Successful mobilization,harvest and transplant of peripheral blood stem cells using AMD3100 and G‐CSF following high dose craniospinal irradiation for medulloblastoma in a young child

Contemporary protocols for the treatment of malignant brain tumors such as medulloblastoma (MB) in children, often involve craniospinal irradiation (CSI) at diagnosis followed by serial courses of high dose chemotherapy and autologous hematopoietic stem cell support. Patients often require several pheresis procedures in order to collect sufficient stem cells for this type of treatment, particularly if they have already had CSI. We describe the successful mobilization, collection and subsequent transplant of a 7‐year‐old female with medulloblastoma after recent CSI using granulocyte colony stimulating factor (G‐CSF) and the CXCR4 antagonist AMD3100 after a failed previous mobilization attempt using G‐CSF alone. Pediatr Blood Cancer 2010;54:613–615. © 2009 Wiley‐Liss, Inc.     

Treatment of pediatric average-risk medulloblastoma using craniospinal irradiation less than 2500 cGy and chemotherapy: single center experience in Korea

Background:Although craniospinal irradiation (CSI) of 2340 cGy plus tumor booster with chemotherapy have been established as a standard treatment of childhood average-risk (AvR) medulloblastoma (MBL) in Western counties,there are a few recent reports in outcomes ofAvR MBL using this strategy in Korean and other Asian children.We investigated the outcome of the Korean children with AvR MBL who were treated with CSI ＜2500 cGy and chemotherapy.Methods:Between January 2001 and December 2010,clinical characteristics and outcomes of 42 patients who were diagnosed with AvR MBL postoperatively and treated with radiation including CSI ＜2500 cGy and chemotherapy in Seoul National University Children's Hospital were analyzed.Results:Their median age was 9 years (range:3-18.8),and 29 were male.Histological subtypes were classic type in 28 patients,nodular/desmoplastic in 7,and large cell/anaplastic (LCA) in 7.All the patients received adjuvant radiotherapy (CSI with median 2340 cGy and booster) and multiagent chemotherapy as the first-fine treatment.With a median follow-up of 54 months,12 patients experienced relapse or progression of the tumor.The 3-and 5-year disease-free survival (DFS) rates were 78.0％±6.5％ and 75.0％±6.9％,respectively,and overall survival (OS) rates were 85.3％±5.6％ and 76.8％±6.9％,respectively.The LCA subtype was associated with poorer DFS (P=0.023) and OS (P=0.008),compared with non-LCA subtypes.Conclusion:The outcomes of children and adolescents with AvR MBL treated with radiation including CSI ＜2500 cGy and chemotherapy,are compatible to those in Western countries;however,the LCA subtype has a poor outcome with this strategy.     

High‐dose chemotherapy with autologous stem cell rescue for treatment of retinoblastoma: Report of five cases

RB is a primarily pediatric cancer arising from the retina, initiated by biallelic loss of the RB1 gene. We report five children with bilateral RB (n = 3), extra‐ocular disseminated RB, or disseminated relapsed RB, who were treated with tandem high‐dose chemotherapy and autologous stem cell rescue. All patients received at least 2.2 × 10⁶/kg CD34⁺ (median, 3.9 × 10⁶/kg) cells. The preparative regimen for course 1 was carboplatin, thiotepa, etoposide, and for course 2, CM and melphalan. ANC of at least 0.5 × 10⁹/L occurred at a median of 11 days (range, 10–12) and 15 days (range, 12–16) after the first and second procedure, respectively. Platelet engraftment occurred at a median of 13 days (range, 12–17) and 15 days (range, 14–22) after the first and second procedure, respectively. All of the five patients treated remain alive and disease free at the last follow‐up time, ranging between 21 and 44 months after completion of autologous transplant. Additional therapy was required in one patient, in whom enucleation had to be performed because of early disease relapse, refractory to local therapy. Intensification of chemotherapy with repeated high‐dose chemotherapy and autologous rescue appears an acceptable choice in selected cases with bilateral or extra‐ocular disease, either recurrent or refractory.     

