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(E3) Has survival improved in the past ten years?
Second International
(E3) IiAS SURVIVAL YEARS? Paul Reynolds, Terry Hamblin
Conference
INVOLVEMENT
IN THE PAST
Anton Kruger, Shalal and David Oscier.
OF
Syndromes
(E7)
IMPROVED
TEN
Sadullah.
The prognosis of MDS depends largely on and the at the time of diagnosis the stage It is not clear rate of disease progression. treatemnt in the form of active whether differentiating agents has chemotherapy or any appreciable impact on the survival made Randomised of these patients. prospects notoriously proved controlled trials have difficult to set up. We have been able to observe the impact of the introduction of more management, both in terms of specific active and in supportive care in a large therapy single institution. of patients in a number The costs of these changes, both in terms of considerable and and morbidity are expense and need carefully to be measured against any conferred by survival benefit potential treatment
REGULATION
on Myelodysplastic
RAR-a
OF MYELOID
IN
THE
RA
INDUCIBLE
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 differentiation 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 cotransfected 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.
Intensive chemotherapy in MIX P. Fenaux, Lille, France. Mostpatients (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 anthracyclineAraCcomblnationsorhighdosa AraChasonlygiven completeremission(CR) rates of 30 to 60% in MDS (irrespectiveof whether treatment was started in MDS phase or after progressionto AML) ie significrntlyless than in de now AML. These lowerCR rates, in MDS, are due to a higher incidenceof leukemic resistancebut also of hypoplasticdeaths (associatedwith longer periods of aplasia)than in de now AML. In additionmedian 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”karyotype (rearrangementsot chromosome5 or 7, or complex rearrangements especially frequent in therapy related MDS) (Gajewskl,Fenaux) reach higher CR rates.We also found that normal karyotypewas associatedwith a 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 linetherapy (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 availibllltyof growthfactors should allowthe utilizationof more intensivechemotherapy protocolsIn MDS, both for Inductionand consolidation.AutologousBMThasvety rarely been altemped in MDS. tl couldprobably be investigatedin ptswhose bone marrow has achieved good quality remission (as assessed by cylogenetics and molecular biology) for adequate harvesting,after one or two courses of IC.
EFFECTIVENESS OF ATTENUATED CHEMOTHERAPY IN THE TREATMENT MYELODYSPLASIA Elizabeth Cyran, John M Bennett, Michael Owens. Cancer Center Medicine, University of Rochester, New York.
OF
Jacob Rowe, and Dept of Rochester,
Cytotoxic agents have been shown to be beneficial in some patients with myelodysplastic 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 well tolerated.
prior treatment. Therapy was Only 1 toxic death occurred. rate was 50% (29% CR; 21% PR)
The response with response duration of 2-14 months. These results suggest that attenuated DAT chemotherapy can be administered safely and effectively to this elderly population.
(E3) IiAS SURVIVAL YEARS? Paul Reynolds, Terry Hamblin
Conference
INVOLVEMENT
IN THE PAST
Anton Kruger, Shalal and David Oscier.
OF
Syndromes
(E7)
IMPROVED
TEN
Sadullah.
The prognosis of MDS depends largely on and the at the time of diagnosis the stage It is not clear rate of disease progression. treatemnt in the form of active whether differentiating agents has chemotherapy or any appreciable impact on the survival made Randomised of these patients. prospects notoriously proved controlled trials have difficult to set up. We have been able to observe the impact of the introduction of more management, both in terms of specific active and in supportive care in a large therapy single institution. of patients in a number The costs of these changes, both in terms of considerable and and morbidity are expense and need carefully to be measured against any conferred by survival benefit potential treatment
REGULATION
on Myelodysplastic
RAR-a
OF MYELOID
IN
THE
RA
INDUCIBLE
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 differentiation 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 cotransfected 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.
Intensive chemotherapy in MIX P. Fenaux, Lille, France. Mostpatients (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 anthracyclineAraCcomblnationsorhighdosa AraChasonlygiven completeremission(CR) rates of 30 to 60% in MDS (irrespectiveof whether treatment was started in MDS phase or after progressionto AML) ie significrntlyless than in de now AML. These lowerCR rates, in MDS, are due to a higher incidenceof leukemic resistancebut also of hypoplasticdeaths (associatedwith longer periods of aplasia)than in de now AML. In additionmedian 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”karyotype (rearrangementsot chromosome5 or 7, or complex rearrangements especially frequent in therapy related MDS) (Gajewskl,Fenaux) reach higher CR rates.We also found that normal karyotypewas associatedwith a 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 linetherapy (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 availibllltyof growthfactors should allowthe utilizationof more intensivechemotherapy protocolsIn MDS, both for Inductionand consolidation.AutologousBMThasvety rarely been altemped in MDS. tl couldprobably be investigatedin ptswhose bone marrow has achieved good quality remission (as assessed by cylogenetics and molecular biology) for adequate harvesting,after one or two courses of IC.
EFFECTIVENESS OF ATTENUATED CHEMOTHERAPY IN THE TREATMENT MYELODYSPLASIA Elizabeth Cyran, John M Bennett, Michael Owens. Cancer Center Medicine, University of Rochester, New York.
OF
Jacob Rowe, and Dept of Rochester,
Cytotoxic agents have been shown to be beneficial in some patients with myelodysplastic 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 well tolerated.
prior treatment. Therapy was Only 1 toxic death occurred. rate was 50% (29% CR; 21% PR)
The response with response duration of 2-14 months. These results suggest that attenuated DAT chemotherapy can be administered safely and effectively to this elderly population.