Transplantation-related mortality, graft failure, and survival after reduced-toxicity conditioning and allogeneic hematopoietic stem cell transplantation in 100 consecutive pediatric recipients.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning is associated with a 10%-40% risk of day +100 transplantation-related mortality (TRM). We evaluated the feasibility and safety of reduced-toxicity conditioning and allo-HSCT in 100 consecutive children and adolescent recipients (mean age, 9.2 ± 6.8 years). The mean duration of follow-up was 1278 ± 1042 days. Fifty patients had malignant disease. The median time to neutrophil recovery was 18 days, and the median time to platelet recovery was 43 days. Median donor chimerism in engrafted patients was 98% on day +100 and 98% on day +365. The cumulative incidence of acute graft-versus-host disease (GVHD) was 20% (95% confidence interval [CI], 12.1%-27.9%), and that of chronic GVHD was 13.5% (95% CI, 6.6%-20.4%). TRM was 3% (95% CI, 0%-6.4%) by day +100 and 13.6% (95% CI, 6.7%-20.5%) for the entire study period. The incidence of primary graft failure (PGF) was 16% overall, 31.4% after umbilical cord blood transplantation (UCBT), and 0% after allo-HSCT with matched unrelated or matched sibling donors (P < .0001). The incidence of PGF in UCBT recipients was 46.7% (14 of 30) in chemotherapy-naive recipients, versus 9.5% (2 of 21) in non-chemotherapy-naive recipients (P = .019). Five-year event-free survival was 59.5% ± 5%, and 5-year overall survival was 72.9% ± 5%. Only PGF and poor-risk disease status were significantly associated with decreased overall survival (P = .03). Reduced-toxicity conditioning allo-HSCT in pediatric recipients is associated with low TRM; however, chemotherapy-naive UCBT recipients have a significantly higher incidence of PGF.

A Phase I study of gemtuzumab ozogamicin (GO) in combination with busulfan and cyclophosphamide (Bu/Cy) and allogeneic stem cell transplantation in children with poor-risk CD33+ AML: a new targeted immunochemotherapy myeloablative conditioning (MAC) regimen.

Children with high-risk acute myelogenous leukemia (AML) (induction failure [IF], refractory relapse [RR], third complete remission [CR3]) have dismal outcomes. Over 80% of AML patients express CD33, a target of gemtuzumab ozogamicin (GO). GO is an active drug in childhood AML but has not been studied in a myeloablative conditioning regimen. We sought to determine the safety of GO in combination with busulfan/cyclophosphamide (Bu/Cy) conditioning before allogeneic hematopoietic stem cell transplantation (alloSCT). GO was administered on day -14 at doses of 3.0, 4.5, 6.0, and 7.5 mg/m(2), busulfan on days -7, -6, -5, -4 (12.8-16.0 mg/kg), and cyclophosphamide on days -3 and -2 (60 mg/kg/day). GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil. We enrolled 12 patients: 8 IF, 3 RR, 1 CR3; median age: 3 years (1-17); median follow-up: 1379 days (939-2305). Nine received umbilical cord blood (UCB), 2 matched unrelated donors (MUDs) and 1 HLA-matched sibling donor: 3 patients each at GO doses of 3.0, 4.5, 6.0, or 7.5 mg/m(2). No dose-limiting toxicities secondary to GO were observed. Day 100 treatment-related mortality (TRM) was 0%. Myeloid and platelet engraftment was observed in 92% and 75% of patients at median day 22 (12-40) and 42 (21-164), respectively. Median day +30 donor chimerism was 99% (85%-100%). The probability of grade II-IV acute graft-versus-host disease (aGVHD) was 42% and chronic GVHD (cGVHD) was 28%. One-year overall survival (OS) and event-free survival (EFS) was 50% (95% confidence interval [CI], 20.8-73.6). GO combined with Bu/Cy regimen followed by alloSCT is well tolerated in children with poor-risk AML. GO at 7.5 mg/m(2) in combination with Bu/Cy is currently being tested in a phase II study.

