Leukemia Research Vol. 14, No. 8, pp. 731-733, 1990.
0145-2126/90 $3.00 + .00 Pergamon Press plc
Printed in Great Britain.
DIFFERENTIATING AND
AGENTS
IN THE TREATMENT
MYELODYSPLASTIC LAURENT
OF LEUKEMIA
SYNDROMES
DEGOS
H6pital Saint Louis, 1, av. Claude Vellefaux, Paris 10e, France (Received 15 January 1990. Accepted 15 March 1990)
Abstract--Differentiation therapies try to change the malignant cell in order to acquire a more mature or normal phenotype. Various ways were tested in leukemia: suppression the proliferative pressure by low dose Ara-C, enhancement of the differentiation by retinoic acid derivatives or by differentiation factors, and modulation of the cell metabolism interrupting an autocrine loop (a growth factor and its receptor). The treatment is given continuously at small doses, during a long period of time. In all these cases it seems necessary to tailor the differentiation therapy to each category of leukemia. Key words: Differentiation therapy, leukemia, low dose Ara-C, all-trans retinoic acid, interferon alpha.
INTRODUCTION
of differentiation without inhibiting proliferation by retinoic acid in promyelocytic leukemia; and (3) cutting of an autocrine loop (growth factor and its receptor) through inducing differentiation by alpha interferon in hairy cell leukemia. To improve differentiation in cases of myelodysplasia is a more complex procedure since the factors currently available also induce proliferation of the malignant cells. In all these cases it seems necessary to tailor the differentiation therapy to each individual tissue and tumor type. Differentiation therapy is often administered continuously, at small doses and over an extended period of time. Relapse occurs when the treatment is interrupted but it is often possible to resume the same treatment with satisfactory results. The correspondance between results in vitro and in vivo is good.
DIFFERENTIATION therapy is in its infancy. It is based on the possibility of restoring the balance between proliferation and differentiation which is damaged in cases of malignancy. This can be attempted in two ways: either by suppressing the pressure of proliferation and consequently releasing differentiation, or by increasing differentiation, thus entailing a subsequent inhibition of the proliferative activity. Leukemia and myelodysplastic syndromes are good models. Through blood and bone marrow samples a precise, informative survey is easily accessible. Moreover, several growth and differentiation factors have been identified and cloned in myeloid and lymphoid lineages. Differentiation therapy lends itself to several different situations: extinction of tumors; improvement of differentiation myelodysplasia; chemoprevention; modulation of phenotype tumor cells (in order to make them more accessible to other agents); adjuncts to chemotherapy or radiotherapy; and extracorporeal purging of tumor cells. It is a new and open field for the therapy of malignancies. We shall concentrate on three models of clinical trials concerning tumor extinction: (1) inhibition of proliferation by low doses of Ara-C; (2) induction
1. Low dose Ara-C and acute myeloid leukemia Because it is mainly in elderly people that the administration of conventional doses of cytotoxic drugs is complicated by severe adverse effects of bone marrow aplasia and because results in vitro show that low concentrations of Ara-C can induce differentiation, low dose (LD)-Ara-C was given as an initial treatment to elderly A M L patients [1-4]. In all categories of leukemia [2] it is possible to obtain complete remission (CR) via the administration of LD-Ara-C (10 m g / m 2 twice daily for 21 days). This is particularly true in the case of elderly patients [3] with hypoplastic bone marrow [5]. A trial comparing the results of conventional intensive
Abbreviations: AML, acute myeloid leukemia; Ara-C, cytosine arabinoside; CR, complete remission; PR, partial remission; RA, retinoic acid; IFN, interferon; HCL, hairy cell leukemia; GM-CSF, granulocyte-macrophage colony stimulating factor. Correspondence to: L. Degos, H6pital Saint Louis, 1, av. Claude Vellefaux, Paris 10e, France. 731
732
L. DEGOS
chemotherapy and LD-Ara-C revealed similar curves [6]. However, the LD-Ara-C treated population presented less CR (35% vs 50%), fewer cases of early death (10% vs 35%) and an increase in the frequency of partial remission (PR) (15% vs 0%) as compared to the population treated by conventional intensive chemotherapy. The number of transfusions (RBC and platelets) in the LD-Ara-C group was 50% inferior to the number necessary in the conventional intensive chemotherapy group and the number of severe infections was also greatly reduced. Moreover, 10% of the LD-Ara-C population achieved CR without transfusion and, in some cases, without hospitalization [6]. In conclusion, in elderly patients, conventional therapy induces an increase in both the CR and the mortality rates whereas LD-Ara-C induces CR and PR with comparatively few complications. The small, continuously adminstered doses, the progressive evolution, the absence of aplasia before remission in some privilegious cases and the occasional simultaneous presence of islets of promyelocytes and leukemic cells are arguments in favour of a differentiating effect; however, in the majority of cases a hypoplastic or aplastic phase occurs with this treatment. Furthermore, when intensive chemotherapy is used to induce severe aplastic anemia in order to destroy leukemic cells, the CR thus obtained is sometimes due to a differentiating effect operating on the malignant cells. Indeed, the mature (granulocytes), so-called normal cells derive from a malignant clone in 30% of the cases [7].
