Diagnosis and treatment of acute myelogenous leukemia in childhood

Critical Reviews in

ONCOLOGY/ HEMA TOLOG Y Critical

ELSEVIER

Reviews in Oncology/Hematology

22 (1996) 1833196

Diagnosis and treatment of acute myelogenous leukemia in childhood Ursula Creutzig* Unioersitiits-Kimderklinik,

Albert-Schweitzer-Str.

33, D-48129 Miinster,

Germany

Accepted 23 January 1996

Contents I.

Introduction ......................................... Diagnosis ........................................... 2.1. Clinical manifestations ............................... 2.2. Morphological and cytochemical classification. ................. 2.3. Immunophenotyping ................................ 2.4. Karyotyping ..................................... 2.5. Molecular genetics. ................................. 2.6. Difficulties with diagnosis ............................. 2.6.1. Down’s syndrome ............................. 2.6.2. Myelodysplastic syndromes ....................... 3. Therapy ............................................ 3.1. Actual treatment modalities 3.1.1 General aspects of treatment ...................... 3.1.2. Remission induction therapy. ...................... 3.1.3. Post-remission therapy .......................... 3.1.3.1. Consolidation and intensification .............. 3.1.3.2. Allogeneic BMT. ....................... 3.1.3.3. Autologous BMT ....................... 3.1.3.4. Maintenance therapy ..................... 3.1.4. CNS prophylaxis and therapy. ..................... 3.1.5. Adjustment of treatment according to prognostic factors ...... 3.2 New treatment modalities ............................. 3.2.1, All-trans-retinoic acid treatment for acute promyelocytic leukemia. Hematopoietic growth factors ...................... 3.2.2. 3.3. Management of complications and supportive care. .............. 3.3.1. Leukostasis. ................................ Hemorrhage ................................ 3.3.2. 3.3.3. Metabolic disorders ............................ 3.3.4. Toxicity of chemotherapy ........................ 4. Future aspects ........................................ Reviewer, ............................................... References ............................................... Biography ................................................

2.

1. Introduction In contrast to adults, acute myelogenous leukemia (AML) in children represents only - 20% of acute leukemias. With some minor exceptions the biology of

183 184 184 184 184 185 185 I85 IS5 186 186 1886 186 186 187 187 188 188 188 I50 I50 190 150 191 191 191 192 I92 192 192 193 193 196

AML is similar in children and adults. Although AML is much more resistant to chemotherapy than acute lymphoblastic leukemia (ALL), treatment results in childhood AML have considerably improved during the last 15 years [50]. With intensive induction chemotherapy 70-80% of children achieve complete remission (CR) which translates into a long-term event-

* Tel.: 49 251 83 64 86: Fax: 49 251 83 64 89. 1040-8428/96/$32.0(1 8 1996 Elsevier Science Ireland Ltd. All rights reserved P/I Sl041)-8428(96)00195-3

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free interval (EFI) in 40-50% of patients with consolidation, intensification and maintenance therapy. Furthermore, allogeneic bone marrow transplantation (BMT) in first remission shows promising results with similar or even longer EFI [13], and therefore may be considered alternatively for post-remission treatment in patients with an HLA matched sibling. Ablative therapy supported by autologous BMT in first remission is another feasible approach although with an obvious risk of reinfusing leukemic blast cells. The strategy of remission induction with the aim of restoring thl: normal function of the bone marrow, and thus, attaining complete remission are widely accepted, whereas the options for post-remission therapy are still debates of controversy as to the optimal treatment. A correcl diagnosis is required to ensure adequate therapy, and especially important when applying riskadapted treatment strategies. Furthermore, reliable comparison’i of different therapy strategies have to be based on common diagnostic, exclusion and inclusion criteria. This paper outlines different treatment strategies of childhood AML, and refers also to adult AML due to the rarity of AML in childhood and difficulties by carrying out phase 1 and 2 trials in children. Furthermore, the advantages and problems of various treatment strategies will be discussed.

2. Diagnosis; 2. I. ClinicrL

mnnljkstutions

Signs anti symptoms in AML may be uncharacteristic with anemia, fever, infection, bleeding manifestations, which result from the reduction and ineffectivity of all three (sell lines of haematopoiesis. The mechanism for the reduction of the normal haematopoiesis is not understood. it may be due to suppressive substances released by leukemic blasts. extramedullary leukemic infiltrations Commonly. affect liver. spleen and lymph nodes and occur in one-third of the patients. CNS involvement ( 2 5 or 2 lo/mm’ leukemic blasts in the CSF or clinical or radiologic signs of intracerebral leukemic infiltration) is found in 5- 10% of children with AML. Infiltrations of the skin occur, especially in monocytic leukemias, and may be important in view of disease control, because leukemic blasts from these sites may reseed in the bone marrow. and thus induce hematological relapse. 2.2. Mo~~~hological

and cytochemical

classfication

The first and most important step in the diagnosis of acute leukemias is the discrimination between AML and ALL. Morphology and cytochemistry tests are

22 (1996) 183- 196

mandatory and immunophenotyping and karyotyping as well as molecular monitoring of gene rearrangements can give additional information. The main criteria for differential diagnosis are shown in Table 1. AML is a morphological heterogenous disease. Since several hematopoietic cell lines may be involved granulopoietic cells, monocytes, erythroblasts and even megakaryocytes are frequently found together. The classification of AML according to the FAB criteria [6,8] is based mainly on cytomorphological features. The first definitions of the FAB group included 6 different subtypes of AML: Ml, M2 and M3 for granulocytic leukemia, M4 and M5 for myelomonocytic and monocytic leukemia and M6 for erythroleukemia [6]. This was supplemented in later years by the variant form of M3 (M~v), the M4 subtype with abnormal eosinophils (M4Eo), acute megakaryoblastic leukemia differentiated acute myeloid (M7), and minimally leukemia (MO) [5,8,9].

