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Results of treatment with an intensive induction regimen using idarubicin in combination with cytarabine and etoposide in children with acute myeloblastic leukemia
Leukemin Research Vol. 20, No. 11112, pp. 973-981, 1996. Copyright 0 1996 Elsevier Science Ltd. All rights resewed Printed in Great Britain 0145-2126196 $15.00 + 0.00
Pergamon PII: SO1452126(96)00071-9
RESULTS OF TREATMENT WITH REGIMEN USING IDARUBICIN CYTARABINE AND ETOPOSIDE MYELOBLASTIC
AN INTENSIVE INDUCTION IN COMBINATION WITH IN CHILDREN WITH ACUTE LEUKEMIA*
Federico Sackmann-Muriel, Pedro Zubizarreta, Maria Sara Felice, Guillermo Chantada, Ana Maria Cygler, Marta Gallego and Jorge Rossi Departments of Hematology/Oncology and Immunology, Hospital de Pediatria SAMIC ‘Prof Dr Juan P. Garrahan’, Buenos Aires, Argentina (Received
12 February
1996. Revision accepted 20 June 1996)
Abstract-We report results achieved in our institution with a study opened in July 1990 (similar to the German AML-BFM-87 in which daunorubicin was replaced by idarubicin in the induction phase and cranial preventive radiotherapy was omitted) and closed in December 1994, for the treatment of newly diagnosed acute myeloblastic leukemia (AML), without prior malignancies except for myelodysplasia. This evaluation included 68 patients, whose mean age was 6 years (range: 1 month-16 years). Thirty-nine were boys and 29 were girls. Complete remission rate was 80.9% (55/68), death on induction rate was 14.7% and induction failure rate was 4.4%. At median follow up of 38 months (range: 12-66 months), the 4-year event-free survival (EFS) estimate was 0.428 (S.E.: 0.062), event-free interval (EFI) estimate was 0.529 (S.E.: 0.07) and overall survival (OS) estimate was 0.44 (S.E.: 0.071). We conclude that idarubicin in combination with cytarabine and etoposide is a highly effective regimen for induction in children with AML. Although preventive cranial irradiation was not delivered, we have observed only one combined CNS relapse. Finally, we corroborate that in this setting two definite risk groups may be identified in children with AML. Copyright 0 1996 Elsevier Science Ltd Key words: children.
Acute
myeloblastic
leukemia,
Ara-C,
Introduction
idarubicin,
etopside,
prognostic
groups,
intensification and continuation therapy, together with appropriate supportive care has resulted in remission rates of 70-80% and has produced significant improvement (approximately 40%) in event-free survival (EFS)
Results of treatment in childhood acute myeloblastic leukemia (AML) have experienced a significant improvement during the last decade. Recently, the administration of intensive induction, consolidation,
PI. The combination of an anthracycline and cytosine arabinoside (Ara-C), is considered standard therapy for remission induction in AML. Idarubicin, an anthracycline derived from daunorubicin, was synthesized in an attempt to find new analogs with an improved spectrum of activity and diminished acute or chronic toxicity compared with the parent drug [2]. Idarubicin was eight times more potent against L1210 or P388 murine leukemia than daunorubicin and five times more potent than doxorubicin when administered intravenously [3]. Multiple animal studies have suggested that idarubicin is less cardiotoxic than daunorubicin or doxorubicin [4,5]. Three randomized studies have suggested that idarubicin is superior to daunorubicin when combined with Ara-C
*Presented at the 36th Annual Meeting of The American Society of Hematology, Nashville, Tennessee,2-6 December 1994. Abbreviations:
AIE, Ara-C, idarubicin, etoposide; ALL, acute lymphoblastic leukemia; AML, acute myeloblastic leukemia; APL, acute promyelocytic leukemia; ATRA, alltram retinoic acid; BFh4, Berlin-Frankfurt-Miinster; BMT, bone marrow transplantation; CNS, central nervous system; CSF, cerebrospinal fluid; EFI, event-free interval; EFS, eventfree survival; FAB, French-American-British; OS, overall survival; S.E., standarderror. Correspondence to: F. Sackmann-Muriel, Departamentode HematogiaiOncologia, Hospital de Pediatria ‘Prof Dr Juan P. Garrahan’, Combatede 10sPozos 1881, (1245) Buenos Aires, Argentina (Fax: 541 941 8532).
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in adult AML remission induction therapy [6-g]. Moreover, idarubicinol, the major circulating metabolite of idarubicin, appears to have a substantial cytotoxic activity against tumor cells [9], and it also achieves good levels in CSF of children with leukemia [lo]. Unlike acute lymphoblastic leukemia, where successful CNS preventive treatment significantly improves survival, clinical trials in AML have not demonstrated that CNS prevention with cranial irradiation therapy improves the results. A remarkable exception may be the German BFM-87 trial [ll]. These supportive preliminary data prompted us to undertake a clinical trial similar to AML-BFM-87 (Berlin-Frankfurt-Minster-87) in which daunorubicin was replaced by idarubicin in induction and cranial preventive radiotherapy was omitted. The preliminary evaluation of this study has previously been presented [ 121. Materials and Methods From July 1990 to December 1994, 81 consecutive patients under 17 years of age with no prior malignancies (except for myelodysplasia) were diagnosed as AML in the Hematology/Oncology Department, Hospital de Pediatria Garrahan, Buenos Aires, Argentina. During the same period, six patients with secondary AML were also diagnosed (two after acute lymphoblastic leukemia, one after non-Hodgkin lymphoma, one after chronic myeloid leukemia, one after Hodgkin disease and one with Fanconi’s anemia). They were excluded from this study because of their different wellknown response to current therapy. Diagnosis of AML The diagnosis of AML was based on the presence of >30% abnormal blasts or promyelocytes as defined by morphological examination of the bone marrow aspirate using May-Griinwald-Giemsa stains, peroxidase, Sudan black, chloracetate and alpha-naphthol acetate and butyrate esterase stains were used for histochemical definition of lineage. Fluoride inhibition was used with alpha-naphthol esterase stain to confirm the presence of monoblasts or monoblast-derived cells. Slides from 78 patients (three were unavailable and/or of poor quality to be evaluated) were reviewed for this presentation based on morphological, cytochemical, immunological and cytogenetic data according to the MIC criteria previously reported [13-151, by a specially designed expert committee. Patients Eighty-one consecutive patients under 17 years of age were entered into this protocol. Thirteen patients were excluded from this evaluation for the following reasons: four patients were incorrectly diagnosed and they
received more than 2 weeks of prior treatment (one nasopharyngeal carcinoma and three acute lymphoblastic leukemia); four patients died as a result of hemorrhage and/or leukostasis before receiving induction therapy; two patients were lost to follow-up; and three patients were of mixed-lineage or biphenotypic leukemia as defined by Matutes and Catovsky’s criteria (more than two points of B or T and more than two points of myeloblastic markers, according to their score) [16]. Their outcome was very poor: two died on induction, one of sepsis and the other of adult respiratory distress syndrome. The third patient achieved complete remission and presented a bone marrow relapse as acute lymphoblastic leukemia 9 months later, and subsequently died of progressive disease. Thus, 68 patients are fully evaluable for this presentation. An informed consent was obtained from the patients’ parents in every case. The protocol was approved by an institutional clinical trial review committee. Treatment The treatment schedule was similar to that of the AML-BFM-87 study except that idarubicin was used instead of daunorubicin in the induction phase (Table 1). Initial treatment consisted of an g-day induction phase with cytarabine in a 48-h infusion (100 mg/m2/d),
Table 1. Treatment schedule Induction therapy Cytarabine 100 mg/m2/d,IV 48-h infusion, days l-2 Cytarabine 100 mgim2, IV every 12 h in 30 min, days 3-8 Idarubicin 12 mg/m2/d,IV in 30 min, days 3-5 Etoposide 150 mg/m2/d, IV in 60 min, days 6-8 Cytarabine+dexamethasone,IT age-relateddosage,day 1 Consolidation therapy Prednisone40 mg/m2/d orally, days l-28 6-Mercaptopurine 60 mg/m*/d orally, days 1-28 Vincristine 1.5 mg/m*/d, IV, days 1, 8, 1.5, 22
Doxorubicin 30 mg/m2, IV, days 1, 8, 15, 22 Cytarabine 75 mg/m2/d, IV, days 3-6, 10-13, 17-20,24-27,
31-34, 38-41 Cyclophosphamide500 mg/m2, IV, days 29, 43 Cytarabinetdexamethasone, IT age-related dosage, days 1, 15, 29, 43 Intensification therapy (two courses) Cytarabine 3 g/m , IV every 12 h in 3-h infusion, days 1-3 Etoposide 125 mg/m’/d, IV in 60 min, days 2-5 (1 h prior to cytarabine dose) Continuation therapy 6-Thioguanine 40 mgrn’id, orally Cytarabine 40 mg/m /d, subcutaneously for4days each month Cytarabine+dexamethasone, IT age-related dosage, every 2 months during the first year of treatment Total treatment duration: 18 months IV: intravenous; IT: intrathecal.
