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1.  Hematopoietic Cell Transplantation for Systemic Mature T-Cell Non-Hodgkin Lymphoma 
Journal of Clinical Oncology  2013;31(25):3100-3109.
To analyze outcomes of hematopoietic cell transplantation (HCT) in T-cell non-Hodgkin lymphoma.
Patients and Methods
Outcomes of 241 patients (112 anaplastic large-cell lymphoma, 102 peripheral T-cell lymphoma not otherwise specified, 27 angioimmunoblastic T-cell lymphoma) undergoing autologous HCT (autoHCT; n = 115; median age, 43 years) or allogeneic HCT (alloHCT; n = 126; median age, 38 years) were analyzed. Primary outcomes were nonrelapse mortality (NRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). Patient, disease, and HCT-related variables were analyzed in multivariate Cox proportional hazard models to determine association with outcomes.
AutoHCT recipients were more likely in first complete remission (CR1; 35% v 14%; P = .001) and with chemotherapy-sensitive disease (86% v 60%; P < .001), anaplastic large-cell histology (53% v 40%; P = .04), and two or fewer lines of prior therapy (65% v 44%; P < .001) compared with alloHCT recipients. Three-year PFS and OS of autoHCT recipients beyond CR1 were 42% and 53%, respectively. Among alloHCT recipients who received transplantations beyond CR1, 31% remained progression-free at 3 years, despite being more heavily pretreated and with more refractory disease. NRM was 3.5-fold higher (95% CI, 1.80 to 6.99; P < .001) for alloHCT. In multivariate analysis, chemotherapy sensitivity (hazard ratio [HR], 1.8; 95% CI, 1.16 to 2.87) and two or fewer lines of pretransplantation therapy (HR, 5.02; 95% CI, 2.15 to 11.72) were prognostic of survival.
These data describe the roles of autoHCT and alloHCT in T-cell non-Hodgkin lymphoma and suggest greater effectiveness earlier in the disease course, and limited utility in multiply relapsed disease. Notably, autoHCT at relapse may be a potential option for select patients, particularly those with anaplastic large-cell lymphoma histology.
PMCID: PMC3753702  PMID: 23897963
Pediatric blood & cancer  2014;61(6):1126-1128.
We report on 27 patients with Down syndrome (DS) and acute lymphoblastic leukemia [ALL] who received allogeneic hematopoietic cell transplantation (HCT) between 2000 and 2009. 78% of patients received myeloablative conditioning and 52% underwent transplantation in second remission. Disease-free survival (DFS) was 24% at a median of 3 years. Post-transplant leukemic relapse was more frequent than expected for children with DS-ALL (54%) than for non-DS ALL. These data suggest leukemic relapse rather than transplant toxicity is the most important cause of treatment failure. Advancements in leukemia control are especially needed for improvement in HCT outcomes for DS-ALL.
PMCID: PMC4080799  PMID: 24391118
hematopoietic stem cell transplantation; Down syndrome; trisomy 21; acute lymhoblastic leukemia; relapse; pediatric
3.  Low-dose chemotherapy and rituximab for post-transplant lymphoproliferative disease (PTLD): A Children's Oncology Group report 
Optimal therapy for post-transplant lymphoproliferative disease (PTLD) remains problematic. A phase II trial adding rituximab to a low-dose cyclophosphamide and prednisone regimen was conducted for pediatric patients with Epstein-Barr virus (EBV) (+), CD20 (+) PTLD. Fifty-five patients were enrolled. Toxicity was similar for cycles of therapy containing rituximab versus those without. Complete remission (CR) rate was 69% [95% confidence interval (CI); 57%-84%). Of 12 patients with radiographic evidence of persistent disease at the end of therapy, 8 were in CR 28 weeks later without further PTLD therapy. There were 10 deaths, 3 due to infections while receiving therapy and 7 from PTLD. The 2-year event free survival (alive with functioning original allograft and no PTLD) was 71% (95% CI: 57%-82%) and overall survival was 83% (95% CI: 69%-91%) with median follow-up of 4.8 years. Due to small numbers, we were unable to determine significance of tumor histology, stage of disease, allograft type or early response to treatment on outcome. These data suggest rituximab combined with low-dose chemotherapy is safe and effective in treating pediatric with EBV (+) PTLD following solid organ transplantation.
