Mite allergy, clinical atopy, and restriction by HLA class II immune response genes

From a community-based study cohort of 1812 elementary schoolchildren we selected 129 unrelated participants to investigate the relevance of HLA-class II molecules (DPB, DQB, and DRB) to the regulation of immune response to the mite allergen Der p 1 and to clinical atopic disorders. On the basis of skin prick test results validated by measurement of specific IgE, individuals were selected and divided into three groups: group I (n = 20), controls without detectable specific IgE to common inhalant allergens; group II (n = 22), children sensitized only to non-mite allergens; group III (n = 85), children sensitized to Der p 1. Clinical history of asthma, eczema, and hay fever was ascertained using standardized questionnaires. In total, 43 different HLA class II alleles (DPB, n = 19; DQB, n = 14; and DRB, n = 10) were determined by sequence-specific oligonucleotide typing with PCR-amplified DNA. We were not able to demonstrate significant differences in gene frequencies of any HLA class II allele between the group of mite-sensitized children and one of the other two groups. However, the presence of certain DRB- and DPB-haplotypes (DRB *0100/*0300/*1100 and DPB *0201/*0401) was significantly associated (p < 0.01) with a history of asthma, hay fever, and atopy (defined as a history of asthma and/or hay fever and/or eczema). Other haplotypes, including DQB *0303/*0503, DRB *0200/*0700, and DPB 0402 were negatively associated with a history of eczema, hay fever, and atopy (p < 0.01). Thus, our findings do not suggest a relevance of HLA-class II molecules to mite allergy; however, some HLA class n haplotypes appear to be predictive of the incidence of atopic disorders.     

HLA-class II and class I genotypes among Japanese children with Type 1A diabetes and their families

Sugihara S, Ogata T, Kawamura T, Urakami T, Takemoto K, Kikuchi N, Takubo N, Tsubouchi K, Horikawa R, Kobayashi K, Kasahara Y, Kikuchi T, Koike A, Mochizuki T, Minamitani K, Takaya R, Mochizuki H, Nishii A, Yokota I, Kizaki Z, Mori T, Shimura N, Mukai T, Matsuura N, Fujisawa T, Ihara K, Kosaka K, Kizu R, Takahashi T, Matsuo S, Hanaki K, Igarashi Y, Sasaki G, Soneda S, Teno S, Kanzaki S, Saji H, Tokunaga K, Amemiya S, and The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT). HLA‐class II and class I genotypes among Japanese children with Type 1A diabetes and their families. Objective: To determine the HLA‐DRB1, DQB1, DPB1, A, C, and B genotypes among Japanese children with autoimmune type 1 diabetes. Methods: Four hundred and thirty patients who were GADAb and/or IA‐2Ab‐positive (Type 1A) were recruited from 37 medical centers as part of a nationwide multicenter collaborative study. DNA samples from 83 siblings of the children with Type 1A diabetes and 149 parent–child trios were also analyzed. A case‐control study and a transmission disequilibrium test (TDT) were then performed. Results: The susceptible and protective DRB1 and DQB1 alleles and haplotypes were confirmed. DPB1 alleles unique to the Japanese population and those common to multiple ethnic groups were also present. A linkage disequilibrium (LD) analysis showed both susceptible and protective haplotypes. The TDT did not reveal any alleles that were transmitted preferentially from the mother or father to children with Type 1A. Homozygosity for DRB1?09:01‐DQB1?03:03 and heterozygosity for DRB1?04:05‐DQB1?04:01 and DRB1?08:02‐DQB1?03:02 were associated with an extremely high risk of Type 1A. A comparison of children with Type 1A and their parents and siblings suggested a dose effect of susceptible DRB1‐DQB1 haplotypes and an effect of protective alleles on immunological pathogenesis. DRB1?09:01 appeared to be strongly associated with an early onset in preschool children with Type 1A diabetes. Conclusions: This study demonstrated the characteristic association of HLA‐class II and class I genes with Type 1A diabetes among Japanese children. A TDT did not reveal the genomic imprinting of HLA‐class II and class I genes in Type 1A diabetes.     