Treatment of acute myeloblastic leukemia in childhood
followed by a 30-min infusion (100 mg/m2) every 12 h for the next 6 days, together with idarubicin (12 mg/m2/ d) in a 30-min infusion on days 3-5 and etoposide (150 mg/m2/d) in a 60-min infusion on days 6-8. The initial response to induction therapy was evaluated on day 15. If the bone marrow aspirate contained d 10% blasts, consolidation therapy was initiated after hematological recovery. A bone marrow aspirate was repeated on days 22 and 29 prior to starting consolidation therapy. However, if the bone marrow aspirate performed on day 15 contained 10% blasts, consolidation therapy was given without delay, providing the patient’s condition was judged stable enough to proceed, and it was not an acute promyelocytic leukemia. On day 28 an extended and intensive 6-week, eightdrug consolidation phase was administered with prednisone, 6-mercaptopurine, vincristine, doxorubicin, cytarabine, cyclophosphamide and intrathecal cytarabine plus dexamethasone. Central nervous system prophylaxis consisted of intrathecal cytarabine plus dexamethasone on day 1 of the induction phase; on days 1, 15, 29 and 43 of the consolidation phase, and every 2 months during the first year of the continuation phase. Age-related dosages were as follows: 0 to 1 year, cytarabine: 20 mg and dexamethasone: 2 mg; >, 1 to 2 years, cytarabine: 30 mg and dexamethasone: 4 mg; 22 to 3 years, cytarabine: 50 mg and dexamethasone: 4 mg; 23 years, cytarabine 70 mg and dexamethasone: 4 mg. Cranial irradiation was not delivered in any case. After a treatment-free interval of 2-4 weeks, two 5day intensification courses (with a 4-week interval) were administered consisting of high-dose cytarabine (3 gim2 every 12 h) in a 3-h infusion, six doses on days 1-3 together with etoposide (125 mg/m2) in a 60-min infusion (1 h before cytarabine), four doses on days 2-5. Continuation therapy was initiated 2-4 weeks after the second intensification course and consisted of daily oral 6-thioguanine (40 mg/m2/d) and cytarabine (40 mg/ m2/d) subcutaneously for 4 days every 4 weeks to complete 18 months of treatment. Bone marrow aspirate was requested by the protocol for diagnosis (biopsy was performed if needed) and on days 15 and 28 of induction, after the first 4 weeks of the consolidation phase, at the beginning of each intensification course, every 2 months during the first year of treatment and every 3 months up to the end of continuation therapy. Bone marrow aspirate was also performed whenever there was any clinical suspicion of relapse. Lumbar puncture with intrathecal chemotherapy was performed as previously described. During the second year of continuation therapy this procedure was done without intrathecai chemotherapy every 3 months. Bone marrow aspirate and lumbar puncture were not required after completion of therapy. All patients were
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monitored for relapse and survival with periodic physical examination and complete blood cell count. Our experience with childhood acute promyelocytic leukemia (APLiFAB M3) treated with standard chemotherapy yields a concerning high mortality on induction due to central nervous system bleeding secondary to overwhelming disseminated intravascular coagulation (DIC) 117-201. The proved capacity of alltram retinoic acid (ATRA) to ‘cool down’ in a few days the hemostatic disorders in APL and the support of the reported experience on associated administration of ATRA together with induction chemotherapy, prompted us to introduce, as an amendment to the protocol, the use of this fascinating biological resource during the first days of the remission induction phase of our protocol [21-231. We decided then to make use of ATRA, from March 1994, strictly in order to manage coagulopathy and put the patient in the best condition to undergo induction chemotherapy which usually enhances the hemostatic disorders. We administered ATRA at 45 mg/m2/day PO during the first 2-7 days after diagnosis and further on only if DIC signs persisted. We profited from the extraordinary effect of ATRA on DIC and cautiously tried to minimize the effects of the ATRA syndrome. The basic aim of remission induction in APL was based on chemotherapy. Definitions and Statistical Methods This was a prospective, non-randomized, single-arm study (Fig. 1). Complete remission (CR) required a bone marrow aspirate showing normal erythrocytic, granulocytic and megakaryocytic regeneration, normal cellularity, less than 5% blasts and no evidence of disease in other sites. Central nervous system leukemia was assumed when there were more than 5 nucleated cells/@ together with the presence of unequivocal blasts in the centrifuged sediment of the cerebrospinal fluid. The Kaplan-Meier lifetable analysis [24] was based on the following definitions and assumptions: Event-free survival (EFS): The analysis was based on the total group of protocol patients. All events leading to remission failures (early death, non-response), first relapse or death during remission were evaluated. l Event-free interval (EFI): The analysis was based on patients achieving complete remission. The time of first relapse was evaluated. Patients who died in first remission were counted as failures. 0 The associated standard error (SE.) was calculated by the method of Peto et al. [25]. l Logrank test was used to compare survival estimates l
WI. l
Toxicity was graded according to the Children’s Cancer Group criteria [27].
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F. Sackmann-Muriel et al.
INDUCTION AIE
CONSOLIDATION
8 days
6 Weeks
INTENSIFICATION
1
HD Ara-C + VP-l 6 5 days
INTENSIFICATION
2
HD Ara-C +VP-16 5 days
CONTINUATION 6-TG I Ara-C Until completing 18 months of therapy.
Patients with > 10 % blast cells in Bone Marrow control of day 15 initiate consolidation regimen on day 15 /2 1 (except for FAB M3). AIE = Ara-c + ldarubicin HD = High dose.
+ Etoposide
Fig. 1. General outline of the protocol.
Prognostic risk groups were retrospectively established according to German BFM criteria [28], subsequently modified [29]. This evaluation reports on 68 patients assessedup to 1 January 1996. Results Patient data The patients’ major clinical and hematological features are summarized in Table 2. Bone marrow samples for cytogenetical study were obtained in 95.6% of cases (65/68). Of them 72.3% (47/ 65) were successfully analyzed. Results of the most significant cytogenetical findings and their outcome are shown in Table 3. Results of treatment Fifty-five (80.9%) of the 68 patients attained complete remission after a median time of 38 days (range: 22-92 days). Six patients achieved complete remission 10 weeks after diagnosis, during the consolidation phase (delayed remission). Ten patients (14.7%) died during the first month of therapy. Sepsis (six patients), hemorrhage (three patients) and both (one patient) being the main causes of early death. Three patients (4.4%) never achieved complete remission and finally died of progressive disease at 4, 5 and 5 months from diagnosis, respectively. With regard to the toxicity of the induction regimen, almost all patients experienced prolonged and severe myelosuppression: 60/68 patients developed severe neutropenia (number absolute of neutrophils < 5001~1) and leukopenia (WBC count < lOOO/pl) and 60/69 developed severe thrombocytopenia (platelet count ~20 OOO/pl). Fifty-two of the 68 patients developed severe or life-threatening infections which were fatal in seven cases as mentioned above. Hepatic and gastrointestinal tract toxicity and massive hemorrhage occurred less frequently. Acute cardiotoxicity was