PMCID: PMC3484187  PMID: 22883417
PTLD; EBV; rituximab; chemotherapy
4.  Children’s Oncology Group’s 2013 Blueprint for Research: Non-Hodgkin Lymphoma 
Pediatric blood & cancer  2012;60(6):979-984.
Non-Hodgkin lymphomas account for approximately 7% of cancers diagnosed in patients less than 20 years of age, with approximately 800 cases diagnosed annually at COG institutions. With current therapies, cure rates range from 70% to over 90%, even for children with disseminated disease. However, two major challenges need to be overcome: (i) to optimize upfront treatment to prevent relapse since prognosis for patients with relapsed disease remains poor and (ii) minimize long-term side effects in survivors. Hence, the future initiatives for the treatment of pediatric NHL are to utilize novel targeted therapies to not only improve outcomes but to decrease bystander organ toxicities and late effects.
PMCID: PMC4327936  PMID: 23255391
children; children’s oncology group; lymphoma
5.  Rituximab pharmacokinetics in children and adolescents with de novo intermediate and advanced mature B-cell lymphoma/leukaemia: A Children’s Oncology Group (COG) report 
British journal of haematology  2013;162(5):678-683.
The ANHL01P1 trial was undertaken to determine pharmacokinetics and safety following the addition of rituximab to French-American-British/ /Lymphome Malins de Burkitt (FAB/LMB96) chemotherapy in 41 children and adolescents with Stage III/IV mature B-cell lymphoma/leukaemia. Patients received rituximab (375mg/m2) days -2 and 0 of two induction cycles and day 0 of two consolidation cycles. Highest peak levels were achieved following the second dose of each induction cycle (299±19 and 384±25 µg/ml (Group-B); 245±31 and 321±32 µg/ml (Group-C)) with sustained troughs and t½ of 26–29 days. Rituximab can be safely added to FAB chemotherapy with high early rituximab peak/trough levels and a long t½..
PMCID: PMC3745786  PMID: 23802659
non-Hodgkin lymphoma; rituximab; pharmacokinetics; pediatric; CD20
Data on outcomes of allogeneic transplantation in children with Down syndrome and acute myelogenous leukemia (DS-AML) are scarce and conflicting. Early reports stress treatment-related mortality as the main barrier; a recent case series points to post-transplant relapse.
Design and methods
We reviewed outcome data for 28 patients with DS-AML reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 2000 and 2009 and performed a first matched-pair analysis of 21 patients with DS-AML and 80 non-DS AML controls.
The median age at transplantation for DS-AML was 3 years and almost half of the cohort was in second remission. The 3-year probability of overall survival was only 19%. In multivariate analysis, adjusting for interval from diagnosis to transplantation, risks of relapse (HR 2.84, p<0.001; 62% vs. 37%) and transplant-related mortality (HR 2.52, p=0.04; 24% vs. 15%) were significantly higher for DS-AML compared to non-DS AML. Overall mortality risk (HR 2.86, p<0.001; 21% vs. 52%) was significantly higher for DS-AML.
Both transplant-related mortality and relapse contribute to higher mortality. Excess mortality in DS-AML patients can only effectively be addressed through an international multi-center effort to pilot strategies aimed at lowering both transplant-related mortality and relapse risks.
PMCID: PMC3707801  PMID: 23467128
hematopoietic stem cell transplantation; Down syndrome; trisomy 21; AML; ALL; relapse; pediatric
7.  The immunophenotype of T-lymphoblastic lymphoma in children and adolescents: a Children’s Oncology Group report 
British journal of haematology  2012;159(4):454-461.
T-lymphoblastic leukaemia (T-ALL) and T-lymphoblastic lymphoma (T-LBL) are neoplasms derived from immature lymphoid cells of T-cell lineage. These neoplasms are biologically similar, but significant differences may exist between the two given their clinical differences. Although ample data regarding the immunophenotypic characterization T-ALL are available, there is a paucity of such data in children and adolescents with T-LBL. We used flow cytometry and/or immunohistochemistry to characterize the immunophenotypic profile of 180 children and adolescents with newly diagnosed T-LBL enrolled in the Children’s Oncology Group 5971 study. Multiple T-cell, B-cell, myeloid, and other markers were evaluated. We identified diagnostically useful immunophenotypic features of T-LBL as well as distinct immunophenotypic subgroups, although none of these was statistically related to event-free or overall survival in this retrospective analysis. Further studies of biologically and immunophenotypically distinct subgroups of T-LBL, such as the early T-cell precursor phenotype, are warranted.
