- Email: [email protected]
Antiapoptotic therapy
Antiapoptotic
Therapy
Leukemia
Research 23 (1999) S77-S79
L~kiZiiZ Research
201
203
ANTI-APOPTOTIC THERAPY: OVER-RIDING THE CELL DEATH PROGRAM IN MDS. A.F. List. The Arizona Cancer Center and the University of Arizona, Tucson, AZ USA Therapeutic strategies that mitigate the accelerated rate of progenitor cell loss in MDS, offer the prospect to restore effective blood cell production. Features inherent to the MDS clone and the microenvironment contribute to a net decrease in trophic signals essential to progenitor survival. With the exception of CMML, MDS progenitors display impaired proliferative response to cytokine stimulation, despite normal receptor number and ligand binding capacity. Cellular expression of the fas receptor (CD95) and its ligand (FL) are up-regulated in MDS CD34fcells and contribute to activation of apoptosis in vitro. The intensity of CD95 expression inversely corr&tes with blast number whereas FL expression is preserved, indicating emergence of myeloblast populations with diminished capacity for fas-induced death with disease progression. Accumulating evidence indicates that small molecules generated by the MDS clone reinforce progenitor loss through the stimulation of pro-apoptotic cytokine elaboration, including TNFa, TGFP, IL-lp and IFNy. Neutralization studies and investigations linking plasma TNFa concentration to cellular depletion of glutathione and DNA oxidation in CD34’cells support an effector role for these cytokines in the pathobiology of MDS. Therapeutic agents which abrogate the generation or elaboration of pro-apoptotic cytokines have shown hemopoietic-promoting activity both in vitro and in preliminary clinical trials. The sulfated polyamine prodrug, amifostine, attenuates the secretion of TNFcr, and IL- 1p from marrow stroma, potent&es growth of primitive progenitors, and reduces the tiaction of apoptotic CD34’ ceils in MDS. Pharmacologic manipulation of apoptotic signals has broadened the opportunity for biologically directed therapeutic intervention.
SEQUENTIAL THERAPY WITH AMIFOSTINE, TOPOTECAN AND ETOPOSIDE INDUCED REPEATED RESPONSES IN PATIENTS WITH MYELODYSPLASTIC SYNDROME C.J. Rosenthal and A. Thapper SUNY Downstate Medical Ctr. and GIslandCollege Hospital-Brooklyn, N.Y. Amifostine (A.), a radiation and chemotherapy protector of normal tissues and Topotecan (T), a topoisomerase I inhibitor, were recently found capable to induce complete remission (CR) in some patients with myelodysplastic syndromes (MDS) (List AF et al, Blood 90: 3364.47; Beran Met al: Sem. Hem 35: 26, 1998) besides agents like pentoxifyline (PTX), ciprofloxacin (Cipro) and dexamethasone (D). The cause of these selective responses and their predictive factors remained unknown. In the current study of 9 patients (pts) with MDS (4 with RARS, 3 with RAEB and 2 with RAEB-T) we administered sequentially: A (200 mg/m’ t.i.w. x 3 wks q 5 wks x 3 cycles) then A (as above-2 cy) + PTX (800 mg po t.i.d.) + Cipro (500 mg po bid) x + D (12 mg po qd) x 15 wks. Ultimately the patient with RAEB and RAFB-T received T 1.5 mg/m*/24h by continuous intravenous infusion (C-1.) x 5 days followed by A 200 mg/m’/d i.v. brlus t.i.w. x 3 wks q 4 wks x 2 cy followed by Etoposide (E) a topoismerose 11 inhibitor (50 mg/n? po bid x 5 d) and T (1 mgim2/24hr) by c.i. x 5d followed by A (same as above). All pts. (4 females, 5 males age 62 to 81) tolerated these regimens with few side effects (bone marrow suppression caused by T and E and one progression to AML). We found that: A led to 50% increase of WBC in 6:9 pts.. I 10% increase of platelets in 4/9 pts and to the prolongation of PRBC’s transfusion interval by >3 fold; A + PTX + Cipro + D led to platelet response in other 3 pts; the duration of these responses was of 22 + 6 wks; T induced CR in 2 pts for 40 + 4 wks; t. or T induced CR in 2 other pts. Among several blood parameters we analyzed. the LDH>ZOO u/dl and erythropoietin ~30 u/d1 nrcdicted response to therapy in >80% of cases.
202
204
AMIFOSTINE IN THE TREATMENT OF MYELODYSPLASTIC SYNDROMES A crrossl, A Fabbn, V. Santmt, F Leoni, G Pagliq G. Longo, S Cmlh. and P Ross1 Femru Dwlsion of Hematology, Pohclmico Careggi, Florence. Italy
TREATMENT OF MYELODYSPLASTIC AMIFOSTINE.