uncommon (one patient), but alopecia was universal (Table 4). Seven patients died in complete remission. The causes of death were: pneumonia (three patients), including one with cytomegalovirus, sepsis (three patients), pulmonary hemorrhage (one patient). Four deaths occurred during the fifth and sixth weeks of consolidation phase. Three deaths occurred after the first intensification course. Up to the date of evaluation (1 January 1996), 19 relapses have occurred: 17 in the bone marrow, one in Table 2. Initial clinical and hematological features Number of evaluated patients Age: mean (years) range Sex: male/female Clinical data: Down’s syndrome Myelodysplasia Chloroma CNS involvement Hepatomegaly (>5 cm below costal margin) Splenomegaly (>5 cm below costal margin) Hematological data: mean range
Hemoglobin: gidl mean range
68 6
1 month-16 years 39129
7(M7=5,MO=l,M4=1) 9
M2Eo = 1) 2(M5b=l,M7=1)
3 (M2 = 2,
31 27
WBC count: (/pl) 38 000 600-250 000 8.2 4-13.3
Platelets: (/pl) mean range
FAB No. (%) AREB-t MO Ml M2 M3 M4 M5 M6 M7
(M2Eo = 4) (M3v = 1) (M4Eo = 3) (M5a = 4, M5b = 2)
54 800 1000-571000 2 (2.9) 3 (4.4) 2 (2.9) 19 (27.9) 11 (16.2) 13 (19.1) 6 (8.8) 4 (5.9) 8 (11.8)
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Treatment of acute myeloblastic leukemia in childhood Table 3. Significant cytogenetical findings Cytogenetical findings
t(8; 21) t(15; 17) -15, -17 Trisomy 8 Monosomy 7 t(9; 11) de1 16 t(9; 22)
de1 11 (q23) t(10; 11) t(7; 12)
t(11; 17)
Number of patients
Outcome
FAB subtype
M2Eo = 3, M2 = 3, M4 = 1 EFS: 0.7.5S.E.: 0.21 M3 EFS: 0.75S.E.: 0.15 M3 Areb-t = 1, M3 = 1, M4 = 1, M4Eo = 1, M6 = 1 EFS: 0.40 S.E.: 0.21 EFS: 0.00 M4=3,M6=1 M5a CR +13 months/BM relapse at 11 months M4Eo CR +33 months M2 BM relapse at 9 months M5b Death on induction M5a BM and CNS relapse at 8 months M4 BM relapse at 10 months M4 Death on induction
7 7 1 5 4 2 1 1 1 1 1 1
EFS: Event free survival (estimates); S.E.: standard error; CR: complete remission; BM: bone marrow; CNS: central nervous system. bone marrow and CNS and one in the bone marrow and
skin. Twenty-nine children are alive and disease free with a median follow-up time of 38 months (range 12-66 months). Only one patient (with FAB: M5a) received an allogeneic HLA-matched bone marrow transplant (BMT) in first remission. He was censored at time of BMT. However, he had been leukemia-free 13 months after diagnosis. If we analyze the seven patients with Down’s syndrome, five belonged to FAB M7, one to FAB M4 and one to FAB MO. Two of them died on induction of sepsis and another two died after achieving complete remission of sepsis and pneumonia, respectively. The other three are in continuous complete remission, +26, +34 and +38 months, respectively. Of the three patients with chloroma all belonged to FAB
M2 (one with
eosinophiliafM2Eo)
and showed
t(8;21) (q22;q22). Two also received radiotherapy due to spinal cord compression. All of them achieved complete remission and are free of disease at +12, +2.5 and +40 months, respectively. Of the two patients with initial CNS involvement, one was a newborn who presented AML FAB M5b and relapsed on bone marrow and skin shortly after
achieving complete remission. She died of progressive disease 3 months after diagnosis. The other one belonged to FAB M7 and achieved complete remission with intrathecal chemotherapy only. Cranial irradiation was not delivered. He is in continuous complete remission (+26 months). Event-free survival estimate of the whole group was 0.428 (S.E.: 0.062) and the event-free interval (EFI) estimate was 0.529 (S.E.: 0.07) and the overall survival (OS) estimate was 0.44 (SE. 0.071) at 4 years (Fig. 2). Results according to FAB types of AML are depicted in Table 5. The rate of induction failure (death on induction plus non-responders) was almost evenly distributed among the four more common FAB types. Life table estimates show that patients with FAB M2, FAB M3 and FAB M7 share similar EFS and EFI probability. It must be pointed out that 5/S (62.5%) patients of the FAB M7 subgroup, had somatic trisomy 21. I -:_
09il
I ‘9
--.--EFI
0 529 (SE 0.07)
Table 4. Toxicity of induction therapy* (n = 68)
WBC Platelets Infections Liver Gastrointestinal tract Kidney Heart Hemorrhage
Grade 3
Grade 4
7 8 31 1 15 0 0 14
60 59 21 3 7 2 1 23
*Number of patients according to CCG’s criteria [27].
Fig. 2. Kaplan-Meier estimate (S.E.: standard error) of eventfree survival (EFS) duration (n = 68), event-free interval (EFI) duration (n = 55) and overall survival (OS) (n = 68) in childhood AML in this trial.
F. Sackmann-Muriel et al.
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Table 5. Results according to AML morphological (FAB) subtypes AREB-t
MO
Ml
M2
M2Eo
M3
M3v
M4
2
3
2
15
4
0 2 1 1
1 2 1 1
1 1 1 0
2 13 1
1 3 0
10 2 8 0
1 0 1 0
10 3 7 1
Number Induction failure* Achieved complete remission Dead in complete remission Relapses EFS (S.E.)?
M4Eo M5a 3 0 3 0
M5b
M6
M7
Total
2 1 1 0 1
4 1 3 0 2
8
68 13 55 7
4 0 4 0
2 0.!2 (0.E) 0.:4 (Op23) 0.348 (0.G) 0.62 (0.12) 0.67 (0.27) 0.50 (0.50)
EFI (S.E.)t
1
7 2 1 19 0.50 0.43 (0.50) (0.06) 0.57 0.53 (0.57) (0.07)
*Induction failure: death on induction+non-responders. TKaplan-Meier estimation at 4 years. S.E.: standard error. EFS: event-free survival.
To analyze prognostic groups, we performed a retrospective stratification of our patients based on the modified [29] prognostic factors originally described by Creutzig er al. [28]. The German group determined two categories defined only by morphology associated with good response to initial chemotherapy. That is, the lowrisk group included patients with FAB Ml/M2 with Auer rods, FAB M3 and FAB M4Eo, all with <5% of blasts in the bone marrow aspirate on day 1.5 of induction (except for FAB M3). The high-risk group included the rest of the population. In our series, the low-risk group (n = 22) had an estimated 4-year EFS of 0.70 (S.E.: 0.105) and an EFI of 0.81 (S.E.: 0.10). This group included 32% of all patients and 35% of the children achieving complete remission. The high-risk group (n = 46) showed an estimated 4-year EFS of only 0.29 (S.E.: 0.069) and an EFI of 0.37 (S.E.: 0.08). The P-value when comparing survival curves (logrank test) was 0.005 for EFS and 0.0038 for EFI, respectively (Figs. 3 and 4).
The management of early hemostatic disorders in APL (i.e. DIC) may be quickly overcome with the administration of ATRA. There were no hemorrhagic deaths on induction of those APL patients who received ATRA during remission induction treatment. But the number of patients is too small to produce further valid observations.
Discussion The results of this prospective trial are comparable to the best results achieved so far in pediatric AML patients [l, 301. The complete remission rate of 81% is in the upper range for children and the probability of continuous complete remission (event-free interval) of 53% after 48 months is encouraging, albeit in a relatively small patient group. Our institution is a large children’s hospital and a referral center in Argentina for general pediatric care. These results are being used to design an upcoming protocol for a larger number of
-.... ,A.......................
i.. .._ ......... 1
--~.-- LOWRISK 0 70 SE: 0 105 (Events 7 I22)
i .. ..__-_
---.- LOWRISK 0.61 SE 0.10 (Events: 4 / 19) _ c _.........c.._.._ .... -- ._.-.........._- ............
I_
, -1 i
4 -1
---
-i
-I- &7 -1 ‘L
---7 __-l_-_---_r-----_-----------
I
HIGHRISK 0 29 SE 0069 (Events: 32 146)
; ‘,--
Lc---,-----,-------------------
HIGHRISK 0 37 SE 0063 (Events 22 / 36)
Logrank test: p = 0.005 00-l
0
10
30
20
‘IO
I 50
Months
Fig. 3. Kaplan-Meier estimate (S.E.: standard error) of eventfree survival (EFS) duration for low-risk (n = 22) and high-risk (n = 46) groups (events/total).
20
30
40
50
Months
Fig. 4. Kaplan-Meier estimates (S.E.: standard error) for event-free interval (EFI) duration for low-risk (n = 19) and high-risk (n = 36) groups (events/total).