PMCID: PMC4008319  PMID: 22994934
T-lymphoblastic lymphoma; early T-cell precursor; immunophenotypic analysis; paediatric lymphoma; T-cell antigens
We examined the role of hematopoietic cell transplantation (HSCT) for patients aged ≤18 years with refractory or recurrent Burkitt (n=41), lymphoblastic (n=53), diffuse large B cell (n=52) and anaplastic large cell lymphoma (n=36), receiving autologous (n=90) or allogeneic (n=92 – 43 matched sibling and 49 unrelated donor) HSCT in 1990–2005. Risk factors affecting event-free survival (EFS) were evaluated using stratified Cox regression. Characteristics of allogeneic and autologous HSCT recipients were similar. Allogeneic donor HSCT was more likely to use irradiation-containing conditioning regimens, marrow stem cells, be performed in more recent years, and for lymphoblastic lymphoma. EFS rates were lower for patients not in complete remission at HSCT, regardless of donor type. After adjusting for disease status, 5-year EFS were similar after allogeneic and autologous HSCT for diffuse large B cell (50% vs. 52%), Burkitt (31% vs. 27%) and anaplastic large cell lymphoma (46% vs. 35%). However, EFS was higher for lymphoblastic lymphoma, after allogeneic HSCT (40% vs. 4%, p<0.01). Predictors of EFS for progressive or recurrent disease after HSCT included disease status at HSCT and use of allogeneic donor for lymphoblastic lymphoma. These data were unable to demonstrate a difference in outcome by donor type for the other histologic sub-types.
PMCID: PMC2911354  PMID: 19800015
Non-Hodgkin lymphoma; allogeneic HSCT; autologous HSCT
Trends in utilization and outcomes after autologous or allogeneic hematopoietic cell transplantation (HCT) for Burkitt Lymphoma (BL) were analyzed in 241 recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1985 and 2007. The autologous HCT cohort had a higher proportion with chemotherapy sensitive disease, peripheral blood grafts and HCT in first complete remission (CR1). The use of autologous HCT has declined over time with only 19% done after 2001. Overall survival (OS) at 5 years for the autologous cohort was 83% for those in CR1, and 31% for non-CR1 recipients. Corresponding progression free survival (PFS) was 78% and 27%, respectively. After allogeneic HCT, OS at 5 years was 53% and 20% for the CR1 and non-CR1 cohorts while PFS was 50% and 19%, respectively. The most common cause of death was progressive lymphoma. Allogeneic HCT performed in a higher risk subset (per NCCN guidelines) resulted in a 5 year PFS of 27%. Autologous HCT, resulted in a 5 year PFS of 44% in those transplanted in second CR.
PMCID: PMC3553321  PMID: 23200705
alloHCT; autoHCT; Burkitt lymphoma
It is uncertain whether late mortality rates after hematopoietic cell transplantation for severe combined immunodeficiency (SCID), non-SCID primary immunodeficiency diseases (non-SCID PIDD) and inborn error of metabolism (IEM) return to rates observed in the general population, matched for age, sex and nationality. We studied patients with SCID (n=201), non-SCID PIDD (n=405) and IEM (n=348) who survived for at least two years after transplantation with normal T-cell function (SCID) or >95% donor chimerism (non-SCID PIDD and IEM). Importantly, mortality rates were significantly higher than for the general population for several years after transplantation. This decreases towards normal rates in patients with SCID and non-SCID PIDD beyond 6 years after transplantation but not for IEM. Active chronic graft-versus-host disease at 2-years was associated with higher risks of late mortality for all diseases (HR 1.87, p=0.05). Additionally, for non-SCID PIDD, late mortality was higher in recipients of T-cell depleted grafts (HR 4.16, p=0.007) and for IEM, after unrelated donor (HR 2.72, p=0.03) and mismatched related donor (HR 3.76, p=0.01) transplants. The higher mortality rates in these long-term survivors for many years after transplantation confirm the need for long-term surveillance.
