NEOPLASMA 18, 5, 197]
`
`493
`
`d-Azacytidine in Childhood Leukemia
`
`O. HropeK, J. VESELY
`
`2nd Children Clinie, Faculty of Pediatrics, Charles University and Lnstitute of Organic
`Chemistry and Biochemistry, Czechoslovak Academy of Sciences, Prague, Czechoslovakia
`
`Received April 21, 1971
`
`5-Azacytidine was given to 20 children with acute leukemia and to
`one chitd with chronic myeloid leukemia. The application of 5-Azaeytidine
`alone during the induction offirst remission resulted, in 90°, eases in a eon-
`siderable (lecrease of leukocyte counts,
`in the clisappearance of blasts from
`the blood or in their depression and in an improvementof clinical symptoms.
`After the addition of Prednisone to 5-Azacytidine or after the initial combi-
`nation of Prednisone with 5-Azacytidine, a complete remission was obtained
`in 10 out of 12 cases (83.3°,). During more advanced periods of leukemia
`evolution the combination of 5-Azacytidine with Prednisone caused deple-
`tion of leukocytes and blasts in the blood in 75, of cases without substantial
`influence on the bone marrow. The tolerance of 5-Azacytidine is good,
`Pronounced clinieal improvement with transient normalization of the blood
`formula was observed in one child with typical chronic myeloid leukemia.
`
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`In recent years numerous analogues which interfere withcellular nucleic acids
`metabolism have been investigatedfor their effect upon various malignant neoplasms
`in both experimental animals and humans,
`5-Azacytidine (5-AzCR), a compound closely resembling cytidine in chemical
`structure (Fig. 1) has been synthesized by PiskALA and Sorm[12]. It is incorpo-
`rated with cell nucleic acids [11] and it affects RNA synthesis de novo by inhibiting
`orotidylic acid decarboxylase [16]. In mice, its effects are directed primarily against
`lymphoid tissue and bone marrow causing a considerable depression of RNA and
`DNAsynthesis especially in large lymphocytes and myeloid cells [17]. The drug is
`capable of provoking interruption of pregnancy in mice [14] and, at nontoxic doses
`to mothers it causes almost complete destruction of
`mouse fetuses or their malformations [13]. Its inhibi-
`tory effect on the growth of leukemic cells in mice is
`particularly remarkable [15, 16]. On account of favou-
`rable action of 5-Azacytidine against experimental
`leukemia
`it
`seemed
`desirable to investigate its
`effect wpon hemoblastosis in children.
`This report summarizes for the first time the re-
`sults obtained with 5-Azacytidine in twenty children
`with acute leukemia, and in one child with chronic mVve-
`loid leukemia treated at the 2nd Children Clinic in
`Prague (16 cases of acute leukemia and 1 case of
`chronic myeloid leukemia), and at
`the Department
`of Pediatrics, Prof. R. GosTor, Prague City Hospital,
`Bulovka(4 cases of acute leukemia in 1967—1970).
`
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`5-AZACYTIDINE IN CHILDHOOD LEUKEMIA 495
`
`Leukemias were classified on the morphological and cytochemical basis. The
`group including blast
`leukemias of nonmyeloid origin (undifferentiated,
`lympho-
`blastic and lymphoreticular) with negative Sudan Black reaction and with PAS
`reaction positive to a different degree was designated as ALL. Leukemias with
`myeloblasts showing positive Sudan Black reaction and negative granular reaction.
`to glycogen were specified as AML.
`For the evaluation of therapeutic response, the internationally accepted criteria
`for the classification of complete remission in children [2, 7] were employed: A. In
`the bone marrow the disappearance of morphological aberrations and the decrease
`of blasts under 5 per cent, lymphocytosis under 20 per cent, normal granulo-, ery-
`thro- and thrombocytopoiesis. B. In the blood hemoglobin values higher than 11
`Gm. per cent, in children younger than 2 years 10 Gm. per cent. normal numberof
`leukoeytes and circulating granulocytes, the thrombocyte count above 100 000 per
`cmm,. C. The disappearance of abnormal physical findings. D. The disappearance
`of the clinical symptoms of the disease.
`that received 5-Azacytidine during
`First group includes 7 children (Table 1)
`the initial phase of the disease as the only medication at the dose level of 1-2 mg
`per kg daily besides
`transfusions which were sometimes inevitable on account
`of serious anemia. 5-Azacytidine was administered only in cases with leukocyte
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`8 years, ALL.