SYNDROME (MDS) WITH
Amlfostme (EthwIB) stimulates in wtro hematowiesis from normal and
myelodysplasuc (MDS) progenitors, and prehnun& data indxated that it may be of use m ameliorating cytopenia of pattents with MDS (List et al. Blood 1997) We treated a group of 26 patients (13 R4 2 RARS, 2 CMML and 9 RAEB with bone mamow blasts less than 10%) with amifostmr (200 mr/m? three times a week) for 4 w&s, and 5 patients with RAJXB (wth bone mmw blasts 1 10%) with amifosnne at the same dosage for 6 weeks in combinanon wnh low-dose ARA-C (10 mp/m’ x Vday from day I to day 21). In the first group Hb increased (>l g/dL) in 6126 patients (23%), reticulcqtes in 11/26 (42%.), neuthrophils (>30% of basal v&xx) in 13/26 (50%) and platelets m Y/26 (34%). Ntne and three pattents presented a bdlnear and a mhnear unprov.ement respectively. Ten patients who were further treated with
a second co,,rsc of armfosnne admmistered at 3OOm@n?x 3 wk did not mproved their respose to treatment. Amifostine done reduced transfusion support (>50%) m 4126 patients. Combination regunen detenmned a CR in I panems and a bdvxxaee imnmvemcnt m 2 more cases: CR was assccmted with @“genetic [-del$q22j] normalization. At day 28 semm transfemn receptor (ST&) was found to be signi&mUy reduced compared to basal levels in I4/24 w&able patients (<0.02. Wilcoxon). A parallel incresase in Hb or ticul~e count and in sTfR was observed only in two patients. As high levels of sTfR are associated wtth In& and\or- meffectrve erythropoiens, its reduction in our ppulaticm of patients may indicate an amelioration of ineffective bone marrow activitv Basal and final EPO and TPO concentratmn~ were not s~gnu%mtIy ddicreht Five of 26 patients treated with amifostine alone and 315 with amifostine plus LD-ARA-C evolved ,nto acute leukemia during the follow up. In our eqetience armfostine was effective in ameliorating cytopeti at least in a group of patients with MDS, with few and nuld therapy-related side effects Ftntha larger studies are needed to bener define the usefuIness and schedule of adrrmustratmn of amifostme Moreover the efficacy of combination regunens with HGFs or ditTerenuatm&ytomxic dmgs is to be evaluated.
0145-2126/99/$-see front matter 0 1999 Published PII: SO1452126(99)00071-S
by Elsevier
The myelodysplastlc syndromes arc a hctcrogcncous group of clonal hematopolebc stem cell duorders characterized by mcffectwe hematopoxw and peripheral blood cytopemas. The chemoprotectwe agent, armfostme (Ethyl), has been reported to stimulate hemampolenc growth m panems wnh MIS both in wfro and in viva We have conducted a phase II study of anxfostme in patxots wrth MDS Armfostmr LSadrmrustrrrd aa a 2 week InductIon course at 340 mglm” IV over I5 nnnutes every Monday-Friday. Those patients showing response are eligible for a ma&nancc &ursc if armfostme gwen at 910 mg/ m’ IV once every week At thn tone, 21 pat,enfs were entered into the study and 20 are evaluable for response and toxxity One patient was excluded due to misdlagnoses The FAB class~ficauon of these patient mcluded 4 wth ret&tory anem,a (RA), I wth refractory anem,a wth rmecd szdcroblaats (RARS). I2 w,th refractorv anenua wfh oxccss blasts (RAEB): and 3 with ref&aory &enun with excess&lasts m hansfomutxon (RAEB-t). At entry, all 20 patients had anemia, 9 had trilmeage pancytopemas, and an addltmnal three had thrombocytopema. At day I5 following reduction therapy, 7 paoents (35%) met the cntena to be clawtied as responders and were placed on weekly mamtenancc therapy. 5 of these patients lasted on maintenance therapy only 2.4 week< hefore blood cowm fell to baseline. The fifth responder was on mantenancc for 7 weeks and deaded to hold therapy during a hohday week. On return two weeks later his hemoglobm had fallen from 9.6 to 8.0. The sixth responder received weekly anufostine for 12 weeks before requestmg removal from the study. In tins patlent, sequennal hone marrow bioprxe showed a greater than 50% decrease in blast cmmts. After stopping therapy, he remaned transfusion mdependent for 13 months. &de effects ofpatients on the study mcluded nausea, hypotension, cons~fratmn, sneezmg, and weakness and fatigue. No major t&&y was encountered. We con&de thar mmfostlne ha;benefic,aI hematopoietic effects on some patients with myelodysplastic syndrome that warmnt further investigarion. Weekly maintenance therapy appeared IO be beneficial m only a small minority of patients.