PMCID: PMC3390445  PMID: 22430083
Late mortality; primary immunodeficiency; inborn error of metabolism
Bone marrow transplantation  2012;48(3):363-368.
Childhood autologous hematopoietic cell transplant (AHCT) survivors can be at risk for secondary malignant neoplasms (SMNs). We assembled a cohort of 1,487 pediatric AHCT recipients to investigate the incidence and risk factors for SMNs. Primary diagnoses included neuroblastoma (39%), lymphoma (26%), sarcoma (18%), CNS tumors (14%), and Wilms tumor (2%). Median follow-up was 8 years (range, <1–21 years). SMNs were reported in 35 patients (AML/MDS=13, solid cancers=20, subtype missing=2). The overall cumulative incidence of SMNs at 10 years from AHCT was 2.60% (AML/MDS=1.06%, solid tumors=1.30%). We found no association between SMNs risk and age, gender, diagnosis, disease status, time since diagnosis, or use of total body irradiation or etoposide as part of conditioning. Overall survival at 5-years from diagnosis of SMNs was 33% (95% CI, 16–52%). When compared to age- and gender-matched general population, AHCT recipients had 24 times higher risks of developing SMNs (95% CI, 16.0–33.0). Notable SMN sites included bone (N=5 SMNs, observed (O)/expected (E)=81), thyroid (N=5, O/E=53), breast (n=2, O/E=93), soft tissue (N=2, O/E=34), AML (N=6, O/E=266), and MDS (N=7, O/E=6603). Risks of SMNs increased with longer follow-up from AHCT. Pediatric AHCT recipients are at considerably increased risk for SMNs and need life-long surveillance for SMNs.
PMCID: PMC3525761  PMID: 22964594
Hematopoietic cell transplantation; Autologous; Pediatric; Second Cancers; Risk factors
12.  Outcome of Lower-Intensity Allogeneic Transplantation in non-Hodgkin Lymphoma After Autologous Transplant Failure 
We studied the outcome of allogeneic transplantation after lower-intensity conditioning regimens (reduced-intensity [RIC] and non-myeloablative [NST]) in non-Hodgkin lymphoma (NHL) relapsing after autologous transplantation. Non-relapse mortality (NRM), lymphoma progression/relapse, progression-free survival (PFS) and overall survival (OS) were analyzed in 263 NHL patients. All had relapsed after a prior autologous transplant and then received allogeneic transplantation from related (n = 26) or unrelated donors (n= 237) after RIC (n = 128) or NST (n = 135), and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1996 and 2006. Median follow-up of survivors was 68 months (range, 3–111). Three-year NRM was 44% (95% CI, 37%–50%). Lymphoma progression/relapse at three years was 35% (95% CI, 29%–41%). Three-year probabilities of PFS and OS were 21% (95% CI, 16%–27%) and 32% (95% CI, 27%–38%) respectively. Superior performance score, longer interval between transplants, total-body irradiation-based conditioning regimen and lymphoma remission at transplantation correlated with improved PFS. Allogeneic transplantation after lower-intensity conditioning is associated with significant NRM, but can result in long-term PFS. We describe a quantitative risk model based on pretransplant risk factors in order to identify those likely to benefit from this approach.
PMCID: PMC3376237  PMID: 22198543
Non-Hodgkin Lymphoma; Allogeneic; Relapse
We conducted a retrospective study of 155 children who received unrelated donor hematopoietic cell transplantation (HCT) between 1990 and 2005 for acute lymphoblastic leukemia (ALL) in third remission. Median age of patients was 11 years, median time from diagnosis to first relapse was 36 months and median time from first to second relapse was 26 months. Stem cell sources were bone marrow (n=115), peripheral blood (n=11) or cord blood (n=29). All patients received a myeloablative transplant-conditioning regimen. The 5-year estimates of leukemia-free survival (LFS), relapse and non-relapse mortality were 30%, 25% and 45%, respectively. In multivariate analysis, the only risk factor associated with relapse was interval between first and second relapse. Second relapses that occurred late, >26 months from first relapse, were associated with lower risk for post-HCT relapse compared to second relapses ≤26 months (RR 0.4; p=0.01). Relapse risks were lowest when late second relapse was preceded by late first relapse (> 36 months from diagnosis) as shown by a 3-year relapse rate of 9%, p=0.0009. Long-term LFS can be achieved for children with ALL in third remission using unrelated donor HCT, especially when the second relapse occurred late.
