Delayed Intensification Phase Research Articles

Delayed Intensification (DI) Enhances Event-Free Survival (EFS) of Children with B-Precursor Acute Lymphoblastic Leukemia (ALL) Who Received Intensification Therapy with Six Courses of Intravenous Methotrexate (MTX): POG 9904/9905: A Childrens Oncology Group Study (COG).

Post-induction (ind) intensification with non-anti-metabolite based blocks of therapy, improved EFS on BFM 76/79, CCG 105 and UKALL X. The DI phase of reinduction-reconsolidation (BFM protocol II) was a major component of these strategies. An anti-metabolite based (MTX/mercaptopurine [MP]) intensification also improved EFS (POG 9005/9006). COG 9904 and 9905 addressed whether addition of DI improved EFS for a subset of lower, standard (std) and a subset of NCI high risk (HR) pts who all received 6 courses (cs) of IV MTX (1 gm/m2/24 hrs vs 2 gm/m2/4 hrs) plus oral MP as intensification. The results of the MTX randomization (4 vs 24 hrs) are still blinded. Ind was a dexamethasone (dex)-based 3-drug (NCI std risk) or prednisone-based 4-drug (NCI HR or std with extramedullary disease) regimen. The 3-drug ind was modified because of excessive mortality with the intrathecal (IT) MTX on day 1 changed to IT Ara-C and 6 doses of native asparaginase (asp) (10,000 IU/m2) replaced with 1 dose of PEG asp. 1124 pts were treated pre-; 477 post-amendment. Post-ind, NCI std risk pts with trisomies of chromosomes 4 and 10 or a TELAML1 (TEL) translocation were classified as lower risk and enrolled on 9904. Only the TEL pts participated in the DI randomization. Std risk pts without and HR pts with favorable blast cytogenetics, or pts who did not meet refined NCI high risk age and WBC criteria were eligible for 9905. Pts with CNS3 disease, t(9;22), t(4;11), or hypodiploidy were excluded from both studies. Consolidation on 9904/9905 included 6 cs of IV MTX with leucovorin rescue for all pts. DI began at wk 16 after the 3rd course of IV MTX and was delivered over 8 wks: 1.5 mg/m2 vincristine and 30 mg/m2 daunomycin (wks 1, 2 and 3), daily dex (6 mg/m2 × 21 days), 2500 IU/m2 PEG asp (wk 1), age adjusted IT MTX (wks 1, 5, 6), 75 mg/m2 Ara-C (IV /SC) daily × 4 days (wks 5 and 6), 1 gm/m2 cyclophosphamide (wk 5) and 60 mg/m2 6-thioguanine daily × 14 doses (wks 6–7). A total of 1403 patients were randomized to +/− DI between April 7, 2000 and April 15, 2005. There were only 2 remission deaths; 1 each in +/− DI arms. There was a statistically significant improvement in EFS for all pts receiving the DI, with no statistically significant interaction (size of treatment differences in 4 yr EFS) between any pair of subsets. The difference, though not significant (study not powered to look at subsets), for the 9905 NCI HR pts with and without favorable cytogenetics, was in the same direction as the overall results, but still suboptimal with EFS below 80%. This may reflect differences between the dex and anthracycline used during the DI phase in this study versus BFM 76/69 and CCG 105 and/or the need for an intervention other than this DI in NCI HR patients.No DIDICohort4 yr EFSN4 yr EFSN1 sided p-value*Overall (9904/9905 NCI Std & High Risk)81.6±2.0%71086.5±1.7%6930.00499904/9905 NCI Standard Risk84.5±2.1%51790.3±1.7%5120.00129904 NCI Std Risk with TELAML191.1±2.6%21793.6±2.2%2160.09009905 NCI Std Risk79.8±3.2%30087.9±2.5%2960.00279905 NCI HR74.3±4.3%9376.2±4.5%1810.3839*p-values are by the logrank test

