Effectiveness of Intrathecal Liposomal Cytarabine in Treatment of Childhood Hematopoietic Malignancies – Experience of Polish Pediatric Leukemia/Lymphoma Study Group

Abstract Abstract 4240 Introduction: Liposomal Cytarabine for intrathecal administration is characterized by prolonged activity and better penetration to central nervous system (CNS). This makes it promising medicine for treating children with hematopoietic malignancies relapsing in CNS or refractory CNS disease. The purpose of the Study: The study aimed at retrospective evaluation of the effectiveness of liposomal Cytarabine (Depocyte®) administrated intrathecally as a part of the treatment of hematopoietic malignancies in Polish children. Patients and methods: The study group consisted of 23 patients, 11 boys and 12 girls, treated in the centers of Polish Pediatric Leukemia/Lymphoma Study Group, including 18 patients with acute lymphoblastic leukemia (ALL), 3 patients with acute myeloid leukemia (AML) and two children with high grade Non-Hodgkin’s Lymphomas (NHL). The median age of the children was 10.8 years (range: 1.3 to 18 years). Liposomal cytarabine treatment was administered on compassionate basis to 20 children with relapsed acute leukemia / NHL, a single child with secondary leukemia, one patient with severe neurotoxicity after intrathecal Methotrexate during front-line treatment and in one child with large granulocytic sarcoma, penetrating into CNS. Thirteen patients received liposomal cytarabine dosage of 50 mg, while the remaining 10 children were exposed to the doses of 25–35 mg, all in association with prophylactic dexamethasone administration. The number of liposomal Cytarabine injections ranged from 1 to 11, mean 5 doses per patient. Results: The clearance of CNS disease was achieved in 15 of 23 patients (65%). Eight children were alive during the follow-up procedure, including 3 patients in complete remission after treatment completion. Grade IV neurotoxicity was observed in five children, which might be also partly related to CNS malignancy. Another side effects occurred in 4 patients, including headache, vertigo, paresthesias and seizures. Conclusion: Liposomal cytarabine administered intrathecally is effective treatment for CNS disease in children with relapsed acute leukemia/NHL with acceptable toxicity profile. Disclosures: No relevant conflicts of interest to declare.

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A Brief Use of Imatinib Immediately Before Hematopoietic Stem Cell Transplantation (HSCT) in Children with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL). Results of the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Study Ph+ALL04

Blood ◽

10.1182/blood.v118.21.2554.2554 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2554-2554

Author(s):

Atsushi Manabe ◽

Hirohide Kawasaki ◽

Motoaki Chin ◽

Atsushi Sato ◽

Kimikazu Matsumoto ◽

...

Keyword(s):

Survival Rate ◽

Medical Information ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Cord Blood Transplantation ◽

High Dose ◽

Induction Phase ◽

Study Group ◽

Pediatric Leukemia ◽

Hematopoietic Stem

Abstract Abstract 2554 Aims: Children with Ph+ALL generally have a poor prognosis when treated with chemotherapy alone. The timing and duration of the use of imatinib has not been determined. We investigated a role of imatinib immediately before HSCT. Methods: All the patients with ALL were screened for diagnosis of Ph+ALL using RT-PCR. Children with Ph+ALL were enrolled on JPLSG Ph+ALL04 Study within 1 week of initiation of treatment for ALL. Treatment regimen consisted of 5 therapeutic phases: Induction phase (5-drug induction), Intensification phase (high-dose cytarabine and BFM Ib), Re-induction phase (4-drug re-induction), 2 weeks of Imatinib monotherapy phase (23 weeks after diagnosis), and HSCT phase (Etoposide+CY+TBI conditioning). Before and after each phase, minimal residual disease (MRD), the amount of BCR-ABL transcripts, was measured with the real-time PCR method (cut-off 50 copies/microgram RNA). The study was registered in UMIN-CTR (Medical Information, University hospital Medical Information Network - Clinical Trials Registry): UMIN ID C000000290. Results: During the period 2004–08, 42 patients were registered in the Ph+ALL04 study. Out of 42 patients, 37 patients (88%) achieved CR and 7 of 37 patients also achieved MRD-negative after induction phase. There were 13 patients who had no MRD at the beginning of imatinib monotherapy phase, and 14 patients were MRD-negative after imatinib phase, consequently, 14 patients were MRD-negative at the time of HSCT. Six patients relapsed before HSCT. In total, 31 patients received HSCT in 1st CR. All the patients had engraftment and no patients died because of complications of HSCT. Five patients relapsed after HSCT and 4 of the 5 patients were MRD-negative before HSCT and the other patient had detectable MRD although it was less than 50 copies. Twenty-six patients continue to be in 1st CR and MRD-negative for median of 3 years after diagnosis. The 3-year event-free survival rate and over-all survival rate for all the patients was 57% and 80%, respectively (figure 1). Five patients did not achieve CR after induction phase and they were treated with imatinib-contained chemotherapy. Four of the 5 patients achieved CR. All of the 4 patients received cord blood transplantation and remains in continued CR. Interpretation: The chemotherapy we employed was based on the previous high-risk regimen of TCCSG (Tokyo Children's Cancer Study Group) L-99-15 Study. The chemotherapy was intensive enough to induce MRD-negative in 13 at the time of imatinib phase and 31 of 42 patients were in CR at the time of HSCT (around 25–28 weeks after diagnosis). We planned to assess the efficacy of imatinib immediately before HSCT but it was not possible because of the low amount of MRD in most patients at the beginning of imatinib phase. Conclusion: Although EFS and OS was excellent in this study, 88% of induction rate appeared unsatisfactory and relapse occurred before HSCT in 6 out of 37 patients who achieved CR after induction phase. Earlier and longer use of imatinib may improve EFS in children with Ph+ALL and HSCT may be omitted in a subset of patients who achieve an early and deep remission status. Disclosures: No relevant conflicts of interest to declare.

