Postgrad Med J: first published as 10.1136/pgmj.61.712.93 on 1 February 1985. Downloaded from Postgraduate Medical Journal (1985) 61, 93- 102

Current issues in the management ofchildren with acute lymphocytic leukaemia

Donald Pinkel Department ofPediatrics, Temple Universiti School of Medicine, Philadelphia, PennslIvania and St Christopler s Hospitalfor Children, Philadelphia, PennsYlvania, USA.

Introduction In the 12 years since curative therapy for acute curative treatment. How can this be accomplished? As lymphocytic leukaemia (ALL) became accepted, the physicians and scientists we can only suggest that lecterns and literature have reflected considerable political leaders place highest priority on child health, concern and activity toward establishing optimal including facilities for curative leukaemia therapy. methods. Many issues have been raised about clas- However, we have the power within our own ranks to sification and prognostic stratification, drug selection, insist that therapeutic research be directed toward drug combination and dosage, duration of therapy, simplification, reduced technology and less cost so prevention of meningeal and testicular relapse, infec- that ready availability and accessibility of curative tion control, psychosocial support and sequelae of therapy will be more feasible. treatment. In addition, the use of alternate methods such as immunotherapy and bone marrow transplan- tation have been explored. Classification and prognostic stratification by copyright. The purpose of this paper is to describe some of these issues and to present some thoughts about them. Biological species of ALL can be identified using a combination ofmorphological, cytochemical, immun- ological, genetic and clinical criteria. Not every strain The goal of management of ALL within a species will demonstrate all criteria. As with enteric bacteria, some strains do not clearly Although palliation was once the goal of leukaemia fall into one species or the other. However, for therapy, most haematologists and cancer therapists purposes of investigation and management, the deter-

have come to accept cure as a reasonable expectation mination of biological species appears to be as impor- http://pmj.bmj.com/ for children with ALL. This means that the criterion tant to leukaemia therapy as to antibacterial therapy. for success is continuous leukaemia-free survival, off Children's ALL can be divided into that of B- all therapy, and at little or no risk of relapse. For the lymphocyte lineage and that of T-lymphocyte deriva- majority of children with ALL, this point appears tion (Table I). The most frequent B-lymphocyte approximately 7 years after diagnosis and 4 years after species is common ALL (Bowman et al., 1981 a; Pullen cessation oftreatment (George et al., 1979). Treatment et al., 1981; Greaves et al., 1981; Greaves et al.. 1983). regimens, therefore, need to be evaluated and com- pared in terms of 7 year cure rates. The custom of on September 23, 2021 by guest. Protected utilizing complete remission durations, persisting from the pre-curative era, can be discontinued. Table I Biological species of acute lymphocytic leukaemia The importance of curative therapy is directly in children proportional to its availability and accessibility for everyone who needs it. For children, who have no Species % ofpatients* control over their socioeconomic status and residence, B-lymphocyte series it is mandatory that there be no barriers to their Common 60 Pre-B 15 Null 10 B-lymphoblastic I Donald Pinkel, M.D. T-lymphocyte series 14 Correspondence: Department of Pediatrics, Temple Univer- sity School of Medicine, 2600 N. Lawrence Street, Philadel- * Approximate % (Greaves et al., 1981; Pullen et al., 1981; phia, PA 19133 USA. Bowman et al., 1981a). ) The Fellowship of Postgraduate Medicine, 1985 Postgrad Med J: first published as 10.1136/pgmj.61.712.93 on 1 February 1985. Downloaded from 94 D. PINKEL

This occurs most often in white children between ages often present. An 11: 14 chromosomal translocation 2 and 6 years who dwell in the temperate zones. Boys has been described in 4 of 16 cases examined (Williams and girls are equally affected. The disease arises in et al., 1984). Mitoses are frequent and thymidine bone marrow and is typically marked by pan- labelling index and percent S phase cells average cytopenia, bleeding, fever, bone and joint pain. The 12-14% (Look et al., 1982; Murphy et al., 1977). The leukaemic lymphoblasts are generally monotonous in disease can progress rapidly with peripheral blood appearance. They display la and common antigens at leukaemia cell counts reaching the hundreds of their surfaces and often are hyperdiploid by cytogen- thousands and early