2. Retinoic acid and promyelocytic leukemia In-vitro studies of leukemic cells have demonstrated retinoic acid's specific ability to induce differentiation of promyelocytic leukemic cells (M3). 13-cis and all trans-retinoic acid (RA) are able to induce differentiation [8]; this is not true of esterethyl. Various controversial results have been obtained with 13-cis but some CR have been reported [91. Conversely, the Chinese have treated more than 24 patients with all trans-RA (45 mg/m 2 daily) thus obtaining 96% with no disseminated intravascular coagulation (DIC) [10]. The WBC increased during the first 2 weeks (x 10) with the simultaneous presence of leukemic and more mature cells. Subsequently, the WBC and the formula became normal. Aplasia was never induced. We confirmed the efficacy of trans-RA [9] and, by in-vitro assays, we found a difference in sensitivity between all trans and 13-cis-RA with a higher sensitivity in the case of the former [9].
Retinoic acid has three nuclear receptors: alpha; beta; and gamma. The alpha receptor has been located on chromosome 17 close to the break point of translocation 15-17; this finding has opened new avenues for research at the DNA and RNA level. The beta receptor is located on chromosome 3.
3. Alpha interferon (1FN) and hairy cell leukemia (HCL) Clinical trials have demonstrated the specific efficacy of alpha (but not gamma) interferon in the treatment of HCL. Recovery is very slowly progressive (1 year). The disappearance of spleen and hairy cells in the blood (1 month) is followed by a recovery from thrombopenia (1 to 2 months), from anemia (3 months), the disappearance of HC in the bone marrow (6 months) and a recovery from neutropenia (6-12 months) [11, 12]. If the treatment is interrupted, there is a recurrence of the disease but it again responds favourably when the same treatment is resumed. Hairy cells are IFN's target. Down regulation of receptors, change in enzyme activity, modulation of oncogenes and the cutting of the autocrine loop BCGF/receptor BCGF have all been demonstrated. The putative BCGF receptor (CD23) is not modulated at the membrane but CD23 is decreased in the supernatant. It is possible that other growth factor autocrine loops may be cut as well. 4. Treatment of myelodysplastic disorders Myelodysplastic disorders are defined by an impairment of myeloid cell maturation. Many trials have been performed: (i) very low dose Ara-C alone or associated with androgen, there have been some favourable results [13]; (ii) 13-cis-RA alone (versus placebo), no positive results have been noted [14]; (iii) 13-cis-RA, 6-mercaptopurine, vincristin and LD-Ara-C, no positive results have been noted [15]; (iv) vitamin D3, or alpha IFN, no positive results have been noted; (v) gamma IFN, there have been some encouraging results [16]; (vi) GM-CSF, there have been some encouraging results but also an increase in blast cells [17]. Several trials are currently being carried out. CONCLUSION There is no longer any doubt that differentiation therapy is a useful tool. The all-RA model in LAM3 has furnished evidence of pure differentiation of malignant cells. LD-Ara-C inhibits proliferation thus entailing an increase in differentiation. In HCL alpha IFN blocks an autocrine loop of growth by modifying the cell's genetic program.
Differentiation therapy of leukemia A new way of effectively treating malignancies has been discovered.