PMCID: PMC3372321  PMID: 21683798
Bone marrow transplant; hematopoietic cell transplant; acute lymphoblastic leukemia; unrelated donor
14.  Comparison of Outcomes after Transplantation of G-CSF Stimulated Bone Marrow Grafts versus Bone Marrow or Peripheral Blood Grafts from HLA-Matched Sibling Donors for Patients with Severe Aplastic Anemia 
We compared outcomes of patients with severe aplastic anemia (SAA) who received G-CSF stimulated bone marrow (G-BM) (n=78), unstimulated bone marrow (BM) (n=547), or peripheral blood progenitor cells (PBPC) (n=134) from an HLA-matched sibling. Transplantations occurred in 1997–2003. Rates of neutrophil and platelet recovery were not different among the three treatment groups. Grade 2–4 acute graft-versus-host disease (GVHD) (RR 0.82, p=0.539), grade 3–4 acute GVHD (RR 0.74, p=0.535) and chronic GVHD (RR 1.56, p=0.229) were similar after G-BM and BM transplants. Grade 2–4 acute GVHD (RR 2.37, p=0.012) but not grade 3–4 acute GVHD (RR 1.66, p=0.323) and chronic GVHD (RR 5.09, p<0.001) were higher after PBPC transplants compared to G-BM. Grade 2–4 (RR 2.90, p<0.001), grade 3–4 (RR 2.24, p=0.009) acute GVHD and chronic GVHD (RR 3.26, p<0.001) were higher after PBPC transplants compared to BM. Mortality risks were lower after transplantation of BM compared to G-BM (RR 0.63, p=0.05). These data suggest no advantage to using G-BM and the observed higher rates of acute and chronic GVHD in PBPC recipients warrants cautious use of this graft source for SAA. Taken together, BM is the preferred graft for HLA matched sibling transplants for SAA.
PMCID: PMC3114180  PMID: 21034842
G-mobilized BM; GVHD; aplastic anemia; survival
15.  Minimal Disease Assessment in the Treatment of Children and Adolescents with Intermediate-Risk (Stage III/IV) B-Cell Non-Hodgkin Lymphoma: A Children’s Oncology Group Report 
British journal of haematology  2011;153(6):758-763.
Children/adolescents with mature B-cell non-Hodgkin lymphoma (B-NHL) have an excellent prognosis but relapses still occur. While chromosomal aberrations and/or clonal immunoglobulin (Ig) gene rearrangements may indicate risk of failure, a more universal approach was developed to detect minimal disease (MD). Children/adolescents with intermediate-risk B-NHL were treated with French-British-American/Lymphome Malins de Burkitt 96 (FAB/LMB96) B4 modified chemotherapy and rituximab. Specimens from diagnosis, end of induction (EOI), and end of therapy (EOT) were assayed for MD. Initial specimens were screened for IGHV family usage with primer pools followed by individual primers to identify MD. Thirty-two diagnostic/staging specimens screened positive with primer pools and unique IGHV family primers were identified. Two patients relapsed; first relapse (4 months from diagnosis) was MD-positive at EOI, the second (36 months from diagnosis) was MD-positive at EOT. At EOI, recurrent rates were similar between the MRD-positive and MRD-negative patients (p=0.40). At EOT, only 13/32 patients had MRD data available with 1 relapse in the MRD-positive group and no recurrences in the MRD-negative group (p=0.077). The study demonstrated molecular-disseminated disease in which IgIGHV primer pools could be used to assess MD. This feasibility study supports future investigations to assess the validity and significance of MD screening in a larger cohort of patients with intermediate-risk mature B-NHL.
