Review of medicines for the treatment of common tumours in children

Transcription

1 18th Expert Committee on the Selection and Use of Essential Medicines Review of medicines for the treatment of common tumours in children Essential drugs for the treatment of acute lymphoblastic leukemia...2 Background...2 Search methods...2 History of chemotherapy...2 Principles of treatment...3 Future directions...5 Table 1: List of recommended drugs...6 Table 2: A stepladder of essential drug requirements...7 Common dose standards and ranges...8 References...10 Appendix Essential drugs for the treatment of Burkitt Lymphoma...20 Background 1, Search methods...21 History of chemotherapy 2, Principles of treatment...22 Future directions References...24 Appendix Essential drugs for the treatment of Wilms Tumour Position Paper...31 Background...31 Search methods...31 History of chemotherapy Principles of treatment...33 Essential Drugs:...34 References...35 Appendix Safety summary table...52

2 Essential drugs for the treatment of acute lymphoblastic leukemia Background Acute lymphoblastic leukemia (ALL) is the commonest form of malignant disease in children (0-14 years of age) worldwide 1, although in some parts of the world other forms of cancer occur more frequently in this age group e.g. retinoblastoma in parts of India and Burkitt lymphoma in numerous countries of sub-saharan Africa 2. With survival rates now of approximately 85% in high income countries 3, the treatment of ALL in childhood has been hailed as one of the marvels of modern medicine. This achievement has been accomplished over the past half-century and more, since the first descriptions of brief responses to single agent therapy, such as the observations by Dr. Sidney Farber in Boston with the use of corticosteroids and aminopterin (an early folate antagonist). Prednisone/dexamethasone and methotrexate remain cornerstones of ALL treatment regimens today. Search methods The improvement in outcomes for children with cancer is attributable mainly to the systematic conduct of randomised clinical trials. These trials have been conducted over the last 40 years by a number of multi-institutional groups, predominantly in North America and Europe. These national and international co-operative clinical trials have led to the continuing refinement of pathology, prognostic factors and multidisciplinary treatments. Results of these trials have been reviewed and referenced. The cytostatic drugs used predominantly for ALL in past trials and in the control arms of current randomised trials were identified. The literature was reviewed for the treatment experience in low income counties (LIC) as well as for articles summarising treatments for ALL. The essential drugs identified by this process are those that are used most frequently in both developed and LIC countries and that form the backbone of all regimens used for ALL. Because of the extent of clinical and prognostic variables which will impact treatment decisions, as well as the varied infrastructure of treatment facilities, a common treatment regimen incorporating the essential drugs was not prescribed. History of chemotherapy The modern era of multi-agent chemotherapy for this disease began at about the same time in Germany (under the leadership of Dr. Hansjorg Riehm, who established the Berlin- Frankfurt-Munster [BFM] group), and in the United States, led by the first director of St. Jude Children s Research Hospital (SJCRH), Dr. Donald Pinkel. These investigators made a series of seminal discoveries that continue to guide clinical practice in this century. Among these are: 1. The need for prolonged treatment (originally 5 years) following successful induction of remission in order to accomplish cure. ALL remains the only malignant disease for which this is true. 2

3 2. The use of multiple agents of different types given in combination to minimize the emergence of drug resistance. This remains a hallmark of current therapeutic protocols. 3. The recognition of pharmacological sanctuaries, notably the central nervous system (CNS) and testes, that were protected from systemic chemotherapy by blood/brain and blood/testes barriers respectively. Florid relapse in the CNS and testes, formerly a common occurrence, led to strategies of prophylactic CNS and testicular irradiation, actually based on the existence of sub-clinical disease in these sites. Such irradiation, while highly effective (e.g. reducing CNS relapse rates from more than 50% to less than 10%), came at considerable cost (e.g. severe neuro-cognitive morbidity and brain tumours on the one hand, and infertility on the other). Prophylactic testicular irradiation has long been abandoned and CNS irradiation is restricted to an everdiminishing proportion of children (at ever-diminishing doses) as systemic chemotherapy has become increasingly effective and intra-thecal chemotherapy is included in all modern treatment regimens. Of course all of these modifications have arisen from a succession of randomized clinical trials (RCT). BFM protocols are used to treat more children with ALL than any other set of regimens, largely as a result of the international BFM (I-BFM) consortium involving approximately 40 countries and the adoption of the BFM treatment framework by the Children s Oncology Group (COG), the largest co-operative clinical trials group in the world in pediatric oncology. It has become abundantly clear that ALL is not a single disease but a family of related disorders that are characterisable as distinct, one from the other, on the basis of the cytogenetic, immunologic, molecular and biochemical features of the constituent lymphoblasts. Combined with clinical (e.g. age), hematological (e.g. while blood cell count) and other criteria it has been possible to develop a widely accepted classification of the risk for treatment failure 4. In turn this has informed the development of treatment strategies of various intensity, to address the various risks of relapse as determined at the time of diagnosis. This approach (supported by sequential RCT) has allowed the shortening of the total duration of treatment to 2-3 years in almost all instances, while cranial irradiation has been reduced by 50% in dose (to 12Gy) for some patients and eliminated altogether for the great majority. At the same time, particularly bad prognostic groups, such as infants (most of whom have lymphoblasts exhibiting the MLL translocation) and older children whose disease is defined by the Philadelphia chromosome (with the functional bcr/abl transcript) are treated much more intensively, including mega-dose (myeloablative) chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Principles of treatment In accordance with the GRADE approach to assessing the quality of evidence and strength of recommendations underlying clinical guidelines 5, these principles are based on the results of randomized trials. For ALL, the major study groups in the world have provided summaries of their clinical trials 6, as listed in detail in Appendix 1. From all of this accumulated experience, several, evidence-based, principles of therapy can be enunciated. 1. The determination of initial response to single agent administration of prednisone (in a therapeutic window preceding all other treatment) is highly predictive of eventual 3