REFERENCES 1. Housset M., Daniel M. T. & Degos L. (1982) Small doses of Ara-C in the treatment of acute myeloid leukemia differentiation of myeloid leukemia cells? Br. J. Haemat. 51, 125. 2. Castaigne S., Daniel M. T., Tilly H., Herait P. & Degos L. (1983) Does treatment with Ara-C in low dosage cause differentiation of leukemic cells? Blood 62, 85. 3. Degos L., Castaigne S., Tilly H., Sigaux F. & Daniel M. T. (1985) Treatment of leukemia with low dose Ara-C: a study of 160 cases. Semin. Oncol. 13, 196. 4. Shtalrid M., Lotem J., Sachs L. & Berrebi A. (1987) Review of clinical and haematological response to lowdose cytosine arabinoside in acute myeloid leukaemia. Eur. J. Haemat. 38, 3. 5. Tilly H., Castaigne S., Bordessoule D., Sigaux F., Daniel M. T., Monconduit M. & Degos L. (1985) Low-dose cytosine arabinoside treatment for acute non lymphocytic leukemia in elderly patients. Cancer 55, 1633. 6. Tilly H., Castaigne S., Bordessoule D., Casassus Ph., Le Pris6 P. Y., Tertian G., Desableux B., Henry-Amar M. & Degos L. (1990) Low-dose cytosine arabinoside versus intensive chemotherapy in the treatment of acute non lymphoblastic leukemia in elderly. J clin. Oncol. 8, 272. 7. Fearon E. R., Burke P. J., Schiffer C. A., Zehnbauer B. A. & Vogelstein B. (1986) Differentiation of leukemia cells to polymorphonuclear leukocytes in patients with acute nonlymphocytic leukemia. New Engl. J. Med. 315, 15. 8. Chomienne C., Balitrand N., Cost H., Degos L. & Abita J. P. (1986) Structure activity relationships of aromatic retinoids on the differentiation of the human histiocytic lymphoma cell line U-937. Leukemia Res. 10, 130l. 9. Chomienne C., Ballerini P., Balitrand N., Amar M., Bernard J. F., Boivin I., Daniel M. T., Berger R., Castaigne S. & Degos L. (1989) Retinoic acid = an
733
alternative therapy of promyelocytic leukemia. Lancet i, 746. 10. Huang M. E., Ye Yi., Chen S. R., Chai J. R., Lu J. X., Zhoa L., Gu L. J., Wang Z. I. (1988) Use of alltrans-retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72, 567. 11. Castaigne S., Sigaux F,, Cantell K., Falcoff E., Boiron M., Flandrin G. & Degos L. (1986) Interferon o~in the treatment of hairy leukemia. Cancer 57, 1681. 12. Flandrin G., Sigaux F., Castaigne S., Billard C., Aguet M., Boiron M., Falcoff E. & Degos L. (1986) Treatment of hairy cell leukemia with recombinant alpha interferon. I. Quantitative study of bone marrow changes during the first months of treatment. Blood 67, 817. 13. Chomienne C., Najean Y., Degos L., Thomas G., Baumelou E., Calvo F., Casassus P., Ciccone F., Fenaux P., Gris J. C., Gros J. C., Grosbois B. V., Guerci O., Lepeu G., Rain J. D., Rolovic A., Turpin R. & Souteyrand F. (1987) Present results of the treatment of myelodysplastic syndromes with low-dose cytosine arabinoside. Acta Haemat. 78, 109. 14. Francis G. E. & Finsky (1988) Clinical trials of differentiation therapy: current trials and future prospects. In The Status of Differentiation Therapy of Cancer (Waxman S., Brossi G. & Takaku F., Eds), Vol. 45, p. 331. Raven Press, New York. 15. Ho A. D., Martin H., Knauf W., Reichardt P., Trumpet L. & Hunstein W. (1987) Combination of low-dose cytarabine and 13-cis retinoic acid in the treatment of myelodysplastic syndromes. Leukemia Res. ll, 1041. 16. Gavosso F., Maiozo A. T., Aglietta M.. Alimena G., Bernasconi C., Castoldi G.. Gazzola M.. Cortelezzi A., Nandelli F., Resegotti L. & Polli E. (1988) Treatment with interferon gamma in myelodysplastic syndromes: a pilot study. In The Status of Differentiation Therapy of Cancer (Waxman S., Brossi G. & Takaku F., Eds), Vol. 45, p. 375. Raven Press, New York. 17. Ganser A., Vokers B., Greher H., Walther F. & Hoelzer D. (1988) Recombinant human granulocytemacrophage colony-stimulating factor in patients with myelodysplastic syndromes--a phase I/ll trial. Onkologie l, 53.