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`S-AZACYTIDINE IN CHILDHOOD LEUKEMIA 497
`
`count more than 4000 per cmm and without grave hemorrhagic diathesis which
`would render the intramuscular application impossible. The therapy was disconti-
`nued when 1. the findings in the bone marrowindicated that the treatment did not
`result in a complete remission after 14 to 30 days, or 2. when the decrease in. the
`leukocyte or thrombocyte count indicated. the discontinuance of 5-Azacytidine and
`corticoid treatment or of the combination of both of these drugs.
`The results are summarized in Table 1. It is evident that in all cases with the
`exception of case number 5 the administration of 5-Azacytidine resulted in a consi-
`derable depression of leukocyte counts as well as of blasts in the blood (case No. 1,
`leukocyte count 11 200 per emm and 78 per cent blasts to 1700 and 13 percent;
`case No. 2, leukocyte count 42 700 per emmand59 per cent blasts to 3900 and blast
`disappearance: case No. 3, leukocyte count 26 000 per cmmand 64 per cent blasts
`to 7250 and 25 per cent;
`case No. 4,
`leukocyte
`count 10500 per
`cmm
`and 37 per cent blasts to 2000 and 5 per cent;
`case No. 6,
`leukocytefed
`count 19 000 per emmand 61 per cent blasts to 4900 and 21 per cent; case No. 7,
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`Fig. 3. Hematological evolution during the induction offirst remission in patient No. 2,
`4 years, ALL.
`
`
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`leukocyte count 10 200 per
`emm to 4470 and 2.5 per
`cent blasts.
`In 6 out of 7 cases (ex-
`cept case No. 7) theclinical
`condition distinctly impro-
`ved: regression of fever and
`of bone pains could be ob-
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`These remissions appeared
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`S-AYACYTIDINE IN CHILDHOOD LEUKEMIA 499
`
`The typical course of changes during the inductionoffirst remission with 5-AzCR
`is shown in Figs 2.3.
`Hig. 2 gives the leukocyte and erythrocyte counts including blasts (per cent)
`in S-years old boy suffering of ALL. 5-Azacytidine was given for 2 weeks at a total
`closage of 800 mg. The leukocyte count decreased during that period progressively
`from 11 200 to 1700 per emmandblasts from 78 to 13 per cent. After another two
`weeks of therapy upon addition of Prednisoneblasts disappeared from the blood and
`bone marrowand the blood formula returned to normal values. First remission with
`6-Mereaptopurine maintenance therapy lasted 16 months.
`Fig. 3 illustrates the evolution in 4-years old girl with ALL. The leukocyte
`count prior to therapy was 42 700 per cmmand 59 per cent blasts. 5-Azacytidine
`Was given over a l-month period at a total dose of 350 mg. Following first injection
`(2 mg/kg)
`the leukocyte count dropped rapidly to 3600 per emm and_ blasts
`diminished to 28 per cent. Following further injections the leukocyte count remained
`stabilized after l-month treatment at 3900 per cmm and no blasts were present.
`In bone marrow smears blasts diminished from 94 to 56 per cent. Complete clinical
`anc hematological remission after further 11 days following Prednisone (2 mg/kg)
`administration was obtained. First remission lasted 6 months with 6-Mercaptopurine
`maintenance therapy.
`The second group includes + children with ALL treated at the Department of
`Pediatrics. Prague City Hospital. Bulovka in 1967—68 (Tab. 2). In three cases ae
`after 5 weeks (case No. 3) combination of 5-Azacytidine with Prwiuienaae was vali.
`
`therapy was initiated with 5-Azacytidine and after 1 week (case No.
`
`1 and 2),
`
`«
`
`nistered, 5-Azacytidine alone promoted a rapid decrease of the leukocyte count
`(case No.
`1 from 6200 to 38100 per cmm, case No. 2 from 239 000 to 147 000) per
`emm and case No. 3 from 5600 and 17 per cent blasts to 3600 per emm and 0). In
`the remaining case the therapy was initiated with Prednisone during the first week
`and then the combination 5-Azacytidine and Prednisone was given. Complete clinical
`and hematological remission was obtained after 6 weeks in case No. 1, 5 weeks
`(case No. 2). 7 weeks (case No. 3) and after 4 weeks in the remaining case. Bone
`marrow examination was performed repeatedly only in case No. 1. Later on 5-Aza-
`cytidine was given in combination with different drugs while the patients were in
`relapse. The resulting remissions, however, were only partial.