4 overall outcome. This observation was made initially by the BFM Group 7, promulgated by the BFM consortium and incorporated by the COG and other groups. 2. Dexamethasone is more potent than prednisone, especially in relation to control of subclinical disease in the CNS 8, but it is associated with more morbidity from infection, greater neurocognitive pathology and increased bony sequelae (demineralization and osteonecrosis). 3. Remission induction is best accomplished with at least 3 drugs; prednisone and vincristine +/- an anthracycline (usually doxorubicin or daunorubicin) +/- asparaginase Treatment beyond induction of remission is most successful if it includes intermittent courses of intensification, consolidation, re-induction before proceeding to maintenance therapy for the remainder of the treatment regimen Immediate post-remission induction strategies virtually all include intermediate e.g g/m 2 or high dose e.g. 5 g/m 2 methotrexate IV requiring leucovorin rescue ; an anthracycline; and asparaginase. Other agents in common use are cyclophosphamide, cytosine arabinoside and etoposide. Although free radical scavengers such as dexrazoxane can minimize the short-term cardiotoxic effects of anthracyclines 11, it is not yet clear whether such prophylaxis will reduce the incidence and severity of the cardiomyopathy which is a late effect of cumulative doses of anthracyclines such as those given to children with high risk ALL. The intensive use of asparaginase either IM or IV, as promoted in particular by the Dana Farber Cancer Institute (DFCI) Childhood ALL Consortium 12, is especially useful in CNS prophylaxis for, although the drug does not enter the cerebro-spinal fluid (CSF) it depletes asparagine (an essential amino acid for ALL but not normal cells) in the CSF as well as the blood. Asparaginase is expensive. It is commercially available as the native E. coli product, a polyethylene glycol (PEG) conjugate and the Erwinia product (which is often in short supply). Numerous studies have addressed the dosing regimens, comparative toxicity profiles and safety/efficacy of these drugs when used as second line agents (especially after major sensitivity reactions or other toxicities of the native E. coli product). At present there appears to be no reasonable alternative to the availability of all 3 forms of asparaginase. 6. Although refinements in utilization, with improved cost-effectiveness, are likely to come with the pharmacodynamic approach to dosing, as undertaken at SJCRH for methotrexate 13, the offsetting cost of measuring drug levels may more than negate any cost saving, but the improvement in effectiveness remains a laudable goal. The same can be said of the individualized dosing strategy adopted for asparaginase by the DFCI consortium. 7. Maintenance/continuation therapy is based on a combination of methotrexate and mercaptopurine 14. Although the bio-availability of both drugs is limited when administered orally, there is no clear advantage, other than compliance, to giving methotrexate IV or IM. There is no commercially available form of mercaptopurine for parenteral use but, at least in one clinical trial (undertaken by the DFCI consortium) 15, there was no advantage to giving this drug by the IV route. Thioguanine is also used in post-remission induction therapy in BFM-based protocols. 8. While argument persists about the number of drugs that should be given as standard intra-thecal therapy (one, two or three), there is no doubt that the effective agents in common use are methotrexate, cytosine arabinoside and hydrocortisone. 4

5 There is much less agreement about the most appropriate management of relapsed disease. However, late relapses (defined variously) are often treated with standard (nonmyeloablative) doses of multiple drugs, including those not used in front line regimens such as IV cytosine arabinoside and etoposide. Early relapses (on front-line therapy or soon after its completion) are associated with a poorer prospect for a durable second remission with conventional chemotherapy alone. Such patients are usually referred for allogeneic HSCT involving myeloablation with mega-dose chemotherapy (most often with cyclophosphamide +/- busulphan +/- etoposide) in combination with total body irradiation 16. Subsequent prophylaxis for graft-versus-host disease is accomplished in the first instance with some combination of steroids, methotrexate and cyclosporin. Imatinib (Gleevec) may be used for patients who had bcr/abl positive disease. Increasing attention is being given to the detection of minimal residual disease (MRD) 17, usually by molecular genetic techniques, and the pre-emptive administration of more intensive therapy to patients in whom MRD is detected, in an effort to prevent clinically manifest relapse. Such interventions are based on those used in patients who have experienced evident recurrence of disease. Future directions Finally, a decidedly thoughtful and authoritative proposal has been made recently 18, to the effect that increasing intensity of ALL treatment protocols in low income countries should be adopted only with progressive experience and incremental resources to avoid unacceptably high rates of treatment-related morbidity and mortality. General acceptance of such an eminently sensible proposal has obvious implications for a formulary of essential drugs. Specifically, Hunger and colleagues identify such key issues as patient nutritional status, available infrastructure for patient and family support, the health care system and its ability to provide intensive supportive care, the costs of the proposed therapy, and the availability of laboratory tests used in leukemia diagnosis and patient management. The risks of toxic death, abandonment of treatment and relapse of disease must be balanced against the benefit of improvement in survival rate. With progressive experience the risks can be reduced to acceptable levels, allowing escalation of the intensity of therapeutic regimens, as has been demonstrated by several groups of investigators in LIC. 19 Based on this principle, the list of recommended drugs (Table 1) can be acquired sequentially as the risk:benefit ratio rises (Table 2). 5