Treatment of acute myeloblastic leukemia in childhood
patients in Argentina and in other Latin American countries. We have improved our supportive care which allowed us to treat our patients with the AML-BFM approach showing the feasibility of this therapeutic strategy in our country. The rationale of the original AML-BFM study has been discussed [31]. The combination of an anthracycline and cytosine arabinoside is considered standard therapy for remission induction in AML. Recently, idarubicin (Cdemethoxydaunorubicin) has been found to be active in AML in adults. In fact, almost all trials in which cytosine arabinoside plus daunorubicin were compared with cytosine arabinoside plus idarubicin for remission induction in adult AML revealed significant advantages for the latter combination [6-8,32,33]. Furthermore, the therapeutic index of idarubicin may be higher than that of daunorubicin regarding cardiotoxicity, a major cause of concern in children. In the pediatric age group this problem has not yet been settled. Recent preliminary data from the German group [34], comparing cytosine arabinoside + idarubicin + etoposide (AIE) versus cytosine arabinoside + daunorubicin + etoposide WE) yielded no significant differences concerning early toxic death, unresponsiveness and remission rate in children with AML. However, in a very recent retrospective evaluation of idarubicin cardiotoxicity in a large population of patients with AML and myelodysplasia, mostly in adults, Anderlini ef al. [35] showed that at least at the dose currently used for AML remission induction (36-72 mg/m’) cardiac toxicity is minimal. In this study we administered a total cumulative dose of 36 mg/m*. the Ara-C + idarubicin + etoposide Nevertheless, combination is toxic, as toxic as any intense combination for remission induction in childhood AML, and our death on induction rate of 14.7% is high. Children have many problems in this phase, but toxic death is mainly due to disseminated intravascular coagulation, sepsis and leukostasis [36]. Obviously, these children should be managed with intense pediatric care in a strict isolation unit. Our death rate in complete remission is also high (7/55, 12.7%). We did not routinely use either antibiotic prophylaxis or gastrointestinal decontamination. During consolidation, children were treated mainly as outpatients. It is worthwhile mentioning here that in the original AML German BFM-87 Study [ll], the complete remission rate was identical to ours: out of a total of 210 children, 164 (78%) achieved complete remission. However, the mortality during induction (1 l/210 patients, 5.2%) and in complete remission (6/164 patients, 3.6%), was much lower than in our study, This fact prompts us to improve our supportive care. Moreover, Kaplan-Meier estimates for EFS and 5-year EFI in the original German AML-BFM-87 study were 0.41
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(S.E. = 0.04) and 0.52 (S.E. = 0.04), respectively, results which are very similar to ours. In spite of this drawback, our results are promising, with an EFS estimation of 0.428 (S.E.: 0.062) and an EFI estimation of 0.53 (S.E.: 0.07) at 4 years with an apparent nice plateau 2 years after diagnosis. Relapses are mainly in the bone marrow. It is noteworthy that we observed only one CNS relapse (combined with bone marrow relapse) in spite of the omission of the preventive cranial radiotherapy used in the original German study. We can speculate with the hypothesis that with the administration of idarubicin on induction, the alcohol metabolite idarubicinol which is cytotoxic and diffuses easily in the CSF [lo], could have some protection against CNS relapse. The German group unexpectedly observed that cranial radiation reduced the risk of bone marrow relapse [ll]. They concluded that cranial radiation should be part of the treatment of childhood AML. This is an interesting yet a controversial point. As a matter of fact, prognostic factors in pediatric AML are not as definite as in ALL. Although recognized to be a heterogeneous group of diseases, FAB subtypes of AML, now with the exception of FAB M3, are identically treated in clinical trials. However, it is very interesting to corroborate with our series that two groups of lower and higher risk of relapse may be identified in children treated with AML/BFM protocols. The group of favorable prognosis is mainly characterized by predominance of granulocytic differentiation in the leukemic blast population: presence of Auer rods in FAB Ml/M2, bone marrow eosinophilia in FAB M4 and FAB M3. Noteworthy, the subtype FAB M7 is usually considered as having a worse prognosis. In the BFM stratification and in the present study these cases were classified in the group with higher risk to relapse. In this series, 62.5% (518) had somatic phenotype of Down’s syndrome, a distinct subgroup that responds well to therapy [37,38]. Perhaps this explains why LMA FAB M7 has a favorable outcome in our setting. Establishing risk categories is very useful because it permits the delivery of a tailored therapy. Certainly, patients enrolled in the low-risk group (one-third of childhood AML) are not candidates for BMT in first remission because of the low incidence of relapses. Contrarily, in the high-risk group allogeneic BMT should be performed in first complete remission and other forms of BMT should be discussed when the former is not feasible. The use of ATRA in remission induction treatment is certainly quite a revolution in leukemia therapy. Our rationale for the use of ATRA in APL, just during short courses to control DIC, has not been mentioned in current literature. Recent reports show that remission induction with ATRA as a single agent or given with
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chemotherapy appears to improve remission rate, early mortality rate and, most interesting, uneventful survival in APL [39]. This fascinating biological resource needs further follow-up to attain its true hierarchy in APL therapy. We conclude that idarubicin in combination with cytosine arabinoside and etoposide is a highly effective remission induction regimen in pediatric AML. We believe that in this setting preventive cranial radiation should be omitted. References 1. Hurwitz C. A., Mounce K. G. & Grier H. E. (1995) Treatment of patients with acute myelogenous leukemia: Review of clinical trials of the past decade. J. Pediatr. Hematol. Oncol. 17, 185. 2. Arcamone F., Bernardi L., Giardini P., Patelli B., Marco A., Casazza A. M., Fratesi G. & Reggiani P. (1976) Synthesis and antitumor activity of 4-demethoxydaunorubicin, 4-demethoxy-7-diepidaunorubicin and their anomers. Cancer Treat. Rep. 60, 829. 3. Casazza A. M., Pratesi G., Giuliani F. & Di Marco A. (1980) Antileukemic activity of 4-demethoxydaunorubicin in mice. Tumori 66, 549. 4. Casazza A. M. (1979) Experimental evaluation of anthracycline analogs. Cancer Treat. Rep. 63, 83.5. 5. Ganzina F., Pacciarini M. A. & De Pietro N. (1986) Idarubicin (4-demethoxydaunorubicin): A preliminary review of pre-clinical and clinical studies. Invest. New Drugs 4, 85. 6. Berman E., Heller G., Santorsa J., McKenzie S., Gee T., Kempin S., Gulati S., Andreeff M., Kolitz J., Gabrilove J., Reich L., Mayer K., Keefe D., Trainor K., Scluger A., Penenberg D., Raymond V., O’Reilly R., Jhanward S., Young C. & Clarkson B. (1991) Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood 77, 1666. 7. Wiernik P. H., Banks P. L. C., Case D. C., Arlin Z. A., Periman P. O., Todd M. B., Ritch P. S., Enck R. E. & Weitberg A. B. (1992) Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood 79, 313. 8. Vogler W. R., Velez-Garcia E., Omura G. & Raney M. (1989) A phase-three trial comparing daunorubicin or idarubicin combined with cytosine arabinoside in acute myelogenous leukemia. Semin. Oncol. 16, 2, 21. 9. Broggini M., Sommacampagna B., Paolini A., Dolfihi E. & Donelli M. S. (1986) Comparative metabolism of daunorubicin and 4-demethoxy-daunorubicin in mice and rabbits. Cancer Treat. Rep. 70, 697. 10. Reid J. M., Pendergrass T. W., Krailo M. D., Hammond G. D. & Ames M. M. (1990) Plasma pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in pediatric leukemia patients: A children’s cancer study group. Cancer Res. 50, 6525. 11. Creutzig U., Ritter J., Zimmermann M. & Schellong G. (1993) Does cranial irradiation reduce the risk of bone marrow relapse in acute myelogenous leukemia? Unex-
pected results of the childhood acute myelogenous study BFM-87. J. Clin. Oncol. 11, 279. 12. Sackmann-Muriel F., Fernandez Barbieri M. A., Santarelli M. T., Matus-Ridley M., Rosso A., Negri-Aranguren P., Cerutti Y., Gomel M. & Kvicala R. (1993) Results of treatment with an intensive combination induction regimen containing idarubicin in children with acute myeloblastic leukemia: Preliminary report of the Argentine Group for Treatment of Acute Leukemia. Semin. Oncol. 6(8), 34. 13. Meeting Report (1988) Morphologic, immunologic and cytogenetic (MIC) working classification of the acute myeloid leukemias. Br. J. Haemat. 68, 487. 14. Cheson B. D., Cassileth P. A., Head D. R., Schiffer C. A., Bennet J. M., Bloomfield C. D., Brunning R., Gale R. P., Grever M. R., Keating M. J., Sawitsky A., Staas S., Weinstein H. & Woods W. G. (1990) Report of the National Cancer Institute-Sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J. Clin. Oncol. 8, 813. 1.5.Creutzig U., Ritter J., Ludwig W. D., Harbott J., Loffler H. & Schellong G. (1993) Klassifikation der AML nasch morphologischen, immunologischen und zytogenetischen kriterien. Ubersicht unter beriicksichtigung der subtypen in der Studie AML-BFM-87. Klin. Padiatr. 205, 272. 16. Matutes E. & Catovsky D. (1994) The value of scoring systems for the diagnosis of biphenotypic leukemia and mature B-cell disorders. Leukemia, Lymphoma 13(l), 11. 17. Rand J., Moloney W. & Sise H. (1969) Coagulation defects in acute promyelocytic leukemia. Arch. Intern. Med. 123, 39. 18. Gralnick H. R. & Abrell E. (1973) Studies of procoagulant and fibrinolytic activity of promyelocytes in acute promyelocytic leukemia. Br. J. Haematol. 24, 89. 19. Gralnick H. R. (1975) Acute promyelocytic leukemia: Haemorrhagic manifestation and morphologic criteria. Br. J. Haematol. 29, 373. 20. Tallman M. & Kwaan H. C. (1992) Reassessing the hemostatic disorder associated with promyelocytic leukemia. Blood 79, 543. 21. Dombret H., Sutton L., Duarte M., Daniel M. T., Leblond V., Castaigne S. & Degos L. (1992) Combined therapy with all-trans-retinoic acid and high-dose chemotherapy in patients with hyperleukocytic acute promyelocytic leukemia and severe visceral hemorrhage. Leukemia 6, 1237. 22. Rodeghiero F. & Castaman G. (1994) The pathophysiology and treatment of hemorrhagic syndrome of acute promyelocytic leukemia. Leukemia S(2), S20. 23. Lemons R. S., Keller S., Gietzen D., Dufner J., Rebentisch M., Feusner J. & Eilender D. (1995) Acute promyelocytic leukemia. J. Pediatr. Hematol. Oncol. 17, 198. 24. Kaplan E. L. & Meier P. (1958) Nonparametric estimation from incomplete observations. J. Amer. Stat. Assoc. 53, 457. 25. Peto R., Pike M. C., Armitage P., Breslow E. N., Cox D. R., Howard S. V., Mantel N., McPherson J., Peto J. & Smith P. G. (1977) Design and analysis of randomized clinical trials requiring prolonged observation on each patient. II. Analysis and examples. Br. J. Cancer 35, 1. 26. Tarone R. E. & Wara J. (1977) On distribution-free test for equality of survival distribution. Biometrika 64, 156. 27. Iacuone J. J., Steinherz L. J. & Ablin A. R. (1993) Modifications for toxicity. Supportive care of children with cancer. In Current Therapy and Guidelines from the Children’s Cancer Group (Ablin Arthur R., Ed.), p. 37. The Johns Hopkins University Press, Baltimore. 28. Creutzig U., Ritter J. & Schellong G. for the AML-BFM
Treatment of acute myeloblastic leukemia in childhood
29.
