival improved in the past ten years?
1
Second International Conference on Myelodysplastic Syndromes (E3) IiAS SURVIVAL IMPROVED IN THE PAST TEN YEARS? Paul Reynolds, Anton Kruger, Shalal Sadullah. Terry Hamblin and David Oscier. The prognosis of MDS depends largely on the stage at the time of diagnosis and the rate of disease progression. It is not clear whether active treatemnt in the form of chemotherapy or differentiating agents has made any appreciable impact on the survival prospects of these patients. Randomised controlled trials have proved notoriously difficult to set up. We have been able to observe the impact of the introduction of more active management, both in terms of specific therapy and in supportive care in a large number of patients in a single institution. The costs of these changes, both in terms of expense and morbidity are considerable and and need carefully to be measured against any potential survival benefit conferred by treatment INVOLVEMENT OF RAR-a IN THE RA INDUCIBLE REGULATION OF MYELOID CELL DIFFERENTIATION B.D. Hardas’ , C.E.P. van Roozendaal’ , A. Patel’ , D. Darling’ , 4. G&ken’ , M. Petkovioh’ . P. Chambon’ 8 F. Farzaneh’ ‘Molecular Medicine Unit. King’s College School of Medicine 8 Dentistry, Denmark Hill, London SE5 6RX, England; and ‘Laboratoire de G6n6tique Mol&ulaire des Eucaryotes du CNRS, Facult6 de M&ecine, 11 rue Humann. 67065 Strasbourg C&ax. France. There is growing interest in usa of differentiation inducing agents, including retinoic acid (RA), in the clinical management of myeloid neoplasia. In order lo analyse the mode of action of RA, we have investigated its role in the induction of differentiation in the wild-type and differentiation resistant variants of the myelocytio oell line HL-60. HL-R5 is a spontaneously arising clonal population of HL-60 variants which is resistant. specifically. lo the induction of granulocytic differentiation by RA. Transfection of HL-R5 cells with the human RA receptora (hRARo-O), confers susceptibility lo the induction of differentiation by RA. However, expression of exogenous hRAR-6 or hRAR-r does not result In RA inducible differentiation in HL-RS cells. The suggestion of RARu involvement in the RA induosd differentia- tion of HL-60 calls has been confirmed by demonstrating a newly acquired oestrogen inducible differentiation in HL-60 cells transfected with a chimeric oestrogen receptor (hER) in which the DNA binding domain (ER. C domain) is substituted for the corresponding Comain of RARo. Interestingly, if the chimera contains not only the C domain but also the A/B domains of RARu, and only D 10 F domains of ER. there is no evidenoe of oestrogen inducible differentiation. This is despite the fact that both chime& receptors can induce the expression of co- transfected RA inducible reporter genes [(lRES),-tk-CAT]. These studies, which demonstrate the involvement of RARu, but not RAR-Qor RAR-r, in (he RA inducible differentiation of HL-60 cells. present the first evidence of functional specificity in the nuclear RAR’s In addition the chlmeric receptor studies suggest an important role for interdomain interactions for the RA/RAR-J induction of differentiation, but not the activation of all RA responsive elements. (E7) Intensive chemotherapy in MIX P. Fenaux, Lille, France. Most patients (pts) with MDS are elderly and treated by supportive care only, by low dose chemotherapy or more recently growth factors. In younger MDS pts, allogeneic BMT is clearly a curative approach but it is currentlylimited to few pts. so that a place seams lo remain for intensive chemotherapy (C). However,induction chemotherapy with anthracycline - AraCcomblnationsorhighdosa AraChasonlygiven completeremission (CR) rates of 30 to 60% in MDS (irrespective of whether treatment was started in MDS phase or after progression to AML) ie significrntly less than in de now AML.These lowerCR rates, in MDS, are due to a higher incidence of leukemic resistancebut also of hypoplastic deaths (associated with longer periods of aplasia)than in de now AML. In addition median DFS. in MDS pts. is less than a year and no more than 5% of pts ara cured by IC. Still,some subgroupsof MDS may benefit from IC : pts less than 50 lo 55 (Tricot), pts with RAEBT at dlagnosis (as opposed to other FAB subtypes)(Bloomfield. Michels, Fenaux), and pts without‘unfavourable” ka- ryotype (rearrangements ot chromosome 5 or 