Science Ltd. All rights reserved
S78
Antiapoptotic Therapy
205 Treatment amifostine
207 of patients
with myelodysplastic
syndromes
with
K.L. Bourantas. St. Tsiara, E. Kapsali, N.Pritsivelis L. Christoo, P. Kaiafas Hematology Unit, University Hospital of Ioannina, Greece. Myelodysplastic syndromes (MDS) are an heterogenous group of diseases characterized by hyperplastic bone marrow and resistant cytopenia in the peripheral blood as a consequence of ineffective hematopoiesis MDS patients are primarily affected by anemia requiring repeated blood transfusions and secondary by severe neutropcnia and thrombocytopenia. Amifostine an aminothiol is a cytoprotective agent which ameliorates the toxicities of anticancer txatment. In vitro promotes the formation and survival of hematopoietic progenitor cells. In order to improve the peripheral blood values we administered amifostine in 7 MDS patients, 4 female and 3 male aged between 67 and 78 years old. The subtypes of MDS were: 2 patients had RAEB, four RA and one RAS. We administered 300mgr/n? amifostine three times a week for four weeks at least. All patients received also EPO 10.000 U three times a week. Three patients, two male with RAEB and RA respectively and a woman with RA, improved the levels of hemoglobin and did not received red cells blood transfusions after the second week of treatment with amifostine. ‘The patient with RAEB increased the total neutrophil count without increasing the blast percentage in bone marrow and peripheral blood. The drag administration was well tolerated. None of the patients experienced nausea, vomiting or hypotension. Conclusion: Amifostine administered at doses 300mgrim* three times weekly is a well tolerated treatment enhances the activity of EPO and reduces the need for blood transfusions in MDS patients.
Amifostine is an aminophosphothiol which was intially used as a cytoprotective agent against ionizing radiation, and subsequently to minimise myelosuppressive/nephrotoxic effects of agents such as cisplatin. Recent studies have suggzsted stimulation and promotion of haemopoietic activity in patients with MDS.‘,’ We have treated five patients with MDS with at least one course of amifostine starting with a dose of 200mg/m’ three times per week for three necks - Table. Three patients were given a second course at double the initial dose. One pnticnt rcccived a second course at the same dose and the final patient only reccivcd one course because of the development of a palpable purpuric rash possibly but not proven to be amifostiner&ted. Othcrwisc there wcrc no ill effects during or at&r administration. In rhc four tnnsfusion-depcndcnt patients there was no appreciable rise in Hb nor dccrcasc in transfusion rcquiremcnt. However, variable dcgrecs of rcticulocytosis were noted in three patients; in one patient (SO) thcrc was also a shyht incrcasc in Hb.
Conclusion: Amiroslinc as used in this slud! was nol assccinlcd will) an) sigllilicsnt clinical knclil Rcrcrcncc~- I. Proceedings ofASC0. Absl 21. 1997: 2. Br J Hacamtol 102~1 (Abst 1373).1998.
208
206 ROLE OF AMIFOSTINE IN PATIENTS MYELODYSPLASTIC SYNDROMES
AMIFOSTfNE IN THETREATMENT OF PATIENTS WITH MYELODYSPLASTIC SYNDROME (MDS). A.Manobaran, S. Iarscn Department of Clinical Haematology, St.Georgc Hospital, Kogarah, NSW, 2217, Australia.
WITH AGGRESSIVE
Reena Nair, Chandrica N. Nair, Suresh H. Advani. Memorial Hospital, INDIA.
Tata
Amifostine (Ethyol) promotes in vitro formation and survival of primitive hemato poietic progenitors from MDS bone marrow To characterize its clinical efficacy we conducted a phase II trial in 5 adult patients of Myelodysplastic Syndrome between April 1997 - March 1998. These patients received Amifostine in the dose of 500 mg weekly for six consecutive weeks followed by 2 weeks of observation. Bone marrow examination was done 2 weeks after the last dose and patients were evaluated for hematological response. Diagnosis included 4 patients of refractory anemia with excess blasts and one patient with refractory anemia with excess blasts in transformation. There were 3 male and 2 female patients in the age range of 42 - 71 years. Steady increase in the hemoglobin was seen in three patients while 2 patients remained transtision dependent on Amifostine. AI1 5 patients showed platelet count recovery to normal range while on Amifostine. Three patient had a partial response, and 2 patients progressed. One patient developed Acute Myeloid Leukemia within 3-6 weeks after stopping Amifostine. While Amifostine promotes multilineage hematopoiesis in vitro and it was well tolerated in our patients, its clinical effkacy in patients with aggressive sub types of MDS is questionable. While its role on the disease process is questionable, Amifostine definitely is useful as supportive care and may be used as adjuvant treatment.
