Leukemia (1999) 13, 25–31  1999 Stockton Press All rights reserved 0887-6924/99 $12.00 http://www.stockton-press.co.uk/leu Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial DKH Webb1, K Wheatley2, G Harrison2, RF Stevens3 and IM Hann1 for the MRC Childhood Leukaemia Working Party

1Great Ormond Street Hospital for Children, London; 2MRC Clinical Trial Service Unit, Radcliffe Infirmary, Oxford; and 3Royal Manchester Children’s Hospital, Manchester, UK

Between May 1988 and March 1995, 359 children with acute courses of intensive chemotherapy; children with a matched myeloid leukaemia (AML) were treated in the MRC AML 10 trial. sibling donor were then eligible for a bone marrow allograft Three risk groups were identified based on cytogenetics and response to treatment. One hundred and twenty-five children (BMT) in first remission, while remaining children were eli- relapsed – 103 in the bone marrow only, 12 in the bone marrow gible for randomisation between an autograft (ABMT) and no combined with other sites, and six had isolated extramedullary further therapy (Figure 1). All children received four courses relapses (site was not known in four cases). Eighty-seven chil- dren received further combination chemotherapy, one all-trans retinoic acid for acute promyelocytic leukaemia, and one a matched unrelated donor allograft in relapse, and 61 achieved a second remission. One patient with no details on reinduction therapy also achieved second remission. Treatment in second remission varied – 44 children received a BMT (22 autografts, 12 matched unrelated donor allografts, 10 family donor allografts), and 17 were treated with chemotherapy alone. The overall survival rate for all children (treated and untreated) was 24% at 3 years, with a disease-free survival of 44% for those achieving a second remission. Length of first remission was the most important factor affecting response rates – children with a first remission of less than 1 year fared poorly (second remission rate 36%, 3 year survival 11%), whereas those with longer first remissions had a higher response rate (second remission rate 75%, 3 year survival 49%, P Ͻ 0.0001). Keywords: acute myeloid leukemia; children; relapse; prognosis

Introduction

Population-based studies have shown an improvement in the 5 year survival for children with acute myeloid leukaemia (AML) from 6% for those diagnosed from 1971 to 1974 to 40% for those diagnosed from 1984 to 1989,1,2 primarily due to improved chemotherapy and supportive care. In the United Kingdom Medical Research Council (MRC) AML 10 trial, overall survival and disease-free survival for children under 15 years of age were 57% and 52% at 7 years.3 Despite these improvements relapse remains the main cause of treatment failure and only a minority of these children are long-term survivors following further therapy. Several factors affecting the likelihood of survival following relapse, particularly length of first remission, have been identified from studies with adults4–6 but there are limited data regarding children.7 Accordingly, and as a basis for future studies, the outcome for those children who suffered a relapse following initial treat- ment in AML 10 is presented.

Materials and methods

Between May 1988 and March 1995, 359 children aged under 15 years were treated in the paediatric arm of AML 10. In summary, all patients were scheduled to receive four