HLA class II genetic association of type 1 diabetes mellitus in Czech children

Abstract:  To examine human leukocyte antigen (HLA) class II association of type 1 diabetes mellitus (DM) in Czech children, we performed a case–control study of 261 patients diagnosed before the age of 15 and 289 non-diabetic control children. Complete HLA-DQA1, DQB1 genotyping and DRB1*04 subtyping were carried out by polymerase chain reactions with sequence-specific primers. The effect of the DRB1*04 subtypes was studied in DRB1*04 alleles carried on DQB1*0302-DQA1*03 haplotypes. The risk was statistically evaluated by testing 2 × 2 tables, considering corrected p-values < 0.05 significant. The DQB1*0302 (odds ratio, OR = 9.0), DQB1*0201 (OR = 3.4) and DQA1*03 (OR = 7.5) alleles were significantly associated with diabetes risk, while the DQB1*0602 (OR = 0.02), DQB1*0301 (OR = 0.08), DQB1*0503 (OR = 0.13), DQB1*0603 (OR = 0.20), DQA1*01 (OR = 0.28) and DQA1*02 (OR = 0.26) alleles were significantly protective. Of the DQA1-DQB1 genotypes, we point out the extremely high risk of OR = 116 conferred by HLA-DQA1*05-DQB1*0201/DQA1*03-DQB1*0302. Among DRB1*04 subtypes, DRB1*0403 was significantly protective (OR = 0.05, CI 95% 0.01–0.45). Since none of the remaining DRB1*04 subtypes was associated with type 1 DM, our study may present another piece of evidence that the DRB1*0401 and DRB1*0404 alleles do not modify type 1 diabetes risk generally in European populations.     

Successful hematopoietic stem cell transplantation from an HLA‐mismatched parent for engraftment failure after unrelated cord blood transplantation in patients with juvenile myelomonocytic leukemia: Report of two cases

JMML is an aggressive hematopoietic malignancy of early childhood, and allogeneic HSCT is the only curative treatment for this disease. Umbilical cord blood is one of donor sources for HSCT in JMML patients who do not have an HLA‐compatible relative, but engraftment failure remains a major problem. Here, we report two cases of JMML who were successfully rescued by HSCT from an HLA‐mismatched parent after development of primary engraftment failure following unrelated CBT. Both patients had severe splenomegaly and underwent unrelated CBT from an HLA‐mismatched donor. Immediately after diagnosis of engraftment failure, both patients underwent HSCT from their parent. For the second HSCT, we used RIC regimens consisting of FLU, CY, and a low dose of rabbit ATG with or without TBI and additionally administered ETP considering their persistent severe splenomegaly. Both patients achieved engraftment without severe treatment‐related adverse effects. After engraftment of second HSCT, their splenomegaly was rapidly regressed, and both patients showed no sign of relapse for over 4 years. These observations demonstrate that HSCT from an HLA‐mismatched parent could be a feasible salvage treatment for primary engraftment failure in JMML patients.     

HLA‐DRB, ‐DQA,and DQB alleles and haplotypes in Iranian patients with diabetes mellitus type I

Specific alleles at the HLA‐DRB1, ‐DQA1, and ‐DQB1 loci seem to be associated with variable risks of developing type 1 diabetes (T1D). This study assessed the distribution of HLA‐DR and ‐DQ alleles among Iranian T1D patients and healthy controls. In this study, HLA‐DRB1, ‐DQA1, and ‐DQB1 alleles were determined in 100 children with T1D and 100 unrelated healthy controls. The following alleles were found to have a strong positive association with T1D: DRB1*0301, DRB1*0401, DRB1*0402, DQA1*0301, DQA1*0501, DQB1*0201, and DQB1*0302. Meanwhile, protective associations were found for DRB1*1001, DRB1*1101, DRB1*15, DRB1*16, DQA1*0102, DQA1*0103, DQB1*0301, DQB1*0501, and DQB1*0602 alleles. The haplotypes found most frequently among patients with T1D were DRB1*0301‐DQA1*0501‐DQB1*0201, DRB1*0401‐DQA1*0301‐ DQB1*0302, and DRB1*0402‐DQA1*0301‐DQB1*0302, whereas DRB1*1101‐DQA1*0501‐DQB1*0301 and DRB1*16‐DQA1*0102‐ DQB1*0501 haplotypes were negatively associated with the disease. These results confirm the previously reported association of specific HLA‐DR and HLA‐DQ alleles and haplotypes with T1D in Iranian population. The notable difference was the identification of DRB1*16‐DQA1*0102‐DQB1*0501 as a protective haplotype and the absence of a negative association of DRB1*1301‐DQA1*0103‐DRB1*0603 with T1D.     