AMIFOSTINE IN COMBINATION WITH ERYTHROPOIETIN AND G-CSF PROMOTES MULTILINEAGE HEMATOPOIESIS IN PATIENTS WITH MYELODYSPLASTIC SYNDROME (MDS) A PLOT STUDY. P. Neumeister, G. J&r, H.H. Schnudt and W. Linkesch. Divismn Hematology, Dept. of Internal Medicine, Karl-FranEens-Univsrslhl
of Grss,
The aminothml amifostine has shown to be effective in 83% of patients with MDS of various subtypes. The aim of our study was to evaluate amifostine in combination with hematopoletic growth factors in elderly patients not eligible for high dose chemotheraW regimens. Patients f&l with anemia < l&/d1 were treated with 250 mrrlm~ amifostine 3 ;;/ week for 4 consec&ve weeks foIlowed by 2 we& observation in combination with erythropoitin 150 I.U./kg bw daily SC. Responding patients received maintenance treatment using the same-B-week schedule. Nanresponder additionally received G-CSF lwg/kg bw daily SC during the second cycle of amifostine treatment. To avoid side effects cretreatrnent with 20 nw dexsmethssone and odansetrone wss administered before each &ifostie infusion. Disgrmses include refractmy anemia (R.4, n=4), RARS (n=ll, and s-RAEB (n=ll and RAEBt (n=3). 819 patients are evaIuable for hematoIa& response and toxicity. 7/S patients experienced smgIe- or multilineage hematologx improvement. 7/S ptr exhibited a ~-509/a increase in absolute neuhoohil count @NC1 (ranne ANC increase: 0.59-10.991. 5 ots ., experienced a > 1 ,O g/dI ;ise in hemoglobin level or a z 50% increase in reticulocyte count (range 4,5-169/01. In 5 thrombopsnic (=T < loOG/l) 3 pts showed a markedly increase in platelet nu&sr (range abs&s increase:~2-58 G/L) -one prior transfusion dependant resulted in completely platelet independency after 2 infusions of amifostine. Due to pretreatment toxicity was low with only one reversible hypotension episode. No progression to acute leukemia wss observed. These fmdings indicate that smifostine together with hematopoietic growth factors is weII tolerated and shows significant effciacy in pts with MD%
,
.-
Antiapoptotic Therapy 209 AMIFOSTINE HAEMATOPOIETIC CELL CYTOPROTECTION DEPENDENT UPON THE CYTOTOXIC STIMULUS. S S El-K&x, MD Hepburn & D T Bowen. Dept of Haematology, Ninewells Hospital & Medical School, Dundee, UK.
IS
Amlfostine is a synthetic antioxidant aminothiol with chemo / radicprotedant properties and which also stimulates in tifro and m viva haematopoiesis in patients with Myelodysplastic Syndromes (MDS). We have tested the m vitro cytopmtective propeties of Amifostine, in haematopoietic cells subject to various cytotoxic stimuli. Cell systems studied were a) MDS cell line P39 treated with all-tram retinoic acid (ATRA 1pM n=5), or with Etoposide (1OpM n=2), and b) normal bone marrow mononuclear cells (BMMNC) treated with ATRA (1pM n=2), Etoposide (1OpM n=2), or TNFa (IO&ml ~4). All cells were preincubated with Amifostine (US Bioscience) at a final concentration of 0.5 mM or with RPMI(IMDM)/FCS alone, at 37?Z for 15 minutes. Cellular qtctoxicity was assayed by single cell gel electrophoresis (SCGE) to detect DNA single strand breaks (SSB) and nucledide oxidation (OPN). Amifostine pre-treatment exerted a protective effect from Etoposide toxicity in BMMNC, reducing SSB frequency m 1 of 2 experiments and OPN frequency in both (median 80% reduction), and also in P39 cells reducing SSB and OPN frequency in both experiments (median 20 and 100% reduction). Amifostine also protected P39 cells from ATRA induced damage reducing SSB frequency in 4 of 5 experiments (median 58% reduction) and OPN frequency in all 5 (median 88% reduction) though no consistent results were seen with ATRA + BMMNC. ln contrast, Amafostine pre-treatment augmented the cytotoxic effect of TNFa u1 BMMNC increasing SSB frequency in 2 of 4 experiments (median II% mcrease) and OPN frequency in 3 of 4 (median 279% increase) Redox effects as evidenced by changes in nucleottde oxidation mediated both cytoprc@ct~on and augmentation of cytotoxicity by Amlfostme. MDS cells are inherently more resistant to m wlro TNFa/Fas induced apoptosis than are nomul cells. Our results suggest that chemoprotection by Amifostine IS dependent both upon the cytotoxic stimulus and factors intrinsic to the target cell.