6 Table 1: List of recommended drugs L. Asparaginase. E. coli-supplied as 10,000 IU vial. L. Asparaginase. PEG product-supplied as 3,750 IU/5ml vial. L. Asparaginase Erwinia product-supplied as 10,000 IU vial. Busulphan- supplied as 2mg. tablets and 10ml vials (6mg/ml) Cyclophosphamide-supplied as 1 and 2g vials. Cyclosporine- supplied as 10, 25, 50 and 100mg. capsules, as an oral solution of 50ml (100mg/ml) and as 1 and 5 ml. ampoules (50mg/ml) for IV administration. Cytosine arabinoside- supplied as 100mg and 1g. vials. Daunorubicin supplied as 20mg. vial. Dexamethasone- supplied as 0.5, 0.75, 2 and 4 mg. tablets; and as multi-dose(5ml-4mg/ml) and single dose (1ml-10mg/ml) vials. Doxorubicin- supplied as 10 and 50 mg vials. Etoposide-supplied as 50mg capsules and 5, 25 and 50 mg. multi-dose vials of 20mg/ml. Hydrocortisone- supplied as 100mg. vial. Imatinib- supplied as 100 and 400mg tablets. Leucovorin- supplied as 5mg tablet, and 5 and 50ml. vials (10mg/ml) Mercaptopurine supplied as 50 mg tablet Methotrexate- supplied as 2.5 and 10mg tablets; and as 1ml (10mg/ml) and 2, 10, 40 and 100ml (25mg/ml) vials. Methylprednisolone- supplied as 5ml (40 mg/ml) multidose and 1ml (40 and 80mg/ml) single dose vials. Prednisone- supplied as 1, 5 and 50 mg. tablets. Thioguanine-supplied as 40mg tablet. Vincristine supplied as 1, 2 and 5 ml vials (1mg/ml) 6

7 Table 2: A stepladder of essential drug requirements Step 1: Step 2: Step 3: Step 4: Step 5: a common protocol for all patients Prednisone (PO), Methyl prednisolone (IV), Dexamethasone (PO), Vincristine (IV), E. Coli Asparaginase (IM), Methotrexate (PO, IM and IT), Mercaptopurine (PO). introduction of additional drugs for high risk patients - Doxorubicin (IV), Daunorubicin (IV), Cyclophosphamide (IV), Cytosine arabinoside (IV and IT), Hydrocortisone (IT), intermediate dose Methotrexate (IV) not requiring rescue, Thioguanine (PO). dose intensification and need for alternate forms of Asparaginase PEG product (IV), Erwinia product (IV) utilization of high dose methotrexate requiring rescue Leucovorin (PO and IV) further intensification and use of HSCT Busulphan (PO and IV), Cyclosporin (PO and IV), Etoposide (PO and IV), Thioguanine (PO) and availability of Imatinib. 7

8 Common dose standards and ranges Drug Dose Standard/Range Schedule L. Asparaginase. E.coli 5,000-25,000 Units/m 2 /dose variable schedule L. Asparaginase. PEG product 2,500 units/m 2 /dose every two weeks L. Asparaginase. Erwinia product 6,000 units/m 2 thrice weekly 1. Busulphan (1) 0.8mg/kg/dose every 6 hrs for 16 doses 1,2 Cyclophosphamide (1)60mg/kg/dose daily for 2 days (2)30-500mg/m 2 /dose variable schedule 3 Cyclosporin mg/m 2 every 12 hrs 4 Cytosine arabinoside a mg/m 2 per day b. 1-2g/m 2 per dose c mg per dose Daunorubicin 30-60mg/m 2 /dose variable schedule Dexamethasone 5-10mg/m 2 /day variable schedule Dexrazoxane 10mg per mg of daunorubicin or doxorubicin Doxorubicin 20-80mg/m 2 /dose variable schedule Etoposide mg/m 2 /dose variable schedule Hydrocortisone (I.T.) 10-15mg per dose variable schedule Imatinib mg/m 2 /day variable duration Leucovorin mg/m 2 /dose variable schedule Mercaptopurine mg/m 2 /day variable duration 5 Methotrexate a mg/m 2 /dose variable schedule b. 5-30g/m 2 /dose c. 5-15mg/dose Methylprednisolone mg/m 2 /day variable schedule Prednisone 30-60mg/m 2 /day variable schedule 8

9 Thioguanine mg/m 2 /day variable schedule Vincristine 1-2 mg/m 2 /dose(max 2 mg) variable schedule 1. Common preparative regimen for hematopoietic stem cell transplantation 2. Highly variable doses and schedules 3. Dose controlled by trough blood levels 4. a. Variable schedule b. High dose regimen, several doses per day c. Intra-thecal therapy, variable schedule 5. a. Variable schedule b. High dose regimen c. Intra-thecal therapy, variable schedule 9

10 References 1. Gurney JG, Bondy ML. Epidemiology of childhood cancer. In- Philip A Pizzo, David G Poplack (eds). Principles and Practice of Pediatric Oncology, 5 th edition. Philadelphia, Lippincott Williams and Wilkins 2006 pp Barr R, Ribeiro R, Agarwal B, Masera G, Hesseling P, Magrath I. Pediatric oncology in countries with limited resources. In-Philip A Pizzo, David G Poplack (eds). Principles and Practice of Pediatric Oncology, 5 th edition. Philadelphia, Lippincott Williams and Wilkins 2006 pp Pui C-H, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med 2006; 354: Smith M, Arthur D, Camitta B et al. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol 1996; 14: GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004; 328: Schrappe M, Carmitta B, Pui C-H. Spotlight on Long Term Results of Pediatric ALL Clinical Trials from 12 Study Groups World Wide. Leukemia 2000; 14: Riehm H, Reiter A, Schrappe M et al. The in vivo response to corticosteroid therapy as an additional prognostic factor in childhood acute lymphoblastic leukemia (therapy study ALL BFM 83). Klin Padiatr 1987; 199: Bostrom BC, Sensel MR, Sather HN et al. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukeimia: a report from the Childrens Cancer Group. Blood 2003; 101: Margolin JF, Steuber CP, Poplack DG. Acute lymphoblastic leukemia. In- Philip A Pizzo, David G Poplack (eds). Principles and Practice of Pediatric Oncology, 5 th edition. Philadelphia, Lippincott Williams and Wilkins 2006 pp Schrappe M, Reiter A, Zimmermann M et al. Long-term result of four consecutive trials in childhood ALL performed by the ALL-BFM study group from Leukemia 2000; 14: Gianni L, Herman EH, Lipshultz SE, Minotti G, Sarvazyan N, Sawyer DB. Anthracycline cardiac toxicity: from bench to bedside. J Clin Oncol 2008; 26: Silverman LB Declerck L, Gelber RD et al. Result of Dana Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia ( ). Leukemia 2000; 14: Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui C-H. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med 1998; 338: Childhood ALL Collaborative Group. Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukemia: an overview of 42 trials involving 12,000 randomised children. Lancet 1996; 347:

11 15. Silverman LB, Gelber RD, Kimball-Dalton V et al. Improved outcome for children with acute lymphoblastic leukemia: Result of Dana-Farber Consortium Protocol Blood 2001; 97: Eapen M, Raetz E, Zhang M-J et al. Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children s Oncology Group and the Centre for International Blood and Marrow Transplant Research. Blood 2006; 107: Cave H, van der Werten, Bosch J, SuciuS et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia N Engl J Med 1998; 339: Hunger S, Sung L, Howard S. Treatment strategies and regimens of graduated intensity for childhood acute lymphoblastic leukemia in low income countries: A proposal. Pediatr Blood Cancer 2009 Jan 6 (epub. ahead of print). 19. Barr RD, Antillon F, Agarwal B, Mehta P, Ribeiro R. Pediatric oncology in countries with limited resources. In Philip A. Pizzo and David G. Poplack (eds). Principles and Practice of Pediatric Oncology, 6 th edition. Philadelphia, Lippincott Williams and Wilkins in press. 11

12 Appendix 1 Conter V, Arico M, Valsecchi MG, et al. Long-term results of the Italian Association of Pediatric Hematology and Oncology (AIEOP) acute lymphoblastic leukemia studies, Leukemia 2000; 14: The first multicentric approach to childhood acute lymphoblastic leukemia (ALL) treatment in Italy started in the early 1970s when the Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) was founded. Since then the AIEOP has conducted nationwide chemotherapy protocols. Results obtained in three different periods ( , , ) are reported here. Treatment schedules have been characterized by a progressive intensification of systemic therapy and by a progressive substitution of protracted intrathecal therapy for cranial irradiation as central nervous system (CNS) preventive therapy. In the third period cranial radiotherapy (CRT) has been administered only to patients at high risk of relapse or with CNS involvement at diagnosis (about 15% of the overall population). A progressive improvement of therapeutic results, with a steady reduction of isolated CNS relapse rates have been obtained in the three periods considered here. The AIEOP experience shows that CRT can be safely omitted in non-high risk patients, unless they are T-ALL patients with WBC count at the diagnosis > or =100,000/mm3, and that intensification of treatment allows the improvement of overall results with a reduction of the impact of NCI prognostic criteria. Over the years, AIEOP has also continued to foster active cooperation at an international level. In the ongoing AIEOP ALL 2000 study, conducted in cooperation with the BFM group, patients are stratified according to the presence of translocations t(9;22) and t(4;11) and to treatment response (either initial steroid therapy or induction) or minimal residual disease). This cooperation will allow an adequate recruitment of patients to answer relevant randomized questions in the context of a study in which patients are stratified according to minimal residual disease findings. Drugs used asparaginase, carmustine, cyclophosphamide, cytosine arabinoside, daunorubicin, dexamethasone, doxorubicin, hydroxyurea, mercaptopurine, methotrexate, methylprednisolone, prednisone, thioguanine, vincristine Schrappe M, Reiter A, Zimmerman M et al. Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to Leukemia 2000; 14: Four thousand, four hundred and forty eligible children of up to 18 years of age were treated in four consecutive trials between 1981 and 1995 with the treatment protocols of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). The probability for event-free survival (pefs) at 8 years improved from 65.8% in study ALL-BFM 81 to 75.9% in study ALL-BFM 90. The cumulative incidence of recurrences with CNS involvement was 10.1% and 9.3% in studies ALL-BFM 81 and 83, but was reduced to less than 5% in study ALL-BFM 90 (for isolated CNS relapses from 5.3% in study ALL- BFM 81 to 1.1% in study ALL-BFM 90). Four major findings were derived from this series of trials performed by 37 to 96 centers in Germany, Austria, and Switzerland: (1) Reintensification is a crucial part of treatment, even in low risk patients; (2) presymptomatic 12

