High risk acute lymphoblastic leukemia in Denmark

In a retrospective study of acute lymphoblasic leukemia (ALL) in Denmark from 1973 to 1981, 95/267 children below 15 years of age fulfilled at least one of the following high risk (HR) criteria: WBC > 50 × 10⁹/1, mediastinal mass, meningeal leukemia, extramedullary leukemia, T-ALL, B-ALL and congenital leukemia. Significantly more of the children in HR had considerable hepato- and/or splenomegaly compared with children in the standard risk (SR) and intermediate risk (IR) groups. Hemoglobin values above 6.0 mmol/l were found in 35% of HR children and in 9% of children in SR and IR (p < 0.0005). Treatment protocols varied. The percentage achieving complete remission (CR) was 93.7. Median relapse free survival (RFS) was 18 months. Twenty-nine children (32.5%) have been in CCR for 24–114 months as of July 1983. Initial WBC was the only independent prognostic parameter. Of children with initial WBC < 50 × 10⁹/l, 62% remained in CCR compared to 15% with WBC > 50 × 10⁹/l. Treatment protocols employed before July 1977 were significantly inferior to protocols employed during the last half of the study period. Fifty-seven patients relapsed most frequently in the bone marrow. In 38.5% of the relapses, the central nervous system (CNS) was involved. When the CNS prophylaxis was initiated early during induction treatment, significantly fewer CNS recurrences arose than when the CNS prophylaxis was started after remission had been induced. Acute lymphoblastic leukemia, children, high risk, prognosis.     

The course of biological parameters and 6-mercaptopurine pharmacokinetics during maintenance treatment of children with acute lymphoblastic leukaemia

Twenty patients on maintenance therapy (MT) for acute lymphoblastic leukaemia (ALL) with oral 6-mercaptopurine (6-MP) and methotrexate (MTX) were studied. White cell and red cell indices and platelets counts were monitored every second week as were drug levels. Mean values for 6-MP and MTX doses, and blood component parameters were calculated for each 6-month period for the whole patient group. 6-MP plasma concentrations and liver-function tests were determined once every six months and mean values calculated. 6-MP and MTX mean doses did not change significantly during MT. The mean area under the concentration versus time curve (AUC) 0-4 hours varied slightly from the start to the end of the MT (257 and 296 ng/ml.h, respectively). The mean plasma peak concentration increased from 98 ng/ml to 195 ng/ml (p less than 0.01) during the same period. There were significant decreases between the initial white blood cell counts (WBC) and red blood cell counts (RBC) as compared to levels at the end of therapy (p less than 0.01 and 0.02, respectively). A linear correlation was found between 6-MP peak concentrations and both WBC (r = 0.96) and RBC (r = 0.87). At the end of MT liver function tests became normal in all except 6 patients. In conclusion, MT have moderate effects on bone marrow and liver and monitoring 6-MP plasma concentration might be of value for determination of the optimal WBC levels during MT.     

The Course of Biological Parameters and 6-Mercaptopurine Pharmacokinetics during Maintenance Treatment of Children with Acute Lymphoblastic Leukaemia

ABSTRACT. Twenty patients on maintenance therapy (MT) for acute lymphoblastic leukaemia (ALL) with oral 6-mercaptopurine (6-MP) and methotrexate (MTX) were studied. White cell and red cell indices and platelets counts were monitored every second week as were drug levels. Mean values for 6-MP and MTX doses, and blood component parameters were calculated for each 6-month period for the whole patient group. 6-MP plasma concentrations and liver-function tests were determined once every six months and mean values calculated. 6-MP and MTX mean doses did not change significantly during MT. The mean area under the concentration versus time curve (AUC) 0-4 hours varied slightly from the start to the end of the MT (257 and 296 ng/ml-h, respectively). The mean plasma peak concentration increased from 98 ng/ml to 195 ng/ml ( p <0.01) during the same period. There were significant decreases betwen the initial white blood cell counts (WBC) and red blood cell counts (RBC) as compared to levels at the end of therapy ( p <0.01 and 0.02, respectively). A linear correlation was found between 6-MP peak concentrations and both WBC ( r =0.96) and RBC ( r =0.87). At the end of MT liver function tests became normal in all except 6 patients. In conclusion, MT have moderate effects on bone marrow and liver and monitoring 6-MP plasma concentration might be of value for determination of the optimal WBC levels during MT.     