Association of maternal histocompatibility at class II HLA loci with maternal microchimerism in the fetus

For investigating the possible influence of maternal-fetal HLA compatibility on maternal microchimerism, DNA samples from blood of 120 maternal-fetal pairs were genotyped at two polymorphic loci: glutathione-S-transferase M1 (GSTM1) and angiotensin-converting enzyme (ACE). Informative pairs (mother heterozygous/fetus homozygous at one of the two loci) were then tested by quantitative real-time PCR for the noninherited maternal allele(s) and genotyped at the HLA-A, B, and C class I loci and/or at the DRB1 and/or DQB1 class II loci. Small numbers of maternal cells were detected in the circulation of 16 of the 30 informative second- and third-trimester fetuses. Comparison with HLA data suggested an association between microchimerism and maternal compatibility at the class II DRB1 and/or DQB1 HLA loci and with the maternal HLA-DQB1*0301 allele. There was no relationship between maternal microchimerism and maternal-fetal HLA compatibility at other HLA loci or with gestational age, fetal anomalies, or red cell or platelet isoimmunity.     

T‐cell‐rich HLA‐haploidentical hematopoietic stem cell transplantation for relapsed/refractory pediatric Philadelphia chromosome‐positive acute lymphoblastic leukemia without posttransplant tyrosine kinase inhibitor therapy

Intensive chemotherapy with tyrosine kinase inhibitor (TKI) improves the prognosis of patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph‐ALL). However, the prognosis of cases of relapsed or refractory Ph‐ALL remains poor. Here, we aimed to assess the efficacy of T‐cell‐rich HLA‐haploidentical hematopoietic stem cell transplantation (TCR‐haplo‐HSCT) in eight patients with relapsed or refractory pediatric Ph‐ALL. Transplant‐related mortality was observed in two patients. All patients discontinued TKI after receiving TCR‐haplo‐HSCT. The 3‐year probability of overall survival and event‐free survival was 75.0 and 62.5%, respectively. These results indicate the efficacy of TCR‐haplo‐HSCT for relapsed/refractory pediatric Ph‐ALL.     

HLA DP antigens and post-streptococcal acute glomerulonephrius

We have typed 58 Japanese patients with post-streptococcal acute glomerulonephritis (PSAGN) for HLA DRB1, DQA1, DQB1, DPA1 and DPB1 genes by the HLA-DNA typing method using a polymerase chain reaction (PCR)-sequence specific oligonucleotide probe (SSOP) technique. The control subjects were 317 healthy unrelated individuals. Frequencies of HLA DPA 1*02022 and DPB 1*0501, which are in linkage disequilibrium and encode HLA-DP5 antigen, were significantly increased in patients with PSAGN than those in control (p_c < 0.0005 and p_c < 0.005, respectively). Frequencies of HLA DPA1*01 and DPA1*0201 were significantly decreased in patients when compared with controls (p_C < 0.05, for both). No significant difference in allele frequencies between the two groups was observed in the DRB1, DQA1 and DQB1 genes. This is the first report documenting the association of HLA-DP alleles with PSAGN. We speculate that H LA- DP5 antigens may be involved in the development of PSAGN.     