High Body Mass Index Increases the Risk for Osteonecrosis in Children With Acute Lymphoblastic Leukemia

The aim of the study was to determine the incidence of and clinical risk factors for radiographic osteonecrosis (ON) in children treated for acute lymphoblastic leukemia (ALL) using the Nordic ALL protocols. Ninety-seven consecutive patients with childhood ALL were studied prospectively by magnetic resonance imaging (MRI) of the lower extremities at the end of the treatment. Twenty-three (24%) of the 97 patients had ON. Seven of the patients (30%) were symptomatic, and three patients (13%) required surgical interventions. Multiple logistic regression analysis showed that high body mass index (BMI; P = .04), female sex (P = .01), older age at diagnosis (P < .001), and higher cumulative dexamethasone dose (P = .03) were independent risk factors for radiographic ON. The cumulative prednisone dose did not differ significantly between the patients with and without ON. The incidence of radiographic ON decreased significantly, from 36% to 7%, when the duration of dexamethasone exposure during the delayed-intensification phase was shortened from 3 to 4 weeks to 2 weeks with a taper (P = .001). ON as determined by MRI was found to be a common complication in children and adolescents after treatment with the Nordic ALL protocols. Revision of the ALL protocols by shortening the single exposure to dexamethasone has diminished the risk for ON remarkably. High BMI was identified as a new significant risk factor for ON.

Increased Infection-Related Mortality for Children with Down Syndrome (DS) in Contemporary Children's Oncology Group (COG) Acute Lymphoblastic Leukemia (ALL) Clinical Trials.

In prior COG ALL trials, children with DS have had increased treatment-related morbidity without major increases in mortality, when compared to children without DS. Recently, COG opened phase III, randomized trials for the treatment of children with high risk (AALL0232) and standard risk (AALL0331) precursor-B ALL. COG AALL0232 uses an augmented BFM backbone regimen with randomized comparisons of 28 days of prednisone (PDN) 60 mg/m2 vs. 14 days of dexamethasone (DXM) 10 mg/m2 during induction (IND), and high dose methotrexate with leucovorin rescue (HD MTX) vs. escalating IV MTX without rescue plus Peg asparaginase using the Capizzi schedule (CMTX) during a two-month interim maintenance (IM) phase of therapy. Children with DS participated in the induction steroid randomization, but were non-randomly assigned to CMTX arm due to known increased sensitivity to HD MTX. During the first 22 months of accrual to AALL0232, there were 4 deaths among 20 patients with DS, 3 of these 4 deaths occurred in pts receiving DXM in IND yielding an IND mortalaity rate of 15%, which is significantly higher than the 4.3% rate in CCG 1961 (the prior high risk trial). COG AALL0331 utilizes a standard 3-drug IND consisting of DXM 6 mg/m2 for 28 days, vincristine and PEG asparaginase. Post-IND therapy includes a 2 × 2 randomization between intensified vs. standard consolidation, and escalating CMTX combined with augmented delayed intensification (DI) vs. standard IM and DI phases. On AALL0331, there were 6 deaths among 26 children with DS during the first 10 months of accrual. The deaths occurred in IND (3), intensified consolidation (1) and standard DI (2). The IND mortality rate for DS children on AALL0331 is 11.5% compared to 1.3% in CCG 1991 and 0% in CCG 1952 which used identical IND therapy. During DI, patients on CCG 1991 received DXM on days 1–7 and 15–21, whereas those on AALL0331 receive DXM on days 1–21; this difference could contribute to an increased risk of infection in the DS population during the DI phases of the latter trial. The majority of deaths have been due to overwhelming infection with cardiovascular collapse during times of neutropenia. Both COG AALL0232 and AALL0331 suspended enrollment to DS patients pending subsequent therapy changes and expanded supportive care guidelines. This experience emphasizes that children with DS carry a significant risk of infection-related mortality and mandates increased vigilance for early detection and treatment of symptoms suggestive of infection.