2.3. Immunophenotyping

Immunophenotyping is required to classify FAB MO and M7 blasts due to their resemblance to lymphoblasts or undifferentiated blasts and negativity of myeloperoxidase (MPO), and at times essential for the differentiation of ALL and AML. In FAB MO the expression of one or more of the panmyeloid-associated antigens (CD13, CD33, CDw65) is necessary. In FAB M7 panmyeloid-associated antigens are often negative, however the megakaryocytic lineage specific markers CD41, CD42, CD61 are positive.

Table 1 Distinctive

features of ALL and AML ALL

AML

Morphology

No granules No Auer rods

Usually granules .4uer rods may be present

MPO-staining

Negative

Positive

lmmuno -phenotyping

B-lineage CDIO, CD19 pos. T-lineage cyCD3 pas., CD7 pos.

Pan-myeloid-associated antigens (CD13, CD33, CDw65) pos.

Karyotype

t&14) (B-ALL) t(9;22) t(1;19) (pre-B-ALL) t(11;14) (pre-T-/T-ALL) t(4;11) (pre:pre-B-ALL)

t(8;21) (FAB t(15;17) (FAB t(9;ll) (FAB inv( 16) (FAB Monosomie Trisomie

M2) M3) M5) M4Eo)

7

8 (unspecific)

U. Creutzig / Critical

Reaiews in Oncology/Hematology

Table 2 Incidence of FAB types in children with AML” .___ n

FAB-type

pi)

___MO MI M2 M? M4 M5 M6 M7 Basophilic-leukemia Patients (n) ___-

17 30 84 15 66 69 8 17 I 307

(6) (10) (27) (5)

(21) (22) (3)

(6) (0.3)

“Data of Study AML-BFM-X7

In the other subtypes of AML, immunophenotyping shows positivity in at least one of the panmyeloid-associated antigens. Coexpression of T-lymphoid associated antigens is common in children with AML (about 40%) [30a], whereas B-associated antigens are generally negative. The non-lineage-restricted marker terminal-deoxynucleotidyl transferase (TdT) which is usually positive in ALL (95%) is present in about 10% of AML patients, and therefore not specific for ALL. The distribution of morphologic subtypes in children is similar to that in adults, except for the higher incidence of acute monocytic leukemia FAB M5, due to the known higher incidence of this subtype in children under 2 years [28,65,68] (Table 2). The improved diagnostic methods of morphological, cytochemical and immunological testing during the last number of years has led to an increase of the rare subtypes MO and M7, e.g. in the German BFM-(Berlin-Frankfurt-Miinster) studies from 0% (study -78) to 2% (study -83) and 6% (study -87, Table 2). Most likely, undifferentiated AML types have previously been diagnosed as ALL.

185

22 (1996) 183-196

MDS and solid tumors [24]. p53 and RBl genes are involved in the progression of leukemias and lymphomas, the latter gene is found, especially in monocytic leukemias. The AMLl /ET0 fusion transcript is consistently detected in AML containing the t(8;21) [48], and fusion of the PML gene from chromosome 15 with the retinoic acid receptor gene on chromosome 17 is characteristic for acute promyelocytic leukemia [53], thus, defining the disease by molecular probes. These analyses are extremely sensitive for detection of minimal residual disease (1 leukemic cell among 100000 or even 1 million cells [24]). 2.6. DifJiculties with the diugnosis 2.6.1. Down 3 syndrome

The most frequent genetic disease associated with leukemia is Down’s syndrome with a 20-fold increased risk of developing acute leukemias compared to other children. Neonates with Down’s syndrome may show blasts in the blood and bone marrow with a morphological picture of AML. However, a spontaneous remission occurs after some weeks or months in these patients without any chemotherapy (transitory myeloproliferative disease, TMD), although some of them may develop AML after some years. Diagnostic problems in the subclassification of AML in children with Down’s syndrome are frequently due to very immature cells or a mixed phenotype. Recently, a distinct relationship between acute leukemia with megakaryoblastic involvement and Down’s syndrome was found [63,76]. Overall, prognosis of children with Down’s syndrome treated according to AML therapy is similar or even better than in other children [59].