0145-2126/90 $3.00 + .00 Pergamon Press plc
Printed in Great Britain.
DIFFERENTIATING AND
AGENTS
IN THE TREATMENT
MYELODYSPLASTIC LAURENT
OF LEUKEMIA
SYNDROMES
DEGOS
H6pital Saint Louis, 1, av. Claude Vellefaux, Paris 10e, France (Received 15 January 1990. Accepted 15 March 1990)
Abstract--Differentiation therapies try to change the malignant cell in order to acquire a more mature or normal phenotype. Various ways were tested in leukemia: suppression the proliferative pressure by low dose Ara-C, enhancement of the differentiation by retinoic acid derivatives or by differentiation factors, and modulation of the cell metabolism interrupting an autocrine loop (a growth factor and its receptor). The treatment is given continuously at small doses, during a long period of time. In all these cases it seems necessary to tailor the differentiation therapy to each category of leukemia. Key words: Differentiation therapy, leukemia, low dose Ara-C, all-trans retinoic acid, interferon alpha.
INTRODUCTION
of differentiation without inhibiting proliferation by retinoic acid in promyelocytic leukemia; and (3) cutting of an autocrine loop (growth factor and its receptor) through inducing differentiation by alpha interferon in hairy cell leukemia. To improve differentiation in cases of myelodysplasia is a more complex procedure since the factors currently available also induce proliferation of the malignant cells. In all these cases it seems necessary to tailor the differentiation therapy to each individual tissue and tumor type. Differentiation therapy is often administered continuously, at small doses and over an extended period of time. Relapse occurs when the treatment is interrupted but it is often possible to resume the same treatment with satisfactory results. The correspondance between results in vitro and in vivo is good.
DIFFERENTIATION therapy is in its infancy. It is based on the possibility of restoring the balance between proliferation and differentiation which is damaged in cases of malignancy. This can be attempted in two ways: either by suppressing the pressure of proliferation and consequently releasing differentiation, or by increasing differentiation, thus entailing a subsequent inhibition of the proliferative activity. Leukemia and myelodysplastic syndromes are good models. Through blood and bone marrow samples a precise, informative survey is easily accessible. Moreover, several growth and differentiation factors have been identified and cloned in myeloid and lymphoid lineages. Differentiation therapy lends itself to several different situations: extinction of tumors; improvement of differentiation myelodysplasia; chemoprevention; modulation of phenotype tumor cells (in order to make them more accessible to other agents); adjuncts to chemotherapy or radiotherapy; and extracorporeal purging of tumor cells. It is a new and open field for the therapy of malignancies. We shall concentrate on three models of clinical trials concerning tumor extinction: (1) inhibition of proliferation by low doses of Ara-C; (2) induction
1. Low dose Ara-C and acute myeloid leukemia Because it is mainly in elderly people that the administration of conventional doses of cytotoxic drugs is complicated by severe adverse effects of bone marrow aplasia and because results in vitro show that low concentrations of Ara-C can induce differentiation, low dose (LD)-Ara-C was given as an initial treatment to elderly A M L patients [1-4]. In all categories of leukemia [2] it is possible to obtain complete remission (CR) via the administration of LD-Ara-C (10 m g / m 2 twice daily for 21 days). This is particularly true in the case of elderly patients [3] with hypoplastic bone marrow [5]. A trial comparing the results of conventional intensive
Abbreviations: AML, acute myeloid leukemia; Ara-C, cytosine arabinoside; CR, complete remission; PR, partial remission; RA, retinoic acid; IFN, interferon; HCL, hairy cell leukemia; GM-CSF, granulocyte-macrophage colony stimulating factor. Correspondence to: L. Degos, H6pital Saint Louis, 1, av. Claude Vellefaux, Paris 10e, France. 731
732
L. DEGOS
chemotherapy and LD-Ara-C revealed similar curves [6]. However, the LD-Ara-C treated population presented less CR (35% vs 50%), fewer cases of early death (10% vs 35%) and an increase in the frequency of partial remission (PR) (15% vs 0%) as compared to the population treated by conventional intensive chemotherapy. The number of transfusions (RBC and platelets) in the LD-Ara-C group was 50% inferior to the number necessary in the conventional intensive chemotherapy group and the number of severe infections was also greatly reduced. Moreover, 10% of the LD-Ara-C population achieved CR without transfusion and, in some cases, without hospitalization [6]. In conclusion, in elderly patients, conventional therapy induces an increase in both the CR and the mortality rates whereas LD-Ara-C induces CR and PR with comparatively few complications. The small, continuously adminstered doses, the progressive evolution, the absence of aplasia before remission in some privilegious cases and the occasional simultaneous presence of islets of promyelocytes and leukemic cells are arguments in favour of a differentiating effect; however, in the majority of cases a hypoplastic or aplastic phase occurs with this treatment. Furthermore, when intensive chemotherapy is used to induce severe aplastic anemia in order to destroy leukemic cells, the CR thus obtained is sometimes due to a differentiating effect operating on the malignant cells. Indeed, the mature (granulocytes), so-called normal cells derive from a malignant clone in 30% of the cases [7].