A SERPINE1 (PAI-1) Single Nucleotide Polymorphism Predicts Osteonecrosis in Children Treated for Acute Lymphoblastic Leukemia: Results of the Children's Oncology Group (COG) Study AALL03B2.

As intensity of glucocorticoid use has increased, osteonecrosis has become an increasingly frequent complication of modern intensive chemotherapy for pediatric patients with acute lymphoblastic leukemia (ALL). Although patient age > 10 years is a well-known risk factor, other host risk factors that may predispose to this complication are not well described. We tested whether 12 polymorphisms in 11 candidate genes were associated with osteonecrosis among up to 344 patients ≥ 10 years old treated on the Children's Cancer Group protocol CCG 1882 for newly diagnosed high-risk ALL, adjusting for gender, age, and treatment arm (augmented versus standard treatment). Genes tested (TYMS, ER, MTHFR, ABCB1, BGLAP (osteocalcin), ACP5, LRP5, ESR, SERPINE1, VDR, PTH, and PTHR) were chosen because they are candidates based on the putative mechanisms underlying osteonecrosis risk, including involvement in antifolate pharmacodynamics, drug pharmacokinetics, thrombosis risk, and possible hormonal influence on glucocorticoid effects. All children received dexamethasone during the delayed intensification phase of therapy, with doses varying by treatment arm (one dexamethasone pulse in the standard chemotherapy arm vs. two dexamethasone pulses in the augmented chemotherapy arm). Of the 11 candidate polymorphisms, a single nucleotide polymorphism (dbSNP rs6092) in the SERPINE1 gene (plasminogen activator inhibitor type 1 or PAI-1) was the only polymorphism associated with an increased risk of osteonecrosis in both univariate (p=0.0039) and multivariate (p=0.0019) analyses (adjusting for gender, age, and treatment arm), with an odds ratio of 2.51 (95% CI 1.32 to 4.74). Overall, 23.9% of the 88 children heterozygous or homozygous for the SERPINE1 T allele, versus 11.1% of the 234 children homozygous for the C allele, developed osteonecrosis. The combined CT or TT genotypes were present in a greater percentage (27%) of whites than in blacks (12%, p = 0.016), consistent with a higher risk (p = 0.003) of osteonecrosis in whites than blacks that was originally reported for CCG-1882 (J Clin Oncol 18:3262–72, 2000). In a multivariate analysis, only the SERPINE1 polymorphism and sex predicted AVN, with the incidence of osteonecrosis lower in boys (odds ratio 0.49, 95% confidence interval 0.25 to 0.96, p = 0.034). No statistically significant gene-gene interactions between SERPINE1 and any other tested genotype were noted. SERPINE1 polymorphisms and PAI-1 serum levels have previously been associated with a clinical pro-thrombotic state. We conclude that polymorphisms in SERPINE1 may contribute to the risk of osteonecrosis in patients treated with glucocorticoids.

Treatment of EBV-associated T cell post-transplant lymphoproliferative disorder with CNS involvement in a pediatric solid-organ transplant patient