HLA,GVHD, and parenteral nutrition are risk factors for hepatic complications in pediatric HSCT

Hepatic dysfunction is common after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this retrospective study was to determine the risk factors, frequency, and outcome of hepatic complications post‐HSCT in children. Two hundred and thirty‐seven cases of allogeneic HSCT in children were included. Data on biochemical liver function at start of HSCT, at +1, +3, +6, and +9 months, and at each subsequent yearly follow‐up were extracted. Patients were stratified into groups with hepatocellular (none and mild, and moderate to severe) and hepatobiliary (none and present) dysfunction. Statistical analysis included variables such as diagnosis, age, conditioning regimen, and HLA type. Results: One hundred and fifty‐six (66%) patients displayed hepatocellular dysfunction post‐HSCT. In most cases transient, but 32% had a persistent abnormality three yr post‐HSCT. Risk factors were chronic GVHD (OR 4.20, p = 0.003) and donor HLA‐A*01 (OR 2.97, p = 0.02). HLA‐DQB1*03 decreased the risk (OR 0.35, p = 0.02). Hepatobiliary dysfunction was less frequent (12%) but carried a poor prognosis. aGVHD grade II–IV (OR 2.7, p = 0.02) and long‐term TPN (OR 3.25, p = 0.01) increased the risk. Conclusion: GVHD is an important risk factor for liver dysfunction post‐HSCT. Specific HLA types may also contribute as a risk factor, while others seem to have a protective effect.     

Haploidentical stem cell transplantation as a salvage therapy for cord blood engraftment failure in a patient with Fanconi anemia

A 7‐year‐old male with Fanconi Anemia who developed primary graft failure following one antigen‐mismatched unrelated cord blood transplantation and a nonradiation‐based conditioning, underwent a second hematopoietic stem cell transplantation (HSCT) from his 2‐loci mismatched haploidentical father, using a nonradiation‐based regimen, 79 days after the first HSCT. A sustained hematological engraftment was achieved at 9 days post‐second HSCT. At 15 months post‐second HSCT; the patient demonstrated normal blood counts, sustained donor chimerism, and no evidence of GVHD. Haploidentical HSCTs as primary or secondary sources of stem cells, with appropriate T‐cell depletion, may be a readily available option in the absence of HLA‐matched related or unrelated donors. Pediatr Blood Cancer. 2010;55:580–582. © 2010 Wiley‐Liss, Inc.     

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.     

Outcome of hematopoietic stem cell transplantation of children with very high risk acute lymphoblastic leukemia in first complete remission

Schechter T, Ishaqi KM, Rojas M, Irina Z, Doyle JJ, Gassas A. Outcome of hematopoietic stem cell transplantation of children with very high risk acute lymphoblastic leukemia in first complete remission.
Pediatr Transplantation 2010:14: 377–382. © 2009 John Wiley & Sons A/S. Abstract: Approximately 10% of children with ALL present at diagnosis with VHR for relapse if treated with chemotherapy alone. They may benefit from allogeneic HSCT in CR1. We have reviewed the outcome of this population in our institution. Forty‐three patients (median age: 8.9 yr) with VHR ALL in CR1 underwent HSCT from October 1994 to April 2006. VHR features included Philadelphia chromosome (n = 17), induction failure (n = 9), hypodiploidy (n = 6), MLL gene rearrangement (n = 5), and others (n = 6). All patients received TBI (1200 cGy) with either CY and/or etoposide. Stem cell source was unrelated (n = 24) and related (n = 19). Incidence of grade III‐IV acute GVHD and chronic extensive GVHD were 25% and 16%, respectively. Twelve patients relapsed (eight received related HSCT). Eleven patients died due to transplant‐related mortality (eight received unrelated HSCT). For a median follow up of 39 months (range 11–110), the event free survival and OS were 0.49 (95% CI: 0.31–0.67) and 0.53 (CI: 0.44–0.71), respectively. Outcomes of children with VHR ALL receiving HSCT in CR1 remain unsatisfactory. Relapse, mainly after related HSCT, and TRM, mainly after unrelated HSCT, continue to be major problems.     

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.     