PMCID: PMC3103617  PMID: 21496005
non-Hodgkin lymphoma; minimal residual disease; lymphoma; polymerase chain reaction; immunoglobulin rearrangement
We describe long-term disease-free survival after unrelated donor bone marrow transplantation (BMT) for myelodysplastic syndrome (MDS) in 118 patients aged ≤18 years. Forty-six patients had refractory cytopenia (RC), 55, refractory anemia with excess blasts (RAEB) and 17, refractory anemia with excess blasts in transformation (RAEB-t). Transplant-related mortality was higher after mismatched BMT (relative risk [RR] 3.29, p=0.002). Disease recurrence was more likely with advanced stages of MDS at the time of BMT: RAEB (RR 6.50, p=0.01) or RAEB-t (RR 11.00, p=0.004). Treatment failure (recurrent disease or death from any cause; inverse of disease-free survival [DFS]) occurred in 68 patients. Treatment failure was higher after mismatched BMT (RR 2.79, p=0.001) and in those with RAEB-t (RR 2.38, p=0.02). Secondary MDS or chemotherapy prior to BMT was not associated with recurrence or treatment failure. Similarly, cytogenetic abnormalities were not associated with transplant outcomes. Eight-year DFS for patients with RC after matched and mismatched unrelated donor BMT was 65% and 40%, respectively. Corresponding DFS for patients with RAEB and RAEB-t was 48% and 28%, respectively. When a matched adult unrelated donor is available, BMT should be offered as first-line therapy and children with RC can be expected to have the best outcome.
PMCID: PMC3033968  PMID: 20813197
pediatric myelodysplastic syndrome; unrelated donor; bone marrow transplantation
17.  Autologous Peripheral Blood Stem Cell Transplantation in Children with Refractory or Relapsed Lymphoma: Results of Children’s Oncology Group Study A5962 
This prospective study was designed to determine the safety and efficacy of cyclophosphamide, BCNU and etoposide (CBV) conditioning and autologous peripheral blood stem cell transplant (PBSCT) in children with relapsed or refractory Hodgkin and non-Hodgkin lymphoma (HL and NHL).
Patients and Methods
Patients achieving CR or PR after 2–4 courses of reinduction underwent a G-CSF mobilized PBSC apheresis with a target collection dose of 5×106 CD34+/kg. Those eligible to proceed received autologous PBSCT after CBV (7200 mg/m2, 450–300 mg/m2, 2400 mg/m2).
Forty-three of 69 patients (30/39 HL, 13/30 NHL) achieved a CR/PR after reinduction. Thirty-eight patients (28 HL, 10 NHL) underwent PBSCT. All initial 6 patients who received BCNU at 450 mg/m2 experienced grade III or IV pulmonary toxicity compared to none of the subsequent 32 receiving 300 mg/m2 (p<0.0001). The probability of OS at 3 years for all patients is 51% and for transplanted patients is 64%. The 3-year EFS is 38% (45% for HL; 30% NHL). The 3-year EFS in transplanted patients is 66% (65% HL; 70% NHL). Initial duration of remission of ≥ 12 vs < 12 months was associated with a significant increase in OS (3 ys OS 70% vs 34%) (p=0.003).
BCNU at 300 mg/m2 in a CBV regimen prior to PBSCT is well tolerated in relapsed or refractory pediatric lymphoma patients. A short duration (< 12 months) of initial remission is associated with a poorer prognosis. Lastly, a high percentage of patients achieving a CR/PR after reinduction therapy can be salvaged with CBV and autologlous PBSCT.
PMCID: PMC3072756  PMID: 20637881
autologous transplant; PBSCT; CBV; lymphoma; NHL; HL
18.  Bilateral Burkitt Lymphoma of the Ovaries: A Report of a Case in a Child with Williams Syndrome 
Case Reports in Medicine  2011;2011:327263.
A 10-year-old female with Williams Syndrome (WS) presented with a two-month history of fatigue, weight loss, and bilateral ovarian masses. Histologic, immunophenotypic, and cytogenetic studies confirmed the diagnosis of Burkitt lymphoma (BL). While there is no established association between the two disorders, this is the third case in the literature of Burkitt lymphoma in a patient with Williams Syndrome.
PMCID: PMC3114539  PMID: 21687537
19.  Prognostic significance of interleukin-6 single nucleotide polymorphism genotypes in neuroblastoma: rs1800795 (promoter) and rs8192284 (receptor) 
Neuroblastoma is a childhood cancer of the sympathetic nervous system and many patients present with high risk disease. Risk stratification, based on pathology and tumor-derived biomarkers, has improved prediction of clinical outcomes, but overall survival rates remain unfavorable and new therapeutic targets are needed. Some studies suggest a link between interleukin-6 and more aggressive behavior in neuroblastoma tumor cells. Therefore, we examined the impact of two IL-6 single nucleotide polymorphisms (SNP) on neuroblastoma disease progression.