Maintenance chemotherapy for childhood acute lymphoblastic leukemia: should dosage be guided by white blood cell counts?

In a retrospective population-based study of 122 children with non-B-cell acute lymphoblastic leukemia (ALL), we analyzed the relation between risk of relapse and the degree of leukopenia achieved during oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance chemotherapy (MT). After a median follow-up of 62 months for patients still in remission, 43 patients had relapsed (including 28 bone marrow relapses). Patients with a mean white blood cell count during MT (mWBCMT) of less than or equal to 3.5 x 10(9)/L had a significantly lower risk of hematological relapse (p = 0.007) as well as of any relapse (p = 0.02) compared to patients with higher mWBCMT. The clinical advantage of leukopenia could be demonstrated for all risk groups and was not explained by differences in year of diagnosis, gender, age, and white blood cell count at diagnosis, or the prescribed dose of MTX and 6MP. Although prospective studies are needed to establish the benefit of upward dose adjustments to achieve leukopenia, these results indicate a clinical advantage of keeping WBCs low during MT.     

PLEUROPULMONARY BLASTOMA: An Aggressive Intrathoracic Neoplasm of Childhood

In a retrospective study of 84 children with standard-risk acute lymphoblastic leukemia diagnosed in 1981-1986, mean white cell count (mWBC) during maintenance chemotherapy (MT) was found to be significantly related to risk of hematological relapse, giving patients with the higher m WBC the poorer outcome. The only other significant relapse-related risk factor was white-cell count at diagnosis. mWBC was not significantly related to white cell count at diagnosis, sex, age, or dose of methotrexate or mercaptopurine. Patients with low mWBC also had relatively low white-cell counts after cessation of therapy when compared with patients with high m WBC.     

White Cell Count During Maintenance Chemotherapy for Standard-Risk Childhood Acute Lymphoblastic Leukemia: Relation to Relapse Rate

In a retrospective study of 84 children with standard-risk acute lymphoblastic leukemia diagnosed in 1981-1986, mean white cell count (mWBC) during maintenance chemotherapy (MT) was found to be significantly related to risk of hematological relapse, giving patients with the higher m WBC the poorer outcome. The only other significant relapse-related risk factor was white-cell count at diagnosis. mWBC was not significantly related to white cell count at diagnosis, sex, age, or dose of methotrexate or mercaptopurine. Patients with low mWBC also had relatively low white-cell counts after cessation of therapy when compared with patients with high m WBC.     

6-巯嘌呤细胞药理学研究对急性淋巴细胞白血病治疗的指导作用

目的建立一种高效、快速、灵敏的方法，探讨6-巯嘌呤（6-MP）细胞药理学。方法应用反相高效液相色谱分析技术，定量测定急性淋巴细胞白血病(ALL)患儿红细胞内6-MP三种代谢产物浓度6-巯嘌呤核苷酸（6-TGN）,6-次黄巯嘌呤单核苷酸(6-TIMP)和6-甲基巯嘌呤（6-MeMP）。选择31例ALL缓解期随访的患儿，口服6-MP50～75mg/（m     

6-Mercaptopurine Cumulative Dose: A Critical Factor of Maintenance Therapy in Average Risk Childhood Acute Lymphoblastic Leukemia

A multivariate survival analysis including gender, age, log white blood cell (WBC) count, liver and spleen size at diagnosis, mean log WBC count during maintenance therapy, and the prescribed cumulative doses of 6-mercaptopurine (6-MP), methotrexate (MTX), vincristine (VCR), and prednisom (PDN) during maintenance therapy was performed on 53 children with average-risk acute lymphoblastic leukemia (ALL). The 6-MP cumulative dose prescribed during maintenance therapy resulted in the most important statistically significant independent prognostic factor. Patients who received less than the median cumulative dose of 6-MP (86% of planned protocol dose) fared significantly worse than the other patients, regardless of WBC count at diagnosis, gender, age, and other factors studied. Therefore, 6-MP cumulative dose during maintenance therapy may be the critical factor for effective maintenance therapy in childhood ALL.     