Weight patterns in children with higher risk ALL: A report from the Children's Oncology Group (COG) for CCG 1961.

BACKGROUND: This retrospective analysis defined and described patterns and predictors of weight change during treatment in children with acute lymphocytic leukemia (ALL) with high-risk features who received treatment on Children's Cancer Group protocol CCG 1961. PROCEDURE: Patients (1,638) were enrolled in CCG 1961 from November 1996 to May 2002. Weight was measured as BMI percent (%), specific for age and gender, and defined as 100 x ln(BMI/median BMI). RESULTS: By the end of treatment, 23% of children were obese (BMI >or=95%), compared with 14% at diagnosis. Children who received post-induction intensified therapy (arms C, D, SER with Doxorubicin or Idarubicin) had higher gastrointestinal toxicities and lower BMI% from consolidation through interim maintenance 1. BMI% then increased for all arms between delayed intensification and maintenance 1 or 2. Children who were of Black or Hispanic race, obese at diagnosis, or who had grade 3 or 4 pancreatitis/glucose toxicities during induction had higher BMI% throughout treatment. Children were more likely to be obese at the end of the study if they were aged 5-9 years at diagnosis or female gender. Cranial radiation was not a predictor of obesity. CONCLUSIONS: Successful treatment of higher risk childhood ALL was associated with obesity, independent of cranial irradiation. The beginning of maintenance therapy may be the best time to intervene with nutritional and behavioral interventions, particularly for children who are obese or aged 5-9 years at diagnosis, female, Black or Hispanic, or those with metabolic toxicities during induction.

Sequential administration of sargramostim and filgrastim in pediatric allogeneic stem cell transplantation recipients undergoing myeloablative conditioning.

G-CSF and GM-CSF both hasten myeloid engraftment post-MA-alloSCT; however, GM-CSF is earlier acting and less expensive. The objective was to evaluate efficacy/safety of sequential administration of GM-CSF followed by G-CSF in children post-MA-alloSCT. From January 2001 to June 2005, 31 children received 32 MA-alloSCT: mean age 6.65 yr; MRD BM or PBSC vs. related or unrelated UCB 11:21; malignant vs. non-malignant disorders 22:10. GM-CSF (250 microg/m(2) IV QD) began on day of stem cell infusion. GM-CSF was switched to G-CSF (10 microg/kg IV QD) when WBC >or= 300/mm(3) x 2 days. G-CSF continued until ANC >or= 2500/mm(3) x 2 days, then tapered to maintain ANC >or= 1000/mm(3). Median time to myeloid engraftment (ANC >or= 500/mm(3) x 3 days) was 17 days [13 days vs. 24 days, MRD BM/PBSC vs. UCB (p < 0.0001)], occurring at a median time of two days after switch to G-CSF. Clinically relevant adverse events were bone pain (n = 8) and large pleural effusion (n = 1). It was estimated that sequential GM-CSF/G-CSF was cost-effective compared with G-CSF alone [cost-savings of $1311/patient ($41,952/study), 2007 Red Book Average Wholesale Price]. In summary, it was demonstrated that sequential administration of GM-CSF/G-CSF post-MA-alloSCT was safe, cost-effective and resulted in prompt myeloid engraftment.

Preliminary results of the safety of immunotherapy with gemtuzumab ozogamicin following reduced intensity allogeneic stem cell transplant in children with CD33+ acute myeloid leukemia.