s79
Therapy
Leukemia
Research 23 (1999) S77-S79
L~kiZiiZ Research
201
203
ANTI-APOPTOTIC THERAPY: OVER-RIDING THE CELL DEATH PROGRAM IN MDS. A.F. List. The Arizona Cancer Center and the University of Arizona, Tucson, AZ USA Therapeutic strategies that mitigate the accelerated rate of progenitor cell loss in MDS, offer the prospect to restore effective blood cell production. Features inherent to the MDS clone and the microenvironment contribute to a net decrease in trophic signals essential to progenitor survival. With the exception of CMML, MDS progenitors display impaired proliferative response to cytokine stimulation, despite normal receptor number and ligand binding capacity. Cellular expression of the fas receptor (CD95) and its ligand (FL) are up-regulated in MDS CD34fcells and contribute to activation of apoptosis in vitro. The intensity of CD95 expression inversely corr&tes with blast number whereas FL expression is preserved, indicating emergence of myeloblast populations with diminished capacity for fas-induced death with disease progression. Accumulating evidence indicates that small molecules generated by the MDS clone reinforce progenitor loss through the stimulation of pro-apoptotic cytokine elaboration, including TNFa, TGFP, IL-lp and IFNy. Neutralization studies and investigations linking plasma TNFa concentration to cellular depletion of glutathione and DNA oxidation in CD34’cells support an effector role for these cytokines in the pathobiology of MDS. Therapeutic agents which abrogate the generation or elaboration of pro-apoptotic cytokines have shown hemopoietic-promoting activity both in vitro and in preliminary clinical trials. The sulfated polyamine prodrug, amifostine, attenuates the secretion of TNFcr, and IL- 1p from marrow stroma, potent&es growth of primitive progenitors, and reduces the tiaction of apoptotic CD34’ ceils in MDS. Pharmacologic manipulation of apoptotic signals has broadened the opportunity for biologically directed therapeutic intervention.
SEQUENTIAL THERAPY WITH AMIFOSTINE, TOPOTECAN AND ETOPOSIDE INDUCED REPEATED RESPONSES IN PATIENTS WITH MYELODYSPLASTIC SYNDROME C.J. Rosenthal and A. Thapper SUNY Downstate Medical Ctr. and GIslandCollege Hospital-Brooklyn, N.Y. Amifostine (A.), a radiation and chemotherapy protector of normal tissues and Topotecan (T), a topoisomerase I inhibitor, were recently found capable to induce complete remission (CR) in some patients with myelodysplastic syndromes (MDS) (List AF et al, Blood 90: 3364.47; Beran Met al: Sem. Hem 35: 26, 1998) besides agents like pentoxifyline (PTX), ciprofloxacin (Cipro) and dexamethasone (D). The cause of these selective responses and their predictive factors remained unknown. In the current study of 9 patients (pts) with MDS (4 with RARS, 3 with RAEB and 2 with RAEB-T) we administered sequentially: A (200 mg/m’ t.i.w. x 3 wks q 5 wks x 3 cycles) then A (as above-2 cy) + PTX (800 mg po t.i.d.) + Cipro (500 mg po bid) x + D (12 mg po qd) x 15 wks. Ultimately the patient with RAEB and RAFB-T received T 1.5 mg/m*/24h by continuous intravenous infusion (C-1.) x 5 days followed by A 200 mg/m’/d i.v. brlus t.i.w. x 3 wks q 4 wks x 2 cy followed by Etoposide (E) a topoismerose 11 inhibitor (50 mg/n? po bid x 5 d) and T (1 mgim2/24hr) by c.i. x 5d followed by A (same as above). All pts. (4 females, 5 males age 62 to 81) tolerated these regimens with few side effects (bone marrow suppression caused by T and E and one progression to AML). We found that: A led to 50% increase of WBC in 6:9 pts.. I 10% increase of platelets in 4/9 pts and to the prolongation of PRBC’s transfusion interval by >3 fold; A + PTX + Cipro + D led to platelet response in other 3 pts; the duration of these responses was of 22 + 6 wks; T induced CR in 2 pts for 40 + 4 wks; t. or T induced CR in 2 other pts. Among several blood parameters we analyzed. the LDH>ZOO u/dl and erythropoietin ~30 u/d1 nrcdicted response to therapy in >80% of cases.
202
204
AMIFOSTINE IN THE TREATMENT OF MYELODYSPLASTIC SYNDROMES A crrossl, A Fabbn, V. Santmt, F Leoni, G Pagliq G. Longo, S Cmlh. and P Ross1 Femru Dwlsion of Hematology, Pohclmico Careggi, Florence. Italy
TREATMENT OF MYELODYSPLASTIC AMIFOSTINE.