2.4. Kur.vo typing

More than two-thirds of the patients with AML present with cytogenetic abnormalities. In contrast to ALL patients, blasts are pseudo- or hypodiploid. Specific chromosomal aberrations are closely associated with FAB types and shown in Table 3. The specific abnormalities t( 8;2l), t( 15;17), inversion 16 are predictive for a favourable outcome, whereas monosomy 7 is unfavourable, indicating secondary leukemia or myelodysplastic syndrome (MDS) [45]. 2.5. Molecular genetics

Genetic abnormalities are common in AML. N-ras is an oncogene activated by mutation in 15-50% of AML patients (less frequent in childhood AML), and is also found in pre-B cell and T-cell lymphoblastic leukemia:

Table 3 Chromosomal aberrations in children with AML karyotypes with FAB types” Karyotype Normal t(s:.!l) t(15;17) inv( 16) t(Y;ll) del Ilq

+ 8“ - 5!‘5q - 7,;7q Random aberrations N

(‘!fp

n 27 23 5 Y 16 8 16 1 6 43

Correlations

and correlation

with FAB types

(20) (17) (4) (7) (12)

17123 (74%) 5:‘5 (100%) 819 (89%) 13:16 @I’%,) ~-

M2 with Auer rods M3 M4Eo M5

(6) (12) (1) (4)

(32)

134

“Data of Study AML-BFM-87. hTotal over 100’%1due to incidences of combined aberrations.

of

186

U. Creutzig / Critical

2.6.2. Myelodysplustic

Reviews in Oncology/Hematology

syndromes (&IDS)

MDS mainly affects older people, and is characterized by an meffective and dysplastic haematopoiesis in one or more cell lines, and a high risk of transformation into acute leukemia. Differential diagnosis of MDS and AML is important for therapeutic and prognostic reasons. In 1982, the FAB group defined 5 subtypes of MDS: refractory anemia (RA), refractory anemia with ringed sideroblasts (RAS), refractory anemia with excess of blasts (RAEB), refractory anemia with excessof blasts in transformation (RAEB-T) and chronic myelomonocytic leukemia (CMML)[7]. Cytopenia in the peripheral blood and normo- or hypercellular bone marrow with less than 30% of blasts are typical. Only CMML patients show peripheral leukocytosis with an absolute monocyte count > lOOO/ /il. In childhood, MDS are rare diseases with an incidence of l-2% of all leukemias [26], although they may have been overlooked in the past. Juvenile CML shows overlapping features with adult CMML [12a], and should therefore be included in this subtype of MDS. The differential diagnosis between M6 and MDS often proves to be difficult when assessingthe percentage of blast cells within the non-erythroid cells ( 2 30% = M6. < 30% = MDS) [8]. Another problem of differential diagnosis occurs especially in children with Down’s syndrome and M7 subtype, because the megakaryoblastic component is below or above the arbitrary level of 30%. Therefore, the classification as RAEB-T or AML FAB M7 may be quite similar from a biological and clinical point of view [42]. 3. Therapy 3.1. Act&

,‘reatmmt modalities

3.1.1. General aspects oJ‘ treatment

As in adults, the main purpose of therapy is to eradicate the leukemic clone with subsequent restoration of a normal haematopoiesis (complete remission, CR). Chemotherapy starting with intensive induction treatment, designed to cause marrow aplasia and render the leukemic clone undetectable is usually far more intensive compared to childhood ALL. The definition of CR according to the NC1 criteria requires less than 5% blasts in the bone marrow, with a marrow cellularity of more 1han 20%, and at least 1500/mm3circulating neutrophiles with a duration of response of at least 4 weeks [23]. Induction therapy is followed by post-remission phases which are applied to destroy residual blasts in the bone marrow or at other sites. However, duration and the optimal kind of post-remission therapy has

22 (1996) 183- 196

not been established yet. Generally, intensive chemotherapy courses called consolidation, and/or intensification are administered together with CNS prophylaxis and/or a less intensive maintenance chemotherapy. Allogeneic or autologous bone marrow transplantation may be included as another form of intensification (Table 4). The use of the differentiating agent all-trans-retinoic acid (ATRA) is a special treatment for patients with the FAB type M3, inducing cell differentiation and maturation instead of cell destruction. Nevertheless, during all treatment phases, especially during the first days and weeks of treatment, acute management and supportive care is necessary. 3.1.2. Remission induction therap)) (Table 4)

Induction therapies aim to achieve CR and improve long-term results. Generally, this can be achieved in most children with AML by a single 7-day course of cytosine arabinoside (Ara-C) and 3 days of anthracyclines. These induction regimens vary in different studies by the kind of administration with short time or continuous infusion of Ara-C (100-200 mg/m’ per day for 7 days), and in combination with daunorubicin (45-60 mg/m* per day for 3 days). Some regimens include additional drugs as well, e.g. 6-thioguanine or VP-16 (Table 4). Currently, most of the pediatric AML studies apply remission induction with one or two courses of this short and intensive therapy. The CALGB study in adults [58] could demonstrate that Ara-C administration for 7 days was superior to a 5-day treatment with Ara-C. By comparison, Ara-C administration for more than 7 days was too toxic and did not raise the remission rate [56]. New data of adults on high-dose (HD, 3 g/m’) vs. standard dose Ara-C in induction showed a longer remission duration in the high-dose group [ll], however, toxicity was considerably high. Daunorubicin given over 3 days achieved best results if applied in the high dose of 60 mg/m2 [17,74]. The introduction of the ADE induction (Ara-C, daunorubicin, etoposide) in the German AML-BFM-83 trial resulted in a major improvement of long-term results in childhood AML [29]. An important new drug used in adult AML trials during induction, consolidation and intensification therapy is idarubicin, and although remission rates were higher as compared to daunorubicin (3 x 45 mg/m* or 3 x 50 mg/m*) [lo], long-term results did not improve. One major criticism was that the dosage of daunorubicin was not comparable. Therefore, our current pediatric trial (AML-BFM-93) compares this drug (12 mg/m2/day x 3) with daunorubicin (60 mg/m*/day x 3) during induction. A second induction course with identical or other drugs is often necessary to achieve remission and is