13 cranial radiotherapy can be safely reduced to 12 Gy, or even be eliminated if it is replaced by early intensive systemic and intrathecal methotrexate applied; (3) maintenance therapy given a total of 24 months from diagnosis provides a lower rate of systemic relapses than treatment for 18 months; (4) inadequate response to an initial 7-day prednisone window (combined with one intrathecal injection of methotrexate on day 1) defines about 10% of the patients with a very high risk of relapse. For patients with adequate early response (90% of all) an 8-year pefs of 80% has been achieved in the most recent trial ALL-BFM 90. While it has proven so far to be impossible to improve the outcome for the small group of high risk patients, the number of recurrences could be effectively reduced for the large group of patients responding adequately to the prednisone in vivo sensitivity test. Apart from inadequate prednisone response, patients with hyperleukocytosis, age <1 year, or the presence of the Philadelphia-chromosome (Ph+ ALL) are at a particularly high risk of failure. Drugs used asparaginase, cyclophosphamide, cytosine arabinoside, daunorubicin, dexamethasone, doxorubicin, mercaptopurine, methotrexate, prednisone, teniposide, thioguanine, vincristine Gaynon PS, Trigg ME, Heerema NA, et al. Children's Cancer Group trials in childhood acute lymphoblastic leukemia: Leukemia 2000; 14: Since 1968, the Children's Cancer Group (CCG) has treated more than 16,000 children with acute lymphoblastic leukemia (ALL). Herein, we report improvements obtained in CCG trials during two successive series of studies ( and ). Overall, 10-year EFS was 62% +/- 10% for the series and 72% +/- 1% for the series (P< ). Five-year cumulative rates of isolated CNS relapses were 5.9% and 4.4%. Therapy based on the Berlin-Frankfurt-Münster 76/79 study improved outcomes for intermediate and higher risk patients in the first series. For intermediate risk patients, delayed intensification (DI) was most crucial for improved outcome and cranial irradiation was safely replaced with maintenance intrathecal methotrexate, providing patients received intensified systemic therapy. In the second series, randomized trials showed better outcome with one vs no DI phase for lower risk patients, with two vs one DI phase for intermediate risk patients, and with the CCG 'augmented regimen' for higher risk patients with a slow day 7 marrow response. Cranial irradiation was safely replaced with additional intrathecal methotrexate for higher risk patients with a rapid day 7 marrow response. In a subsequent study, substitution of dexamethasone in place of prednisone in induction and maintenance improved outcome for standard risk patients. All patients received dexamethasone in DI. These successful treatment strategies form the basis for our current ALL trials. Drugs used asparaginase, carmustine, cyclophosphamide, cytosine arabinoside, daunorubicin, dexamethasone, doxorubicin, mercaptopurine, methotrexate, prednisone, thioguanine, vincristine Harms DO, Janka-Schaub GE on behalf of the COALL Study Group. Co-operative study group for childhood acute lymphoblastic leukemia: Long-term follow-up of trials 82, 85, 89 and 92. Leukemia 2000; 14;

14 The German Co-operative Study Group COALL for treatment of acute lymphoblastic leukemia (ALL) in childhood started the first trial in This report gives an overview of the long-term results of the four consecutive studies COALL-82, COALL-85, COALL-89 and COALL-92. Besides improvement in long-term survival major objectives were reduction of treatment-related toxicity by transferring asparaginase (ASP) from induction therapy to intensive phase and omitting CNS irradiation by stepwise increase of the initial white blood count (WBC) up to 50 x 10(9)/l (exception T-ALL) as criterion for irradiation. In study COALL-85 in high risk patients slow vs rapid rotational treatment was randomized. In study COALL-92 initial response to daunorubicin (DNR) as a 1-h vs 24-h infusion and its prognostic value was investigated. Furthermore, 6-mercaptopurine (6-MP) and 6- thioguanine (6-TG) were randomized in maintenance treatment. In total, 1191 eligible patients were enrolled. Induction treatment without ASP has been shown to be as effective and less hazardous than the former four-drug induction. CNS control could be obtained in most without cranial irradiation (CNS relapse-free survival >95%). The leukemic cell kill with a 24-h DNR infusion was equivalent to that of a 1-h infusion. DNR response was of less prognostic significance than prednisone response. The rapid rotation regimen failed to improve outcome as well as 6-TG in maintenance treatment. However, intensification of systemic treatment resulted in an increase in overall event-free survival (EFS) to approximately 80% which is comparable to other groups. Drugs used asparaginase, cyclophosphamide, cytosine arabinoside, daunorubicin, dexamethasone, doxorubicin, ifosphamide, mercaptopurine, methotrexate, prednisone, teniposide, thioguanine, vincristine Kamps WA, Veerman AJP, van Wering ER, van Weerden JF, Slater R, van der Does-van den Berg A. Long-term follow-up of Dutch Childhood Leukemia Study Group (DCLSG) protocols for children with acute lymphoblastic leukemia, Leukemia 2000; 14: Here we report the long-term results of the DCLSG protocols ALL-6 and -7 with special emphasis on the incidence of CNS relapse after treatment without cranial irradiation. In DCLSG protocol ALL-6 ( ), designed for patients with ALL non-high risk (ALL- NHR) (WBC <50 x 10(9)/l, no mediastinal mass, no B cell phenotype and no CNS involvement at diagnosis, comprising 71% of all ALL patients), CNS prophylaxis consisted of a combination of three methods of chemotherapeutic CNS prophylaxis (the use of dexamethasone during induction and maintenance therapy, i.v. medium dose methotrexate and prolonged administration of intrathecal triple therapy). Total duration of treatment: 116 weeks. 190 patients were enrolled in the study. At 10 years, the EFS rate for all patients is /- 2.8%, the survival rate /- 2.7%, and the cumulative incidence of isolated CNS relapse 1.1 +/- 0.8%. The 10-year survival rate for the 139/190 (73.1%) patients with standard risk non-t lineage ALL according to the NCI risk criteria is /- 3.4%. DCLSG protocol-7 was identical to the intensive ALL-BFM-86 protocol, but cranial irradiation was restricted to patients with initial CNS involvement. Patients were stratified into three risk groups (SRG, RG and EG). Treatment duration was 18 months. 218 patients were enrolled in the study. At 10 years, the EFS rate for all patients is /- 3.3%, the survival rate /- 3.0%, the 5- year cumulative incidence of isolated CNS relapse 5.7 +/- 1.8%. The EFS rate at 10 years of the 127/218 (58.3%) patients with standard risk non-t-lineage ALL according to the NCI risk 14