SYNDROME (MDS) WITH
Amlfostme (EthwIB) stimulates in wtro hematowiesis from normal and
myelodysplasuc (MDS) progenitors, and prehnun& data indxated that it may be of use m ameliorating cytopenia of pattents with MDS (List et al. Blood 1997) We treated a group of 26 patients (13 R4 2 RARS, 2 CMML and 9 RAEB with bone mamow blasts less than 10%) with amifostmr (200 mr/m? three times a week) for 4 w&s, and 5 patients with RAJXB (wth bone mmw blasts 1 10%) with amifosnne at the same dosage for 6 weeks in combinanon wnh low-dose ARA-C (10 mp/m’ x Vday from day I to day 21). In the first group Hb increased (>l g/dL) in 6126 patients (23%), reticulcqtes in 11/26 (42%.), neuthrophils (>30% of basal v&xx) in 13/26 (50%) and platelets m Y/26 (34%). Ntne and three pattents presented a bdlnear and a mhnear unprov.ement respectively. Ten patients who were further treated with
a second co,,rsc of armfosnne admmistered at 3OOm@n?x 3 wk did not mproved their respose to treatment. Amifostine done reduced transfusion support (>50%) m 4126 patients. Combination regunen detenmned a CR in I panems and a bdvxxaee imnmvemcnt m 2 more cases: CR was assccmted with @“genetic [-del$q22j] normalization. At day 28 semm transfemn receptor (ST&) was found to be signi&mUy reduced compared to basal levels in I4/24 w&able patients (<0.02. Wilcoxon). A parallel incresase in Hb or ticul~e count and in sTfR was observed only in two patients. As high levels of sTfR are associated wtth In& and\or- meffectrve erythropoiens, its reduction in our ppulaticm of patients may indicate an amelioration of ineffective bone marrow activitv Basal and final EPO and TPO concentratmn~ were not s~gnu%mtIy ddicreht Five of 26 patients treated with amifostine alone and 315 with amifostine plus LD-ARA-C evolved ,nto acute leukemia during the follow up. In our eqetience armfostine was effective in ameliorating cytopeti at least in a group of patients with MDS, with few and nuld therapy-related side effects Ftntha larger studies are needed to bener define the usefuIness and schedule of adrrmustratmn of amifostme Moreover the efficacy of combination regunens with HGFs or ditTerenuatm&ytomxic dmgs is to be evaluated.
0145-2126/99/$-see front matter 0 1999 Published PII: SO1452126(99)00071-S
by Elsevier
The myelodysplastlc syndromes arc a hctcrogcncous group of clonal hematopolebc stem cell duorders characterized by mcffectwe hematopoxw and peripheral blood cytopemas. The chemoprotectwe agent, armfostme (Ethyl), has been reported to stimulate hemampolenc growth m panems wnh MIS both in wfro and in viva We have conducted a phase II study of anxfostme in patxots wrth MDS Armfostmr LSadrmrustrrrd aa a 2 week InductIon course at 340 mglm” IV over I5 nnnutes every Monday-Friday. Those patients showing response are eligible for a ma&nancc &ursc if armfostme gwen at 910 mg/ m’ IV once every week At thn tone, 21 pat,enfs were entered into the study and 20 are evaluable for response and toxxity One patient was excluded due to misdlagnoses The FAB class~ficauon of these patient mcluded 4 wth ret&tory anem,a (RA), I wth refractory anem,a wth rmecd szdcroblaats (RARS). I2 w,th refractorv anenua wfh oxccss blasts (RAEB): and 3 with ref&aory &enun with excess&lasts m hansfomutxon (RAEB-t). At entry, all 20 patients had anemia, 9 had trilmeage pancytopemas, and an addltmnal three had thrombocytopema. At day I5 following reduction therapy, 7 paoents (35%) met the cntena to be clawtied as responders and were placed on weekly mamtenancc therapy. 5 of these patients lasted on maintenance therapy only 2.4 week< hefore blood cowm fell to baseline. The fifth responder was on mantenancc for 7 weeks and deaded to hold therapy during a hohday week. On return two weeks later his hemoglobm had fallen from 9.6 to 8.0. The sixth responder received weekly anufostine for 12 weeks before requestmg removal from the study. In tins patlent, sequennal hone marrow bioprxe showed a greater than 50% decrease in blast cmmts. After stopping therapy, he remaned transfusion mdependent for 13 months. &de effects ofpatients on the study mcluded nausea, hypotension, cons~fratmn, sneezmg, and weakness and fatigue. No major t&&y was encountered. We con&de thar mmfostlne ha;benefic,aI hematopoietic effects on some patients with myelodysplastic syndrome that warmnt further investigarion. Weekly maintenance therapy appeared IO be beneficial m only a small minority of patients.