Correspondence: D Webb, Department of Haematology, Great Ormond Street Hospital for Children, Great Ormond Street, London WCIN 3JH, UK; Fax: 171 813 8410 Received 17 April 1998; accepted 9 October 1998 Figure 1 AML 10: protocol flow chart. Medical Research Council AML 10 trial DKH Webb et al 26 of ‘triple’ intrathecal chemotherapy (cytarabine, methotrexate Table 1 Sites of relapse (n = 125) and hydrocortisone), and cranial irradiation was reserved for those with CNS disease at diagnosis (defined as Ͼ5 white Bone marrow 103 cells/mm3 in the cerebrospinal fluid with recognisable blasts Bone marrow and CNS 5 Bone marrow and testis 3 on CSF cytospin, or cranial nerve palsy). There was no single Bone marrow and orbit 1 recommended strategy for the management of relapsed dis- Bone marrow and other 1 ease which was at the discretion of the treating physician, but Skin and node 3 details of children with relapse including further therapy, Isolated skin 3 remission rates and outcome were obtained prospectively by Isolated CNS 1 standard trial forms. The length of first remission was calcu- Isolated testis 1 Unknown 4 lated as the time from initial complete remission (CR) to first relapse, overall survival after relapse was the time from relapse to death, and disease-free survival was the time from second complete remission to any event (relapse or death). information regarding further treatment was available in 122 Surviving patients were censored on July 1 1998 when data cases. Reinduction was attempted in 89 cases (87 children were complete for over 97% of patients registered, and those were treated with combination chemotherapy, one was given children lost to follow-up were censored on the last date they all-trans retinoic acid (ATRA) for acute promyelocytic leu- were known to be alive. Median follow-up is 6.5 (range 3.3– kaemia (AML M3) and one child received a matched unre- 10.1) years. Second CR rates were compared using the Mantel lated donor allograft in relapse). Care was not aimed at Haenzel test for trend and Fishers exact test (in 2 × 2 tables), achieving second CR in 33 (10 single agent, 23 palliation) and actuarial survival curves were calculated by the method patients. A further four children received transplants in relapse of Kaplan and Meier. The effects of length of first remission (two BMT, two ABMT) when reinduction chemotherapy and risk group on survival from relapse and disease-free sur- failed. There was no significant difference in length of first vival were assessed by means of the log rank test. Outcomes remission between children receiving further intensive therapy after 2nd CR following chemotherapy alone, and chemo- or palliative care only (P = 0.09). Reinduction was attempted therapy plus BMT or ABMT were compared by Mantel–Byar in 89% of good risk patients but only in 68% of standard risk analysis, which provides an adjustment to the log rank test to and 60% of poor risk patients (trend P = 0.02). For children allow for the time to transplant. given combination chemotherapy, 48 received re-induction with standard courses from AML 10, while 39 were treated with other multi-agent regimens (Table 2), including sequen- Results tial high-dose cytarabine and asparaginase (CLASP, n = 3)8 or fludarabine, high-dose cytarabine, and granulocyte colony- In children entered in AML 10 the complete remission rate stimulating factor (FLAG, n = 8).9 was 93%, disease-free survival was 52%, and overall survival The number of courses of chemotherapy given varied from was 57% at 7 years. There were no differences in overall sur- one to three, with a median of two courses. The child with vival between treatment groups, but relapse was less common AML M3 entered second remission following ATRA, but the in children randomised to ABMT (31% vs 52% at 7 years, other 10 children receiving single agent therapy did not remit. P = 0.03), and among those children with a bone marrow Three children who received transplants in relapse remitted donor compared with no donor (30% compared with 45%, (one BMT and one ABMT following courses of chemotherapy P = 0.02). Three risk groups (good, standard and poor) were and one child who received a matched unrelated donor allo- identified based on cytogenetics, FAB type and the percentage graft rather than chemotherapy). Among the 87 children of blasts in the bone marrow after one course of chemo- treated with combination chemotherapy, 59 entered second therapy.3 Good risk children (n = 89) had t(15; 17) or FAB type remission, the majority after one course (range 1–3 courses), M3, t(8;21), or inversion 16. Standard risk children (n = 165) had responsive disease defined as Ͻ15% blasts in the bone marrow after recovery from the first course of chemotherapy, Table 2 Response to reinduction therapy and neither favourable or unfavourable cytogenetics, while poor risk children (n = 58) had monosomy 7, monosomy 5, Reinduction regimen No. treated Complete remission deletions of 5q, abnormalities of 3q, complex cytogenetics rate (%) with four or more separate abnormalities, or resistant disease defined as Ͼ15% blasts in the bone marrow on recovery from ADE 29 69 course 1. The overall survival rates from first remission for DAT 7 57 these groups at 7 years were 79, 60 and 34%, respectively, MACE 9 67 FLAG 8 88 while the disease-free survival rates were 59, 55 and 31%, MidAC 3 33 respectively. ATRA 1 100 By July 1 1998, 125 children had relapsed at a median of BMT 1 100 295 days from first remission, and relapse was most common CLASP 3 100 in the first year (27%), with rates of 11, 3 and 1% for the Others 28 64 second, third, and fourth years, respectively, with no relapses to date beyond 4 years. The bone marrow was the most com- Small numbers and lack of randomised allocation to treatments pre- mon site of relapse (Table 1) and relapse in the central nervous cludes comparisons between regimens. ADE, cytarabine, daunorubicin, etoposide; DAT, daunorubicin, system was very uncommon, occurring in only seven cases. cytarabine, thioguanine; MACE, amsacrine, cytarabine, etoposide; Details of risk group were available for 120 relapsing children