2. Retinoic acid and promyelocytic leukemia In-vitro studies of leukemic cells have demonstrated retinoic acid's specific ability to induce differentiation of promyelocytic leukemic cells (M3). 13-cis and all trans-retinoic acid (RA) are able to induce differentiation [8]; this is not true of esterethyl. Various controversial results have been obtained with 13-cis but some CR have been reported [91. Conversely, the Chinese have treated more than 24 patients with all trans-RA (45 mg/m 2 daily) thus obtaining 96% with no disseminated intravascular coagulation (DIC) [10]. The WBC increased during the first 2 weeks (x 10) with the simultaneous presence of leukemic and more mature cells. Subsequently, the WBC and the formula became normal. Aplasia was never induced. We confirmed the efficacy of trans-RA [9] and, by in-vitro assays, we found a difference in sensitivity between all trans and 13-cis-RA with a higher sensitivity in the case of the former [9].
Retinoic acid has three nuclear receptors: alpha; beta; and gamma. The alpha receptor has been located on chromosome 17 close to the break point of translocation 15-17; this finding has opened new avenues for research at the DNA and RNA level. The beta receptor is located on chromosome 3.
3. Alpha interferon (1FN) and hairy cell leukemia (HCL) Clinical trials have demonstrated the specific efficacy of alpha (but not gamma) interferon in the treatment of HCL. Recovery is very slowly progressive (1 year). The disappearance of spleen and hairy cells in the blood (1 month) is followed by a recovery from thrombopenia (1 to 2 months), from anemia (3 months), the disappearance of HC in the bone marrow (6 months) and a recovery from neutropenia (6-12 months) [11, 12]. If the treatment is interrupted, there is a recurrence of the disease but it again responds favourably when the same treatment is resumed. Hairy cells are IFN's target. Down regulation of receptors, change in enzyme activity, modulation of oncogenes and the cutting of the autocrine loop BCGF/receptor BCGF have all been demonstrated. The putative BCGF receptor (CD23) is not modulated at the membrane but CD23 is decreased in the supernatant. It is possible that other growth factor autocrine loops may be cut as well. 4. Treatment of myelodysplastic disorders Myelodysplastic disorders are defined by an impairment of myeloid cell maturation. Many trials have been performed: (i) very low dose Ara-C alone or associated with androgen, there have been some favourable results [13]; (ii) 13-cis-RA alone (versus placebo), no positive results have been noted [14]; (iii) 13-cis-RA, 6-mercaptopurine, vincristin and LD-Ara-C, no positive results have been noted [15]; (iv) vitamin D3, or alpha IFN, no positive results have been noted; (v) gamma IFN, there have been some encouraging results [16]; (vi) GM-CSF, there have been some encouraging results but also an increase in blast cells [17]. Several trials are currently being carried out. CONCLUSION There is no longer any doubt that differentiation therapy is a useful tool. The all-RA model in LAM3 has furnished evidence of pure differentiation of malignant cells. LD-Ara-C inhibits proliferation thus entailing an increase in differentiation. In HCL alpha IFN blocks an autocrine loop of growth by modifying the cell's genetic program.
Differentiation therapy of leukemia A new way of effectively treating malignancies has been discovered.