30. 31.
32. 33. 34.
Study Group (1990) Identification of two risk groups in Childhood Acute Myelogenous Leukemia after therapy intensification in study AML-BFM-83 as compared with study AML-BFM-78. Blood 75, 1932. Creutzig U., Ritter J., Zimmermann M., Bender-Giitze C. & Scellong G. (1995) Seven-year survival exceeding 70% without bone-marrow transplantation in first remission in standard risk children with acute myelogenous leukemia. Results of studies AML-BFM-83 and 87. Blood 86, 1, 433a. Ritter J., Creutzig U. & Schellong G. (1992) Treatment results of three consecutive German childhood AML trials: BFM-78, 83, and 87. Leukemia 6, 2, 59. Creutzig U., Ritter J., Riehm H., Langermann H. J., Hewze G., Kabisch H., Stollmann B., Lassow U., Kaufmann U., Liiffler H. & Schellong G. (1985) Improved treatment results in childhood acute myelogenous leukemia: a report of the German Cooperative Study AML-BFM-78. Blood 65, 298. Wiernik P. H. (1995) Idarubicin in induction therapy of AML. Ann. Hematol. 70, Suppl II, A99. Btichner T. L. (1995) State of the art and the contribution of idarubicin in acute myeloid leukemia. Ann. Hematol. 70, II, AlOO. Ritter J., Creutzig U. & Zimmermann M. for the cooperative childhood AML-BFM Study Group (1995) The specific role of idarubicin during induction therapy of childhood AML. Ann. Hematol. 70, II, A99.
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35. Arderlini P., Benjamin R. S., Wong F. C., Kantarjian H. M., Andreeff M., Kornblan S. M., O’Brien S., Mackay B., Ewer M. S., Pierce S. A. & Estey E. H. (1995) Idarubicin cardiotoxicity: a retrospective study in acute myeloid leukemia and myelodysplasia. J. Clin. Oncol. 13, 2827. 36. Creutzig U., Ritter J., Budde M., Sutor A. & Schellong G. the German BFM Study Group (1987) Early deaths due to hemorrhage and leukostasis in childhood acute myelogenous leukemia. Cancer 60, 3071. 37. Ravindranath Y., Abella E., Krischer J. P., Wiley J., Inoue S., Harris M., Chauvenet A., Alvarado C. S., Dubowy R., Ritchey A. K., Land V., Steuber C. P. & Weinstein H. (1992) Acute myeloid leukemia (AML) in Down’s syndrome is highly responsive to chemotherapy: Experience on Pediatric Oncology Group AML Study 8498. Blood 80, 2210. 38. Ravindranath Y., Abella E., Krischer J. P. & Weinstein H. for the Pediatric Oncology Group (POG) (1993) Acute myeloid leukemia (AML) in Down’s syndrome: response and toxicity with high dose arabinoside cytosine. Proc. Am. Sot. Clin. Oncol. 12, 323. 39. Kanamuru A., Yoshinobu T., Mitsune T., Murakami H., Asou N., Kobayashi T., Kuriyama K., Ohmoto E., Sakamaki H., Tsubaki K., Hiraoka A., Yamada O., Oh H., Saito K., Matsuda S., Minato K., Ueda T., Ohno R. & the Japan Adult Leukemia Study Group (1995) All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia. Blood 85, 1202.
Pergamon PII: SO1452126(96)00071-9
RESULTS OF TREATMENT WITH REGIMEN USING IDARUBICIN CYTARABINE AND ETOPOSIDE MYELOBLASTIC
AN INTENSIVE INDUCTION IN COMBINATION WITH IN CHILDREN WITH ACUTE LEUKEMIA*
Federico Sackmann-Muriel, Pedro Zubizarreta, Maria Sara Felice, Guillermo Chantada, Ana Maria Cygler, Marta Gallego and Jorge Rossi Departments of Hematology/Oncology and Immunology, Hospital de Pediatria SAMIC ‘Prof Dr Juan P. Garrahan’, Buenos Aires, Argentina (Received
12 February
1996. Revision accepted 20 June 1996)
Abstract-We report results achieved in our institution with a study opened in July 1990 (similar to the German AML-BFM-87 in which daunorubicin was replaced by idarubicin in the induction phase and cranial preventive radiotherapy was omitted) and closed in December 1994, for the treatment of newly diagnosed acute myeloblastic leukemia (AML), without prior malignancies except for myelodysplasia. This evaluation included 68 patients, whose mean age was 6 years (range: 1 month-16 years). Thirty-nine were boys and 29 were girls. Complete remission rate was 80.9% (55/68), death on induction rate was 14.7% and induction failure rate was 4.4%. At median follow up of 38 months (range: 12-66 months), the 4-year event-free survival (EFS) estimate was 0.428 (S.E.: 0.062), event-free interval (EFI) estimate was 0.529 (S.E.: 0.07) and overall survival (OS) estimate was 0.44 (S.E.: 0.071). We conclude that idarubicin in combination with cytarabine and etoposide is a highly effective regimen for induction in children with AML. Although preventive cranial irradiation was not delivered, we have observed only one combined CNS relapse. Finally, we corroborate that in this setting two definite risk groups may be identified in children with AML. Copyright 0 1996 Elsevier Science Ltd Key words: children.
Acute
myeloblastic
leukemia,
Ara-C,
Introduction
idarubicin,
etopside,
prognostic
groups,
intensification and continuation therapy, together with appropriate supportive care has resulted in remission rates of 70-80% and has produced significant improvement (approximately 40%) in event-free survival (EFS)
Results of treatment in childhood acute myeloblastic leukemia (AML) have experienced a significant improvement during the last decade. Recently, the administration of intensive induction, consolidation,
PI. The combination of an anthracycline and cytosine arabinoside (Ara-C), is considered standard therapy for remission induction in AML. Idarubicin, an anthracycline derived from daunorubicin, was synthesized in an attempt to find new analogs with an improved spectrum of activity and diminished acute or chronic toxicity compared with the parent drug [2]. Idarubicin was eight times more potent against L1210 or P388 murine leukemia than daunorubicin and five times more potent than doxorubicin when administered intravenously [3]. Multiple animal studies have suggested that idarubicin is less cardiotoxic than daunorubicin or doxorubicin [4,5]. Three randomized studies have suggested that idarubicin is superior to daunorubicin when combined with Ara-C
*Presented at the 36th Annual Meeting of The American Society of Hematology, Nashville, Tennessee,2-6 December 1994. Abbreviations:
AIE, Ara-C, idarubicin, etoposide; ALL, acute lymphoblastic leukemia; AML, acute myeloblastic leukemia; APL, acute promyelocytic leukemia; ATRA, alltram retinoic acid; BFh4, Berlin-Frankfurt-Miinster; BMT, bone marrow transplantation; CNS, central nervous system; CSF, cerebrospinal fluid; EFI, event-free interval; EFS, eventfree survival; FAB, French-American-British; OS, overall survival; S.E., standarderror. Correspondence to: F. Sackmann-Muriel, Departamentode HematogiaiOncologia, Hospital de Pediatria ‘Prof Dr Juan P. Garrahan’, Combatede 10sPozos 1881, (1245) Buenos Aires, Argentina (Fax: 541 941 8532).
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F. Sackmann-Muriel et al.