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Nation-Wide Survey of Relapsed Infantile Acute Lymphoblastic Leukemia In Japan: Treatment and Outcome From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) MLL03 Study.

Blood ◽

10.1182/blood.v116.21.1025.1025 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1025-1025

Author(s):

Takako Miyamura ◽

Katsuyoshi Koh ◽

Daisuke Tomizawa ◽

Takashi Sato ◽

Koji Kato ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Relapse Rate ◽

Treatment Strategy ◽

Poor Prognosis ◽

Lymphoblastic Leukemia ◽

Conditioning Regimen ◽

Study Group ◽

Pediatric Leukemia ◽

The Future ◽

Lymphoma Study Group

Abstract Abstract 1025 Introduction: Infantile acute lymphoblastic leukemia (ALL) is a rare leukemia subtype in infants with poor prognosis. Its outcome has gradually improved due to the development of treatment, including intensive chemotherapy or hematopoietic stem cell transplantation (SCT). However, prognosis of relapsed patients is extremely poor, which prompt us to establish the new treatment strategy for them. To establish the future treatment strategy for the relapsed cases, we here investigated the incidence of relapse, treatment, prognosis, and possible risk factors of relapsed cases with infantile ALL treated by the Japanese Pediatric Leukemia /Lymphoma Study Group (JPLSG) MLL03 study. Subjects: All relapsed cases with infantile ALL who underwent the MLL03 study between April 2004 and June 2009 were eligible for the study. The questionnaires were sent to all participants, asking the relapsed patients with infantile ALL by the MLL03 study. The questionnaires consisted of the time and site of relapse, treatment after relapse, presence or absence of remission prior to the second SCT, conditioning regimen for the second SCT, and age, white blood cell count, and presence or absence of central nervous system (CNS) infiltration at initial onset. Results: Total 63 patients were treated in this study period (mean follow-up, 31.8 months). Among them, 24 patients relapsed at any site after first complete remission (38%). These include 7 boys and 17 girls. Age at onset was less than 6 months in 19, and 6–12 months in 5. The overall survival (OS) rate of 24 patients was 60.2 ± 11.1% at 3 years; 44.6 ± 12.7% at 4 years, and 23.5 ± 13.4% at 5 years. Twenty-one of 24 patients (87.5%) relapsed after initial SCT; only three patients (12.5%) relapsed before SCT. Two patients relapsed early within 6 months after initial treatment terminally died. All four patients who relapsed at extramedullary site except CNS have survived, suggesting better prognosis. Patients diagnosed at age of less than 6 months also showed poor prognosis after relapse (5 year OS rate was 14.9 ± 13.0%). Presence or absence of remission prior to the second SCT was not a significant prognostic factor (28.3 ± 21.8% versus 15.6 ± 14.2%). Discussion: In the JPLSG MLL03 study, 38% of patients with infantile ALL relapsed. Only four patients relapsed prior to the initial SCT, indicating that the aim of the MLL03 study, to reduce the early relapse rate by performing the early SCT, could have been achieved. On the other hand, 87.5% of the patients relapsed after initial SCT in this study. Most of them were less than 6 months at onset. Several reasons for the high relapse rate after SCT should be considered, which include low graft-versus-leukemia (GVL) effect for infantile ALL, remained minimal residual disease (MRD) before SCT, or inappropriate conditioning regimen in this study. Since we have analyzed MRD before and after SCT in each patient treated by the MLL03 study, one reason could be resolved. In addition, the treatment strategy to induce GVL effect for infantile ALL should be established and we should reconsider the treatment strategy. Finally, appropriate treatment strategy for relapsed cases should be organized in the future. Disclosures: No relevant conflicts of interest to declare.