development of frank meningeal etic analysis and flow cytometry (Look et al., 1982). leukaemia. Metabolic complications are common. Mitotic activity is low and thymidine labelling index It is popular to use various clinical and laboratory and percent S phase are usually less than 6% (Murphy features of patients with ALL to estimate prognosis et al., 1977; Look et al., 1982). The course of the and to select therapy according to this assessment. The disease tends to be relatively slow. Complete remis- validity of this approach is questionable. First, these sions are readily induced, remission durations are long prognostic criteria are usually based on complete and, with conventional combination chemotherapy, remission duration rather than cure rate. Since some the cure rate is in the 60% range. species of ALL tend to relapse late and other species Pre-B ALL is a more frequent species in black tend to relapse early, this gives undue weight to children with leukaemia than in white (Crist et al., biological and clinical features associated with the 1984). The cells display cytoplasmic immunoglobulin species in which relapses tend to occur early. For heavy chains as well as the surface antigens noted in example, thymic ALL tends to relapse within 18 common ALL. A 1: 19 chromosomal translocation months while non-T non-B ALL continues to relapse has been recently identified in 7 of23 pre-B ALL cases over 4 to 5 years (Sallan, 1981). Use of complete tested (Williams et al., 1984). Duration of remission remission duration as a criterion for prognosis can and cure rate with conventional therapy are less than exaggerate the importance of thymic species as an for common ALL. unfavourable sign. It also results in exaggeration ofthe Specific cell surface or cytoplasmic markers have importance of features more often associated with not been identified in null ALL (Greaves et al., 1981). thymic species, such as male sex, older age, mediastinal by copyright. Its B-lymphocyte lineage has been identified by gene mass, high initial white blood cell count and normal rearrangement studies (Waldmann & Korsmeyer, haemoglobin value in predicting a poor prognosis. 1983). This species of ALL is more often seen in Secondly, methods ofprognostic stratification often infants, adolescents and adults (Bowman et al., 1981 b; ignore the most important prognostic factor - Greaves et al., 1983). Remission duration and cure appropriate treatment. Combination chemotherapy rate are less than in common or pre-B (Pullen et al., results in higher cure rates than single drug treatment 1983; Greaves et al., 1981; Pullen et al., 1981; Bowman and full dosage of drugs is more effective than half et al., 198 la). dosage. Selection of drugs according to biological B-lymphoblastic ALL ('Burkitt-like' cell leuk- species of ALL can also alter outcome. For example, aemia) occurs more frequently in boys than girls and in one comparative study, the long-term leukaemia- http://pmj.bmj.com/ tends to rise from submucosal lymphoid tissue, lymph free survival rate for children with thymic ALL was the nodes and viscera (Preud'homme et al., 1981). The same as for those with non-thymic ALL provided the cells have a distinct morphology with deep basophilic children with thymic ALL received periodic infusions cytoplasm and cytoplasmic vacuoles and a distinctive ofcytosine arabinoside and cyclophosphamide (Lauer 8:14 chromosomal translocation. Immunoglobulin is et al., 1983). Thus the prognostic disadvantage ofmale secreted at the cell surfaces. Mitoses are frequent sex, older age, mediastinal mass and high initial white and percent S phase cells are in the 20-25% range blood cell count was overcome in children who on September 23, 2021 by guest. Protected (Look et al., 1982). The disease progresses rapidly with received chemotherapy more appropriate to their severe metabolic complications. Although remissions species of ALL. are produced by treatment, they are often incomplete It appears that present systems of prognostic and transient. Early mortality is high and survival is stratification of ALL are largely artefacts resulting poor. from our failure to identify biological species of ALL Thymic (T-cell) ALL usually arises in thymic tissue. and to treat each accordingly. Our impression, for Patients are more frequently boys, more often older example, that male sex, mediastinal mass and high than 6 years and initially tend to have higher peri- white blood cell count are bad prognostic signs and pheral blood values for haemoglobin, granulocytes these patients require 'more intensive' therapy is and platelets than patients with ALL of B-lymphocyte probably incorrect. It is simply that such patients have derivation (Greaves et al., 1981). The cells have thymic a distinct biological species of ALL that requires antigens at their surfaces and often form heat stable different therapy and that we need to use cure rate and rosettes with sheep red blood cells. Pseudodiploidy is not remission duration as our criterion of success. Postgrad Med J: first published as 10.1136/pgmj.61.712.93 on 1 February 1985. Downloaded from CURRENT ISSUES IN PAEDIATRIC ALL 95