FLAG, fludarabine, cytarabine, G-CSF; MidAC, mitoxantrone, and relapse rates were 34% in the good risk group, 58% in the cytarabine; ATRA, all-trans retinoic acid; CLASP, cytarabine, standard risk group, and 66% in the poor risk group. Adequate asparginase. Medical Research Council AML 10 trial DKH Webb et al 27 remaining children given chemotherapy only include one with standard risk AML at diagnosis with a first remission of 453 days who remains in second remission at 5 years, and one with good risk disease (inversion of chromosome 16) with first remission under 6 months who is in third remission 3 years following further chemotherapy for a second relapse. Accordingly, the data for those children given chemotherapy alone remain unstable. There was a marginally significant dif- ference in relapse risk between transplanted and non- transplanted patients (P = 0.04, Table 3). Relapse remained the primary cause of death, but 13 children died of treatment related toxicity – eight due to sepsis, and one each from car- diac failure, haemorrhage, respiratory failure, liver failure and Figure 2 AML 10: survival from relapse. multiple causes. Eight of these toxic deaths followed a bone marrow transplant. Among children treated by chemotherapy only there were six further relapses and five toxic deaths giving an overall remission rate in children receiving reinduc- before the median time from second remission to BMT of 67 tion therapy of 69% (61/89). Among 11 children who received days. The second remission rate, overall survival, disease-free reinduction chemotherapy following an ABMT or BMT in first survival, and relapse rate were affected by length of first remission four entered second remission, three following remission and risk group (all P Ͻ 0.01) (see Tables 4 and 5). multiple drug combinations, and one following ATRA. One of Risk group and length of first remission were highly correlated, the three children with missing reinduction therapy data also ie good risk children tended to have longer first remissions achieved second remission. (Tables 6 and 7) and on bivariate analysis length of first Treatment in second remission varied – 44 children remission (P = 0.002, P = 0.003 for patients where reinduction received a bone marrow transplant (22 ABMT, 12 unrelated was attempted) was of greater significance than risk group donor BMT, 10 family donor BMT – nine full match, one HLA (P = 0.04, P = 0.1 for patients where reinduction was mismatch), and 17 were treated with chemotherapy alone. attempted) for remission rate and for overall survival (length Two children received a second high-dose procedure (both of first remission controlling for risk group: P = 0.0003, BMT) following a transplant in first CR. There were a median P = 0.0005 in reinduction attempts; risk group controlling for of two (range 1–3) courses of chemotherapy given prior to length of first remission P = 0.06, P = 0.1 in reinduction transplant and the procedures were performed at a median of attempts). The effect of length of first remission on survival 67 (range 1–289) days from second remission. Children who and disease-free survival is shown in Figures 4 and 5. received a BMT had significantly longer first remissions than those treated by chemotherapy only (Wilcoxon two sample = test P 0.0001). Discussion The overall survival from relapse for all 125 children was 24% at 3 years with a disease-free survival of 44% for the 62 Despite improved first-line therapy for AML in childhood, children who entered second remission (Figures 2 and 3), at relapse remains the primary cause of treatment failure irres- a median follow-up at the time of analysis of 1303 (range pective of whether therapy is by intensive chemotherapy 329–2238) days from second remission. Twenty-nine have alone or combined with bone marrow transplantation, with achieved remission inversion (second remission longer than relapse rates of 30–50% in modern studies.3,10–15 In AML 10 first remission), 26 following BMT. Two children who relapsed the bone marrow was the only site of relapse in 82% of cases, following BMT in first remission and one child transplanted and central nervous system relapse was very uncommon fol- in relapse following unsuccessful reinduction chemotherapy lowing a protocol without routine cranial irradiation, indicat- remain alive and disease-free. When sub-divided on the basis ing that radiotherapy should be reserved for children with of consolidation treatment given in second remission there frank CNS disease. Survival following a first relapse has been were no significant differences in survival between groups on poor and in this study, the overall survival following relapse Mantel–Byar analysis but one of three surviving children given was 24% at 3 years, similar to other reports,7,16–21 but 18% of chemotherapy only suffered a second relapse and is alive fol- children received palliative care only, and there were sub- lowing a mismatched family donor BMT in relapse. The two groups of patients with a high chance of achieving prolonged second remissions. The length of first remission was of primary importance in determining the likelihood of successful retreatment, with poor response rates for children relapsing within 1 year of first remission, and this finding confirms sev- eral other reports of outcome, predominantly in adults. In AML 10, three risk groups were identified, but these risk groups had only a weak independent effect on the rate of second remission, and on survival as length of first remission and risk group were strongly correlated, and on bivariate analysis length of first remission was the more important fac- tor. Creutzig et al7 reported similar results following relapse in children treated on BFM protocols, with 21% overall sur- vival at 5 years. Length of first remission affected prognosis, with a 3 year survival of 12% for children relapsing before 18 Figure 3 AML 10: disease-free survival from 2nd remission. months, compared with 47% for later relapses. Keating et al4 Medical Research Council AML 10 trial DKH Webb et al 28 Table 3 Comparison of outcome by treatment received as consolidation in second remission