Allogeneic bone marrow transplantation in the treatment of acute leukemias of children. Study of 26 patients

Twenty-six children with acute leukemia were treated with allogeneic marrow transplantation from HLA identical siblings after a conditioning regimen with Cyclophosphamide-total body irradiation (19 patients), Melphalan-total body irradiation (6 patients) or Busulfan-cyclophosphamide (1 patient). Eighteen were transplanted in complete remission (4 with acute non lymphoblastic leukemia in first remission, 14 with acute lymphoblastic leukemia: 6 in first, 6 in second and 2 in subsequent remission): 2 died of cytomegalovirus pneumoniae, 1 relapsed and 15 survive in continuous complete remission from 5 to 42 months after transplantation (median = 22 months). Eight were transplanted in relapse, 7 achieve complete remission, 5 of them relapsed, 1 died of G.V.H. and 1 survives in continuous complete remission 46 months after transplantation. Actuarial analysis shows a disease free survival rate at 3 years of 82% for patients transplanted in remission and 12% for patients transplanted in relapse (p less than 0.01).     

Simultaneous control of third-degree graft-versus-host disease and prevention of recurrence of juvenile myelomonocytic leukemia (JMML) with 6-mercaptopurine following fulminant JMML relapse early after KIR-mismatched bone marrow transplantation

The authors describe a young boy with juvenile myelomonocytic leukemia (JMML) who relapsed 45 days after HLA and killer immunoglobulin-like receptor (KIR) mismatched unrelated donor bone marrow transplant (MMUD-BMT) and subsequently developed life-threatening graft-versus-host disease (GvHD). Treatment with 6-mercaptopurine (6-MP) appeared to control severe GvHD and possibly prevented recurrence of leukemic relapse.     

Treatment of relapsing acute lymphoblastic leukemia in childhood. II. Experiences with 45 first bone marrow and 24 isolated central nervous system relapses observed 1981-1984

Of 45 children with ALL who had a first hematological recurrence between 1981 and 1984, 33 relapsed while still on treatment and 12 after cessation of therapy. Of the former 1 of 16 high risk (initial WBC greater than or equal to 20 x 10(9)/l and/or enlargement of the mediastinum) and 5 of 17 low risk patients (initial WBC less than 20 x 10(9)/l and no enlargement of the mediastinum), of the latter 6 patients survived after a minimum follow-up of 20 months. During the same time period, a first isolated CNS relapse was observed in 24 children of whom 16 survived. These results suggest that at the time of evaluation 1. the prognosis of children with ALL in first hematological relapse during the years 1981-1984 was not significantly different from that of similar children treated earlier; and 2. the prognosis of children with isolated CNS relapse had improved.     

Prognostic significance of methotrexate and 6-mercaptopurine dosage during maintenance chemotherapy for childhood acute lymphoblastic leukemia.

Tolerance of full-dose methotrexate/6-mercaptopurine (MTX/6MP) maintenance therapy for childhood acute lymphoblastic leukemia (ALL) without side effects could reflect insufficient systemic drug exposure, and drug withdrawals due to toxicity might reduce the chance of cure. The present study included 122 children with non-B cell acute lymphoblastic leukemia with a median follow-up of 84 months. Leukopenia and hepatotoxicity were calculated as weighted means of all white cell counts and all serum aminotransferase measurements, respectively, registered for each patient. Forty-five patients relapsed (30 in bone marrow). Patients tolerating an average dose of MTX of more than 75% of the recommended protocol doses and having cumulated drug withdrawals of less than 1% of the period of maintenance therapy had an increased risk of hematological relapse (p = 0.008) as well as of any relapse (p = 0.03) when compared to the remaining patients. Patients with a cumulative withdrawal of MTX or of 6MP for greater than 10% of the maintenance therapy period had an increased risk of hematological relapse (MTX: p = 0.009, 6MP: p less than 0.0001) and of any relapse (MTX: p = 0.16, 6MP: p = 0.0002). Liver toxicity was the main reason for cumulative long-term drug withdrawals. However, patients with a mean aminotransferase level above the upper normal limit (40 IU/l) who were kept on therapy (cumulative withdrawals of neither drug for more than 5% of their maintenance therapy period) had a significantly lower risk of hematological relapse (p = 0.02) as well as of any relapse (p = 0.06) than the remaining children. The concept of treating to toxicity seems warranted for maintenance therapy of childhood lymphoblastic leukemia.     