U. Creutzig / Critical Reviews in Oncobgy/Hmatology Table 4 Overview

on therapy strategies in pediatric AML

Study/duration

(Reference)

187

protocols CNS-Prophylaxis

Consolidation/ intensification

BMT

Maintenance (duration. years)

ADR (DNR) + Ara-C(3 + 7) x 2

I.t. MTX18

4

Allog. BMT vs. none

Continuous w. cyclic (2 or 3)

DNR, Ara-C (3 + 7) vs. Denver

1.t. Ara-C

2 courses HD-Am-C/Asp + 3 months ChT

Allog. BM’I vs. none

Continuous (1 5) vs. none

CCG 213 P/1983 -1085 (Wells et al. 1993)

DNR, Ara-C (3 + 7) vs. Denver

1.t. Ara-C

Timing of HD-Ara-C/Asp every 28 days vs. 7 days

Allog. BMT vs. none

Continuous (I 5) vs. none

POG-849%2:1986- 1988 (Ravindranath et al. 1991)

DNR, Ara-C, TG (3 + 7 + 7)

1.t. Ara-C

2 x HD-Ara-C, ISC (12 months)

POG-8821:198881993 (Ravindranath et al. 1994)

DNR, Ara-C, TG (3 + 7 + 7)

1.t. Ara-C

HD-Ara-C, VP/AZ, ISC

ABMT

St. Jude/1980--1983 (Dahl et al. 1990)

DNR, Am-C (3 + 7) x 2

1.t. MTX

ISC (12 months)

Allog. BMT vs. ISC

VAPA/19761990)

VC, ADR,

4

ISC (14 months)

CCG-251:1979-1983 al. 1994) CCG-213/1983al. 1993)

Induction

22 (1996) 183- 196

(Nesbit et

1989 (Lange et

1980 (Grier et al.

AIEOP/198771990 al. 1993)

(Amadori

et

DNR, DNR,

(duration,

days)

P, Ara-C

Ara-C (3 + 7) Ara-C (2 + 5)

x 2

1.t.

ha-c

Gy CrRT

+

DNR, ha-c. TG ISC (9 months)

P

BFM-83/1982al. 1990)

1986 (Creutzig et

DNR, Ara-C, VP (3 + 8 + 3)

I.t. Ara-C + CrRT

Consolidation 8 weeks, 7-drugs

BFM-87/1987-al. 1993)

1992 (Creutzig et

DNR, Ara-C, VP (3 + 8 + 3)

1.t. Ara-C

Consolidation 6 weeks. 7-drugs + 2 x HD-Ara-C/VP

k CrRT

-

Cyclic (I )

vs. ISC Cyclic (1) Cyclic (1) Cyclic (I .2)

Allog. BMT vs. ABMT vs ISC

Cyclic (0.75)

Continuous (1.75) (Allog.

BMT)

Continuous (1)

Abbreciations: Denver, ha-c, DNR, VP, TG, dexamethasone (5 days); Ara-C, cytosine-arabinoside; HD-Ara-C, high-dose cytosine-arabinoside: ADR, adriamycin; Asp, asparaginase; AZ, azacytidine; DNR, daunorubicin; MTX, methotrexat; P, Prednison; VP, VP-16,213 (Etoposid); TG, thioguanine; BMT, bone marrow transplantation; Allog., allogeneic; ABMT, autologous BMT: CrRT, cranial irradiation; ChT, chemotherapy: ISC. intensive sequential chemotherapy; I.t., intrathecal.

given in many trials. Biichner et al. [17] could demonstrate in adults that by intensive double induction therapy long-term results have been improved. 3.1.3. Post-remission therapy 3.1.3.1. Consolidation and interkjkation (Table 4). After induction therapy further intensive treatment aims to eradicate the remaining leukemic cells which are not visible by microscope but may be detected by new molecular biological techniques. The persistence of a leukemic clone may be clinically important for the occurrence of relapse, however, up to now the significance of the detection of minimal residual disease is not known. The term consolidation therapy refers to the

repeated administration of two or more courses of the drugs used in the induction phase. Non-cross-resistant sequential drug combinations are administered during intensification chemotherapy cycles to circumvent drug resistance. These cycles may be given for several months or up to more than 1 year (e.g. VAPA study [68]) or as in the last German BFM trial with a 6-week consolidation with 7 different drugs [29] and two blocks of intensification with HD-Ara-C. Data of several studies revealed a lower relapse rate in children and adults after the introduction of high intensive chemotherapy with HD-Ara-C in post-remission treatment [21.60,69,72]. The importance of dose scheduling was demonstrated by the CCG 213P-study (Table 4) by administering two