15 criteria was /- 4.3%, which is not significantly different from the results achieved in this category of patients with the moderately intensive treatment according to protocol ALL-6 (logrank P = 0.17). These DCLSG studies indicate that omission of cranial irradiation does not jeopardize the overall good results. Drugs used asparaginase, cyclophosphamide, cytosine arabinoside, daunorubicin, dexamethasone, doxorubicin, ifosphamide, mercatopurine, methotrexate, mitoxantrone, prednisone, teniposide, thioguanine, vincristine, vindesine Silverman LB, Declerck L, Gelber RD et al. Results for Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia ( ). Leukemia 2000; 14: The Dana-Farber Cancer Institute (DFCI) ALL consortium has been conducting clinical trials in childhood acute lymphoblastic leukemia (ALL) since The treatment backbone has included intensive, multi-agent remission induction, early intensification with weekly, highdose asparaginase, cranial radiation for the majority of patients, frequent vincristine/ corticosteroid pulses during post-remission therapy, and for high-risk patients, doxorubicin during intensification. Between 1981 and 1995, 1,255 children with newly diagnosed ALL were evaluated on four consecutive protocols: ( ), ( ), ( ) and ( ). The 5-year event-free survival (EFS) rates (+/- standard error) for all patients by protocol were as follows: 74 +/- 3% (81-01), 78 +/- 3% (85-01), 77 +/- 2% (87-01) and 83 +/- 2% (91-01). The 5-year EFS rates ranged from 78 to 85% for patients with B-progenitor phenotype retrospectively classified as NCI standard-risk, 63-82% for NCI high-risk B-progenitor patients, and 70-79% for patients with T cell phenotype. Results of randomized studies revealed that neither high-dose methotrexate during induction (protocol 87-01) nor high-dose 6-mercaptopurine during intensification (protocol 91-01) were associated with improvement in EFS compared with standard doses. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities. Drugs used asparaginase, cytosine arabinoside, dexamethasone, doxorubicin, mercaptopurine, methotrexate, prednisone, vincristine Vilmer E, Suciu S, Ferster A et al. Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report. Leukemia 2000; 14: We present here the long-term results of three randomized clinical trials conducted on children with newly diagnosed acute lymphoblastic leukemia (ALL) between 1983 and 1998 by the Children Leukemia Cooperative Group (CLCG) from EORTC. In study 58831/32, the overall event-free survival (EFS) rates (+/- s.e.) at 6 and 10 years were 66% +/- 1.8% and 65% +/- 1.8%, respectively, and the risk of isolated central nervous system (CNS) relapse was 6% +/- 1% and 7% +/- 1%, respectively. In patients with a standard risk of relapse the omission of cyclophosphamide had no adverse effect on disease-free survival rates at 10 years (trial 58831). In medium- and high-risk patients the omission of radiotherapy did not increase the risk of CNS or systemic relapse (trial 58832). In study ( ) the overall EFS rate 15

16 at 8 years was 68.4% +/- 1.2% and the risk of isolated CNS relapse was 4.2%+/-0.5%. In this trial which adressed three randomized questions, the following results were obtained: the combination of cytarabine at high doses with methotrexate at high doses during interval therapy did not improve prognosis. The addition of 6-mercaptopurine iv during maintenance increased the risk of late relapse. E. coli asparaginase was more toxic and has a higher efficacy than Erwinia asparaginase. Leukocyte counts >100 x 10(9)/l, specific genetic abnormalities, a poor initial response to steroids or a high level of minimal residual disease at early time points were consistently associated with an adverse prognosis in the trial. Drugs used asparaginase, cyclophosphaminde, cytosine arabinoside, daunorubicin, dexamethasone, doxorubicin, etoposide, ifosphamide, mercaptopurine, methotrexate, mitoxantrone, prednisolone, prednisone, thiaguanine, vincristine, vindesine Gustafsson G, Schmiegelow K, Forestier E et al. Improving outcome through two decades in childhood ALL in the Nordic countries: the impact of high dose methotrexate in the reduction of CNS irradiation. Leukemia 2000; 14: In this population-based material from the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), 2860 children below 15 years of age were diagnosed with acute lymphoblastic leukemia (ALL) from July 1981 to June The annual incidence was 3.9/100,000 children and was stable throughout the study period. The development from regional or national protocols to common Nordic treatment protocols for all risk groups was completed in 1992 through a successive intensification with multidrug chemotherapy, including pulses of methotrexate in high doses and avoidance of cranial irradiation in most children. The overall event-free survival (EFS) at 5 years has increased from /- 1.7% in the early 1980s to /- 1.4% during the 1990s. The main improvements were seen in children with non-high risk leukemia. In high-risk patients, progress has been moderate, especially in children with high WBC (> or =100 x 10(9)/l) at diagnosis. During the last time period (January 1992-June 1998), only 10% of the patients have received cranial irradiation in first remission, while 90% of the patients have received pulses of high dose methotrexate (5-8 g/m2) isolated or combined with high-dose cytosine arabinoside (total dose 12 g/m2) plus multiple intrathecal injections of methotrexate as CNS-targeted treatment, not translating into increased cumulative incidence of CNS relapse. Drugs used asparaginase, carmustine, cyclophosphamide, cytosine arabinoside, daunorubicin, dexamethasone, doxorubicin, hydroxyurea, mercaptopurine, methotrexate, prednisone, thioguanine, vincristine Maloney KW, Shuster JJ, Murphy S, Pullen J, Camitta BA. Long-term results of treatment studies for childhood acute lymphoblastic leukemia: Pediatric Oncology Group studies from Leukemia 2000; 14: This paper presents the long-term results of treatment for children with acute lymphoblastic leukemia (ALL) as conducted by the Pediatric Oncology Group (POG) from 1986 to The data are presented using standard NCI/Rome risk criteria. The overall event-free survival (EFS) at 5 and 10 years were 70.9% and 67.3% for children with B-precursor ALL, 16

