22 Third International Symposium on Myelodysplastic Syndromes

Update on Juvenile CML: Pathogenesis and Treatment

PETER D. EMANUEL, M.D. University of Alabama at Blrmlngham, Birmingham, AL, USA

Juvenile chronic myelogenous leukemia (JCML) is a myelo- proliferative d&order affecting children under the age of 4. It has similarities to, but appears to be distinct from, monosomy 7 syndrome. JCML patients respond poorly to conventional chemotherapy. Bone marrow tinsplait has resulted in some cures but the relapse rate remains high. The flnal results of a pilot trial using 13-cis retlnoic acid in previously untreated JCML oatients will be oresented. Although retinoic add does not appe& curative, it may serve as an important adjunct prior to transplant, or potentially post-transplant to prevent relapse.

In vitro, JCML peripheral blood progenitor cells grow “spontaneously” forming exuberant numbers of predominantly, but not exclusively, monocytic colonies. The pathophysiology of JCML has been-iinked td a selective growth-hyp&se&itiv@ to GM-CSF inherent ln the JCML hematopoietic progenitor cells. Over the last 8 years, we haw studled 60- JCML &d &onosomy 7 patient samples in vitro. “Spontaneous” colony growth has been a unifying, but not pathognomonic, feature. 39 of the JCML patient samples have been evaluated for ability of anti- GM-CSF to inhibit “spontaneous” growth. The median inhibition was 88% ? 10 SEM. 42 JCML patient samples have been tested for selective hypersensitivity to GM-CSF and all 42 have demonstrated this characteristic. Further data will be presented to show that other cvtoklnes do not play a role in this hypersensitive growth- response. Additional cases will be oresented that show the notential utilitv of usinn GM-CSF hypersensitivity dose respohse assays as ah early inldicator of disease relapse post-transplant.

Phase III multicenter randomized trial in RAEB patients of more than 60 years of age: Am-C 3mg/m2 versus symptomatic treatment

C. CHOMIENNE, CHEVRET S, R. BEAUNE, NAJEiAN Y AND THE GFM: Drs FENAUX, GUERCI. SOUTEYRAND. LEPEU, BOULAT’, DOR, SOLARY. MIJOVIC. GRIS. SCHEVD. GROBOIS, JAISSON. SALLE& ZItiOUN; BLETRY; NEUMANN, DEVIDAS, MOLHO-SABATIER. BRICE. BUSSEL) Service +z Mt?dec%e Nuc@ire, yparte+nt &. Biostastistiq~e et kzqz hii$le, HSp~tal Samt Louts, Pans, France. Upjohn

. To evaluate the efficacy of monthly nzgimens of Am-C on the stival of RAEB patients of more than 60 years of age. 98 patients were randomized since october 1989, in group A (n=47): Am-C 3mg/m2x2 daily s.c.(15davs a month for 12 months) and arouo B(n=51) with sym~tomiic treatment with or without androgen~timedian f&ow- up after randomisation (til death or the last information) was of 8 months (15days to 43 months). The mean survival of the RAEB patients was similar in both groups. with 41 deaths in group A versus 42deathsingroupB,andamediansurvivalof9monthsingroupA versus 10 months in group B. Amongst the 83 deaths observed, the main cause of death was leukemia (group A, n=lO versus group B, n=17) or infection (group A, =16 versus group B, n=13).In conclusion, compared to a control group. very low dose am-C does not increase survival in RAEB patients. However, when the population was strat&d in homogeneous orottnostic grouos, a trend in improved survival in am-C r&xl pad&s {A: d&en& between control and am-c treated patients)was ohserv& in RAEB patknts with plateletxloO.l09/l (n=&, A=i7months,p=O.25, log I& test) or in RAEB patients with platelets<loO. 109/l and absence of infection at diagnosis (n=28, A=l8months.p=O.l6. log rank test). These results strongly suggest that thcrapcutic hails in MDS should he conducted in groups of homogeneous prognosis.

Treatment of Advanced Primary Myebdysplastk Syndro- mes with AML-Type Cbemotbempy: Raults in 76 Patients

C. AUL. V. RUNDE, N. GAlTERMAN N. U. GERMING. W. SCHNEIDER Departmem of Internal Medicine, Hematology and Gncology Division, Heinrich- Heme-University, Diisseldorf, Germany Objective: Previous studies have suggested that intensive chemotherapy in MDS is Bssoeiptcd with low rates of colnplctc ranksions and considerable toxicity. These easumpti~ however, arc baaed on small ptknt serks. Maferlul~: We rcnospectively aaalyzed the outcome of 76 patients (median age 54 yrs. range 16-72 yrs) with advaaxd pinmy MDS who were treated with aggnxsive mtileukemk regimens at our hospital from 1979 to 1993. Tbe median time from Uisgmsis of MDS to initiatkm of clxmo tlpy was 1.5 montbs (range, 051 mo). FABtypesattrcahnentbcginwereRAEBm ,CMMLm4,aadRAEB~m33ca- ses; 33

r ‘em had plnady fsansfomxd tn AML. The Kamnfsky score was c 70%

in13.7 -9O%in37and>9O%in26patients.chromosam sludie..s were perfolmed in 51 patients of whom 22 (43%) prese~~ted with an abnormal karyotype. 58 patients received TAD, 9 ~stkn& idambicm + Am<, 6 patients a double-induction regimen, and 3 pi3Uem other protocols for remission induction. Results: 48 patkn& (63%) catered complete remission, aad 10 patients (13%) bad a

e rcsponsc.Esrlydeathoccumdin11cases(15%),and7patients(99b)hadre-

tory Lsease. No onusnal toxicities of chanotkapy were noted. The nxdian du- ration of honk marrow aplasia (kukocytes < 1x109/1 and/or platelets < 20~10911) for patients achieving CR after TAD was 17 days. After entering CR, 38 patients recei- ved 1 to 2 cycles of consolidation cbemotkm py and 18 patients monthly myelosup- prfssive maintenance c hemokrapy over a maximum period of 3 years. Median fol- low-up of tbe patients is now 16 manths. Median overall survival after the start of cbemnthempy is 13 nxmtbs. Dii-free. survival estimated by lie-table analysis is 29% at 3 years and 21% at 5 years. Using univariate analyses, the following para- meters were found to be significantly correlated with successful remission induction the fenx

y: 1. meduliary blast cell count < 30% (CR rates 78% vs. 42%; p < 0.05). 2. sex (77% vs. 53%; p < 0.05), and 3. absence of bkedii at the start of che-

mothmpy (77% vs. 47%, p c 0.05). Patients with normal cytogenetics had higher CR rates than those with an abnormal karyotype (76% vs. 54%). but tbis difference did not reach statistkal significance. Conclusir~~: Intensive AML-type chemotherapy CM be successfully administexd to patients with high-risk MDS. In selected patients, this approach offers a chance of long-&m remission and potential cure.