`The third group includes three children with ALL wherethefirst remission was
`induced with Prednisone in combination with 5-Azacytidine (Table 3). In the first
`child suffering of peracute leukemia with leukocyte count 163 000 per emm and
`8 per cent blasts in the blood, the combination of both drugs normalized the leuko-
`cevte count and depressed blasts to 16 per cent. Clinical condition improved but the
`amelioration in the bone marrow was only partial. Further therapy with 6-Mer-
`captopurine in combination with Prednisone resulted in further depletion of leuko-
`eytes and blasts in the blood while in the bone marrowtheir percentage did not
`change. The disease ended after 4 weeks without remission. The patient developed
`a serious aplasia and expired.
`In the second child with ALL, hematological examination revealed leukocyte
`count 51 000 per cmm and 63 per cent blasts in the blood. 5-Azacytidine with Pred-
`nisone were given with good effect (lenkoeyte count 1600 and 9 per cent blasts but
`to obtain a complete remission prolonged treatment with Prednisone and Precni-
`sone-6-Mercaptopurine-Oncovin combination was necessary. The remission lasted
`5 months,
`
`
`
`

`

`500
`
`HRODEK, VESELY
`
`13 000 per cmm and 33 per
`In the third child with ALL (leukocyte count
`cent blasts in the blood) the combination therapy resulted within 2 weeks in a rapid
`fall of leukocyte count to 1500 per emmand3 per cent blasts. Complete remission
`was obtainedafter further week of treatment with Prednisone alone. First remission
`lasted 7 wecks.
`In the last group including 6 children there were 3 patients with ALL that re-
`
`LEUKOCYTES
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`ERYTHROCYTES
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`TRANSFUSION
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`MYLECYTAN
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`Fig. 4. Hematological evolution during the induction of first remission in 5-years old
`patient suffering of chronic myeloid leukemia. (Mylecytan 2 mg daily and less.)
`
`

`

`
`
`5-AZACYTIDINE IN CHILDHOOD LEUKEMIA 5oT
`
`ceived 5-Azacytidine or Prednisone in combination with 5-Azacytidine during the
`first relapse, and 3 cases (2 with ALL and 1 with AML) that were given the same
`medication during the terminal stage of the disease following the development of
`resistance to different analogues. The decreased leukocyte count with a considerable
`drop of blasts in the blood could be registered in 4 out of 6 cases (2 during thefirst
`relapse and 2 during the terminal stage): however, bone marrow remained. unaffec-
`ted. In one child during the first relapse that did not react with a complete remission
`to the combination of Prednisone with 5-Azacytidine such a remission could be
`obtained with Prednisone and Oncovin.
`Of considerable interest
`is the case of 5-years old boy suffering of typical
`chronic myelosis. Before admission his parents noted fever, anorexia and enlarged
`abdomen. Physical examination revealed an enormous splenomegaly; the enlarge-
`ment of the liver was less considerable while the lymph nodes were not palpable.
`Hematological examination revealed serious anaemia and hyperleukocytosis (hemo-
`globin 42 per cent and red blood count 2 millions per emm; leukocyte count 460 000
`per cmm all maturation stages of white cells were present). The numberof basophils
`and eosinophils was elevated, the thrombocyte count was normal. Leukocytic alka-
`line phosphatases were low (score under 5), fetal hemoglobin 5 per cent. The course
`of the disease and the response to 5-Azacytidine (1-3 mg/kg daily) is illustrated in
`the Fig. 4. Within four weeks of treatment with 5-azacytidine (total dosage 760 mg)
`the leukocyte count dropped to 111 000 per emm. The therapy was discontinued
`and further depression to 3600 per emmwith transitory normalization ofdifferential
`count lasting 3 weeks was observed. The spleen decreased to about half the pre-
`treatment size and the erythrocyte count improved, while the thrombocyte count
`remained normal; only one transfusion was given following the admission. Later
`on, however, the leukocyte count increased to 26 000 per emm, all maturation forms
`again appearedincluding blasts (7 per cent). At this moment, 5-Azacytidine treatment
`was re-instituted. Atfirst the leukocyte count increased to 97 000 per cmmand then
`returned to normal values. However, the improvement was not of long duration.