7, or complex rearrangements especially frequent in therapy related MDS) (Gajewskl,Fenaux) reach higher CR rates.We also found that normal karyotype was associated witha median DFS of 15 months,as opposed to 3 monthsin pts with abnormal karyotype; our 15 pts with RAE5T at diagnosisand normal karyotype had a CR rate of 60%, and a median DFS of 16 months, although most of them eventually relapsed. AllogeneicBMT, In RAE&T, seems to carry a high risk of relapse when performed asfirst line therapy (Appelbaum), and resultsobtainedwith ICsuggestthatthistreatmentcouldbetriedtoinducrCR(orpartialremistion) before BMT is attemped in RAEBT. In other types MDS allogeneic EMT, whenever possible,should probably be attempted as first line therapy. The availiblllty of growthfactors should allowthe utilization of more intensive chemotherapy protocols In MDS, both for Induction and consolida- tion.Autologous BMThasvety rarely been altemped in MDS. tl couldprobably be investigated in ptswhose bone marrow has achieved good quality remis- sion (as assessed by cylogenetics and molecular biology) for adequate harvesting, after one or two courses of IC. EFFECTIVENESS OF ATTENUATED CHEMOTHERAPY IN THE TREATMENT OF MYELODYSPLASIA Elizabeth Cyran, John M Bennett, Jacob Rowe, Michael Owens. Cancer Center and Dept of Medicine, University of Rochester, Rochester, New York. Cytotoxic agents have been shown to be beneficial in some patients with myelodys- plastic syndromes (MDS). The advanced age of most patients contributes to unacceptable toxicities with aggressive chemotherapy treatment programs. An attenuated combination chemotherapy program was piloted as an alternative approach. 14 patients with MDS. ages 46-79, (mean 65.6 years) were treated with2Daunorubicin 60 mg/m iv day 1. Ara-C 120 mg/m2 SQ q 12 hours x 5 days and 6-TG 120 mg/m PO q 12 hours x 5 days (attenuated DAT). No patient had prior treatment. Therapy was well tolerated. Only 1 toxic death occurred. The response rate was 50% (29% CR; 21% PR) with response duration of 2-14 months. These results suggest that attenuated DAT chemotherapy can be administered safely and effectively to this elderly population.
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Transcript of (E3) Has survival improved in the past ten years?
Second International Conference on Myelodysplastic Syndromes
(E3) IiAS SURVIVAL IMPROVED IN THE PAST TEN YEARS?
Paul Reynolds, Anton Kruger, Shalal Sadullah. Terry Hamblin and David Oscier.
The prognosis of MDS depends largely on the stage at the time of diagnosis and the rate of disease progression. It is not clear whether active treatemnt in the form of chemotherapy or differentiating agents has made any appreciable impact on the survival prospects of these patients. Randomised controlled trials have proved notoriously difficult to set up. We have been able to observe the impact of the introduction of more active management, both in terms of specific therapy and in supportive care in a large number of patients in a single institution. The costs of these changes, both in terms of expense and morbidity are considerable and and need carefully to be measured against any potential survival benefit conferred by treatment
INVOLVEMENT OF RAR-a IN THE RA INDUCIBLE REGULATION OF MYELOID CELL DIFFERENTIATION
B.D. Hardas’, C.E.P. van Roozendaal’, A. Patel’, D. Darling’, 4. G&ken’, M. Petkovioh’. P. Chambon’ 8 F. Farzaneh’ ‘Molecular Medicine Unit. King’s College School of Medicine 8 Dentistry, Denmark Hill, London SE5 6RX, England; and ‘Laboratoire de G6n6tique Mol&ulaire des Eucaryotes du CNRS, Facult6 de M&ecine, 11 rue Humann. 67065 Strasbourg C&ax. France.
There is growing interest in usa of differentiation inducing agents, including retinoic acid (RA), in the clinical management of myeloid neoplasia. In order lo analyse the mode of action of RA, we have investigated its role in the induction of differentiation in the wild-type and differentiation resistant variants of the myelocytio oell line HL-60.
HL-R5 is a spontaneously arising clonal population of HL-60 variants which is resistant. specifically. lo the induction of granulocytic differentiation by RA. Transfection of HL-R5 cells with the human RA receptora (hRARo-O), confers susceptibility lo the induction of differentiation by RA. However, expression of exogenous hRAR-6 or hRAR-r does not result In RA inducible differentiation in HL-RS cells.