9040 Background: Post-transplant lymphoproliferative disorder (PTLD) is a known complication of immunosuppression following solid organ and stem cell transplantation. It ranges from benign lymphoid hyperplasia to fulminant systemic disease with high mortality. Most cases are B lineage and associated with Epstein-Barr virus (EBV+). T cell PTLD is rare and usually EBV negative. To date only 5 cases of EBV+ T cell PTLD have been reported in pediatric patients and none have had documented involvement of the central nervous system (CNS). Methods: We provide clinical, histologic, immunophenotypic and molecular details of a case of fulminant EBV+ T cell PTLD with CNS involvement and compare our data to the clinical presentations, biology and outcomes of the other reported cases of pediatric T cell PTLD (these include 5 EBV+ CNS− cases, 3 EBV− CNS+ cases, and 4 EBV− CNS− cases with dissemination or marrow involvement). Results: A 4.5 year old male developed EBV+ T cell PTLD with CNS involvement 3 years following a cadaveric renal transplantation. His fulminant presentation included fever, hypotension, splenomegaly, pancytopenia, coagulopathy, and bilateral pleural effusions. He had lymphocytosis in his CSF and his MRI showed brain white matter changes consistent with leukoencephalopathy. T lineage was confirmed by the presence of T cell markers CD3, 5, 7, 45 and TCRγ. The presence of EBV was demonstrated by in situ hybridization for EBER. His treatment followed the Children’s Oncology Group protocol A5971 for disseminated lymphoblastic lymphoma that employs a standard NHL/BFM-95 regimen with cyclophosphamide and anthracycline intensification during the induction and delayed intensification phases with a treatment duration of 2 years. He has received no irradiation. After 16 months, he has no measurable disease. Conclusions: EBV+ T cell PTLD is extremely rare in pediatrics and has resulted in mortality in 12 of 17 reported cases. This is the first report of EBV+ T cell PTLD with CNS involvement in a pediatric patient. Although no standardized treatment exists, the fulminant presentation, T lineage disease, and CNS involvement warranted aggressive systemic and intrathecal chemotherapy. No significant financial relationships to disclose.

Treatment of High Risk T-Cell Acute Lymphoblastic Leukemia (T-ALL): Comparison of Recent Experience of the Children's Cancer Group (CCG) and Pediatric Oncology Group (POG).

Recent CCG and POG treatment stategies for patients with T-ALL are significantly different. POG treats T-ALL patients on a separate protocol from that used for B precursor ALL (B-ALL) while CCG treats T-ALL patients on the same protocols utilized for B-ALL patients with protocol assignment determined by the NCI risk classification. We recently reviewed the outcome of patients with T-ALL and high-risk features (age ≥ 10 years and/or initial WBC > 50,000/ul) treated on either the CCG-1961 or POG-9404 clinical trials. POG utilized an intensive anthracycline based multidrug regimen based on the DFCI treatment program and randomized patients at registration to receive or not receive additional high dose methotrexate(HDMTX) with leucovorin rescue. All patients received cranial irradiation (CRT). CCG therapy for high risk T-ALL was based on CCG modified BFM(S-BFM) and Augmented BFM(A-BFM). Patients with <25% blasts on day 7 bone marrow(RER) who achieved remission were randomized in a 2X2 design to standard or augmented intensity and standard duration(1 interim maintenance(IM) and 1 delayed intensification(DI) phase or prolonged duration (2 IM and DI phases). Only RER patients with CNS-3 status received CRT. Patients with a slow response(SER) to induction therapy received A-BFM therapy +/− idarubicin/cyclophosphamide courses during DI phases. All SER patients received CRT. In the POG trial, HDMTX produced a significant improvement in event free survival (EFS). In the CCG trial, for RER patients, augmented intensity regimens produced a better EFS than standard intensity regimens. There was no difference in outcome for patients receiving standard or prolonged duration therapy. Thus we compared the high dose MTX arm from POG 9404 to a composite EFS result for CCG l961 based on induction failure/toxic death rate, augmented intensity therapy(1 or 2 DI phases) for RER patients and A-BFM therapy for SER patients. POG 9404, (opened 6/1996; closed 9/2001) and enrolled 363 T-ALL patients, with 77% having high risk features of which 155 were randomized to HDMTX arms. 5 yr EFS for patients on these arms was 75% and overall survival (S) of 84%. CCG 1961(opened 11/1996;closed 5/2002) entered 2077 patients of which 410 had T-cell disease with 263 RERs. The projected composite 5 year EFS and S estimated for high risk T-ALL patients treated on CCG l961 was 76.9% and 82.5% respectively. Isolated CNS relapse accounted for approximately 2/3 of the relapses in RER patients patients.CNS 3 patients treated on 9404 demonstrated 75% 5 yr EFS as compared to 82% for patients on 1961. Outcome for higher risk T-ALL patients treated by POG and CCG were quite similar. However, the BFM based strategy utilizes significantly less anthracycline and appears to produce a lower rate of bone marrow relapse. We postulate that incorporating low dose cranial RT(1200 cGy) will significantly reduce the incidence of CNS relapse and improve the overall EFS rate. Therefore, COG will utilize an augmented intensity BFM backbone for the first T-ALL protocol.