Inducing remission These results suggest that children with typical thymic ALL can survive as frequently as children with There is more agreement about methods of initial non-T non-B ALL provided they are given repeated induction ofcomplete remission of ALL than perhaps courses of Ara-C and cyclo in addition to the usual any other features of management. Prednisone, vincr- therapy. It also suggests that Ara-C and cyclo are istine and asparaginase are the standard combination. specifically useful in thymic ALL and not useful in Asparaginase appears to be more readily and safely non-T non-B ALL. administered by the intramuscular route. These observations fit well with laboratory data Patients with thymic ALL and B-lymphoblastic regarding drug specificity of thymic ALL. For exam- ALL are less likely to experience a prompt complete ple, Ara-C and cyclo are the most effective combina- remission than patients with other species (Greaves et tions in the mouse AKR leukaemia, which is a thymic al., 1981; Preud'homme et al., 1981). For this reason ALL poorly responsive to methotrexate and mercap- additional chemotherapy is frequently used. Daun- topurine (Frei et al., 1974). On the other hand, orubicin is often administered as a fourth drug to methotrexate and mercaptopurine are highly effective patients with thymic ALL. Cyclophosphamide, in mouse L1210 leukaemia, a non-T non-B ALL. cytosine arabinoside and high dose methotrexate are It would seem probable that further experimenta- often included in remission induction chemotherapy tion will detect differences in drug sensitivity among for children with B-lymphoblastic ALL (Bowman et the species of ALL derived from the B-lymphocyte al., 1983). lineage. The genetic peculiarities of these different species of ALL suggest that there might be opportun- ities to exploit specific phenotypic characteristics in Drug selection by biological species designing drug therapy. Whether this will be true or not, it seems reasonable at this point to continue to It is reasonable to think that the variations in explore the specific tailoring of anti-leukaemia biological properties among species ofALL are reflec- therapy to fit the several species of ALL of B-lym- ted differences in metabolism by binding, penetration, phocytic lineage as we have for thymic ALL. by copyright. and disposition of anti-leukaemia drugs. This would mean that one would achieve more efficacy in therapy by selecting, combining, scheduling and dosing drugs Combining drugs for synergism in accordance with the biological species of ALL. To go a step further, it is reasonable to expect that perhaps The combining of drugs has been a cornerstone of different approaches to treatment would be management ofALL. It has not been clear whether the appropriate for different biological species. resultant increase in efficacy has represented additive There is considerable evidence that different or synergistic effects in all cells, whether the various chemotherapy should be used for thymic ALL than for drugs in the combinations have affected different cells non-thymic ALL (Pinkel, 1983b). The most significant or whether they have affected the same cells at http://pmj.bmj.com/ clinical data, cited previously, are the results ofa study different phases of their life cycles. The benefits of reported by Lauer et al. (1983). They randomized certain drug combinations such as vincristine and children with ALL in initial complete remission to prednisone have been abundantly clear without the receive or not receive 3 day courses of cytosine need for comparative studies. The advantages ofmany arabinoside (Ara-C) and cyclophosphamide (cyclo) other drug combinations in current use are not proven every 8 weeks during remission. All patients received and in one instance the outcome of a 4 drug combina- otherwise similar remission induction, meningeal tion for continuation therapy of ALL was inferior to irradiation and continuation chemotherapy. The re- that of a 2 drug combination (Aur et al., 1978). on September 23, 2021 by guest. Protected peated courses ofAra-C and cyclo had no effect on the In recent years, laboratory techniques have de- leukaemia-free survival ofthe 150 children with non-T veloped that allow better opportunities for testing non-B ALL* in the study. For children