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in adult AML remission induction therapy [6-g]. Moreover, idarubicinol, the major circulating metabolite of idarubicin, appears to have a substantial cytotoxic activity against tumor cells [9], and it also achieves good levels in CSF of children with leukemia [lo]. Unlike acute lymphoblastic leukemia, where successful CNS preventive treatment significantly improves survival, clinical trials in AML have not demonstrated that CNS prevention with cranial irradiation therapy improves the results. A remarkable exception may be the German BFM-87 trial [ll]. These supportive preliminary data prompted us to undertake a clinical trial similar to AML-BFM-87 (Berlin-Frankfurt-Minster-87) in which daunorubicin was replaced by idarubicin in induction and cranial preventive radiotherapy was omitted. The preliminary evaluation of this study has previously been presented [ 121. Materials and Methods From July 1990 to December 1994, 81 consecutive patients under 17 years of age with no prior malignancies (except for myelodysplasia) were diagnosed as AML in the Hematology/Oncology Department, Hospital de Pediatria Garrahan, Buenos Aires, Argentina. During the same period, six patients with secondary AML were also diagnosed (two after acute lymphoblastic leukemia, one after non-Hodgkin lymphoma, one after chronic myeloid leukemia, one after Hodgkin disease and one with Fanconi’s anemia). They were excluded from this study because of their different wellknown response to current therapy. Diagnosis of AML The diagnosis of AML was based on the presence of >30% abnormal blasts or promyelocytes as defined by morphological examination of the bone marrow aspirate using May-Griinwald-Giemsa stains, peroxidase, Sudan black, chloracetate and alpha-naphthol acetate and butyrate esterase stains were used for histochemical definition of lineage. Fluoride inhibition was used with alpha-naphthol esterase stain to confirm the presence of monoblasts or monoblast-derived cells. Slides from 78 patients (three were unavailable and/or of poor quality to be evaluated) were reviewed for this presentation based on morphological, cytochemical, immunological and cytogenetic data according to the MIC criteria previously reported [13-151, by a specially designed expert committee. Patients Eighty-one consecutive patients under 17 years of age were entered into this protocol. Thirteen patients were excluded from this evaluation for the following reasons: four patients were incorrectly diagnosed and they
received more than 2 weeks of prior treatment (one nasopharyngeal carcinoma and three acute lymphoblastic leukemia); four patients died as a result of hemorrhage and/or leukostasis before receiving induction therapy; two patients were lost to follow-up; and three patients were of mixed-lineage or biphenotypic leukemia as defined by Matutes and Catovsky’s criteria (more than two points of B or T and more than two points of myeloblastic markers, according to their score) [16]. Their outcome was very poor: two died on induction, one of sepsis and the other of adult respiratory distress syndrome. The third patient achieved complete remission and presented a bone marrow relapse as acute lymphoblastic leukemia 9 months later, and subsequently died of progressive disease. Thus, 68 patients are fully evaluable for this presentation. An informed consent was obtained from the patients’ parents in every case. The protocol was approved by an institutional clinical trial review committee. Treatment The treatment schedule was similar to that of the AML-BFM-87 study except that idarubicin was used instead of daunorubicin in the induction phase (Table 1). Initial treatment consisted of an g-day induction phase with cytarabine in a 48-h infusion (100 mg/m2/d),
Table 1. Treatment schedule Induction therapy Cytarabine 100 mg/m2/d,IV 48-h infusion, days l-2 Cytarabine 100 mgim2, IV every 12 h in 30 min, days 3-8 Idarubicin 12 mg/m2/d,IV in 30 min, days 3-5 Etoposide 150 mg/m2/d, IV in 60 min, days 6-8 Cytarabine+dexamethasone,IT age-relateddosage,day 1 Consolidation therapy Prednisone40 mg/m2/d orally, days l-28 6-Mercaptopurine 60 mg/m*/d orally, days 1-28 Vincristine 1.5 mg/m*/d, IV, days 1, 8, 1.5, 22
Doxorubicin 30 mg/m2, IV, days 1, 8, 15, 22 Cytarabine 75 mg/m2/d, IV, days 3-6, 10-13, 17-20,24-27,
31-34, 38-41 Cyclophosphamide500 mg/m2, IV, days 29, 43 Cytarabinetdexamethasone, IT age-related dosage, days 1, 15, 29, 43 Intensification therapy (two courses) Cytarabine 3 g/m , IV every 12 h in 3-h infusion, days 1-3 Etoposide 125 mg/m’/d, IV in 60 min, days 2-5 (1 h prior to cytarabine dose) Continuation therapy 6-Thioguanine 40 mgrn’id, orally Cytarabine 40 mg/m /d, subcutaneously for4days each month Cytarabine+dexamethasone, IT age-related dosage, every 2 months during the first year of treatment Total treatment duration: 18 months IV: intravenous; IT: intrathecal.
Treatment of acute myeloblastic leukemia in childhood
followed by a 30-min infusion (100 mg/m2) every 12 h for the next 6 days, together with idarubicin (12 mg/m2/ d) in a 30-min infusion on days 3-5 and etoposide (150 mg/m2/d) in a 60-min infusion on days 6-8. The initial response to induction therapy was evaluated on day 15. If the bone marrow aspirate contained d 10% blasts, consolidation therapy was initiated after hematological recovery. A bone marrow aspirate was repeated on days 22 and 29 prior to starting consolidation therapy. However, if the bone marrow aspirate performed on day 15 contained 10% blasts, consolidation therapy was given without delay, providing the patient’s condition was judged stable enough to proceed, and it was not an acute promyelocytic leukemia. On day 28 an extended and intensive 6-week, eightdrug consolidation phase was administered with prednisone, 6-mercaptopurine, vincristine, doxorubicin, cytarabine, cyclophosphamide and intrathecal cytarabine plus dexamethasone. Central nervous system prophylaxis consisted of intrathecal cytarabine plus dexamethasone on day 1 of the induction phase; on days 1, 15, 29 and 43 of the consolidation phase, and every 2 months during the first year of the continuation phase. Age-related dosages were as follows: 0 to 1 year, cytarabine: 20 mg and dexamethasone: 2 mg; >, 1 to 2 years, cytarabine: 30 mg and dexamethasone: 4 mg; 22 to 3 years, cytarabine: 50 mg and dexamethasone: 4 mg; 23 years, cytarabine 70 mg and dexamethasone: 4 mg. Cranial irradiation was not delivered in any case. After a treatment-free interval of 2-4 weeks, two 5day intensification courses (with a 4-week interval) were administered consisting of high-dose cytarabine (3 gim2 every 12 h) in a 3-h infusion, six doses on days 1-3 together with etoposide (125 mg/m2) in a 60-min infusion (1 h before cytarabine), four doses on days 2-5. Continuation therapy was initiated 2-4 weeks after the second intensification course and consisted of daily oral 6-thioguanine (40 mg/m2/d) and cytarabine (40 mg/ m2/d) subcutaneously for 4 days every 4 weeks to complete 18 months of treatment. Bone marrow aspirate was requested by the protocol for diagnosis (biopsy was performed if needed) and on days 15 and 28 of induction, after the first 4 weeks of the consolidation phase, at the beginning of each intensification course, every 2 months during the first year of treatment and every 3 months up to the end of continuation therapy. Bone marrow aspirate was also performed whenever there was any clinical suspicion of relapse. Lumbar puncture with intrathecal chemotherapy was performed as previously described. During the second year of continuation therapy this procedure was done without intrathecai chemotherapy every 3 months. Bone marrow aspirate and lumbar puncture were not required after completion of therapy. All patients were
975
monitored for relapse and survival with periodic physical examination and complete blood cell count. Our experience with childhood acute promyelocytic leukemia (APLiFAB M3) treated with standard chemotherapy yields a concerning high mortality on induction due to central nervous system bleeding secondary to overwhelming disseminated intravascular coagulation (DIC) 117-201. The proved capacity of alltram retinoic acid (ATRA) to ‘cool down’ in a few days the hemostatic disorders in APL and the support of the reported experience on associated administration of ATRA together with induction chemotherapy, prompted us to introduce, as an amendment to the protocol, the use of this fascinating biological resource during the first days of the remission induction phase of our protocol [21-231. We decided then to make use of ATRA, from March 1994, strictly in order to manage coagulopathy and put the patient in the best condition to undergo induction chemotherapy which usually enhances the hemostatic disorders. We administered ATRA at 45 mg/m2/day PO during the first 2-7 days after diagnosis and further on only if DIC signs persisted. We profited from the extraordinary effect of ATRA on DIC and cautiously tried to minimize the effects of the ATRA syndrome. The basic aim of remission induction in APL was based on chemotherapy. Definitions and Statistical Methods This was a prospective, non-randomized, single-arm study (Fig. 1). Complete remission (CR) required a bone marrow aspirate showing normal erythrocytic, granulocytic and megakaryocytic regeneration, normal cellularity, less than 5% blasts and no evidence of disease in other sites. Central nervous system leukemia was assumed when there were more than 5 nucleated cells/@ together with the presence of unequivocal blasts in the centrifuged sediment of the cerebrospinal fluid. The Kaplan-Meier lifetable analysis [24] was based on the following definitions and assumptions: Event-free survival (EFS): The analysis was based on the total group of protocol patients. All events leading to remission failures (early death, non-response), first relapse or death during remission were evaluated. l Event-free interval (EFI): The analysis was based on patients achieving complete remission. The time of first relapse was evaluated. Patients who died in first remission were counted as failures. 0 The associated standard error (SE.) was calculated by the method of Peto et al. [25]. l Logrank test was used to compare survival estimates l
WI. l
Toxicity was graded according to the Children’s Cancer Group criteria [27].
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F. Sackmann-Muriel et al.
INDUCTION AIE
CONSOLIDATION
8 days
6 Weeks
INTENSIFICATION
1
HD Ara-C + VP-l 6 5 days
INTENSIFICATION
2
HD Ara-C +VP-16 5 days
CONTINUATION 6-TG I Ara-C Until completing 18 months of therapy.
Patients with > 10 % blast cells in Bone Marrow control of day 15 initiate consolidation regimen on day 15 /2 1 (except for FAB M3). AIE = Ara-c + ldarubicin HD = High dose.
+ Etoposide
Fig. 1. General outline of the protocol.