`Intermittent leukocytosis at that stage was partially controlled with Myleran (0.06
`mg/kg daily). The spleen was palpable 3—4 cm belowthe costal margin. Also the
`thrombocyte count had an intermittent character.
`
`Conclusions
`
`1. The application of 5-Azacytidine alone during the induction phase of the
`first remission resulted in 90 °, of children in a considerable depression of leukocyte
`count, decrease or disappearance of blasts in the blood accompanied with thealle-
`viation of clinical symptoms and of abnormal physical findings. The improvement
`in the bone marrowwas either partial or insignificant.
`Complete remission was obtained only wpon addition of Prednisone generally
`at the dose level of 1—2 mg/kg daily: In ALL in 10 out of 12 children (83.3 °,)
`and in AMLin1 out of 2 patients. The average duration of remissions was 5.3 months
`with 6-Mercaptopurine maintenance therapy.
`2. The combination therapy with 5-Azacytidine and Prednisone during the
`induction phase of the first remission had similar effects on the hematological and
`clinical findings as 5-Azacytidine alone, Leukopenia, however,
`indicated the dis-
`continuance of 5-Azacytidin application so that ultimately children were treated
`with Prednisone alone. This group of 3 patients is too small to allow any valid compa-
`
`
`
`

`

`a2
`
`HRODEK, VESELY
`
`is not possible to estimate to
`vison with other therapeutic procedures. Equally it
`what extent 5-Azacytidine accounted for the complete remission in these instances.
`3. During the later phases of the disease the effect of 5-Azacytidine or ofits
`combination with Prednisone was generally unsatisfactory. Although the leukocyte
`count and the depletion of blasts in the blood oceurred in 75°, of cases no beneficial
`effect on the bone marrow was noted. Mild amelioration of clinical condition was
`onlytransitory.
`4+. In one observed case of chronic myeloid leukemia the response to 5-Azacy-
`tidine was favourable but of short duration. More cases of chronic myeloid leukemia
`treated with 5-Azacytidine will be required to verify the first experience.
`5. Tolerance of the drug, its toxicity andside-effects:
`In general the tolerance
`of 5-Azacytidine is good: in two cases vomiting was observed two to four hours
`following the intramuscular injection. In the first child vomiting occured following
`14th injection and on re-institution of the therapy at
`the cose level of 2 mg/kg
`daily. In the second child vomiting appeared after the Ist and 2nd injection so that
`the therapy was discontinued. Intramuscular application in children with consi-
`derable thrombopenia resulted in hematomas. Other side-effects were not observed.
`The effects obtained during the induction of the induction of the first remission
`with 5-Azaeytidine alone and later on in combination with Prednisone (83.39,
`in
`ALL) is more favourable than with Prednisone alone (57°, of remissions) or with
`other drugs given individually [3, 5. 4]. They correspond to the effects of Prednisone
`in combination with 6-Mercaptopurine (82 °,). as well as to the effects of Prednisone
`with Oncovin according to FRET et al. (S4°,) [8]. and to our own previous observa-
`tions [8. 9].
`However, they are lower than in case of combination of Prednisone and Oncovin
`(SS °,) [10], in case of combination of Prednisone with high 1. v. doses of Methotre-
`xate (93 °,). and in case of Prednisone. Oncovin and Rubidomycin combination
`which is considered at present by different authors as most successful [1, 10] since
`it induces 90—100 °, of remissions. The therapeutic value of 5-Azacytidine requires
`further investigation especially in combination with other drugs and within the
`frame of other therapeutic procedures.
`The importance of 5-azacytidine for the maintenance therapy has not been
`further considered on account of its intramuscular appheation,
`Nevertheless.
`it would be appropriate to examine its action in the short-term
`reinduetion during the remission and in the so called complementary therapy for
`the remission induction [6]. More cases of CML treated with 5-Azaeytidine will be
`required to test the effect of the drug also in this respect.
`
`The authors wish to express their thanks to Professor F. Sor for stimulating inte-
`vest, and to Professor R. Gosror for permiting them to use the clinical data of patients
`treated at his Department.