A population-based study of childhood acute lymphoblastic leukemia diagnosed from July 1981 through June 1985 in the five Nordic countries. Incidence, patient characteristics and treatment results

Six hundred and fifty-six children with acute lymphoblastic leukemia (ALL) have been diagnosed in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) during the period from July 1981 through June 1985. Annual incidence of ALL was 3.6/100,000 children aged less than 15 years, with an incidence for males of 3.8 and for females of 3.4 respectively. Half of the children were younger than 5 years of age at diagnosis, with a peak incidence between 2-3 years of age. The leukemias were classified as Standard Risk (SR), Intermediate Risk (IR) or High Risk (HR) leukemia according to prognostic criteria at diagnosis. The remission rate was 95%. In children greater than or equal to 1 year of age with non-B-cell ALL at diagnosis, the Event-Free Survival (EFS) was 0.58; 0.65 for SR-children, 0.51 for IR-children and 0.52 for HR-children. WBC count at diagnosis was the most important prognostic factor and a WBC count of 11-20 X 10(9)/l was associated with the worst prognosis of all WBC values (EFS = 0.30), independent of other prognostic factors. Male sex was the second most important adverse prognostic criterion. The follow-up in January 1986 (observation time 6-54 months), showed that 442 of the 656 children (67%) were in complete continuous remission. The total results indicate a possibility to improve the prognosis for most of the risk groups of ALL with a more intensive treatment.     

A Population-Based Study of Childhood Acute Lymphoblastic Leukemia Diagnosed from July 1981 through June 1985 in the Five Nordic Countries

Six hundred and fifty-six children with acute lymphoblastic leukemia (ALL) have been diagnosed in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) during the period from July 1981 through June 1985. Annual incidence of ALL was 3.6/100000 children aged < 15 years, with an incidence for males of 3.8 and for females of 3.4 respectively. Half of the children were younger than 5 years of age at diagnosis, with a peak incidence between 2–3 years of age. The leukemias were classified as Standard Risk (SR), Intermediate Risk (IR) or High Risk (HR) leukemia according to prognostic criteria at diagnosis. The remission rate was 95%. In children 1 year of age with non-B-cell ALL at diagnosis, the Event-Free Survival (EFS) was 0.58; 0.65 for SR-children, 0.51 for IR-children and 0.52 for HR-children. WBC count at diagnosis was the most important prognostic factor and a WBC count of 11-20×10⁹/l was associated with the worst prognosis of all WBC values (EFS=0.30), independent of other prognostic factors. Male sex was the second most important adverse prognostic criterion. The follow-up in January 1986 (observation time 6–54 months), showed that 442 of the 656 children (67%) were in complete continuous remission. The total results indicate a possibility to improve the prognosis for most of the risk groups of ALL with a more intensive treatment.     

ACUTE LYMPHOBLASTIC LEUKEMIA IN SWEDISH CHILDREN 1973–1978

ABSTRACT. Gustafsson, G., Kreuger, A. and Dohlwitz, A. (Departments of Paediatrics, University Hospital, Uppsala, and County Hospital, Nykoping, Sweden). Acute lymphoblastic leukemia in Swedish children 1973–1978. Acta Paediatr Scand, 70:609,.–Three hundred and sixty-seven children with acute lymphoblastic leukemia have been diagnosed in Sweden 1973–1978, 345 of whom were treated according to the national uniform regimens of the Swedish Child Leukemia Group (SCLG). The patients were classified into an SR (standard risk) and an IR (increased risk) group. Remission was obtained in 354 patients (96%). With 12–84 months observation time the total survival was 54% and the diseasefree survival 44 %. A more intensive cytostatic regimen in the induction period increased considerably the diseasefree survival for the SR and to some extent also for the IR patients. Relapses were significantly more common in the IR group in spite of a more intensive cytostatic regimen. The most decisive IR criteria were B-LPK and age at diagnosis. Prognosis was significantly worse for boys in all groups. After 3 years in CCR treatment was discontinued in 95 out of 246 children (38%) of whom 19 later relapsed (20%)     