with thymic drug synergism in patients. High performance liquid ALL results were different. Of 15 children with thymic chromatography (HPLC) is especially useful for ALL who received the Ara-C and cyclo courses, onlv 6 measuring small amounts of drugs in plasma and for experienced relapse. On the other hand, relapse assessing nucleotide alterations in cell preparations. occurred in 7 of 8 children with thymic ALL who did The following is an example of applications of these not receive the Ara-C and cyclo courses. The frequen- methods in assessing synergy of the combination of cies of very high initial white blood cell counts and methotrexate and cytosine arabinoside in children mediastinal masses were similar in both groups. with ALL. After several conflicting reports about the synerg- * The term non-T non-B ALL as used here refers collectively ism of methotrexate and cytosine arabinoside in to common, pre-B and null ALL. mouse leukaemias, it was finally determined that the Postgrad Med J: first published as 10.1136/pgmj.61.712.93 on 1 February 1985. Downloaded from 96 D. PINKEL agents were synergistic under appropriate conditions Group (Krance et al., 1984). Over 50 children with (Cadnam & Eiferman, 1979; Jackson & Harkrader, ALL have received intermittent administration of 1980). The leukaemia cells had to be sensitive to methotrexate and cytosine arabinoside as described methotrexate, the methotrexate needed to be adminis- above in addition to conventional chemotherapy. tered prior to the cytosine arabinoside and critical Their long-term leukaemia-free survival experience levels of both drugs had to be achieved. In vitro will provide some insight into its efficacy and a basis chemical studies with L1210 mouse leukaemia cells for comparative study with other drug regimens. suggested a rationale for the synergism. When metho- trexate-sensitive L1210 cells were pretreated with methotrexate > 1 ltM and subsequently exposed to Route of drug administration cytosine arabinoside >I jLM, intracellular accumula- tion ofcytosine arabinoside was enhanced. At concen- The route by which drugs are administered is based on trations of methotrexate above 10 tM, there was also convenience as well as pharmacological considera- depletion of intracellular deoxycytidine triphosphate tions. Mercaptopurine and methotrexate, the basic (dCTP). The reduction ofdCTP was thought to reduce combination for continuation therapy ofnon-T non-B inhibition of deoxycytidine kinase and thus increase ALL have been usually taken orally for the sake of phosphorylation of cytosine arabinoside to its convenience. Their pharmacological effects in patients metabolically active form, cytosine arabinoside tri- are apparent from the neutropenia, lymphopenia, phosphate. The reduced dCTP would also result in less macrocytosis of red blood cells and hypersegmenta- competition with the cytosine arabinoside triphos- tion of neutrophils that usually accompany their oral phate for DNA polymerase binding, the mechanism of administration. its anti-leukaemia effect. However, recent studies indicate that methotrexate To test whether achievement of similar sequence absorption from the gastrointestinal tract is variable, and levels ofmethotrexate and cytosine arabinoside in that the product of concentration and time of metho- patients would result in the same cellular nucleotide trexate is consistently lower with oral administration alterations associated with in vitro synergism in mouse than with parenteral injection and that red blood cell leukaemia cells, we designed the following experiment methotrexate polyglutamate levels are higher in by copyright. (Newman et al., 1983). Children in first remission of patients receiving intramuscular methotrexate than in ALL received a 24 h infusion of methotrexate, 1 g/m2. those receiving it orally (Balis et al., 1983; Kamen et At hour 12 of the methotrexate infusion, a 24 h al., 1984). Since there is correlation between the infusion ofcytosine arabinoside, 1 g/m2, was initiated. storage of methotrexate as the polyglutamate and its Blood levels ofmethotrexate and cytosine arabinoside effectiveness in certain experimental systems, con- were tested during the infusions. At the end of the siderable concern has been raised about continued use cytosine arabinoside infusion, haematopoietic bone ofmethotrexate by mouth. However, at present, there marrow was aspirated for determination of in- are no comparative data indicating that intramuscular tracellular nucleotide levels. Leucovorin 'rescue' was methotrexate is more effective in curing ALL than the http://pmj.bmj.com/ subsequently carried out. oral form. It would seem reasonable to continue We found in our patients that we could