The suggestion of RARu involvement in the RA induosd differentia- tion of HL-60 calls has been confirmed by demonstrating a newly acquired oestrogen inducible differentiation in HL-60 cells transfected with a chimeric oestrogen receptor (hER) in which the DNA binding domain (ER. C domain) is substituted for the corresponding Comain of RARo. Interestingly, if the chimera contains not only the C domain but also the A/B domains of RARu, and only D 10 F domains of ER. there is no evidenoe of oestrogen inducible differentiation. This is despite the fact that both chime& receptors can induce the expression of co- transfected RA inducible reporter genes [(lRES),-tk-CAT].
These studies, which demonstrate the involvement of RARu, but not RAR-Q or RAR-r, in (he RA inducible differentiation of HL-60 cells. present the first evidence of functional specificity in the nuclear RAR’s In addition the chlmeric receptor studies suggest an important role for interdomain interactions for the RA/RAR-J induction of differentiation, but not the activation of all RA responsive elements.
(E7)
Intensive chemotherapy in MIX P. Fenaux, Lille, France.
Most patients (pts) with MDS are elderly and treated by supportive care only, by low dose chemotherapy or more recently growth factors. In younger MDS pts, allogeneic BMT is clearly a curative approach but it is currently limited to few pts. so that a place seams lo remain for intensive chemotherapy (C). However, induction chemotherapy with anthracycline - AraCcomblnationsorhighdosa AraChasonlygiven completeremission (CR) rates of 30 to 60% in MDS (irrespective of whether treatment was started in MDS phase or after progression to AML) ie significrntly less than in de now AML. These lower CR rates, in MDS, are due to a higher incidence of leukemic resistance but also of hypoplastic deaths (associated with longer periods of aplasia) than in de now AML. In addition median DFS. in MDS pts. is less than a year and no more than 5% of pts ara cured by IC.
Still, some subgroups of MDS may benefit from IC : pts less than 50 lo 55 (Tricot), pts with RAEBT at dlagnosis (as opposed to other FAB subtypes)(Bloomfield. Michels, Fenaux), and pts without ‘unfavourable” ka- ryotype (rearrangements ot chromosome 5 or 7, or complex rearrangements especially frequent in therapy related MDS) (Gajewskl, Fenaux) reach higher CR rates. We also found that normal karyotype was associated with a median DFS of 15 months, as opposed to 3 months in pts with abnormal karyotype; our 15 pts with RAE5T at diagnosis and normal karyotype had a CR rate of 60%, and a median DFS of 16 months, although most of them eventually relapsed. Allogeneic BMT, In RAE&T, seems to carry a high risk of relapse when performed asfirst line therapy (Appelbaum), and resultsobtained with ICsuggestthatthistreatmentcouldbetriedtoinducrCR(orpartialremistion) before BMT is attemped in RAEBT. In other types MDS allogeneic EMT, whenever possible, should probably be attempted as first line therapy.
The availiblllty of growth factors should allow the utilization of more intensive chemotherapy protocols In MDS, both for Induction and consolida- tion. Autologous BMThasvety rarely been altemped in MDS. tl could probably be investigated in ptswhose bone marrow has achieved good quality remis- sion (as assessed by cylogenetics and molecular biology) for adequate harvesting, after one or two courses of IC.
EFFECTIVENESS OF ATTENUATED CHEMOTHERAPY IN THE TREATMENT OF
MYELODYSPLASIA
Elizabeth Cyran, John M Bennett, Jacob Rowe, Michael Owens. Cancer Center and Dept of Medicine, University of Rochester, Rochester, New York.
Cytotoxic agents have been shown to be beneficial in some patients with myelodys- plastic syndromes (MDS). The advanced age of most patients contributes to unacceptable toxicities with aggressive chemotherapy treatment programs. An attenuated combination chemotherapy program was piloted as an alternative approach. 14 patients with MDS. ages 46-79, (mean 65.6 years) were treated with2Daunorubicin 60 mg/m iv day 1. Ara-C 120 mg/m2 SQ q 12 hours x 5 days and 6-TG 120 mg/m PO q 12 hours x 5 days (attenuated DAT). No patient had prior treatment. Therapy was well tolerated. Only 1 toxic death occurred. The response rate was 50% (29% CR; 21% PR) with response duration of 2-14 months. These results suggest that attenuated DAT chemotherapy can be administered safely and effectively to this elderly population.