急性淋巴细胞性白血病患儿巯嘌呤耐受性研究

目的 调查急性淋巴细胞性白血病(acute lymphoblastie leukemia,ALL)患儿,维持化疗期间巯嘌呤(6-mercaptopurine,6-MP)的耐受性,为进一步研究6-MP耐受性差异的原因提供依据.方法 选择规范应用北京儿童医院急性淋巴细胞性白血病2003年化疗方案(BCH-ALL-2003),随访至2008年9月30日的患儿.全部患儿处于骨髓缓解期,且维持化疗≥13个月.详细记录患儿6-MP服用情况,包括服用剂量以及恶心、呕吐、皮疹等用药反应,以调查6-MP的耐受性.所有患儿每周复查血常规,间隔4周复查肝功能,并根据检查结果进行6-MP毒性分级.记录6-MP停止时间和剂量减少程度.结果共133例,男81例,女52例,中位年龄67个月(18～188个月),中位缓解时间26个月(6～47个月).6-MP维持化疗(13.5±7.4)个月(3～25个月),其中6-MP标准剂量、全疗程者72例(54%),剂量46 ms/(m~2·d),白细胞(WBC)(3～4)×10~9/L,中性粒细胞(ANC)(1.5～2.0)×10~9/L,肝脏毒性小于Ⅱ级,4例(3%)患儿ANC持续在3×10~9/L以上,6-MP剂量增加为标准剂量125%.余61例患儿均为严重不耐受6-MP者,其中骨髓抑制48例(同时伴肝毒性9例),单纯肝脏功能异常12例,反复皮疹1例.平均毒性反应出现时间为2.5周.19例患儿平均停用6-MP 7 d,42例患儿平均6-MP实际剂量25～30 ms/(m~2·d).结论 ALL患儿个体间6-MP的耐受性差异很大,46%ALL患儿对6-MP的标准治疗剂量表现为明显的骨髓抑制和肝功能异常等不耐受反应,临床需要根据血常规不断调整6-MP的剂量,以避免较大的毒性反应的发生,而3%患儿给予标准剂量6-MP,表现为无轻度骨髓抑制等化疗反应,临床需要增加6-MP剂量以减少复发危险性.但如何更准确地进行6-MP剂量调整是临床研究的难题之一.选择6-MP严重不耐受患儿进行6-MP代谢酶活性和基因多态性研究,以明确ALL儿童6-MP耐受性差异的原因,为进一步进行个体化药物剂量的调整提供理论依据.     

Insulin-like growth factor-I and insulin-like growth factor binding protein-3 during maintenance chemotherapy of acute lymphoblastic leukemia in children.

PURPOSE: To assess the effect of maintenance chemotherapy (MT) on growth factors and growth in children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Twenty-one children (10 girls, 11 boys) with standard risk pre-B ALL treated with chemotherapy had serum insulin-like growth factor-I (IGF-I), serum IGF binding protein-3 (IGFBP-3) levels, and linear growth and weight data measured every 3 months during MT. The levels of the cytotoxic metabolites of methotrexate (MTX) and 6-mercaptopurine (6MP) (i.e., erythrocyte MTX polyglutamates [E-MTX], and erythrocyte 6-thioguanine nucleotides [E-6TGN]), s-aminotransferases, and white blood counts (WBC) were measured at least monthly. RESULTS: At the beginning of MT, the median IGF-I standard deviation scores (SDS) and IGFBP-3 SDS were -0.52 and -0.09, respectively, which declined during MT to -1.67 (P < 0.001) and -1.82 (P < 0.001), respectively. At the time of diagnosis, the median height SDS was -0.4, which declined during MT to a median height SDS of -0.9 at cessation of therapy. No significant correlations were found between growth factor levels, growth and body mass index (BMI) versus the doses of MTX, and 6MP, E-MTX, E-6TGN, s-aminotransferases, or WBC. CONCLUSIONS: A significant decline in IGF-I, IGFBP-3, and growth retardation may not be directly related to the treatment intensity during MT.     

Cranial computed tomographic findings in children with newly diagnosed acute lymphoblastic leukemia: A prospective follow-up study during treatment

Cranial computed tomography (CT) was performed on 40 consecutive children with newly diagnosed acute lymphoblastic leukemia (ALL) on admission before any chemotherapy, 5 months after CNS therapy (n = 39) and after 2 to 3 years of therapy (n = 31). Changes related to leukemia were found in only 10% of the patients at the time of diagnosis (4/40). These initial changes, two intracranial hemorrhages, one dural thickening and one contrast enhancement, all disappeared during therapy. The findings which persisted unchanged in the next two CT scans were thought to be normal variations or caused by earlier disorders. CNS therapy consisted of intrathecally and intravenously administered methotrexate in 20 standard risk (SR) patients and cranial irradiation in addition to chemotherapy in 19 intermediate risk (IR) or high risk (HR) patients. Four SR patients developed changes during therapy. Three had enlarged cerebrospinal fluid (CSF) spaces and one developed a focal low density area suggesting disturbances in brain blood circulation and also experienced disturbances in level of consciousness. Of the 19 IR or HR patients, eight developed changes related to the therapy, including four with white matter hypodensity areas, of whom three also had enlarged CSF spaces, and four others who developed enlarged CSF spaces. The medians of the widths of the cortical sulci (P < .001), insular cisterns (P < .01), third ventricles (P < .01), and frontal horns (P < .05), and also of Evans' ratios (P < .05) increased significantly after CNS therapy as compared with the findings at diagnosis in the patients who had received cranial irradiation. Most of these changes persisted during the follow-up. We conclude that the clinical value of CT scanning during therapy for ALL is restricted to patients with neurological symptoms or those who have undergone CNS irradiation. © 1992 Wiley-Liss, Inc.     