achieve monitoring the biological effects of methotrexate on consistent plasma methotrexate levels ofapproximate- red blood cells and neutrophils while treating children ly 10 tM and cytosine arabinoside levels of approx- in remission. If red cells are large and neutrophils imately 1 14M. The haematopoietic cells demonstrated hypersegmented, it is likely that dosage, absorption marked reduction of deoxycytidine triphosphate and and distribution to haematopoietic tissue are ad- high concentrations of cytosine arabinoside triphos- equate, regardless of route of administration. phate. Thus the chemical findings in these patients With regard to mercaptopurine, recent studies have on September 23, 2021 by guest. Protected were those associated with drug synergy in vitro. The indicated that only a small fraction ofthe drug reaches flaw in the human experiment is that we were testing the systemic circulation unaltered when given orally normal haematopoietic cells and not leukaemia cells. (Zimm et al., 1982). However, if granulocyte counts Ethical considerations prevented us from using this are kept consistently low, it would appear that max- drug combination in children with ALL presenting at imum mercaptopurine effect is being achieved and diagnosis. Nevertheless, the fact that drug sequencing that perhaps there need not be concern about the and dosage which result in synergy in vitro can be fraction absorbed or blood levels achieved. duplicated in patients and give rise to the same modifications of cellular nucleotides indicates a way toward more precise investigation of drug synergy in Intensity and duration of drug administration vivo in human ALL. The possible advantage ofthis drug synergy is being A West German group has expanded the administra- assessed by a current study of the Pediatric Oncology tion of multiple anti-leukaemia drugs in high dosage Postgrad Med J: first published as 10.1136/pgmj.61.712.93 on 1 February 1985. Downloaded from CURRENT ISSUES IN PAEDIATRIC ALL 97

early in remission, a practice dating back to early Preventing testicular relapse Leukaemia Study Group B and St Jude studies (Frei et al., 1965; Aur et al., 1972; Henze et al., 1981). Testicular relapse tends to occur late in the course of Although toxicity is severe, the West German group ALL, often after cessation of chemotherapy (Pinkel, reports that the proportion of children remaining in 1983a). Several observations suggest that it is a complete remission is higher than with other drug manifestation ofvisceral relapse resulting from failure regimens and the unfavourable prognosis associated ofsystemic chemotherapy. At least 3 ofthe drugs used with thymic ALL is eliminated. The studies have been in ALL diffuse well into the interstitial portion of the questioned because they do not compare the intense testes, where relapse is centered (Forrest et al., 1981; regimens with more traditional drug therapy. In Riccardi et al., 1982). Testicular relapse is often addition, it is possible that the improved prognosis for followed shortly by haematological relapse. In one thymic ALL is related to the inclusion of cyclophos- study, laparotomy revealed a high frequency of intra- phamide and cytosine arabinoside in the drug re- abdominal relapse in boys with clinically isolated gimen. Since this combination has been shown to be testicular relapse (Byrd, 1981). ineffective in extending remissions and increasing cure Testicular biopsy is customarily performed at cessa- rate of children with non-T non-B ALL (Lauer et al., tion of chemotherapy. However, some boys with no 1983), exposing all children with ALL to these drugs in evidence of testicular leukaemia at cessation of treat- order to benefit the minority with thymic ALL may ment develop frank testicular relapse later on (Askin et not be appropriate. It would seem more reasonable to al., 1981). The finding of testicular relapse at any time select drugs and drug schedules by biological species of indicates the need for repeating remission induction ALL rather than to submit all children to all anti- chemotherapy and administering an additional 2 to 3 leukaemic drugs. years of continuation chemotherapy, probably incor- Several lines of evidence suggest that patients with porating different drugs. Both testes and spermatic rapidly proliferating ALL should receive shorter and cords are usually irradiated as well. Testicular relapse more closely scheduled drug therapy while those with after cessation of chemotherapy has a significant cure slowly proliferating ALL should receive more prolon- rate (Tiedemann et al., 1982). by copyright. ged and widely spaced treatment (Pinkel, 1983b). Prevention of testicular relapse appears to be a matter of improving