PURPOSE: Myeloablative allogeneic stem cell transplantation (SCT) has been successful in the treatment of childhood acute myeloid leukemia (AML), but may be associated with significant toxicity and recurrent disease. Reduced-intensity allogeneic SCT may offer a less toxic approach to patients with AML. Targeted immunotherapy with gemtuzumab ozogamicin has been shown to be safe, well tolerated in children, and, as a single agent, gemtuzumab ozogamicin has induced responses in 30% of patients with recurrent CD33+ AML. There are no safety data with gemtuzumab ozogamicin post allogeneic SCT in children. Therefore, we explored the feasibility and toxicity of targeted immunotherapy following reduced-intensity allogeneic SCT in children with CD33+ AML. EXPERIMENTAL DESIGN: Eight patients with CD33+ AML received a reduced-intensity allogeneic SCT following fludarabine 30 mg/m2 for 6 days and busulfan 3.2 mg/kg (<4 years, 4 mg/kg/d) for 2 days. Donor sources included six 6/6 HLA-matched related peripheral blood stem cells, one 6/6 sibling cord blood, and one 4/6 unrelated cord blood. RESULTS: Day 30 and day 60 donor chimerisms in seven of eight evaluable patients were 96 +/- 2% (n = 7) and 94 +/- 3% (n = 6), respectively. Five of six patients (too early for one patient) received two doses of gemtuzumab ozogamicin and one patient received only one dose. After each dose, all patients developed grade 4 neutropenia, with recovery on median days 16 and 13, respectively, after dose 1 and dose 2. Grade 4 thrombocytopenia was only observed in 2 of 11 gemtuzumab ozogamicin courses. No patients have developed dose-limiting toxicity secondary to gemtuzumab ozogamicin. CONCLUSIONS: The administration of gemtuzumab ozogamicin post reduced-intensity allogeneic SCT in children with average risk AML is feasible and well tolerated with minimal toxicity. The maximal tolerated dose has yet to be determined for gemtuzumab ozogamicin post reduced-intensity allogeneic SCT in children with CD33+ AML. Additional studies in a larger group of patients will be required to adequately assess the safety of this approach.

Complementary and alternative medicine in pediatric oncology.

OBJECTIVES: To summarize research in complementary and alternative medicine (CAM) therapies used for children with cancer and to explore issues and directions for measuring outcomes of CAM therapies in children. DATA SOURCES: Scientific and research articles, internet for active research studies. CONCLUSION: CAM is increasingly used as adjunctive cancer therapies in pediatrics. Mind-body and touch therapies have the greatest evidencefor effectiveness in reducing psychological and physical stressors. Supplements and herbal therapies receive the greatest interest, however, and more research is needed to determine efficacy in improving symptoms or outcomes in children with cancer. IMPLICATIONS FOR NURSING PRACTICE: Mind-body and touch therapies can be used by nurses to reduce symptoms and anxiety in children. Potential risks and benefits should be determined for therapies that have no evidence.

Complementary and alternative medicine research initiatives in the Children's Oncology Group and the role of the pediatric oncology nurse.

Complementary and alternative medicine (CAM) has emerged as a new area of investigation in cancer research and treatment. CAM modalities are widely used, but little is known about their efficacy. The Children's Oncology Group has made a major commitment to CAM research in childhood and adolescent cancer, beginning with studies of CAM in the area of supportive care. Pediatric oncology nurses, as implementing clinicians and collaborating researchers, are critical to the success of these studies.

Evidence for symptom management in the child with cancer.

The use of complementary/alternative medicine (CAM) has been well documented among children with cancer. This report summarizes the research evidence on the role of CAM therapies for prevention and treatment of the most commonly reported cancer-related symptoms and late effects among children with cancer. Small clinical trials document evidence of effectiveness for select therapies, such as acupuncture or ginger for nausea and vomiting, TRAUMEEL S for mucositis, and hypnosis and imagery for pain and anxiety. Several relatively small clinical trials of varying quality have been conducted on these CAM therapies in children with cancer. Some herbs have demonstrated efficacy in adults, but few studies of herbs have been conducted in children. Larger randomized clinical trials are warranted for each of these promising therapies. Until the evidence is more conclusive, the providers' role is to assess and document the child's use of CAM, critically evaluate the evidence or lack of evidence, balance the potential risks with possible benefits, and assist the family in their choices and decisions regarding use of CAM for their child with cancer.

Future directions of CAM research in pediatric oncology.

Children with cancer are using complementary and alternative medicine (CAM) to relieve symptoms, reduce side effects of treatment, and cope with the emotional aspects of having a life-threatening illness. Parental decisions about using CAM should be based on studies of efficacy and safety. Unfortunately, little evidence of efficacy is available for the majority of CAM therapies. This article discusses the methodological challenges to conducting CAM research in children and the evidence needed to support integrative medicine in pediatric oncology.

Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children's Oncology Group study CCG-1941.

PURPOSE: To compare conventional sibling bone marrow transplantation (CBMT), BMT with alternative donor (ABMT), and chemotherapy (CT) for children with acute lymphoblastic leukemia (ALL) and an early first marrow relapse. PATIENTS AND METHODS: After informed consent, 214 patients with ALL and early marrow relapse began multiagent induction therapy. One hundred sixty-three patients with fewer than 25% marrow blasts and count recovery at the end of induction (second remission [CR2]) were allocated by donor availability. Fifty patients with sibling donors were allocated to CBMT. Seventy-two patients were randomly allocated between ABMT and CT while 41 patients refused allocation. RESULTS: Overall, 3-year event free survival from entry is 19% +/- 3%. Thirty-two of 50 CBMT patients (64%) and 19 of 37 ABMT patients (51%) underwent transplantation in CR2 with 3-year disease-free survival of 42% +/- 7% and 29% +/- 7%. The 3-year DFS is 29% +/- 7%, 21% +/- 7%, and 27% +/- 8% for patients allocated to CBMT, ABMT, and CT, respectively. Contrary to protocol, 12 of 35 patients allocated to CT underwent BMT in CR2. Of these, five patients died after BMT and 5 patients relapsed. CONCLUSION: More than one half of patients died, failed reinduction, or relapsed again before 3 months after CR2 (median time to BMT). Intent-to-treat pair-wise comparison of ABMT with CT, CT with CBMT, and CBMT with ABMT yields hazards of 1.2, 1.1, 0.8 with P values of .56, .80, and .36, respectively. Outcomes remain similar and poor for children with ALL and early marrow relapse. BMT is not a complete answer to the challenge of ALL and early marrow relapse.

A low incidence of nontuberculous mycobacterial infections in pediatric hematopoietic stem cell transplantation recipients.

Hematopoietic stem cell transplantation (HSCT) is being used to treat a wide spectrum of clinical disorders but opportunistic infection remains an important factor determining outcomes for these patients. Nontuberculous mycobacterial (NTM) infections are being reported more frequently in HSCT recipients and the incidence of NTM infections in adult recipients is reported to be 0.4%-4.9%. However, the incidence and severity of NTM infections are less well described in pediatric HSCT recipients. Centers for Disease Control and Prevention guidelines were used to define definite and probable NTM infection among 132 children undergoing 169 HSCT between January 2000 and December 2004 at our institution. NTM infection was diagnosed in 5 of 132 pediatric recipients (3.8%). There were no NTM infections diagnosed in the autologous HSCT recipients and the incidence of NTM in allogeneic HSCT recipients was 6.4% (95% confidence interval, 0.8-11.9). The mean age of the HSCT recipients who developed NTM infections was 8 years (range, 2-19 years); 3 were male and 2 were female. Four conditioning regimens included alemtuzumab and 3 had antithymocyte globulin. Of the 5 patients with NTM infections, 2 met the criteria for definite infection and 3 for probable infection. Of the 2 patients with definite NTM infection, 1 had disseminated disease with Mycobacterium avium complex and the other had Mycobacterium chelonae catheter-related bloodstream infection. The probable NTM infections were 1 skin infection with Mycobacterium kansasii and 2 lower respiratory tract infections with M avium complex. Median time to NTM infection was 115 days (range, 14-269 days) after HSCT. Two patients had graft-versus-host disease at the time of NTM infection. All 5 patients received 3-4 antimycobacterial drugs and all NTM infections resolved. In summary, the incidence of NTM infection in pediatric HSCT recipients appears similar to that described in adult HSCT recipients and the outcome appears to be excellent with the proper antibiotic therapy. The increased use of anti-T cell antibodies appears to be associated with an increased risk of NTM infections in pediatric HSCT recipients. Multicenter studies are needed to identify the risk factors, early diagnostic criteria, and optimal therapy.