188

U. Creutzig i Critical Reviews in Oncology/Hematolo~y 22 (1996) 183- 196

courses of HD-Ara-C/asparaginase at 7-day intervals resulting in superior survival rates compared to 28-day intervals [70]. 3.1.3.2. Alhgeneic bone marrow transplantation (BMT). The antileukemic effect of allogeneic BMT is the result of the conditioning regimen with ablative chemothergraft-versus leukemic apy, and the immunological effect. Allogeneic BMT has been evaluated by the CCSG in study 251 and 213. In the first study results with allogeneic BMT were significantly better than in patients with conventional post-remission chemotherapy (Table 5) [34,54], however this could not be confirmed in study 213 [49]. We pursued this issue by performing matched-pair analysis among patients of studies AML-BFM-83 and -87 with equal results of event-free interval for 16 children with or without allogeneic BMT [25]. In the St. Jude’s study (1980- 1983) [3 l] there was also no significant difference in the duration of continuous CR with or without allogeneic BMT in a program of intensive sequential chemotherapy but post-remission failures resulted more often from bone marrow relapse in the sequential 1:hemotherapy group (23 of 42 patients, 2 deaths in CR) compared to the BMT group (5 of 19 patients with bone marrow relapse, 5 deaths in CR) (Table 5). Nevertheless, outcome for children receiving allogeneic BMT in first CR of AML has improved during the last decade. Michel et al. [52] attribute this to a decreased risk of transplant-related mortality from 36% between 1979- 1986 to 3% between 1987-1990. The Seattle experience in adult patients reported by Appelbaurn et al. [3] showed a lower relapse rate in the transplanted group compared to the chemotherapy group given intensive post-remission consolidation and maintenance. Toxicity of BMT includes major organ toxicity, e.g. hepatic veno occlusive disease or interstitial pneumonia, acute graft-versus-host disease (GvHD) clinically manifested as rash, hepatic dysfunction, diarrhoea and fever. Late toxioty may include growth impairment, endocrinological disturbances, late cardiotoxicity and chronic GvHD. Considering all these adverse factors a risk factor analysis should try to identify patients in whom allogeneic BMT is mandatory. In summary, allogeneic BMT is an effective but highly toxic antileukemic therapy. Some comparable non-randomized studies demonstrate a survival advantage for patients undergoing BMT; however, comparisons with conventional therapy are highly biased by patient selections [66]. It should be emphasized that some patients will be cured already by chemotherapy without BMT. Thus. it is suggested that given the cure-rate with conventional treatment, overall survival of the young patients transplanted after the first relapse would be the same even though BMT may be less

effective after relapse. Patients cured by chemotherapy alone would be spared the potential morbidity of the transplant procedures. Unrelated donor transplantation is as effective in eradicating leukemic cells as BMT with a related donor. This method, however, should not be considered in first CR in children with AML due to the severe morbidity associated with acute and chronic GvHD [20,44]. transplantation 3.1.3.3. Autologous bone marrow (ABMT). High doses of chemotherapy and radiotherapy can be administered if rescue by ABMT is available. Although less toxic than allogeneic BMT due to the eliminated risk of GvHD it proves to be less effective with the possible risk of reinfusion of leukemic stem cells. The concept of in-vitro purging tries to rid the marrow of these cells. Purging agents in AML have been cyclophosphamide derivates, e.g. 4-hydroxy-peroxy-cyclophosphamide (4-HC) [75] or Mafosfamide [3X]. Most reports demonstrate a l -3-year survival rate of 30-50% of patients in 1.CR and - 20% for patients in 2.CR. In the randomized study 8821 [61] of the Pediatric Oncology Group (POG), the efficacy of ABMT and intensive consolidation chemotherapy (ICC) was compared. First results did not show any difference in outcome either when analyzed by intendto-treat (ICC 37% vs. ABMT 37%) or as treated (ICC 39% vs. ABMT 40%). Leukemia relapse rate was lower but treatment mortality higher in ABMT compared to ICC (20% vs. 3%). Similar results were obtained by another study in Europe (AIEOP/LAM 87) for ABMT vs. post-remission chemotherapy but superior results in children with allogeneic BMT [2] (Table 5). Up to now ABMT alone does not seem to improve cure rates in childhood AML. However, better results might be achieved by improving purging and preparative regimens.

3.1.3.4. Maintenance therapy. The mode and duration of maintenance regimens for AML in children and adults is still controversial. As in ALL, maintenance chemotherapy has been employed in childhood AML to prolong the duration of remission, however the impact on cure is not as clear as in ALL. In two recent adult studies prolonged maintenance regimens did not contribute to long-term results when applied after four consolidation courses [51] or by a high intensive single consolidation course [ 191. On the other hand in a meta-analysis performed by Btichner et al. [12] patients with standard or intensive maintenance showed a 5-year continuous complete remission rate of 25% compared to only 13% in patients assigned to a reduced dose or no maintenance. These results may indicate that depending on the kind and intensity of pretreatment, maintenance can contribute to an increased long-term survival [15].

U. Creutzig / Critical Reviews in Oncology/Hematology

22 (1996) 183- 196

189

190

U. Creutzig ! Critical

Reciews in Oncology/Hemutology

In the German AML-BFM study -87, a reduction of duration of maintenance from 2 years to 1.5 years did not have an influence on the relapse rate after cessation of therapy. Results in the study CCG-213 [70] indicate that maintenance therapy may not be necessary after induction and a post-remission intensification phase with HD-Ara C with an aggressive (q-7 days) timing. However, toxici1.y and mortality rates were high in this group, and maintenance seemedto play a role in those patients who had received the less aggressive Ara-C intensification timings [73]. These data support the strategy of an intensive treatment during induction, consolidation and intensification with at least some months of maintenance therapy. Further clinical trials with different duration of maintenance therapy are necessary to back-up these results. 3.1.4. CNS ,vrophJlaxis and therapy