effectiveness of systemic chemotherapy with regard to selection, dosage and Preventing meningeal relapse scheduling of drug therapy. Specific meningeal therapy is required to destroy leukaemia cells in the superficial and perivascular Preventing infections arachnoid tissue and thus to prevent meningeal re- lapse. Several methods have been utilized. The most Numerous recent publications deal with issues of advantageous appears to be intrathecal administra- controlling infection in patients receiving immunosup- http://pmj.bmj.com/ tion of methotrexate, cytosine arabinoside and hy- pressive and haematosuppressive treatment (Pizzo et drocortisone weekly during remission induction and al., 1984). Prevention is the best method. Most periodically throughout the first year or two of important in prevention is the careful examination of continuation chemotherapy (Pinkel, 1983b). Triple each child prior to and during chemotherapy for intrathecal therapy appears to be as effective as sources of infection such as dental abscesses and methods incorporating irradiation (Sullivan et al., paronychia. Next is the monitoring oflymphocyte and 1982). It avoids the encephalotoxic and + carcinogenic phagocyte (granulocyte monocyte) counts, keeping on September 23, 2021 by guest. Protected effects ofirradiation and is more readily available and the values for each above 0.7 x 109/l. The administra- less expensive than irradiation. Further, children with tion of prophylactic cotrimoxazole is effective in isolated meningeal relapse have more favourable preventing Pneumocystis carinii pneumonia. Active courses after central nervous system irradiation when immunization of susceptible children with varicella- they have not been previously irradiated (Nesbit et al., zoster vaccine during remission or passive immuniza- 1982). tion with varicella-zoster immune globulin shortly Addition of cranial irradiation may be indicated in after exposure prevents mortality and morbidity from patients with thymic ALL, particularly those who varicella. present with florid disease in their peripheral blood. Good hygiene and sanitation and minimizing hosp- However, preventive central nervous system irradia- ital admissions and stays are additional measures tion appears to have no value in patients with B- worthy of continuous emphasis. lymphoblastic ALL. Postgrad Med J: first published as 10.1136/pgmj.61.712.93 on 1 February 1985. Downloaded from 98 D. PINKEL

Bone marrow transplantation associated with ALL (Levy et al., 1983). Preliminary results indicate that leukaemia cell counts can be While bone marrow ablation and transplantation decreased and lymphomatous masses reduced by this from a compatible sibling are accepted as a standard method, but haematological remissions have not treatment for acute non-lymphocytic leukaemia, its resulted. Obstacles to effectiveness include poor bind- role in children with ALL is not clearly defined. In one ing of antibody to target cells, blockage of antibodies report, 6 of 22 patients with ALL transplanted in 2nd by free antigen, antigenic modulation, formation of or subsequent remissions remained in remission for anti-mouse Ig antibodies and lack of effector macro- over 5 years and were apparently cured (Thomas et al., phages. 1983). In some centres, patients with ALL in first It is possible that monoclonal antibody therapy remission who are expected to have poor outcomes might be better tested in patients with ALL in with chemotherapy alone are receiving marrow trans- remission who harbour minimal numbers of leuk- plantation. However, sufficient data are not yet publi- aemia cells. The intent would be to contribute to shed to determine its value relative to chemotherapy destruction of residual leukaemia cells while target alone as primary therapy. cells are fewest in number and perhaps therefore more Two points need to be remembered when consider- susceptible to serotherapy. The efficacy would be ing the issue of marrow transplantation in ALL. The tested by subsequent relapse experience as compared main purpose of marrow transplantation is to allow to patients who receive chemotherapy alone. more intensive eradicative treatment of the leukaemia with drugs, irradiation or both. With selection of drugs according to biological species, by utilization of Psychosocial support drug synergism and avoidance of drug antagonism, and with appropriate scheduling ofdrugs according to The basic responsibility of educating the child and his growth rates, it might be possible to attain anti- family about leukaemia and its treatment and of leukaemia effects of the pre-transplant 'conditioning' helping them to cope constructively with its hardships without need for the transplant itself. remains with the physician who treats the child. Social Secondly, children with ALL who experience workers, psychologists, child life workers, nurse- by copyright. haematological relapse 6 months or more after cessa- clinicians and psychiatrists all may have important tion of chemotherapy have a good chance of prolon- contributions, but they need the guidance and leader- ged second remission and possible cure with chemoth- ship of the responsible paediatrician in conducting erapy alone (Rivera. 