Myelotoxicity, pharmacokinetics, and relapse rate with methotrexate/6-mercaptopurine maintenance therapy of childhood acute lymphoblastic leukemia

White blood cell and absolute neutrophil counts (WBC, ANC), aminotransferase (AT) levels, methotrexate (MTX) and 6-mercaptopurine (6MP) doses, metabolites in erythrocytes (E-MTX and E-6TGN), and the prognostic significance of these parameters were studied in 58 children receiving MTX/6MP maintenance therapy for acute lymphoblastic leukemia diagnosed from July 1986 to December 1991. At the end of follow-up July 1995, 13 patients had relapsed (pEFS = 0.77). Weighted means of AT, WBC, and ANC during and after maintenance therapy (mAT, mWBCON, mWBCOFF, mANCON, mANCOFF), E-MTX (mE-MTX), and E-6TGN (mE-6TGN) were calculated, as well as the product of mE-MTX and mE-6TGN (mE-MTX*6TGN), as MTX and 6MP probably act synergistically. Beyond higher MTX and 6MP doses to patients with high mWBCON, neither mWBCON, (median 3.5 x 10(9)/L), mANCON, nor mAT was correlated with the dose of MTX and 6MP, mE-MTX, mE-6TGN, or risk of relapse. Patients with mE-MTX*6TGN above or below 828 (nmol/mmol Hb)2 (median value) had pEFS values of 0.84 and 0.70, respectively (P = .16). All 5 patients who relapsed during therapy had mE-MTX*6TGN < 828 (nmol/mmol Hb)2 (P = .03). mWBCOFF and the degree of myelosuppression (= mWBCSHIFT = mWBCOFF - mWBCON; median: 2.5 x 10(9)/L) were related to age (rs = -0.50, P = .001 and rs = -0.40, P = .006, respectively). All eight relapses off therapy occurred in patients with mWBCSHIFT < 2.5 x 10(9)/L (P = .02). WBC levels during MTX/6MP therapy may underestimate the degree of MTX/6MP treatment intensity, especially in order children. Pharmacokinetic monitoring could be useful for optimizing MTX/6MP maintenance therapy.     

Treatment‐related mortality in relapsed childhood acute lymphoblastic leukemia

1 Background

Treatment of relapsed childhood acute lymphoblastic leukemia (ALL) is particularly challenging due to the high treatment intensity needed to induce and sustain a second remission. To improve results, it is important to understand how treatment‐related toxicity impacts survival.

2 Procedure

In this retrospective population‐based study, we described the causes of death and estimated the risk for treatment‐related mortality in patients with first relapse of childhood ALL in the Nordic Society of Paediatric Haematology and Oncology ALL‐92 and ALL‐2000 trials.

3 Results

Among the 483 patients who received relapse treatment with curative intent, we identified 52 patients (10.8%) who died of treatment‐related causes. Twelve of these died before achieving second remission and 40 died in second remission. Infections were the cause of death in 38 patients (73.1%), predominantly bacterial infections during the chemotherapy phases of the relapse treatment. Viral infections were more common following hematopoietic stem cell transplantation (HSCT) in second remission. Independent risk factors for treatment‐related mortality were as follows: high‐risk stratification at relapse (hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.3–3.9; P < 0.01), unfavorable cytogenetic aberrations (HR 3.4; 95% CI 1.3–9.2; P = 0.01), and HSCT (HR 4.64; 95% CI 2.17–9.92; P < 0.001). In contrast to previous findings, we did not observe any statistically significant sex or age differences. Interestingly, none of the 17 patients with Down syndrome died of treatment‐related causes.

4 Conclusions

Fatal treatment complications contribute significantly to the poor overall survival after relapse. Implementation of novel therapies with reduced toxicity and aggressive supportive care management are important to improve survival in relapsed childhood ALL.