Treatment No. No. of Expected No. P value No. of Expected No. P value treated deaths of deathsa relapses of relapses

BMT/ABMT 44 17 19.9 0.2 10 13.4 0.04 ABMT 22 9 9.7 0.4 7 6.3 0.2 UD 12 5 4.6 0.7 1 3.2 0.04 Family donor 10 3 5.6 0.1 2 3.9 0.09 No BMTb 17 14c 11.1 11 7.6

aExpected number of deaths, relapses and P values in all treatment groups obtained from Mantel–Byar analysis comparing transplanted with non-transplanted children. bOne of these children had a BMT and one an ABMT in first remission. cSix of these deaths (plus five early 2nd relapses) occurred within 40 days of second remission, the median time to BMT. Small numbers and lack of randomised allocation to treatments precludes conclusions from these data, but indicates the need for appropri- ate clinical trials.

Table 4 Effect of length of first remission (CR1) on response to further treatment

Length of CR1 No. relapsed No. with 2nd remission rate Disease-free Survival from relapse at 3 years reinduction survival from attemptedAll patients % Reinduction 2nd remission All patients % Reinduction attempted %at 3 years % attempted %

Ͻ6 months 23 13 13*** 23*** 33** 9 15*** 6–12 months 58 40 45 63 23 12 15 12–24 months 32 26 72 88 61 44 54 Ͼ24 months 12 10 83 100 66 64 77 Ͻ1 year 81 53 36*** 53*** 24** 11*** 15*** Ͼ1 year 44 36 75 92 62 49 60

Details on reinduction therapy unavailable for three children, one of whom went into second remission. **P Ͻ 0.001; ***P Ͻ 0.0001.

Table 5 Effect of risk group on response to further therapy

Risk group No. relapsed No. with 2nd remission rate Disease-free Survival from relapse at 3 years reinduction survival from attemptedAll patients % Reinduction 2nd remission All patients % Reinduction attempted %at 3 years attempted %

Good 28 25 75*** 84** 75* 64*** 71*** Standard 57 39 54 77 29 18 23 Poor 35 21 26 43 17 3 6

Details on reinduction therapy unavailable for three children and details of risk group unavailable for a further five patients, three of whom went into second remission. *P Ͻ 0.01; **P Ͻ 0.001; ***P Ͻ 0.0001.

identified duration of first remission, age, and serum lactate dehydrogenase (LDH), but not cytogenetics, as significant fac- Table 6 Relationship between length of first remission and risk group tors influencing second remission rate in adults, and duration of first remission, age, serum bilirubin, percentage blasts and Length of first remission No. of patients promyelocytes in the blood, and serum alkaline phosphatase as factors affecting survival. Estey6 described a simplified strat- Good risk Standard Poor risk egy based on length of first remission, and previous treatment risk to guide approaches to salvage chemotherapy, suggesting that individuals with relapse within 1 year of first CR had little Ͻ6 months 2 8 11 chance of either remission or survival with conventional regi- 6–12 months 6 31 18 mens and should be considered eligible for phase I and II stud- 12–24 months 13 15 4 ies. Thalhammer et al5 described the outcome of 168 patients 24–48 months 7 3 2 retreated following a first relapse – 39% achieved second remission, and the probability of second remission and Test for trend P Ͻ 0.0001. survival were affected by the length of first remission with a disease-free survival of 35% at 3 years for those with a first Medical Research Council AML 10 trial DKH Webb et al 29 Table 7 Effects of length of first remission (CR1) and risk group on overall survival (%) at 3 years from first relapse

Risk group Length of first Length of P value for effect of remission first remission length of remission in Ͻ1 year Ͼ1 year each risk group

All Reinduction All Reinduction All Reinduction patients attempted patients attempted patients attempted n% n % n% n %