1981). For this reason, it seems them. appropriate to confine the use of marrow transplanta- tion to children with ALL who develop haematological relapse while on chemotherapy or Sequelae within 6 months of its cessation. Gale and Champlin (1984) compared the relapse Quality of survival is a major consideration in the rate of patients with acute myelocytic leukaemia who management of children with serious disease. To be http://pmj.bmj.com/ received bone marrow grafts from monozygotic twins truly cured, children not only need to survive the to the relapse rate of those who received grafts from disease, but to retain the capacity for normal growth, HLA-identical siblings. The relapse rate in the twins development and maturation -- physically, intellec- was three times higher than for the non-twins. The tually, emotionally and socially. authors suggest that allogeneic bone marrow trans- In the past, the focus was on immediate and plantation might have an immunotherapeutic effect. intermediate effects ofALL and its treatment. Visceral

Experimental transplantation studies are in and neural leukaemia, gastrointestinal disorders, on September 23, 2021 by guest. Protected progress utilizing autologous marrow treated with haematosuppression, immunosuppression, inter- monoclonal antibodies directed toward the differen- current infection, bleeding and psychosocial distur- tiation antigens characteristic of the patient's ALL bances were major concerns. With many children now (Ritz et al., 1983). surviving off therapy at little risk of relapse, the focus has switched to long-term sequelae. Physical growth and development have been asses- Immunotherapy sed in survivors. Reduction of linear skeletal in- crements often occurs during treatment, but after The use of biological agents to stimulate immune cessation of therapy normal growth patterns usually response in children with ALL has been largely resume (Verzosa et al., 1976). Some children demon- abandoned. However, there is considerable interest in strate 'catch-up' growth during the first year off the administration of monoclonal antibody prepara- treatment. tions directed against differentiation antigens Normal haematopoiesis and immunological com- Postgrad Med J: first published as 10.1136/pgmj.61.712.93 on 1 February 1985. Downloaded from CURRENT ISSUES IN PAEDIATRIC ALL 99

petence are usually restored by 6 months after cessa- range of intelligence several years after completing tion of therapy. Many children exhibit a pronounced treatment. However, children first treated before age 7 immunological 'rebound' during the first 3 months of years had lower intelligence quotients (lQs) than their this period (Borella et al., 1972). This normal phen- normal siblings. Children treated when less than 3 omenon can be confused with haematological relapse. years old had lower IQs than those who were treated Endocrinological studies have demonstrated abnor- when past 3 years of age. Deficiencies in reading and malities of growth hormone secretion after cranial arithmetic were frequent. irradiation for ALL (Shalet et al., 1979; Blatt et al., Intravenous administration of moderately high 1984). However, most ofthese children grow normally doses of methotrexate accompanied by intrathecal once they are removed from chemotherapy. Only a methotrexate resulted in abnormal electroencepha- small minority of children demonstrate clinical lograms (EEG) in 68% of a group of children with evidence of growth hormone deficiency. Trials of ALL (Cohen et al., 1982). One-fifth of the children growth hormone therapy should be reserved for with abnormal EEGs experienced clinical seizures. children in complete remission who have been off all In a current study at St Jude Children's Research chemotherapy for a year or more and have not Hospital, the effects of moderately high dose intraven- resumed a normal growth pattern (Romshe et al.. ous methotrexate are being compared with those of 1984). 