Outcome for Adolescent and Young Adults 16–21 years of age (AYA) with Acute Lymphoblastic Leukemia (ALL) Treated on the Children' s Cancer Group (CCG) 1961 Study.

AYA Patients 16–21 years of age with ALL are treated on both pediatric and adult ALL protocols. Recent publications have suggested that AYA patients treated on pediatric protocols have a significantly better outcome than those treated on adult protocols. From November 1996 to May 2002, 262 AYA ALL patients were entered on the CCG 1961 protocol. Treatment was based on the following observations from the previous CCG 1882 Protocol (1989–1995). 1) For patients with rapid early response (< = 25% blasts in a day seven bone marrow aspirate-RER), in the context of CCG modified BFM therapy (S-BFM), pre-symptomatic central nervous system therapy with intensive intrathecal (IT) methotrexate (MTX) alone provided equivalent results to standard IT MTX and cranial radiation (CRT). 2) For patients with slow early response (> than 25 blasts on day 7-SER), the augmented BFM (A-BFM) regimen produced a significant improvement in outcome compared to S-BFM. A-BFM featured a significant increase in dose intensity for vincristine (VCR), L-asparaginase (L-ASP), and steroid, the use of intravenous MTX without rescue in conjunction with VCR and L-ASP in interim maintenance (IM), and a second IM and delayed intensification (DI) phase. RER patients on 1961 were randomized to one of four arms; S-BFM, S-BFM with a second standard IM and DI phase, A-BFM with only 1 IM/DI phase, and full A-BFM. SER patients were randomized to A-BFM or A-BFM with Idarubicin/Cytoxan pulses added to the 2 DI phases. One hundred ninety patients had < 50K WBC (73.4%) and 21% had T cell immunophenotype. Seven patients had a t (9/22) and three patients had a t (4/11). Five year EFS for AYA patients treated on CCG 1961 was 68% ± 3.7% and the five-year survival was 77% ± 3.2%. The majority of events were isolated bone marrow relapses. For RER AYA patients, five year EFS for patients treated on the augmented intensity arms (N=87) was 83.2% compared to 60.8% for patients treated on the standard intensity arms (N=76) (P = .10). Within the augmented intensity arms, there was no difference in EFS for patients randomized to one or two DI phases. There was no difference in EFS for the 2 SER treatment arms. 5 year EFS was 78% for the Idarubicin/Cytoxan arm and 74% for the ABFM arm. Five year EFS for AYA patients with < 50K WBC was 73.2% (N=190) versus 54% for AYA patients with > 50K WBC. Unlike younger patients, there was no difference in outcome for males and females. Conclusions: 1) AYA patients with ALL have a 68% 5 year EFS when treated with BFM based chemotherapy. 2) WBC < 50K predicts for a favorable outcome. 3) Early augmented intensity therapy appears to improve outcome for AYA ALL patients showing a rapid response to induction therapy.

Intensification of Therapy for Children With Lower-Risk Acute Lymphoblastic Leukemia: Long-Term Follow-Up of Patients Treated on Children’s Cancer Group Trial 1881