Prophylactic cranial irradiation has not generally been included in therapy protocols for AML in adults and children. Most investigators agree that cranial irradiation will prevent CNS relapses, however its effect on overall rem&ion duration has not been determined yet [4,28,32,47.57]. Results of ALL trials in children [55,62] and of the AML study 72-75 reported by Dahl et al. [32] indicated that cranial irradiation had an impact only on the number of CNS relapses but not on overall survival. Most studies in AML in children and adults use intrathecal MTX or Ara-C or a combination of these agents with hydrocortisone. Study AML-BFM-87 tested prospectively if cranial irradiation could be replaced by late intensification therapy with HD-Ara-C and etoposide. Results showed that the probability of relapse-free interval of 5 years was significantly better in irradiated patients compared to non-irradiated (78”/1 vs. 41%). This was due to the total number of relapses (isolated bone marrow and combined bone marrow/ CNS relapses). Thus, indicating that residual blasts in the CNS may escape systemic chemotherapy and lead to a recurrence of the initial disease not only in the CNS but also in the bone marrow [30]. However, these findings still have to be confirmed by other pediatric AML trials. 3.1.5. Adjustment qf’ treatment according to prognostic

,filL’tOl.S The main goal of risk factor analyses is the definition of the individual risk at diagnosis or as soon as possible thereafter in regard to the overall risk of failure or the risk of early death, treatment failure, relapse and death in CCR. Although considering (1) that most prognostic variables are not independent, and (2) that therapy intensity can change the significance of risk factors. In childhcod AML, young age is considered an adverse prognostic factor. A poor outcome, especially for

22 (1996) 183- 196

infants compared to older children was reported by Grier et al. [39] and Buckley et al. [14] and confirmed in study AML-BFM-87 but not in the first two AMLBFM studies. All studies suggesting young age to be a significant adverse factor could show this only by univariate analysis. The significance was lost when the data were analysed by multivariate methods. Other factors predicting an unfavourable prognosis were: high white blood cell count (WBC), FAB types M4 and M5 [14,39]. According to our results a high WBC ( > lOOOOO/ mm”) was associated with an increased risk of early death due to hemorrhage and/or leukostasis, particularly, in patients with M5 and concurrent hyperleukocytosis [23]. The significance of a high WBC count in regard to the risk of failure remains unclear. Whereas an important correlation with other parameters, e.g. blast cell reduction until day 15 was revealed by multivariate analysis. Due to the heterogeneity of AML the prognostic significance of a high WBC count varies in the different FAB subtypes, e.g. patients with M3 usually present with a low WBC but have a higher risk of early death by disseminated intravascular coagulation, and children with M7 even without an increased WBC are at a higher risk for treatment failure. Comparison of studies AML-BFM-78 and -83 showed an improvement of prognosis in the FAB types with predominantly granulocytic differentiation (FAB M 1-M4) after intensification of chemotherapy in study -83. Based on these results two different risk groups (low and high) could be established by predominantly pretherapeutic parameters including FAB types and morphological findings, e.g. Auer rods and eosinophils and also the WBC count. Recent analysis of study AML-BFM-87 confirmed these risk groups in patients receiving cranial irradiation, indicating again, that risk factors can be regarded only in the context of the overall treatment strategy. Cytogenetic data revealed an association between FAB types and cytogenetic findings which may specify the definition of risk groups (Table 6).

The definition of risk groups in childhood AML allows a more stratified therapy, e.g. early intensification of chemotherapy (which will increase toxicity), and/or allogeneic BMT in first remission for children of the high risk group, and avoiding toxicity by less-intensive therapy in standard risk patients. 3.2. New treatment modalities 3.2.1. All-trans-retinoic acid treatment for acute promyelocytic leukemia (FAB M3)

Recent studies have demonstrated high complete remission induction rates in patients with acute promyelocytic leukemia treated with all-trans-retinoic acid

U. Creutzig / Critical

Reciews in Oncology/Hematology

(ATRA) alone or with ATRA and chemotherapy [35,67]. ATRA develops its differentiating potential by binding to a nuclear receptor (retinoic acid receptor x = RARa). The gene coding RARcl was located on the breakpoint of chromosome 17 involved in the t(l5;17) of acute promyelocytic leukemia. The rearrangement of a PML-RARc( fusion messenger RNA is essentially involved in the maturation block and leukemogenesis of FAB M3 [I]. The clinical effect of ATRA therapy is not cell destruction but cell differentiation which could be shown by the persistence of the t( 15;17) in more mature cells [67]. Response to ATRA is associated with an improvement of the hemostatic disorders by normalization of the fibrinogen level and the disappearance of fibrin degradation products, thus, reducing the number of early deaths due to bleeding [22]. However, complete remission induced and maintained with ATRA alone, generally had a short duration. Hence, the new principle of differentiation treatment with ATRA has to be supplemented by an adequate chemotherapy. Adverse side effects of ATRA are headache occurring several hours after digestion of the drug, and in some patients, especially in children, intracranial hypertension (pseudotumor cerebri) a known consequence of vitamin A toxicity, probably due to the higher sensibility of the nervous system in children. A syndrome characterized by fever, respiratory distress, radiographic pulmonary infihrates, pleural infusion and weight gain. the so called ‘retinoic acid syndrome’ was described in m 25% of the adult patients [37]. The syndrome occurs with increasing leukocytosis but also with a normal leukocyte count. Progression of this syndrome can be stopped by early treatment with corticoid steroids (dexamethasone 10 mg/m’ intravenously every 12 h for 3 days) [37]. In summary. the use of differentiating agents seems to be a new approach for specific subgroups.