High-dose chemotherapy and autologous stem cell rescue in children with newly diagnosed high-risk or relapsed medulloblastoma or supratentorial primitive neuroectodermal tumor

BACKGROUND: Single or tandem double high-dose chemotherapy (HDCT) was used to treat children with newly diagnosed high-risk or relapsed medulloblastoma and supratentorial primitive neuroectodermal tumor (MB/sPNET) in order to defer or avoid radiotherapy in young children. PROCEDURE: Thirty-seven HDCTs were given to 25 children with newly diagnosed high-risk or relapsed MB/sPNET. Tandem double HDCT was used for 12 of 15 patients initially intended to receive double HDCT. RESULTS: Three-year EFS (+/-SE) in 6 newly diagnosed high-risk (>3 years old), 8 newly diagnosed (<3 years old), and 11 relapsed MB/sPNET was 83.3 +/- 15.2%, 62.5 +/- 20.5%, and 29.1 +/- 15.7%, respectively. Three-year EFS for patients in CR or PR and in less than PR at first HDCT was 67.4 +/- 11.0% and 16.7 +/- 15.2%, respectively (P = 0.001). Three-year EFS in patients initially intended to receive double HDCT and single HDCT was 66.0 +/- 12.4% and 40.0 +/- 15.5%, respectively. For 19 patients in CR or PR at first HDCT, 3-year EFS was 88.9 +/- 10.5% in tandem double HDCT group, and 44.4 +/- 16.6% in single HDCT group, respectively (P = 0.037). Although four treatment-related mortalities (TRMs) occurred during 25 first HDCTs, no TRM occurred during 12 second HDCTs. In four of eight young children, craniospinal radiotherapy was successfully withheld without subsequent relapse. CONCLUSIONS: High-dose chemotherapy may improve the survival of children with newly diagnosed high-risk MB/sPNET, and, to some extent, the survival of those with relapsed MB/sPNET. Further study is necessary to elucidate the efficacy of tandem double HDCT.     

Biological modification strategies following marrow ablative,high‐dose chemotherapy (HDCT) with autologous hematopoietic stem cell rescue (AHSCR) for pediatric brain tumors

Maintenance biology‐based therapy following HDCT/AHSCR in pediatric brain tumors has not been tested as yet. Failure of the HDCT/AHSCR might be due to tumor‐immunity dysregulation, reactivation of the angiogenic switch and other mechanisms. Angiogenesis has been shown to be reactivated following chemotherapy. The angiogenic factors engaged in this process in childhood brain tumors following HDCT/AHSCR have not been tested in the clinic. Metronomic chemotherapy has been found to be safe and angiogenesis inhibitors are currently tested in children. Other good possible candidates for clinical trials in this setting include retinoic acid and immunotherapy. Pediatr Blood Cancer 2010;54:654–656. © 2010 Wiley‐Liss, Inc.     

Multimodal treatment including tandem high‐dose chemotherapy and autologous stem cell transplantation in children with anaplastic ependymomas

In this study, we evaluated the results of multimodal treatment that included tandem HDCT/auto‐SCT in children with anaplastic ependymomas. Fourteen patients with anaplastic ependymomas were enrolled from 2006 to 2014. Six cycles of induction chemotherapy were administered to all patients before they underwent tandem HDCT/auto‐SCT. Patients who were older than 3 years of age were administered RT after two cycles of induction chemotherapy. In patients under 3 years of age, RT was either omitted or delayed until they reached 3 years of age, if the patients experienced CR after tandem HDCT/auto‐SCT. All patients, including two who experienced disease progression during induction treatment, underwent the first HDCT/auto‐SCT, and 13 subsequently underwent the second HDCT/auto‐SCT. One patient died from hepatic VOD during the second HDCT/auto‐SCT; other toxicities occurring during tandem HDCT/auto‐SCT were manageable. Relapses or progression occurred in seven patients, and five of seven of them remain alive till date after salvage treatment, including surgery and RT. The 5‐year overall and event‐free survival rates were 85.1% ± 9.7% and 50.0% ± 13.4%, respectively. These findings suggest that multimodal treatment including tandem HDCT/auto‐SCT could be a feasible option for improving survival in children with anaplastic ependymomas.     