Autologous transplantation of CD133 selected hematopoietic progenitor cells for treatment of relapsed acute lymphoblastic leukemia

A 21-year-old white male with relapsed acute lymphoblastic leukemia (ALL) developed an invasive Zygomycosis infection 3 weeks after beginning re-induction chemotherapy. Because of the high risk of fatal recurrence of the fungal infection, neither long-term maintenance chemotherapy nor allogeneic hematopoietic stem cell transplant (HSCT) was considered appropriate. Because his ALL blasts expressed CD34 but lacked CD133, he received a CD133 selected autologous graft following high-dose consolidation chemotherapy. The patient survives in remission 19 months after HSCT.     

Intracellular ribonucleotide pools of lymphoblastic leukemic cells in untreated and relapsed ALL children

Intracellular ribonucleotide pools were analyzed by HPLC with leukemic blasts obtained from 20 children, including 13 untreated ALL, 5 relapsed ALL, and 2 lymphomas with hematological relapse. Nucleotide pools were, in general, found more expanded among relapsed cases. Also, the larger mono and diphosphate ribonucleotide levels found in relapsed cells, for instance adenine nucleotide pools, were significantly larger among the relapsed patients, as measured 216.97 +/- 53.30 nmol/10(8) cells, in contrast to 109.70 +/- 39.54 nmol/10(8) cells with untreated children (p less than 0.005). Furthermore, AMP and ADP occupied only 18% of the total adenine pool in untreated children, but 34% in relapsed children. The similar pattern of nucleotide pools was observed in guanine, cytidine, and uridine nucleotide pools. Inosine mono phosphates were measured 5.07 +/- 6.02 nmol/10(8) cells with untreated ALL, and 3.55 +/- 1.44 nmol/10(8) cells with relapsed ALL, but thymidine mono phosphates, as a key pyrimidine nucleotide of salvage pathway, were larger (p less than 0.01) among with relapsed patients measuring 31.47 +/- 8.11 nmol/10(8) cells as compared with that of untreated ALL, 11.19 +/- 12.84 nmol/10(8) cells. The present results may suggest that there is a difference in nucleotide metabolism between untreated and relapsed leukemic cells, and nucleotide profiles provide more accurate information of leukemia chemotherapy.     

Hematopoietic stem cell transplantation after first marrow relapse of non-T, non-B acute lymphoblastic leukemia: a pediatric oncology group pilot feasibility study

BACKGROUND: Relapsed acute lymphoblastic leukemia (ALL) in children is associated with a poor outcome, especially for those patients whose relapse occurs during the first 36 months after diagnosis. The best therapy for these patients is not known. This study was designed to evaluate the feasibility of enrolling children with recurrent ALL in a standardized treatment protocol that included receipt of a hematopoietic stem cell transplant (HSCT). PROCEDURE: Eligible patients with a bone marrow relapse of non-T, non-B ALL underwent a common induction and consolidation followed by receipt of either an allogeneic HSCT from a human leukocyte antigen (HLA)-identical sibling or an autologous HSCT purged with B-4 blocked ricin. A common conditioning regimen was used for all patients. RESULTS: Twenty-eight patients from eight institutions were enrolled. Fourteen patients did not receive a transplant during the study, because of toxicity (4), relapse (1), inadequate purging (1), and parental or physician preference for an alternative donor transplant (8). Six patients received allogeneic HSCTs. Five of them have remained in remission for a median of 78 months. Eight patients received autologous HSCTs purged with B4-blocked ricin. Four have remained in remission for a median of 94 months. Of the nine patients who received alternative donor transplants, only two remain in remission. CONCLUSION: We conclude that well designed and controlled prospective studies are necessary to define the role of HSCTs in children with recurrent ALL. In order to be successful, such studies must have the full support of participating centers. Autologous HSC transplantation may have a role in the treatment of relapsed ALL, but further studies are needed.     