1800 R of cranial irradiation by serial neurological Gonadal function has been investigated in children examination, computed tomography (CT) brain surviving ALL. Blatt et al. (1981) reported normal scans, myelin basic protein levels in spinal fluid and testicular function in prepubertal and intrapubertal neuropsychological evaluation (Ochs et al., 1982). A boys. Shalet et al. (1981) concluded that boys with preliminary report describes a high frequency of ALL advance through puberty normally, but sugges- seizures in the radiated patients and of abnormal CT ted that many would be oligospermic because of scans in the high-dose methotrexate patients. Evidence tubular damage by cytotoxic chemotherapy. for neuropsychological dysfunction, EEG abnor- Prepubertal girls usually progress normally through malities and myelin basic protein determinations were subsequent puberty and develop normal reproductive similar for both groups. ability. Adolescent girls often experience amenorrhoea More information is required before we can by copyright. during chemotherapy, but usually recover ovulatory evaluate conclusively the long-term neurological and function after its cessation (Siris et al., 1976). Many neuropsychological sequelae of leukaemia therapy. survivors ofALL, both male and female, have become However, it is legitimate to conclude from reports parents ofhealthy children and there is no evidence to available that central nervous system irradiation date of abnormal incidence of fetal loss or congenital should be avoided whenever possible, especially in anomalies (Moe et al., 1979; Meadows et al., 1983a). preschool children and certainly in infants. Secondly, Neurological and neuropsychological effects of no more intrathecal therapy should be administered ALL and its treatment have been a major concern. than is demonstrated to be necessary for preventing

While intracranial leukaemia can leave neurological meningeal relapse. Thirdly, intravenous methotrexate http://pmj.bmj.com/ impairment. irradiation and chemotherapy can and cytosine arabinoside should be administered produce effects ranging from mild learning disorders cautiously and their frequency and dosage limited to to disabling leukoencephalopathy. what is found to be necessary for control of systemic Leukoencephalopathy and mineralizing microan- leukaemia. Fourthly, the hazards ofpreventive menin- giopathy have been attributed to cranial irradiation geal therapy are far less than the morbidity and and subsequent methotrexate therapy (Price & Bird- mortality of meningeal relapse. Calculated risks are well, 1978; Price & Jamieson, 1975). However, Essel- part of the treatment of children with ALL and in no tine et al. (1981) found no differences in the frequency facet of treatment is this more true than in the on September 23, 2021 by guest. Protected of abnormal computed tomography brain scans bet- prevention of meningeal leukaemia. ween children receiving cranial radiotherapy and Children surviving leukaemia are subject to in- those receiving only intrathecal methotrexate. creased risk of secondary neoplasms (Mosijczuk & Distractibility and memory deficits have been re- Ruymann, 1981). How much of this risk is related to ported in children with ALL who received cranial the child's innate susceptibility to cancer and how irradiation when less than 8 years old (Goff et al., much is related to therapy is an unanswered question. 1980). In contrast, no global or specific neuropsy- One of the future challenges to leukaemia therapists chological deficits were detected in children with ALL will be to assess the relative carcinogenic risks of the who received intrathecal methotrexate without drugs used in leukaemia therapy and to weigh them in irradiation (Tamaroffet al., 1982). Jannoun (1983), in the scales against their anti-leukaemia values. the largest study reported, found that children with Education, job training and access to health in- ALL treated with combination chemotherapy and surance were problems for some of the early survivors cranial radiation were functioning within the normal of ALL. However, thanks to the more enlightened Postgrad Med J: first published as 10.1136/pgmj.61.712.93 on 1 February 1985. Downloaded from 100 D. PINKEL attitudes toward people who are different that mark The current degree of success in curing children of our era, most children surviving leukaemia are finding ALL should serve as a stimulus to continued research few obstacles to their career development, work concerning its pathogenesis and treatment. It is vital opportunities and customary social benefits. to progress that children with ALL be referred to leukaemia research centres where they can receive the most up-to-date care and participate in investigations Conclusion designed to give them the most benefit at the least risk (Meadows et al., 1983b). The management of ALL in children is constantly changing as new information and insights accumulate.

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