Science Ltd. All rights reserved
S78
Antiapoptotic Therapy
205 Treatment amifostine
207 of patients
with myelodysplastic
syndromes
with
K.L. Bourantas. St. Tsiara, E. Kapsali, N.Pritsivelis L. Christoo, P. Kaiafas Hematology Unit, University Hospital of Ioannina, Greece. Myelodysplastic syndromes (MDS) are an heterogenous group of diseases characterized by hyperplastic bone marrow and resistant cytopenia in the peripheral blood as a consequence of ineffective hematopoiesis MDS patients are primarily affected by anemia requiring repeated blood transfusions and secondary by severe neutropcnia and thrombocytopenia. Amifostine an aminothiol is a cytoprotective agent which ameliorates the toxicities of anticancer txatment. In vitro promotes the formation and survival of hematopoietic progenitor cells. In order to improve the peripheral blood values we administered amifostine in 7 MDS patients, 4 female and 3 male aged between 67 and 78 years old. The subtypes of MDS were: 2 patients had RAEB, four RA and one RAS. We administered 300mgr/n? amifostine three times a week for four weeks at least. All patients received also EPO 10.000 U three times a week. Three patients, two male with RAEB and RA respectively and a woman with RA, improved the levels of hemoglobin and did not received red cells blood transfusions after the second week of treatment with amifostine. ‘The patient with RAEB increased the total neutrophil count without increasing the blast percentage in bone marrow and peripheral blood. The drag administration was well tolerated. None of the patients experienced nausea, vomiting or hypotension. Conclusion: Amifostine administered at doses 300mgrim* three times weekly is a well tolerated treatment enhances the activity of EPO and reduces the need for blood transfusions in MDS patients.
Amifostine is an aminophosphothiol which was intially used as a cytoprotective agent against ionizing radiation, and subsequently to minimise myelosuppressive/nephrotoxic effects of agents such as cisplatin. Recent studies have suggzsted stimulation and promotion of haemopoietic activity in patients with MDS.‘,’ We have treated five patients with MDS with at least one course of amifostine starting with a dose of 200mg/m’ three times per week for three necks - Table. Three patients were given a second course at double the initial dose. One pnticnt rcccived a second course at the same dose and the final patient only reccivcd one course because of the development of a palpable purpuric rash possibly but not proven to be amifostiner&ted. Othcrwisc there wcrc no ill effects during or at&r administration. In rhc four tnnsfusion-depcndcnt patients there was no appreciable rise in Hb nor dccrcasc in transfusion rcquiremcnt. However, variable dcgrecs of rcticulocytosis were noted in three patients; in one patient (SO) thcrc was also a shyht incrcasc in Hb.
Conclusion: Amiroslinc as used in this slud! was nol assccinlcd will) an) sigllilicsnt clinical knclil Rcrcrcncc~- I. Proceedings ofASC0. Absl 21. 1997: 2. Br J Hacamtol 102~1 (Abst 1373).1998.
208
206 ROLE OF AMIFOSTINE IN PATIENTS MYELODYSPLASTIC SYNDROMES
AMIFOSTfNE IN THETREATMENT OF PATIENTS WITH MYELODYSPLASTIC SYNDROME (MDS). A.Manobaran, S. Iarscn Department of Clinical Haematology, St.Georgc Hospital, Kogarah, NSW, 2217, Australia.
WITH AGGRESSIVE
Reena Nair, Chandrica N. Nair, Suresh H. Advani. Memorial Hospital, INDIA.
Tata
Amifostine (Ethyol) promotes in vitro formation and survival of primitive hemato poietic progenitors from MDS bone marrow To characterize its clinical efficacy we conducted a phase II trial in 5 adult patients of Myelodysplastic Syndrome between April 1997 - March 1998. These patients received Amifostine in the dose of 500 mg weekly for six consecutive weeks followed by 2 weeks of observation. Bone marrow examination was done 2 weeks after the last dose and patients were evaluated for hematological response. Diagnosis included 4 patients of refractory anemia with excess blasts and one patient with refractory anemia with excess blasts in transformation. There were 3 male and 2 female patients in the age range of 42 - 71 years. Steady increase in the hemoglobin was seen in three patients while 2 patients remained transtision dependent on Amifostine. AI1 5 patients showed platelet count recovery to normal range while on Amifostine. Three patient had a partial response, and 2 patients progressed. One patient developed Acute Myeloid Leukemia within 3-6 weeks after stopping Amifostine. While Amifostine promotes multilineage hematopoiesis in vitro and it was well tolerated in our patients, its clinical effkacy in patients with aggressive sub types of MDS is questionable. While its role on the disease process is questionable, Amifostine definitely is useful as supportive care and may be used as adjuvant treatment.