17 51.0% and 50.2% for patients with T cell ALL, and 22.4% and 20.9% for infants with ALL. Concomitant biologic studies found that in B-precursor ALL a DNA index (DI) of > or =1.16 and trisomies of both chromosomes 4 and 10 were good prognostic indicators for patients with B-precursor ALL. The traditional prognostic indicators (age and white count), DI and trisomies did not predict outcome in patients with T cell disease. Infants continued to do poorly overall despite more intensive therapy with rotating pairs of chemotherapy. We recommend continued reporting of study results using common risk criteria in order to facilitate comparisons both within and across study groups. Drugs used asparaginase, cyclophosphamide, cytosine arabinoside, doxorubicin, etoposide, hydrocortisone, mercaptopurine, methotrexate, prednisone, teniposide, vincristine Pui C-H, Boyett JM, Rivera GK et al. Long-term results of Total Therapy studies 11, 12 and 13A for childhood acute lymphoblastic leukemia at St. Jude Children s Research Hospital. Leukemia 2000; 14: We present the long-term results of three consecutive clinical trials (Total Therapy studies 11, 12 and 13A) conducted for children with newly diagnosed acute lymphoblastic leukemia (ALL) between 1984 and In study 11 ( ), the overall event-free survival rates (+/-1 s.e.) were /- 2.4% and /- 2.4%, and the cumulative risks of isolated central nervous system (CNS) relapse 5.6 +/- 1.2% and 5.9 +/- 1.3%, at 5 and 10 years, respectively. In study 12 ( ), event-free survival rates were /- 3.4% and 61.5+/- 9.0%, and isolated CNS relapse rates were /- 2.3% and /- 2.3%, respectively. Early intensive intrathecal therapy in study 13A ( ) has yielded a very low 5-year isolated CNS relapse rate of 1.2 +/- 0.9%, boosting the 5-year event-free survival rate to /- 3.3%. Factors consistently associated with an adverse prognosis included male sex, infant or adolescent age group, leukocyte count >100 x 10(9)/l, nonhyperdiploidy karyotype and poor early response to treatment. Risk classification based on age and leukocyte count had prognostic significance in B-lineage but not T-lineage ALL. Early therapeutic interventions or modifications for patients with specific genetic abnormalities or persistent minimal residual leukemia may further improve long-term results. Drugs used asparaginase, cyclophosphamide, cytosine arabinoside, daunorubicin, etoposide, hydrocortisone, mercaptopurine, methotrexate, prednisone, teniposide, vincristine Tsuchida M, Ikata K, Hanada R et al. Long-term follow-up of childhood acute lymphoblastic in Tokyo Children s Cancer Study Group Leukemia 2000; 14: The objectives were as follows: Firstly, to estimate the overall probability of event-free survival (EFS) and isolated CNS relapse in the studies for children with acute lymphoblastic leukemia (ALL) during the 1980s and 1990s. Secondly, to report the EFS according to presenting features and lineage. Thirdly, to evaluate the treatment results re-classified by the risks of NCI criteria. Four consecutive protocol studies were performed in the Tokyo 17

18 Children's Cancer Study Group: L81-10 protocol ( , 189 patients), L84-11 ( , 484 patents), L89-12 ( , 418 patients) and L92-13 ( , 347 patients). Overall EFS at 5 years in each protocol was /- 3.8(1 s.e.)%, /- 2.1%, /- 2.3%, and /- 2.7%, respectively. The cumulative isolated CNS relapse rate at 5 years was 8.1 +/- 2.1%, 3.5 +/- 0.9%, 3.6 +/- 1.0%, 1.0 +/ The EFS in SR/HR (standard risk/high risk) according to the NCI criteria in B-precursor ALL at 5 years was /- 4.3%/41.4 +/- 7.4% (lineage was not confirmed.), /- 2.6%/63.4 +/- 5.0%, /- 2.7%/56.3 +/- 4.7%, and /- 3.4%/56.7 +/- 5.4% in each protocol. Also EFSs according to NCI SR/HR at 5 years of T-ALL in protocols L84-11, L89-12 and L92-13 were /- 16.6%/60.9 +/- 10.1%, /- 13.4%/51.6 +/- 9.1%, and /- 14.4%/53.6/10.1%, respectively. The truncation of maintenance therapy to 6 months resulted in a decreased EFS in L92-13, particularly due to an increase of bone marrow relapse after cessation of therapy in SR and HR. The NCI risk criteria work properly even in the patients treated by different intensities, so that it makes the comparison possible among the patients in various groups. The overall EFSs in childhood ALL improved in 1980s, but it seemed stable or decreased in 1990s. The short maintenance therapy resulted in poor outcome in SR on the L92-13 protocol. Many of these late relapsers were effectively rescued and overall survival remained at a high level. The proportion of patients who received cranial irradiation reduced without any increase of the CNS events. Drugs used aclarubicin, asparaginase, cyclophosphamide, cytosine arabinoside, daunorubicin, dexamethasone, doxorubicin, etoposide, hydrocortisone, mercaptopurine, methotrexate, mitoxantrone, prednisolone, vincristine Eden OB, Harrison G, Richards S et al. Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukemia, Leukemia 2000; 14: Results of three consecutive completed UK trials ( ) for childhood lymphoblastic leukaemia are presented. National accrual has progressively increased so that over 90% of all the country's ALL cases were treated on the latest trial reported, UKALLXI. From 1980 to 1990, event-free and overall survival progressively improved, following adoption of an American therapy template and use of two post-remission intensification modules. Since 1990 despite demonstration of the benefit of a third intensification module overall event-free survival (EFS) has not improved further. Survival remains high due to a good retrieval rate especially for those relapsing off treatment after receipt of two intensification pulses. Possible reasons for the plateau in event-free survival (including type and dose of induction steroid, dropping of induction anthracycline, type and dose of asparaginase, gaps early in therapy following intensification, and overall lack of compliance in maintenance) are being explored in the latest protocol ALL '97. Cranial irradiation had been successfully replaced by a long course of intrathecal methotrexate injections for the majority of patients. Age (<1 year >10 years) sex (male) and white count >50 x 10(9)/l plus slow initial bone marrow clearance were consistently the most important independent prognostic indicators during this time period. Rome/NCI criteria accurately predict standard and high-risk groups for B cell lineage, but not consistently for T cell disease. This international collaborative venture might help us to define those truly at highest risk, and how we can optimise therapy for specific subgroups including T-ALL and those with unfavourable cytogenetics. 18