Successful treatment of relapsed anaplastic large cell lymphoma with vinblastine monotherapy and allo‐HSCT with reduced intensity conditioning regimen

Relapsed anaplastic large cell lymphoma (ALCL) is chemosensitive, but recurrence is common. Although vinblastine (VLB) monotherapy is an effective treatment for relapsed ALCL, the optimal treatment duration is unknown, and some patients experience further relapse after completing the treatment. Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is also an effective treatment for relapsed ALCL, although transplant‐related toxicity is a problem. Here, we report an 11‐year‐old patient with relapsed ALCL who underwent induction therapy with VLB monotherapy and achieved complete remission (CR) after 12 courses. CR was confirmed on positron emission tomography–computed tomography. The patient then underwent allo‐HSCT with reduced intensity conditioning (fludarabine, melphalan, and low‐dose total body irradiation). He developed grade II acute graft‐versus‐host disease (GVHD), which was successfully treated with methylprednisolone. There was no evidence of chronic GVHD. He has remained in CR without any complications for 19 months after allo‐HSCT.     

Control of graft‐versus‐host disease with rabbit anti‐thymocyte globulin,rituximab, and bortezomib in TCRαβ/CD19‐depleted graft transplantation for leukemia in children: a single‐center retrospective analysis of two GVHD‐prophylaxis regimens

Both acute GVHD and chronic GVHD remain the leading cause of morbidity and death after allogeneic HSCT. We conducted a retrospective analysis comparing two GVHD‐prophylaxis regimens: 35 patients received “Regimen 1” (horse ATG, tacrolimus, and methotrexate) and 46 “Regimen 2” (rabbit ATG, rituximab, and peritransplant bortezomib). All 81 patients with a median age of 9 (0.6‐23) years with ALL (n = 31) or AML (n = 50) in complete remission received TCRαβ/CD19‐depleted transplants between May 2012 and October 2016, from 40 HLA‐matched unrelated and 41 haploidentical donors. After a median follow‐up of 3.9 years, the CI of acute GVHD II‐IV was 15% (95% CI: 7‐30) in the “Regimen 2” group and 34% (95% CI: ?54) in the “Regimen 1” group, P = .05. “Regimen 2” was also more effective in the prevention of chronic GVHD; the CI at 1 year after HSCT was 7% (95% CI: 2‐19) vs 31% (95% CI: 19‐51), P = .005. The CI of relapse at 3 years adjusted for the GVHD‐prophylaxis regimen groups 31% (95% CI: 19‐51) for the “Regimen 1” vs 21% (95% CI: 11‐37) for the “Regimen 2”, P = .3. The retrospective observation suggests that the use of the rATG, rituximab, and bortezomib was associated with significantly lower rate of GVHD without the loss of anti‐leukemic activity.     

The utility of performing the initial lumbar puncture on day 8 in remission induction therapy for childhood acute lymphoblastic leukemia: TCCSG L99-15 study

Background

Traumatic lumbar puncture with leukemic blasts (TLP+), which has been reported to occur 5–10%, in the previous studies, adversely affects the outcome of children with acute lymphoblastic leukemia (ALL). Based on the results from our previous study, we deferred the initial lumbar puncture until day 8 in remission induction therapy in order to reduce the frequency of cases with TLP+.

Procedure

The study was conducted as a prospective cohort study within the Tokyo Children's Cancer Study Group (TCCSG) L99‐15 study. Between April 1999 and June 2003, 754 children with newly diagnosed ALL enrolled. The patients received the initial intrathecal chemotherapy after 7 days of prednisolone treatment. The incidence of central nervous system (CNS)‐positive (the presence of leukemic blasts in cerebrospinal fluid or cranial nerve palsy) including TLP+ cases and cumulative incidence of CNS relapse were examined.

Results

The incidence of CNS‐positive and TLP+ was 2.9% (n = 22) and 0.8% (n = 6), respectively. These incidences were much lower than those in the representative study groups employing the initial IT on day 1. Of 22 patients with CNS‐positive, only one patient relapsed in CNS, whereas 22 of the remaining CNS‐negative 723 patients suffered from CNS relapse. Overall, event‐free survival at 4 year was 78.2 ± 1.6%. Four‐year cumulative incidence of any CNS relapse was 3.3 ± 0.7%, which improved from our previous study in spite of limiting the use of cranial irradiation.

Conclusions

Our strategy reduced the frequency of CNS‐positive patients who required reinforcement of CNS‐directed therapy without compromising overall outcome. Pediatr Blood Cancer 2012; 58: 23–30. © 2011 Wiley Periodicals, Inc.