Table 6 Modified definition of risk groups based on the results of studies AML-BFM-83 and -87 Risk group

Standard risk FAB MI /M2 with Auer rods FAB M3 FAB M4 Eo

Correlating karyotype

Prognosis EFI of 5 years

t(821) t(l5:17) ink(l6)

0.74 (S.D. 0.05)

Also required: blasts in the BM on day 15 <5’%1 (except for M3) High risk: all other EFI, event-free interval (Probability

0.48 (SD. 0.04) of continuous

CR).

22 (1996) 183-196

191

3.2.2. Hematopoietic growth factors

As hematopoietic growth factors (GM-CSF and GCSF) stimulate the proliferation of clonogenic leukemic cells in vitro [39,40] it was regarded with reservation to use growth factors in leukemic patients. However, Biichner et al. treated adults with AML with GM-CSF after chemotherapy and could demonstrate an earlier granulocytic recovery without adverse effects [16]. In addition to supportive effects growth factors were tested for their ‘priming effect’ on the antileukemic chemotherapy. The aim is to recruit cells into sensitive phases of the cell cycle to increase their sensitivity to cycle active chemotherapeutic agents. This effect could be demonstrated in vitro [43], whereas the first results in treating AML patients with chemotherapy plus GMCSF have been controversial by divergent antileukemic or protective effects seen in patients [l&33]. Estey et al. [33] reported a higher rate of persistent leukemia after one induction course in the GM-CSF group compared to a historical control group. Biichner et al. tested in a randomized study GM-CSF before, during and after chemotherapy courses compared to chemotherapy alone. First results showed a superior remission duration in patients treated with GM-CSF

1181.

However, results of the study from Estey et al. are difficult to interpret because survival and remission duration in the GM-CSF group were highly censored with short durations. In addition the dosage of GMCSF was lower and timing of the priming phase which has a major effect on outcome was different from the Biichner study. Thus, more information is needed to judge the benefit of priming strategies. 3.3. Management of’ complications anti supportive care

The proportion of children failing to achieve CR ranges between 20”/0 and 25%. Approximately one half of these patients have refractory leukemia; the others die of early fatal complications due to leukostasis, hemorrhages or infections before treatment response could be achieved. After achieving CR the rate of fatal complications is much lower, e.g. 4% in the AML-BFM studies. A high risk of early death due to hemorrhage or leukostasis [27] is associated particularly with mono- or myelomonocytic leukemia, FAB M4 or M5 and hyperleukocytosis (WBC 2 100000/mm3). Therefore, strategies reducing these early leukemia-related complications have been established. 3.3.1. Leukostasis

L,eukostasis defined as the vascular accumulation of leukemic cells [41] is associated with a high circulating blast count. Due to the higher volume of the myeloblasts and even more to the monoblasts the vis-

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cosity is higher in AML compared to ALL. Clinical symptoms of leukostasis include neurologic symptoms (confusion and drowsiness or cardio-pulmonary signs, e.g. dyspnea). Emergency care with intensive monitoring, careful hydration with concurring urine alkalinization and administration of allopurinol is recommended. Blood transfusion should be retained to avoid the risk of an additional increase of the cytocrit ( = leukocrit + hematocrit). whereas exchange transfusion can be lifesaving. Blood exchange is advantageous, particularly in young children due to the additional blood cell reduction. Furthermore, metabolic imbalance and abnormal hemostasis can be corrected and greater shifts in volume prevented, particularly in young children. To prevent further proliferation of blast cells immediate administration of hydroxyurea or cytosine-arabinoside is recommended. Early fatal hemorrhages can develop in context with by spontaneous or leukostasis or independently chemotherapeutical induced blast cell lysis. The most significant coagulation parameter for predicting fatal hemorrhage was a low plasminogen level [64]. Meticulous monitoring of the hemostatic disturbances, both initially and during induction therapy is crucial. Therapeutic guidelines for coagulation disturbances in acute myelogenous leukemia include exchange transfusion in patients with extremely high WBC counts and fresh frozen plasma in those with isoiated plasmatic hemostasiologic disturbances. Thrombocyte concentrate is indicated in cases of thrombocytopenic and/or thrombocytopathic hemorrhage. In acute promyelocytic leukemia the risk of hemorrhage induced by cell lysis could be reduced by all-trans-retinoic acid which can induce differentiation in these patients. 3.3.3. Othe; ilcute complications Due to extreme cytolysis renal insufficiency may occur. In these cases forced diuresis, urine alkalinization and cautious cytoreduction is indicated. Hemodialysis is mandatory in patients with renal insufficiency or uncontrollable metabolic disturbances. 3.3.4. ToxicYty of’ chemotherupy Treatment of children with AML is often associated with acute and chronic complications. Intensive induction therapy results in severe bone marrow aplasia associated with infections and hemorrhages from thrombocyt openia. To prevent fatal infection antimicrobial prophylaxis consisting of non-absorbable antibiotics and cotrimoxazol, in addition adequate bathing and care of mucous membranes is advisable. Fever of unknown origin (FUO) in the granulocytopenic phase should be attributed to bacterial or fungal sepsis.