REFERENCES 1. Housset M., Daniel M. T. & Degos L. (1982) Small doses of Ara-C in the treatment of acute myeloid leukemia differentiation of myeloid leukemia cells? Br. J. Haemat. 51, 125. 2. Castaigne S., Daniel M. T., Tilly H., Herait P. & Degos L. (1983) Does treatment with Ara-C in low dosage cause differentiation of leukemic cells? Blood 62, 85. 3. Degos L., Castaigne S., Tilly H., Sigaux F. & Daniel M. T. (1985) Treatment of leukemia with low dose Ara-C: a study of 160 cases. Semin. Oncol. 13, 196. 4. Shtalrid M., Lotem J., Sachs L. & Berrebi A. (1987) Review of clinical and haematological response to lowdose cytosine arabinoside in acute myeloid leukaemia. Eur. J. Haemat. 38, 3. 5. Tilly H., Castaigne S., Bordessoule D., Sigaux F., Daniel M. T., Monconduit M. & Degos L. (1985) Low-dose cytosine arabinoside treatment for acute non lymphocytic leukemia in elderly patients. Cancer 55, 1633. 6. Tilly H., Castaigne S., Bordessoule D., Casassus Ph., Le Pris6 P. Y., Tertian G., Desableux B., Henry-Amar M. & Degos L. (1990) Low-dose cytosine arabinoside versus intensive chemotherapy in the treatment of acute non lymphoblastic leukemia in elderly. J clin. Oncol. 8, 272. 7. Fearon E. R., Burke P. J., Schiffer C. A., Zehnbauer B. A. & Vogelstein B. (1986) Differentiation of leukemia cells to polymorphonuclear leukocytes in patients with acute nonlymphocytic leukemia. New Engl. J. Med. 315, 15. 8. Chomienne C., Balitrand N., Cost H., Degos L. & Abita J. P. (1986) Structure activity relationships of aromatic retinoids on the differentiation of the human histiocytic lymphoma cell line U-937. Leukemia Res. 10, 130l. 9. Chomienne C., Ballerini P., Balitrand N., Amar M., Bernard J. F., Boivin I., Daniel M. T., Berger R., Castaigne S. & Degos L. (1989) Retinoic acid = an
733
alternative therapy of promyelocytic leukemia. Lancet i, 746. 10. Huang M. E., Ye Yi., Chen S. R., Chai J. R., Lu J. X., Zhoa L., Gu L. J., Wang Z. I. (1988) Use of alltrans-retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72, 567. 11. Castaigne S., Sigaux F,, Cantell K., Falcoff E., Boiron M., Flandrin G. & Degos L. (1986) Interferon o~in the treatment of hairy leukemia. Cancer 57, 1681. 12. Flandrin G., Sigaux F., Castaigne S., Billard C., Aguet M., Boiron M., Falcoff E. & Degos L. (1986) Treatment of hairy cell leukemia with recombinant alpha interferon. I. Quantitative study of bone marrow changes during the first months of treatment. Blood 67, 817. 13. Chomienne C., Najean Y., Degos L., Thomas G., Baumelou E., Calvo F., Casassus P., Ciccone F., Fenaux P., Gris J. C., Gros J. C., Grosbois B. V., Guerci O., Lepeu G., Rain J. D., Rolovic A., Turpin R. & Souteyrand F. (1987) Present results of the treatment of myelodysplastic syndromes with low-dose cytosine arabinoside. Acta Haemat. 78, 109. 14. Francis G. E. & Finsky (1988) Clinical trials of differentiation therapy: current trials and future prospects. In The Status of Differentiation Therapy of Cancer (Waxman S., Brossi G. & Takaku F., Eds), Vol. 45, p. 331. Raven Press, New York. 15. Ho A. D., Martin H., Knauf W., Reichardt P., Trumpet L. & Hunstein W. (1987) Combination of low-dose cytarabine and 13-cis retinoic acid in the treatment of myelodysplastic syndromes. Leukemia Res. ll, 1041. 16. Gavosso F., Maiozo A. T., Aglietta M.. Alimena G., Bernasconi C., Castoldi G.. Gazzola M.. Cortelezzi A., Nandelli F., Resegotti L. & Polli E. (1988) Treatment with interferon gamma in myelodysplastic syndromes: a pilot study. In The Status of Differentiation Therapy of Cancer (Waxman S., Brossi G. & Takaku F., Eds), Vol. 45, p. 375. Raven Press, New York. 17. Ganser A., Vokers B., Greher H., Walther F. & Hoelzer D. (1988) Recombinant human granulocytemacrophage colony-stimulating factor in patients with myelodysplastic syndromes--a phase I/ll trial. Onkologie l, 53.