The challenges of high‐dose chemotherapy in CNS tumors

High‐dose, myeloablative chemotherapy with hematopoietic stem cell rescue is used in children and young adults with brain tumors for which conventional therapy is either excessively toxic (e.g., radiotherapy in infants) or ineffective. Thus, the aims of such strategies are to improve both quantity and quality of life. Whether high‐dose chemotherapy is less neurotoxic and more effective than other therapeutic approaches is still controversial. We will consider the difficulties in analyzing published data and the challenges of designing effective clinical trials that test high‐dose chemotherapy in patients with brain tumors. Pediatr Blood Cancer 2010;54:652–653. © 2010 Wiley‐Liss, Inc.     

Feasibility and effectiveness of treatment strategy of tandem high‐dose chemotherapy and autologous stem cell transplantation in combination with 131I‐MIBG therapy for high‐risk neuroblastoma

This study was performed to evaluate the safety and effectiveness of tandem HDCT/ASCT combined with targeted radiotherapy using ¹³¹I‐MIBG for high‐risk neuroblastoma. Patients with high‐risk neuroblastoma were treated with 8 to 10 cycles of induction chemotherapy before tandem HDCT/ASCT. Patients received ¹³¹I‐MIBG treatment before the second HDCT/ASCT. Local radiotherapy and maintenance therapy were performed after tandem HDCT/ASCT. Between 2012 and 2016, 19 patients were diagnosed with high‐risk neuroblastoma in our institution and 18 of them received tandem HDCT/ASCT combined with ¹³¹I‐MIBG therapy. For the first HDCT/ASCT regimen, 12 patients received busulfan/melphalan and six patients received melphalan/etoposide/carboplatin. The second HDCT included ThioCy. The median dose of ¹³¹I‐MIBG was 17.2 mCi/kg for the first eight patients, while 12 patients in the latter period of the study received reduced dose of 10.7 mCi/kg. The 5‐year OS and EFS rates were 79% and 61%, respectively, for all 19 patients with high‐risk neuroblastoma, and 83% and 64%, respectively, for 18 patients who completed tandem HDCT/ASCT combined with ¹³¹I‐MIBG therapy. Six patients experienced disease relapse and five patients died. Treatment‐related mortality was not observed. Among 15 evaluable patients, 11 patients (73%) developed hypothyroidism, six patients (40%) had CKD, and six patients (40%) had growth failure. Hypothyroidism and growth failure were less frequent in patients who received reduced doses of ¹³¹I‐MIBG therapy. Tandem HDCT/ASCT combined with HD ¹³¹I‐MIBG therapy could be feasible for patients with high‐risk neuroblastoma with acceptable toxicity profiles and favorable outcomes.     

Outcome for children <4 years of age with malignant central nervous system tumors treated with high-dose chemotherapy and autologous stem cell rescue

BACKGROUND: Children <4 years of age (yo) with malignant central nervous system (CNS) tumors have a dismal prognosis. In an attempt to delay or obviate radiation therapy (XRT) and improve outcome, our institution has treated children <4 yo with newly diagnosed malignant CNS tumors with high-dose chemotherapy (HDC) and autologous stem cell rescue (ASCR) followed by selective XRT. PROCEDURE: Fifteen children (age 4-38 months) with malignant CNS tumors have completed treatment with HDC/ASCR. All patients received three cycles of induction chemotherapy (cisplatin 3.5 mg/kg- day 0, cyclophosphamide 60 mg/kg- day 1 and 2, etoposide 2.5 mg/kg- day 0-2, vincristine 0.05 mg/kg, day 0, 7, 14) followed by three cycles of HDC (carboplatin 17 mg/kg and thiotepa 6 mg/kg, day 0 and 1) with ASCR. Histology included five medulloblastomas, four primitive neuroectodermal tumors (PNET), five malignant gliomas, and one ependymoma. Outcome and treatment toxicities were evaluated by retrospective chart review. RESULTS: Median follow-up time of the 15 patients is 22 months (range 8-82 months). The 1- and 2-year progression-free survival (PFS) is 86.1% and 52.2% and overall survival (OS) 91.6% and 72.1%, respectively. Ten patients are alive and disease free 3-77 months (median 18 months) after having completed HDC/ASCR, thereoff five received XRT. Toxicity was primarily myelosuppression. There was no treatment mortality. CONCLUSIONS: We are encouraged by the outcome of 15 children <4 yo with malignant CNS tumors treated with tandem cycles of HDC and ASCR at our institution. The treatment regimen is relatively well tolerated.