From December 1988 through December 1992, the Children's Cancer Group (CCG) conducted a randomized trial (CCG-1881) designed to evaluate the impact of adding a single delayed intensification phase of therapy to standard therapy for patients with newly diagnosed low-risk acute lymphoblastic leukemia (ALL). Patients (n = 778) with newly diagnosed ALL, 2 to 9 years of age at diagnosis with an initial WBC count less than 10,000/microL, were eligible for this protocol. All patients received induction, consolidation, and interim maintenance phases of therapy over the first 16 weeks. At week 16, patients remaining in remission were randomly assigned to receive or not receive a single 7-week delayed intensification (DI) phase of therapy. Maintenance therapy was given in lieu of or after DI, with total duration of therapy approximately 3 years for boys and 2 years for girls. Patients randomized to receive DI experienced fewer relapse events in all categories. Kaplan-Meier life-table estimates for continuous complete remission (CCR) at 7 years for the randomized regimens were 77% (SE, 2.4%) for the standard regimen and 83% (SE, 2.7%) for the DI regimen (P =.072). The only prognostic factor of significance post-randomization in this selected low-risk population was the day 14 marrow response (P =.0001). The addition of a single DI phase of therapy was well tolerated and augmented 7-year CCR by 6% (SE of the difference, 3.3%), resulting in 26% fewer adverse events. Overall survival for eligible patients at 7 years is 90% (SE, 1.2%).

A randomized comparison of nativeEscherichia coliasparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study

AbstractFor this study, 118 children with standard-risk acute lymphoblastic leukemia (ALL) were given randomized assignments to receive native or pegylated Escherichia coli asparaginase as part of induction and 2 delayed intensification phases. Patients treated with pegaspargase had more rapid clearance of lymphoblasts from day 7 and day 14 bone marrow aspirates and more prolonged asparaginase activity than those treated with native asparaginase. In the first delayed intensification phase, 26% of native asparaginase patients had high-titer antibodies, whereas 2% of pegaspargase patients had those levels. High-titer antibodies were associated with low asparaginase activity in the native arm, but not in the pegaspargase arm. Adverse events, infections, and hospitalization were similar between arms. Event-free survival at 3 years was 82%. A population pharmacodynamic model using the nonlinear mixed effects model (NONMEM) program was developed that closely fit the measured enzyme activity and asparagine concentrations. Half-lives of asparaginase were 5.5 days and 26 hours for pegaspargase and native asparaginase, respectively. There was correlation between asparaginase enzymatic activity and depletion of asparagine or glutamine in serum. In cerebrospinal fluid asparagine, depletion was similar with both enzyme preparations. Intensive pegaspargase for newly diagnosed ALL should be tested further in a larger population.

Double-delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group

AbstractAddition of a delayed-intensification (DI) phase after standard induction/consolidation therapy was previously shown to improve outcome for patients younger than 10 years of age with intermediate-risk acute lymphoblastic leukemia (ALL). The current trial randomized 1204 patients to regimens containing a single DI phase (405 patients), 2 DI phases (DDI) (402 patients), or a single DI phase in conjunction with increased vincristine and prednisone pulses during maintenance (DIVPI) (397 patients). Estimates of event-free survival (EFS) and survival at 6 years are 79% ± 1% and 89% ± 1%, respectively. EFS was improved on DDI compared with either DI (log-rankP = .04; Kaplan-Meier [KM] P = .04; relative risk [RR] = 1.38) or DIVPI (log-rankP = .04; KM P = .01; RR = 1.39).There was no difference in EFS for the DI and DIVPI regimens (log-rankP = .96; KM P = .75). Survival estimates at 6 years were 87% (SD = 2%) for DI; 91% (SD = 2%) for DDI; and 90% (SD = 2%) for DIVPI (P = .17). Significant univariate risk factors for the overall cohort included poor day-7 marrow response, black race, and age of at least 5 years. These data demonstrate that DDI improves EFS of patients younger than 10 years of age with intermediate-risk ALL.