AMIFOSTINE IN COMBINATION WITH ERYTHROPOIETIN AND G-CSF PROMOTES MULTILINEAGE HEMATOPOIESIS IN PATIENTS WITH MYELODYSPLASTIC SYNDROME (MDS) A PLOT STUDY. P. Neumeister, G. J&r, H.H. Schnudt and W. Linkesch. Divismn Hematology, Dept. of Internal Medicine, Karl-FranEens-Univsrslhl
of Grss,
The aminothml amifostine has shown to be effective in 83% of patients with MDS of various subtypes. The aim of our study was to evaluate amifostine in combination with hematopoletic growth factors in elderly patients not eligible for high dose chemotheraW regimens. Patients f&l with anemia < l&/d1 were treated with 250 mrrlm~ amifostine 3 ;;/ week for 4 consec&ve weeks foIlowed by 2 we& observation in combination with erythropoitin 150 I.U./kg bw daily SC. Responding patients received maintenance treatment using the same-B-week schedule. Nanresponder additionally received G-CSF lwg/kg bw daily SC during the second cycle of amifostine treatment. To avoid side effects cretreatrnent with 20 nw dexsmethssone and odansetrone wss administered before each &ifostie infusion. Disgrmses include refractmy anemia (R.4, n=4), RARS (n=ll, and s-RAEB (n=ll and RAEBt (n=3). 819 patients are evaIuable for hematoIa& response and toxicity. 7/S patients experienced smgIe- or multilineage hematologx improvement. 7/S ptr exhibited a ~-509/a increase in absolute neuhoohil count @NC1 (ranne ANC increase: 0.59-10.991. 5 ots ., experienced a > 1 ,O g/dI ;ise in hemoglobin level or a z 50% increase in reticulocyte count (range 4,5-169/01. In 5 thrombopsnic (=T < loOG/l) 3 pts showed a markedly increase in platelet nu&sr (range abs&s increase:~2-58 G/L) -one prior transfusion dependant resulted in completely platelet independency after 2 infusions of amifostine. Due to pretreatment toxicity was low with only one reversible hypotension episode. No progression to acute leukemia wss observed. These fmdings indicate that smifostine together with hematopoietic growth factors is weII tolerated and shows significant effciacy in pts with MD%
,
.-
Antiapoptotic Therapy 209 AMIFOSTINE HAEMATOPOIETIC CELL CYTOPROTECTION DEPENDENT UPON THE CYTOTOXIC STIMULUS. S S El-K&x, MD Hepburn & D T Bowen. Dept of Haematology, Ninewells Hospital & Medical School, Dundee, UK.
IS
Amlfostine is a synthetic antioxidant aminothiol with chemo / radicprotedant properties and which also stimulates in tifro and m viva haematopoiesis in patients with Myelodysplastic Syndromes (MDS). We have tested the m vitro cytopmtective propeties of Amifostine, in haematopoietic cells subject to various cytotoxic stimuli. Cell systems studied were a) MDS cell line P39 treated with all-tram retinoic acid (ATRA 1pM n=5), or with Etoposide (1OpM n=2), and b) normal bone marrow mononuclear cells (BMMNC) treated with ATRA (1pM n=2), Etoposide (1OpM n=2), or TNFa (IO&ml ~4). All cells were preincubated with Amifostine (US Bioscience) at a final concentration of 0.5 mM or with RPMI(IMDM)/FCS alone, at 37?Z for 15 minutes. Cellular qtctoxicity was assayed by single cell gel electrophoresis (SCGE) to detect DNA single strand breaks (SSB) and nucledide oxidation (OPN). Amifostine pre-treatment exerted a protective effect from Etoposide toxicity in BMMNC, reducing SSB frequency m 1 of 2 experiments and OPN frequency in both (median 80% reduction), and also in P39 cells reducing SSB and OPN frequency in both experiments (median 20 and 100% reduction). Amifostine also protected P39 cells from ATRA induced damage reducing SSB frequency in 4 of 5 experiments (median 58% reduction) and OPN frequency in all 5 (median 88% reduction) though no consistent results were seen with ATRA + BMMNC. ln contrast, Amafostine pre-treatment augmented the cytotoxic effect of TNFa u1 BMMNC increasing SSB frequency in 2 of 4 experiments (median II% mcrease) and OPN frequency in 3 of 4 (median 279% increase) Redox effects as evidenced by changes in nucleottde oxidation mediated both cytoprc@ct~on and augmentation of cytotoxicity by Amlfostme. MDS cells are inherently more resistant to m wlro TNFa/Fas induced apoptosis than are nomul cells. Our results suggest that chemoprotection by Amifostine IS dependent both upon the cytotoxic stimulus and factors intrinsic to the target cell.
s79