Prognostic risk groups were retrospectively established according to German BFM criteria [28], subsequently modified [29]. This evaluation reports on 68 patients assessedup to 1 January 1996. Results Patient data The patients’ major clinical and hematological features are summarized in Table 2. Bone marrow samples for cytogenetical study were obtained in 95.6% of cases (65/68). Of them 72.3% (47/ 65) were successfully analyzed. Results of the most significant cytogenetical findings and their outcome are shown in Table 3. Results of treatment Fifty-five (80.9%) of the 68 patients attained complete remission after a median time of 38 days (range: 22-92 days). Six patients achieved complete remission 10 weeks after diagnosis, during the consolidation phase (delayed remission). Ten patients (14.7%) died during the first month of therapy. Sepsis (six patients), hemorrhage (three patients) and both (one patient) being the main causes of early death. Three patients (4.4%) never achieved complete remission and finally died of progressive disease at 4, 5 and 5 months from diagnosis, respectively. With regard to the toxicity of the induction regimen, almost all patients experienced prolonged and severe myelosuppression: 60/68 patients developed severe neutropenia (number absolute of neutrophils < 5001~1) and leukopenia (WBC count < lOOO/pl) and 60/69 developed severe thrombocytopenia (platelet count ~20 OOO/pl). Fifty-two of the 68 patients developed severe or life-threatening infections which were fatal in seven cases as mentioned above. Hepatic and gastrointestinal tract toxicity and massive hemorrhage occurred less frequently. Acute cardiotoxicity was
uncommon (one patient), but alopecia was universal (Table 4). Seven patients died in complete remission. The causes of death were: pneumonia (three patients), including one with cytomegalovirus, sepsis (three patients), pulmonary hemorrhage (one patient). Four deaths occurred during the fifth and sixth weeks of consolidation phase. Three deaths occurred after the first intensification course. Up to the date of evaluation (1 January 1996), 19 relapses have occurred: 17 in the bone marrow, one in Table 2. Initial clinical and hematological features Number of evaluated patients Age: mean (years) range Sex: male/female Clinical data: Down’s syndrome Myelodysplasia Chloroma CNS involvement Hepatomegaly (>5 cm below costal margin) Splenomegaly (>5 cm below costal margin) Hematological data: mean range
Hemoglobin: gidl mean range
68 6
1 month-16 years 39129
7(M7=5,MO=l,M4=1) 9
M2Eo = 1) 2(M5b=l,M7=1)
3 (M2 = 2,
31 27
WBC count: (/pl) 38 000 600-250 000 8.2 4-13.3
Platelets: (/pl) mean range
FAB No. (%) AREB-t MO Ml M2 M3 M4 M5 M6 M7
(M2Eo = 4) (M3v = 1) (M4Eo = 3) (M5a = 4, M5b = 2)
54 800 1000-571000 2 (2.9) 3 (4.4) 2 (2.9) 19 (27.9) 11 (16.2) 13 (19.1) 6 (8.8) 4 (5.9) 8 (11.8)
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Treatment of acute myeloblastic leukemia in childhood Table 3. Significant cytogenetical findings Cytogenetical findings
t(8; 21) t(15; 17) -15, -17 Trisomy 8 Monosomy 7 t(9; 11) de1 16 t(9; 22)
de1 11 (q23) t(10; 11) t(7; 12)
t(11; 17)
Number of patients
Outcome
FAB subtype
M2Eo = 3, M2 = 3, M4 = 1 EFS: 0.7.5S.E.: 0.21 M3 EFS: 0.75S.E.: 0.15 M3 Areb-t = 1, M3 = 1, M4 = 1, M4Eo = 1, M6 = 1 EFS: 0.40 S.E.: 0.21 EFS: 0.00 M4=3,M6=1 M5a CR +13 months/BM relapse at 11 months M4Eo CR +33 months M2 BM relapse at 9 months M5b Death on induction M5a BM and CNS relapse at 8 months M4 BM relapse at 10 months M4 Death on induction
7 7 1 5 4 2 1 1 1 1 1 1
EFS: Event free survival (estimates); S.E.: standard error; CR: complete remission; BM: bone marrow; CNS: central nervous system. bone marrow and CNS and one in the bone marrow and
skin. Twenty-nine children are alive and disease free with a median follow-up time of 38 months (range 12-66 months). Only one patient (with FAB: M5a) received an allogeneic HLA-matched bone marrow transplant (BMT) in first remission. He was censored at time of BMT. However, he had been leukemia-free 13 months after diagnosis. If we analyze the seven patients with Down’s syndrome, five belonged to FAB M7, one to FAB M4 and one to FAB MO. Two of them died on induction of sepsis and another two died after achieving complete remission of sepsis and pneumonia, respectively. The other three are in continuous complete remission, +26, +34 and +38 months, respectively. Of the three patients with chloroma all belonged to FAB
M2 (one with
eosinophiliafM2Eo)
and showed
t(8;21) (q22;q22). Two also received radiotherapy due to spinal cord compression. All of them achieved complete remission and are free of disease at +12, +2.5 and +40 months, respectively. Of the two patients with initial CNS involvement, one was a newborn who presented AML FAB M5b and relapsed on bone marrow and skin shortly after
achieving complete remission. She died of progressive disease 3 months after diagnosis. The other one belonged to FAB M7 and achieved complete remission with intrathecal chemotherapy only. Cranial irradiation was not delivered. He is in continuous complete remission (+26 months). Event-free survival estimate of the whole group was 0.428 (S.E.: 0.062) and the event-free interval (EFI) estimate was 0.529 (S.E.: 0.07) and the overall survival (OS) estimate was 0.44 (SE. 0.071) at 4 years (Fig. 2). Results according to FAB types of AML are depicted in Table 5. The rate of induction failure (death on induction plus non-responders) was almost evenly distributed among the four more common FAB types. Life table estimates show that patients with FAB M2, FAB M3 and FAB M7 share similar EFS and EFI probability. It must be pointed out that 5/S (62.5%) patients of the FAB M7 subgroup, had somatic trisomy 21. I -:_
09il
I ‘9
--.--EFI
0 529 (SE 0.07)
Table 4. Toxicity of induction therapy* (n = 68)
WBC Platelets Infections Liver Gastrointestinal tract Kidney Heart Hemorrhage
Grade 3
Grade 4
7 8 31 1 15 0 0 14
60 59 21 3 7 2 1 23
*Number of patients according to CCG’s criteria [27].
Fig. 2. Kaplan-Meier estimate (S.E.: standard error) of eventfree survival (EFS) duration (n = 68), event-free interval (EFI) duration (n = 55) and overall survival (OS) (n = 68) in childhood AML in this trial.
F. Sackmann-Muriel et al.
978
Table 5. Results according to AML morphological (FAB) subtypes AREB-t
MO
Ml
M2
M2Eo
M3
M3v
M4
2
3
2
15
4
0 2 1 1
1 2 1 1
1 1 1 0
2 13 1
1 3 0
10 2 8 0
1 0 1 0
10 3 7 1
Number Induction failure* Achieved complete remission Dead in complete remission Relapses EFS (S.E.)?
M4Eo M5a 3 0 3 0
M5b
M6
M7
Total
2 1 1 0 1
4 1 3 0 2
8
68 13 55 7
4 0 4 0
2 0.!2 (0.E) 0.:4 (Op23) 0.348 (0.G) 0.62 (0.12) 0.67 (0.27) 0.50 (0.50)
EFI (S.E.)t
1
7 2 1 19 0.50 0.43 (0.50) (0.06) 0.57 0.53 (0.57) (0.07)
*Induction failure: death on induction+non-responders. TKaplan-Meier estimation at 4 years. S.E.: standard error. EFS: event-free survival.
To analyze prognostic groups, we performed a retrospective stratification of our patients based on the modified [29] prognostic factors originally described by Creutzig er al. [28]. The German group determined two categories defined only by morphology associated with good response to initial chemotherapy. That is, the lowrisk group included patients with FAB Ml/M2 with Auer rods, FAB M3 and FAB M4Eo, all with <5% of blasts in the bone marrow aspirate on day 1.5 of induction (except for FAB M3). The high-risk group included the rest of the population. In our series, the low-risk group (n = 22) had an estimated 4-year EFS of 0.70 (S.E.: 0.105) and an EFI of 0.81 (S.E.: 0.10). This group included 32% of all patients and 35% of the children achieving complete remission. The high-risk group (n = 46) showed an estimated 4-year EFS of only 0.29 (S.E.: 0.069) and an EFI of 0.37 (S.E.: 0.08). The P-value when comparing survival curves (logrank test) was 0.005 for EFS and 0.0038 for EFI, respectively (Figs. 3 and 4).
The management of early hemostatic disorders in APL (i.e. DIC) may be quickly overcome with the administration of ATRA. There were no hemorrhagic deaths on induction of those APL patients who received ATRA during remission induction treatment. But the number of patients is too small to produce further valid observations.