A Critical Risk-Benefit Assessment Argues Against the Use of Anthracyclines in Induction Regimens for Newly Diagnosed Childhood Acute Lymphoblastic Leukemia

Although anthracyclines are associated with significant cardiac toxicity and their benefit remains unclear, they are included in nearly all current protocols for the treatment of childhood acute lymphoblastic leukemia (ALL). Currently open trials from most major groups use anthracyclines in the induction phase for all high-risk patients and in the delayed intensification phase for all patients regardless of risk classification. Our review of published randomized studies reveals no benefit for the addition of anthracyclines to induction phase of childhood ALL regimens consisting of vincristine, prednisone, and L-asparaginase (WL), with or without a delayed intensification phase. No randomized studies have evaluated the use of anthracyclines in the delayed intensification phase of therapy. Furthemore, studies of relapsed patients indicated no benefit for the addition anthracyclines to maintenance regimens. Recent evidence from preclinical studies suggests that a combination of VPL with an anti-CD 19 immunotoxin is more effective than VPL plus anthracyclines combination. Accumulated evidence exists that anthracyclines are associated with late-onset cardiac morbidity in about 25% of childhood ALL and other cancer survivors, and about 5% develop overt heart failure, with some requiring cardiac transplantation. Anthracycline-induced cardiotoxicity in children has no safe dose threshold and all doses are likely to cause significant myocardial damage. New data suggests that a unique cardiac mitochondrial exogenous NADH dehydro-genase is responsible for the anthracycline-induced oxygen radicals damage to the heart, and that chelators currently evaluated may not prevent late-onset cardiotoxicity in children. In view of these findings we urge extreme caution in using anthracyclines as part of multimoda-lity ALL treatment programs, and strongly recommend reevaluation of what should be considered the best induction regimen for high-risk childhood ALL.

Osteonecrosis during the treatment of childhood acute lymphoblastic leukemia: a prospective MRI study.

Since the survival rates of childhood leukemia have improved, attention is increasingly focused on the long-term effects of the treatment. Osteonecrosis may complicate the treatment of acute lymphoblastic leukemia (ALL). To have more information about the natural history and clinical course of the development of osteonecrosis, a prospective MRI study was designed. The development of osteonecrosis was studied prospectively in 24 consecutive children with ALL who underwent T1-weighted magnetic resonance imaging (MRI) scanning of the lower extremities at the beginning of, during, and at the cessation of the chemotherapy. The general bone marrow signal intensity was assessed together with focal lesions. Circumscribed lesions with a rim of low signal intensity were considered typical of osteonecrosis. Nine of the 24 patients (rate 38%) developed osteonecrosis during the treatment. Six of them were asymptomatic. MRI lesions regressed in size in six patients, and in three patients the MRI finding returned to normal. No operative treatment was needed. The osteonecroses appeared immediately or within a few months after the delayed intensification phase with intensive dexamethasone medication. Corticosteroids have been considered to be the main pathogenetic factor in the development of osteonecrosis in children with malignancies, which was also suggested by our findings. However, there is a lack of systematic prospective studies concerning the natural history and long-term follow-up observations of the prognosis of osteonecrosis, especially in pediatric patients. Based on our results, the lesions are often asymptomatic and cause no disability, and spontaneous improvement or even resolution may occur.

Osteonecrosis in children treated for acute lymphoblastic leukemia: a magnetic resonance imaging study after treatment.

The purpose of the study was to find out the prevalence of osteonecrosis in children with acute lymphoblastic leukemia (ALL) in complete bone marrow remission at the end of the treatment. Twenty-eight children with ALL underwent MRI of the upper and/or lower extremities. Bone marrow signal intensity was analyzed on T1-weighted images, where circumscribed lesions with a rim of low signal intensity were considered typical of osteonecrosis. Osteonecrosis was found in 9 of the 28 children (32%, 95% CI 16% to 52%). Five of them were asymptomatic. They had been treated with high risk and intermediate risk protocols, both of which include a delayed intensification phase with dexamethasone. None of the patients with standard risk ALL were found to have developed osteonecrosis. Osteonecroses occurred unexpectedly in symptomless patients and in patients with mild transient symptoms treated with high risk and intermediate risk protocols. Our study suggests that the intensification phase of the treatment protocols with intensive dexamethasone medication might be responsible for the development of osteonecrosis.