The toxic side-effects of individual chemotherapeutic agents include among others, cardiomyopathy by anthracyclines, neurotoxicity by vincristine and HD-AraC, and hepatotoxicity by mitoxantrone and Ara-C. Due to the higher rate of children with AML being cured, late effects of chemotherapy have to be considered in the design of new therapy protocols. 4. Future aspects Survival rates in children with AML have improved during the last two decades from less than 10% to 50%. This was possible by great efforts in intensification of chemotherapy and better supportive care. Comparison of therapy strategies and results in childhood AML (Tables 4 and 5) indicate that successful treatment regimens should include intensive induction courses with anthracyclines in an adequate dosage, consolidation and/or intensification with HD-Am-C, CNS prophylaxis with cranial irradiation and at least some months of maintenance chemotherapy. Bone marrow transplantation with an appropriate matched HLA compatible allogeneic sibling donor is another promising approach. The treatment in AML involves greater risks and is more difficult than in ALL due to a higher risk of initial life-threatening complications, e.g. hemorrhages and/or leukostasis and to the fact that most of the drugs eliminating myelogenous leukemic cells will also destroy normal residual myelopoiesis. Further intensification of therapy alone will only minimally improve results of therapy. The treating physician will have to take advantage of new information in pharmacokinetics, supportive care, cytokine and differentiating agent use: as well as immunotherapy and minimal residual disease monitoring to optimize treatment for future pediatric AML patients: (a) Taking into consideration the pharmacokinetic parameters and the interaction of cytostatic drugs. For example, an in vitro model for the cellular pharmacokinetic of the nucleotide cytosine arabinosidetriphosphate (Ara-CTP) (cellular uptake and intracellular phosphorylation are determinants for the cytostatic effect of Ara-C) showed marked differences of Ara-CTP retention in the morphologically classified types of leukemia. The similar cellular accumulation of Ara-CTP in all types with a significantly more rapid decrease in T-ALL and AML compared to non-TALL, comprises a pharmacokinetical rationale for continuous Ara-C infusion in these subgroups as an alternative to the intensification by HD-Ara-C schedules [12]. (b) The new principle of using hematopoietic growth factors and differentiating agents. With a better knowledge of these factors it may be possible to control growth and differentiation of leukemic blasts

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Reviews in Oncolog~:L’:Ht~n7ntoll)g~ 22 (I 996) lg.?- 196

which is already starting in acute promyelocytic leukemia by using the differentiating agent all-transretinoic-acid. (c) Supportive care. Hematopoietic growth factors can be used to reduce the time period of therapy-induced neutropenia, an approach which would be very useful with increasing intensity of AML chemotherapy. However, more information about the security of this approach is necessary. With appropriate supportive care, i.e. for the control and prevention of fungal infections, the therapyrelated morbidity and mortality will be reduced. This is not only important during induction but also during treatment intensification with high dose chemotherapy, and especially in connection with BMT for improving survival after the intensive myeloablative conditioning regimens. (d) Immunotherapy. Non-specific immunotherapy e.g. Calmette-Guerin bacillus (BCG), methanol extraction residual of tubercle bacillus (MER), Corynebacand Levamisol have not been terium parvum convincing in the past [36]. Recently, interleukin 2 (IL-2) has been used as maintenance therapy in AML to promote immun-mediated eradication of any residual leukemic cells [71]. In addition IL-2 has been given following ABMT, but results are still preliminary. (e) Monitoring residual disease. Since cytogenetic and molecular markers can identify residual disease at the time of clinical remission a new definition of complete remission at the microscope or at the molecular level is possible Therefore, monitoring of residual disease may be helpful in decisions on the cessation of therapy. On the other hand, the significance of one abnormal gene rearrangement in one cell in one thousand needs to be determined, because the clinical relevance is not known. It may be possible that the persistence of dn abnormal gene rearrangement will indicate a later relapse which has been shown in patients with acute promyelocytic leukemia with a detectable RARc( rearrangement [53]. On the other hand the AMLl/ETO rearrangement which is found in the translocation 8;21 [48] was seen in patients with a long-term remission without indicating a relapse

[461. As the molecular genetics gave new insights into gene rearrangements and altered gene products the possibility of corrections on a molecular level are given. Future strategies for curing AML may include methods of gene transfer or in other instances the target of the gene product would be affected. Besides this exciting development of knowledge on molecular biology a fundamental comprehension of the dysregulation of proliferation and differentiation of the malignant clone is necessary for the development of a more specific and less toxic therapy in the future.

193

Reviewer This paper was reviewed by Gary V. Dahl, M.D., Professor of Pediatrics, Stanford University Medical Center, Stanford, California 94305-5 119, USA.

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56, 1987

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Bhwb L’rsuh Ci-eutzig was born December 30th, 1946 in Bremen. She obtained a Doctor’s degree in 1972 and a certification in pediatrics in 1978. Since 1977 she has been a staff member of the pediatric hematology/oncol-

22 (1996) 183- 196

ogy department of the University Children’s Hospital Miinster. During the last 16 years she has been principal investigator together with Professor G. Schellong and Prof. J. Ritter of the 4 cooperative German AML Studies in Childhood. She obtained habilitation in pediatric hematology and oncology in 1990.