`
`References
`
`[1] Bersarp. J.. JAc@ti7nat. Cr.. Wett. Al.. Borrow. M.. Tanzer, J.: Present results
`on daunorubicine. Recent Results in Cancer Research 34, Springer-Verlag, Berlin.
`Heidelberg. New York 1970. 3.
`[2] DamesHerk. W.. Gunz. F.: Leukemia. 2. Ed. Grune and Stratton. New York, London
`L964..022.
`[3] Frer E.. ILL. Karow. M.. Levix. R. H.. Frerreicn, E. J.. Taytorn, R. J.. Ha-
`NANTAN. J.. Senawry, O.. Hottanp. J. F.. Hoocstratres. B.. Wormax, I. 4J..
`
`

`

`S-AZACYTIDINE IN CHILDHOOD LEUKEMIA
`
`
`503
`
`[4]
`
`f=
`
`[6]
`
`Lv]
`
`[8]
`
`Apir, E., Sawirsky, A., Ler, §., Mirus, 8. D., Burcert, E. O., Jr., Spurr, Cu. L.,
`Patrrersox, R. B.. EepaueuH. F. G., JaAues, G. W., TIL. Moon, J. H.: The effeeti-
`veness of combinations of antileukemic agents in inducing and maintaining remission
`in children with acute leukemia. Blood 24, 1965, 642.
`Frereecu, E. J., Fret, E.: Recent advances in acute leukemia. Progress in Hema-
`tology, IV. Grune and Stratton, New York, London 1964, 187.
`Hertt. M., Lanppeck, G.: Leukidimie bei Kindern. Georg Thieme Verlag, Stuttgart
`1968, 84.
`Houianp, J. F., GLIDEWELL, O.: Complementary chemotherapy in acute leukemia.
`Recent Results in Cancer Research 30, Springer-Verlag, Berlin, Heidelberg. New
`York 1970, 95.
`Hroper, 0.: Our experience with Buthiopurin treatment of acute infantile hacmo-
`blastoses. Neoplasia $, 1961. 593.
`Hropek, O.. HermMansxy, F.: Zvtolovische Diagnostik und kliniseche Ereebnisse
`bei Leukamien im Kindesalter. Chemo- und [mmunotherapie der Leukosen unc
`maienen Lymphome (Internationale Arbeitstagung in Wien). Bohmann-Verlag.
`Wien 1969, 185.
`Hropek, O., JANELE, J., VAvrova, V.: Our experience with the treatment of acute
`haemoblastoses. Neoplasma 7, 1960, 312.
`JTACQUILLAT. Ch., ScHATSON, C.. Wetn. M.. Gearon, M. F.: Traitement des leueémies
`aigues de lenfant. Le Pédiatre 6, 1970, 289.
`Jurovcik, J.. RaASKA, K., Sorm, F., SopmovA, Z.: Anabolic transformations of the
`new antimetabolite 5-azacytidine and its incorporation into ribonucleic acid. Collec-
`tion Czech. Chem. Commun. 37, 1965, 3370.
`] Piskata, A., Sorm, F.: Nucleic acid components and their analogues. LI. Synthesis
`of l-glycosyl derivatives of 5-azauracil and 5-azaevtosine. Collection Czech. Chem.
`Commun. 29, 1964, 2060.
`SErrFERTOVA, M., VeseLy, J., Soro, F.: Effect of 5-azaeytidine on developing mouse
`embryo. Experientia 24, 1968, 457.
`Svar, M., RaSkxa, K., Sorm, F.: Interruption of preenaney by 5-azacytidine. Expe-
`rientia 27, 1966, 22.
`| Soro, F.. Veseiy, J.: The activity of a new antimetabolite 5-azaecyticdine against
`ivmphoid leukemia in AIS mice. Neoplasma //, 1964, 123.
`VESELY, J.. CrHAx, A.. Sonm. F.: Biochemical mechanism of drug resistance. VT.
`Inhibition of orotic acid metabolism by 5-azacvtidine in leukemic mice sensitive
`and resistant to 5-azaevticine. Biochem. Pharmacol. £7, 1968. 519.
`VeESELY. J.. Sorm, F.: The evtologic ancl metabolic effects of a newantileukemic
`analog A-azacyticine in normal mice followed autoradiographically with tritium,
`Neoplasma 2, 1965, 3.
`
`[9]
`
`[10]
`
`[Lo]
`
`
`
`