19 Drugs used asparaginase, cyclophosphamide, cytosine arabinoside, daunorubicin, dexamethasone, etoposide, mercaptopurine, methotrexate, prednisolone, thioguanine, vincristine. 19

20 18th Expert Committee on the Selection and Use of Essential Medicines Essential drugs for the treatment of Burkitt Lymphoma Background 1,2 Fifty years ago Dennis Burkitt described the original African lymphoma which has since borne his name and been recognized internationally. The WHO lymphoma classification recognized Burkitt and atypical Burkitt lymphoma (BL) as similar diseases biologically. The African BL is considered to be endemic with epidemiological links to malaria and Epstein Barr virus infection. The clinical presentation may be nodal and /or extranodal, with or without bone marrow or central nervous system (CNS) involvement. The most common site of the endemic disease in Africa is the jaw, while non-endemic disease presents frequently as an abdominal tumour. Staging is dependent on the extent of anatomical disease and is necessary to plan the details (including the intensity and duration) of treatment. BL and Burkitt- like lymphoma/leukaemia are mature B cell tumours in which the malignant cells express the surface antigens CD19, CD20 and CD22. The distinction between the diagnosis of leukaemia and lymphoma is arbitrary with the classical definition of leukaemia being over 25% involvement of the marrow. However it is accepted that there is no distinct biological difference and that pure B cell leukaemia should be treated with protocols designed for advanced Burkitt lymphoma. CNS involvement at diagnosis is considered the strongest risk factor for relapse and, as a consequence, patients presenting with CNS disease should be treated more intensively. Approximately 80% of BL tumours contain chromosomal translocations such as t (8; 14) (q24; q32). BL accounts for 40-50% of lymphoma cases in non-endemic areas and approximately 80% in endemic areas. In African countries situated within 15 degrees of the equator, BL may account for up to 45% of childhood cancer. 3 BL is a tumour with a very high growth fraction and short cell cycle times. Due to the rapid replication of tumour cells, one of the major complications during treatment is the Tumor Lysis Syndrome resulting in renal failure with severe electrolyte imbalance. Appropriate supportive care is required during initial induction treatment to prevent or minimize this potentially life-threatening complication. However, the rapid cell division makes BL exquisitely sensitive to cytotoxic agents and accounts in large measure for the success of intensive chemotherapeutic regimens. 20

21 Search methods The improvement in outcomes for children with cancer is attributable mainly to the systematic conduct of randomised clinical trials. These trials have been conducted over the last 40 years by a number of multi-institutional groups, predominantly in North America and Europe. These national and international co-operative clinical trials have led to the continuing refinement of pathology, prognostic factors and multidisciplinary treatments. Results of these trials have been reviewed (appendix 1) and considered high grade evidence. The cytostatic drugs used predominantly for BL in past trials and in the control arms of current randomised trials were identified. The literature was reviewed for the treatment experience in low income counties (LIC) as well as for articles summarising treatments for BL. The essential drugs identified by this process are those that are used most frequently in both developed and LIC and form the backbone of all regimens used for BL. Because of the extent of clinical and prognostic variables which will impact treatment decisions, as well as the varied infrastructure of treatment facilities, a common treatment regimen incorporating the essential drugs was not prescribed. History of chemotherapy 2,4-18 In one of the original series of BL treatments in Uganda, patients received cyclophosphamide intravenously or orally, methotrexate orally and vincristine intravenously, a regimen to which 82% of patients had an initial response. Subsequent studies in Africa and elsewhere confirmed that these are active drugs. A subsequent Ugandan study reported a 25% survival rate and another in Ghana a 33% survival rate using cyclophophamide-based regimens. In the late 1970s, escalation of doses of methotrexate was reported to result in improved durable response rates. Additional drugs have been evaluated in combination therapy. Anthracyclines and corticosteroids were added to the core three agents. The Children s Cancer Study Group showed that the COMP (cyclophosphamide, vincristine, methotrexate, prednisone) regimen was an effective combination for non-lymphoblastic lymphoma, including BL Dose intensity has become an important principle of BL therapy due to the observation that patients would relapse in between courses if there was a delay in commencing the next cycle of treatment. The intensive therapeutic protocols pioneered by the national clinical groups in Germany (BFM studies) and France (SFOP studies) led to protocols designed specifically for B cell non- Hodgkin lymphoma (NHL) and B cell acute lymphoblastic leukaemia. A series of protocols based on the original French studies have culminated in the achievement of an event-free survival rate exceeding 90%. This series of trials added the drugs etoposide and cytosine arabinoside. The French LMB 89 protocol has been used as the standard therapy to which subsequent trials have been comparing alternative dosing and scheduling. International collaborative studies have shown subsequently that it is possible to reduce the intensity of treatment in children with low and intermediate risk B cell NHL. The drugs included in all of these protocols of the last decade are: cyclophosphamide, vincristine, prednisone, cytosine arabinoside, doxorubicin, etoposide and methotrexate. This combination of drugs is considered the backbone of standard therapy, and therefore the essential drugs required to treat with the expectation of an acceptable cure rate. Adaptations of these protocols used in Europe and North America have been utilized in developing countries with limited resources (LIC) At the 10 th International Conference on Malignant Lymphoma, a 21