Good 8 25 7 29 20 79 18 88 0.0006 0.0002 Standard 39 13 25 16 18 11 14 36 0.03 0.05 Poor 29 3 17 6 6 0 4 0 0.07 0.8 P value for effect of risk group in 0.9 0.8 0.0002 Ͻ0.0001 each age group

remission of over 1 year, compared with 0% for patients with shorter remissions. The overall survival for the whole group was 24% at 3 years. The possibility of improving outcome for children with early relapse is severely limited with current therapies, as in our study only 36% of patients with relapse in the first year entered second remission, and survival was 11% at 3 years. Over 60% of all relapses occurred within 1 year from first remission, and there is no evidence that retreatment with stan- dard therapies will help the majority of these children, who should be considered for novel therapies. For children with initial remissions of over 1 year, however, response and sur- vival rates were more encouraging, justifying further intensive therapy in this group. It is not possible to reliably assess the relative benefits of different chemotherapy regimens for reinduction from this study, nor to compare different strategies for consolidation due to the small numbers and the non-randomised selection of treatments. However, intensive regimens with or without anthracyclines appeared similarly effective, and this has important implications for the avoidance of cardiotoxicity in children with high cumulative exposure to anthracyclines – cardiotoxicity was a cause of morbidity and mortality in AML 10 where children received 300 mg/m2 of daunorubicin and 50 mg/m2 of mitoxantrone,3 and avoidance of further anthra- cyclines and/or strategies for cardioprotection should be employed wherever possible. Survival rates of 20–40% have been reported in selected patients receiving consolidation with intensive chemotherapy, ABMT or BMT in second Figure 4 AML 10: Survival from relapse by duration of 1st remission,17–19,22–28 and similar outcomes were observed both remission for (a) all patients and (b) patients with induction attempted. in this study, and by the BFM group.7 Children who received chemotherapy alone in our study had significantly shorter first remissions than those treated by BMT, and 11/18 of this group relapsed again or died of toxicity prior to the median time to transplant indicating selection bias between treatment groups. These data emphasise the need for proper randomised studies to address issues of salvage chemotherapy and the role of dif- ferent types of bone marrow transplantation, and due to the small numbers of children with AML international colla- borative studies are crucial to allow these issues to be appropriately addressed.

References

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Appendix Professor OB Eden (Chairman), Dr P Emerson, Dr DIK Evans, Professor JJ Fennelly, Professor DAG Galton, Dr B Gibson, Membership of the MRC Childhood Leukaemia Mr RG Gray, Dr IM Hann, Professor RM Hardisty (past Working Party during AML 10: Chairman), Dr C Haworth, Dr M Hewitt, Dr FGH Hill, Dr J Kernahan, Dr DJ King, Dr SE Kinsey, Professor JS Dr CC Bailey, Dr P Barbor, Dr ND Barnes, Dr C Barton, Lilleyman, Dr M Madden, Dr J Mann, Dr J Martin, Professor Dr V Broadbent, Dr SC Cartwright, Professor J Chessells, TJ McElwain (past Chairman), Dr ST Meller, Dr C Mitchell, Dr R Collins, Dr PJ Darbyshire, Dr SI Dempsey, Dr IJ Durrant, Dr PH Morris Jones, Dr A Oakhill, Professor J Peto, Dr M Medical Research Council AML 10 trial DKH Webb et al 31 Radford, Dr JKH Rees, Dr S Richards, Dr RS Shannon, Dr G Green, Dr DN Hart, Dr ME Jenney, Dr JE Kingston, Dr RF Stevens, Dr GP Summerfield, Dr E Thompson, Dr J Kohler, Dr DM Layton, Dr IJ Lewis, Dr S May, Dr H Dr F Varga-Khadem, Dr D Walker, Dr H Wallace, Dr D McDowell, Dr DW Milligan, Dr DJ Moir, Dr MW Moncrieff, Webb, Dr K Wheatley and Dr A Will. Professor MG Mott, Dr CS Nelson, Professor AC Newland, Dr KG Patterson, Professor CR Pinkerton, Professor MJ Pippard, Dr GC Rastogi, Dr D Samson, Dr SA Schey, Dr L Clinicians entering patients but not on the MRC Sinclair, Professor IJ Temperley and Dr A Thomas. Childhood Leukaemia Working Party:

Dr L Ball, Dr F Breatnach, Dr JE Chandler, Dr AA Dawson, Dr ZR Desai, Professor EL Egan, Dr A Foot, Dr N Foreman,