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Double CEBPA Mutations Are Not Associated With Favorable Clinical Outcome In Pediatric AML: A Report From The Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)

Blood ◽

10.1182/blood.v122.21.4942.4942 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4942-4942

Author(s):

Hidemasa Matsuo ◽

Mio Kajihara ◽

Daisuke Tomizawa ◽

Tomoyuki Watanabe ◽

Akiko Moriya Saito ◽

...

Keyword(s):

Clinical Outcome ◽

Conflicts Of Interest ◽

Normal Karyotype ◽

Study Group ◽

Prognostic Impact ◽

Pediatric Leukemia ◽

Favorable Prognosis ◽

Pediatric Aml ◽

Cebpa Mutations ◽

Lymphoma Study Group

Abstract Background CCAAT/enhancer binding protein alpha (CEBPA) is a transcription factor that coordinates cellular differentiation. Mutations in the CEBPA genes are found in about 10% of patients with AML and are associated with favorable prognosis. However, recent data suggests that the favorable prognosis is restricted only to the patients with double CEBPA mutations and normal karyotype. These data have large implications for risk-stratified therapy and require confirmation. In this study, we investigated CEBPA mutation status and clinical outcome of the pediatric AML patients treated in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study. Patients & Methods AML-05 study, registered at http://www.umin.ac.jp/ctr/as UMIN000000511, is a nation-wide multi-institutional study for children (age <18 years) with de novo AML enrolled from 11/1/2006 to 12/31/2010. Cases with acute promyelocytic leukemia or Down syndrome were excluded. Patients were stratified by the specific cytogenetic characters and morphological treatment response into 3 risk groups; CBF-AML patients to the low risk (LR) group, those with either unfavorable cytogenetics (-7, 5q-, t(16;21)(p11;q22), Ph1, FLT3-ITD) or poor induction responders to the high risk (HR) group, and the rest to the intermediate risk (IR) group. In this trial, morphology was prospectively diagnosed by a central review system. Cytogenetic tests were carried out in regional laboratories, but the reports were reviewed centrally. FLT3-internal tandem duplication (ITD) was examined for all patients. Using the surplus RNA from the AML-05 study, CEBPA gene mutation was analyzed by RT-PCR and direct sequencing. Results Of the 317 evaluable patients, 73 patients (23.0%) had normal karyotype, 42 patients (13.2%) were FLT3-ITD positive, and 19 patients (6.0%) had both normal karyotype and FLT3-ITD. Among the 54 cases with normal karyotype and negative FLT3-ITD, 16 patients (29.6%) had a single CEBPA mutation and 17 patients (31.5%) had double or more (hereafter described as Double) CEBPA mutations. Between the CEBPA wild type (WT) and Double mutated patients, there were no statistically significant differences in relapse-free survival (RFS) (53.9% vs. 71.1%, P=0.27) nor overall survival (OS) (68.9% vs. 64.7%, P=0.57). An in-frame insertion of 6bp (ACCCGC) in CEBPAtrans-activator (TAD2) domain, resulting in a His-Pro duplication (HP196-197 ins), was detected in 131 patients (41.3% of all patients) in the current study, a considerably high incidence. However, this insertion was previously reported as polymorphism in adult AML (Leukemia 2008). When categorizing this insertion cases as CEBPA WT, 24 patients were CEBPA mutated among the 54 cases with normal karyotype and negative FLT3-ITD; 11 patients (20.4%) with single CEBPA mutation and 13 patients (24.1%) with Double CEBPA mutations. Although not statistically significant, there was a tendency of higher RFS (83.3% vs. 55.5%, P=0.20) and OS (79.1% vs. 63.3%, P=0.39) in patients with Double CEBPA mutations versus WT patients. Conclusions The current study is the first Japanese nation-wide investigation of the clinical significance of CEBPA mutations in pediatric AML. Our results suggest that CEBPA mutations have no prognostic impact on children with AML. Disclosures: No relevant conflicts of interest to declare.

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