Discussion The results of this prospective trial are comparable to the best results achieved so far in pediatric AML patients [l, 301. The complete remission rate of 81% is in the upper range for children and the probability of continuous complete remission (event-free interval) of 53% after 48 months is encouraging, albeit in a relatively small patient group. Our institution is a large children’s hospital and a referral center in Argentina for general pediatric care. These results are being used to design an upcoming protocol for a larger number of
-.... ,A.......................
i.. .._ ......... 1
--~.-- LOWRISK 0 70 SE: 0 105 (Events 7 I22)
i .. ..__-_
---.- LOWRISK 0.61 SE 0.10 (Events: 4 / 19) _ c _.........c.._.._ .... -- ._.-.........._- ............
I_
, -1 i
4 -1
---
-i
-I- &7 -1 ‘L
---7 __-l_-_---_r-----_-----------
I
HIGHRISK 0 29 SE 0069 (Events: 32 146)
; ‘,--
Lc---,-----,-------------------
HIGHRISK 0 37 SE 0063 (Events 22 / 36)
Logrank test: p = 0.005 00-l
0
10
30
20
‘IO
I 50
Months
Fig. 3. Kaplan-Meier estimate (S.E.: standard error) of eventfree survival (EFS) duration for low-risk (n = 22) and high-risk (n = 46) groups (events/total).
20
30
40
50
Months
Fig. 4. Kaplan-Meier estimates (S.E.: standard error) for event-free interval (EFI) duration for low-risk (n = 19) and high-risk (n = 36) groups (events/total).
Treatment of acute myeloblastic leukemia in childhood
patients in Argentina and in other Latin American countries. We have improved our supportive care which allowed us to treat our patients with the AML-BFM approach showing the feasibility of this therapeutic strategy in our country. The rationale of the original AML-BFM study has been discussed [31]. The combination of an anthracycline and cytosine arabinoside is considered standard therapy for remission induction in AML. Recently, idarubicin (Cdemethoxydaunorubicin) has been found to be active in AML in adults. In fact, almost all trials in which cytosine arabinoside plus daunorubicin were compared with cytosine arabinoside plus idarubicin for remission induction in adult AML revealed significant advantages for the latter combination [6-8,32,33]. Furthermore, the therapeutic index of idarubicin may be higher than that of daunorubicin regarding cardiotoxicity, a major cause of concern in children. In the pediatric age group this problem has not yet been settled. Recent preliminary data from the German group [34], comparing cytosine arabinoside + idarubicin + etoposide (AIE) versus cytosine arabinoside + daunorubicin + etoposide WE) yielded no significant differences concerning early toxic death, unresponsiveness and remission rate in children with AML. However, in a very recent retrospective evaluation of idarubicin cardiotoxicity in a large population of patients with AML and myelodysplasia, mostly in adults, Anderlini ef al. [35] showed that at least at the dose currently used for AML remission induction (36-72 mg/m’) cardiac toxicity is minimal. In this study we administered a total cumulative dose of 36 mg/m*. the Ara-C + idarubicin + etoposide Nevertheless, combination is toxic, as toxic as any intense combination for remission induction in childhood AML, and our death on induction rate of 14.7% is high. Children have many problems in this phase, but toxic death is mainly due to disseminated intravascular coagulation, sepsis and leukostasis [36]. Obviously, these children should be managed with intense pediatric care in a strict isolation unit. Our death rate in complete remission is also high (7/55, 12.7%). We did not routinely use either antibiotic prophylaxis or gastrointestinal decontamination. During consolidation, children were treated mainly as outpatients. It is worthwhile mentioning here that in the original AML German BFM-87 Study [ll], the complete remission rate was identical to ours: out of a total of 210 children, 164 (78%) achieved complete remission. However, the mortality during induction (1 l/210 patients, 5.2%) and in complete remission (6/164 patients, 3.6%), was much lower than in our study, This fact prompts us to improve our supportive care. Moreover, Kaplan-Meier estimates for EFS and 5-year EFI in the original German AML-BFM-87 study were 0.41
979
(S.E. = 0.04) and 0.52 (S.E. = 0.04), respectively, results which are very similar to ours. In spite of this drawback, our results are promising, with an EFS estimation of 0.428 (S.E.: 0.062) and an EFI estimation of 0.53 (S.E.: 0.07) at 4 years with an apparent nice plateau 2 years after diagnosis. Relapses are mainly in the bone marrow. It is noteworthy that we observed only one CNS relapse (combined with bone marrow relapse) in spite of the omission of the preventive cranial radiotherapy used in the original German study. We can speculate with the hypothesis that with the administration of idarubicin on induction, the alcohol metabolite idarubicinol which is cytotoxic and diffuses easily in the CSF [lo], could have some protection against CNS relapse. The German group unexpectedly observed that cranial radiation reduced the risk of bone marrow relapse [ll]. They concluded that cranial radiation should be part of the treatment of childhood AML. This is an interesting yet a controversial point. As a matter of fact, prognostic factors in pediatric AML are not as definite as in ALL. Although recognized to be a heterogeneous group of diseases, FAB subtypes of AML, now with the exception of FAB M3, are identically treated in clinical trials. However, it is very interesting to corroborate with our series that two groups of lower and higher risk of relapse may be identified in children treated with AML/BFM protocols. The group of favorable prognosis is mainly characterized by predominance of granulocytic differentiation in the leukemic blast population: presence of Auer rods in FAB Ml/M2, bone marrow eosinophilia in FAB M4 and FAB M3. Noteworthy, the subtype FAB M7 is usually considered as having a worse prognosis. In the BFM stratification and in the present study these cases were classified in the group with higher risk to relapse. In this series, 62.5% (518) had somatic phenotype of Down’s syndrome, a distinct subgroup that responds well to therapy [37,38]. Perhaps this explains why LMA FAB M7 has a favorable outcome in our setting. Establishing risk categories is very useful because it permits the delivery of a tailored therapy. Certainly, patients enrolled in the low-risk group (one-third of childhood AML) are not candidates for BMT in first remission because of the low incidence of relapses. Contrarily, in the high-risk group allogeneic BMT should be performed in first complete remission and other forms of BMT should be discussed when the former is not feasible. The use of ATRA in remission induction treatment is certainly quite a revolution in leukemia therapy. Our rationale for the use of ATRA in APL, just during short courses to control DIC, has not been mentioned in current literature. Recent reports show that remission induction with ATRA as a single agent or given with
F. Sackmann-Muriel et al.
980
chemotherapy appears to improve remission rate, early mortality rate and, most interesting, uneventful survival in APL [39]. This fascinating biological resource needs further follow-up to attain its true hierarchy in APL therapy. We conclude that idarubicin in combination with cytosine arabinoside and etoposide is a highly effective remission induction regimen in pediatric AML. We believe that in this setting preventive cranial radiation should be omitted. References 1. Hurwitz C. A., Mounce K. G. & Grier H. E. (1995) Treatment of patients with acute myelogenous leukemia: Review of clinical trials of the past decade. J. Pediatr. Hematol. Oncol. 17, 185. 2. Arcamone F., Bernardi L., Giardini P., Patelli B., Marco A., Casazza A. M., Fratesi G. & Reggiani P. (1976) Synthesis and antitumor activity of 4-demethoxydaunorubicin, 4-demethoxy-7-diepidaunorubicin and their anomers. Cancer Treat. Rep. 60, 829. 3. Casazza A. M., Pratesi G., Giuliani F. & Di Marco A. (1980) Antileukemic activity of 4-demethoxydaunorubicin in mice. Tumori 66, 549. 4. Casazza A. M. (1979) Experimental evaluation of anthracycline analogs. Cancer Treat. Rep. 63, 83.5. 5. Ganzina F., Pacciarini M. A. & De Pietro N. (1986) Idarubicin (4-demethoxydaunorubicin): A preliminary review of pre-clinical and clinical studies. Invest. New Drugs 4, 85. 6. Berman E., Heller G., Santorsa J., McKenzie S., Gee T., Kempin S., Gulati S., Andreeff M., Kolitz J., Gabrilove J., Reich L., Mayer K., Keefe D., Trainor K., Scluger A., Penenberg D., Raymond V., O’Reilly R., Jhanward S., Young C. & Clarkson B. (1991) Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood 77, 1666. 7. Wiernik P. H., Banks P. L. C., Case D. C., Arlin Z. A., Periman P. O., Todd M. B., Ritch P. S., Enck R. E. & Weitberg A. B. (1992) Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood 79, 313. 8. Vogler W. R., Velez-Garcia E., Omura G. & Raney M. (1989) A phase-three trial comparing daunorubicin or idarubicin combined with cytosine arabinoside in acute myelogenous leukemia. Semin. Oncol. 16, 2, 21. 9. Broggini M., Sommacampagna B., Paolini A., Dolfihi E. & Donelli M. S. (1986) Comparative metabolism of daunorubicin and 4-demethoxy-daunorubicin in mice and rabbits. Cancer Treat. Rep. 70, 697. 10. Reid J. M., Pendergrass T. W., Krailo M. D., Hammond G. D. & Ames M. M. (1990) Plasma pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in pediatric leukemia patients: A children’s cancer study group. Cancer Res. 50, 6525. 11. Creutzig U., Ritter J., Zimmermann M. & Schellong G. (1993) Does cranial irradiation reduce the risk of bone marrow relapse in acute myelogenous leukemia? Unex-
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