Experimental design
DNA samples from 96 high risk neuroblastoma patients were screened for two SNP that are known to regulate the serum levels of IL-6 and the soluble IL-6 receptor (IL-6R), rs1800795 and rs8192284 respectively. The genotype for each SNP was determined in a blinded fashion and independent statistical analysis was performed to determine SNP-related event free survival (EFS) and overall survival (OS) rates.
The rs1800795 IL-6 promoter SNP is an independent prognostic factor for EFS and OS in -high risk neuroblastoma patients. In contrast, the rs8192284 IL-6 receptor SNP revealed no prognostic value.
The rs1800795 SNP (-174 IL-6 (G>C) represents a novel and independent prognostic marker for both EFS and OS in high risk neuroblastoma. Since the rs1800795 SNP (-174 IL-6 (G>C) has been shown to correlate with production of IL-6, this cytokine may represent a target for development of new therapies in neuroblastoma.
PMCID: PMC2740837  PMID: 19671870
20.  Intensive Chemotherapy for Systemic Anaplastic Large Cell Lymphoma in Children and Adolescents: Final Results of Children's Cancer Group Study 5941 
Pediatric blood & cancer  2009;52(3):335-339.
Anaplastic large cell lymphoma (ALCL) is characterized by advanced disease at presentation (70-80% of pediatric cases) and accounts for 10-15% of all childhood lymphomas. Treatment strategies for pediatric ALCL vary from short pulse B-NHL chemotherapy to prolonged leukemia like therapy. The optimal treatment strategy is unknown.
CCG-5941 used a compressed aggressive multiagent T-cell lineage chemotherapy regimen consisting of a three week induction therapy (vincristine, prednisone, cyclophosphamide, daunomycin, asparaginase) followed by a three-week consolidation period (vincristine, prednisone, etoposide, 6-thioguanine, cytarabine, asparaginase, methotrexate) followed by six courses of maintenance chemotherapy at 7-week intervals (cyclophosphamide, 6-thioguanine, vincristine, prednisone, doxorubicin, asparaginase, methotrexate etoposide, cytarabine). Total therapy was 48 weeks.
86 children (male 56%, female 44%) with non-localized ALCL (CD30+) were treated. The majority of tumors were positive for ALK (90%) and of T lineage (83%). Extranodal disease was common (mediastinum 35%, skin 15%, lung 14%, bone 12%, bone marrow 13%, liver 6%, and other viscera 17%). Grade 4 neutropenia occurred in 82% of patients. The 5 year EFS was 68% (95% CI of 57-78%) and the 5 year OS was 80% (95% CI of 69-87%). There were 21 relapses and 4 toxic deaths as first events. Relapse occurred early with 17 (81%) relapses occurring within 2 years of diagnosis and 12 (57%) while receiving therapy. Univariate analysis for risk factors only identified bone marrow involvement predicting lower EFS (P=0.03).
CCG-5941 demonstrated efficacy similar to previously reported regimens but with significant hematologic toxicity.
PMCID: PMC2769495  PMID: 18985718
Anaplastic Large Cell Lymphoma; CD30; ALK positive lymphoma; Pediatric; non-Hodgkin lymphoma; t(2;5)
21.  A Study of Rituximab and Ifosfamide, Carboplatin, and Etoposide Chemotherapy in Children with Recurrent/Refractory B-cell (CD20+) Non-Hodgkin Lymphoma and Mature B-Cell Acute Lymphoblastic Leukemia: A Report from the Children's Oncology Group 
Pediatric blood & cancer  2009;52(2):177-181.
To estimate the response rate and therapy related toxicities of the anti-CD20 monoclonal antibody rituximab when combined with chemotherapy including ifosfamide, carboplatin, and etoposide (ICE) in patients with relapsed and refractory B-cell non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia (B-ALL).
Patients received rituximab and ICE for 1 to 3 cycles, depending upon response. Rituximab (375 mg/m2) was given on day 1 and 3 of each cycle (day 1 only for cycle 3), with ifosfamide (3000 mg/m2) and etoposide (100 mg/m2) given on days 3, 4, and 5 and carboplatin (635 mg/m2) given on day 3 only.
Twenty-one patients were enrolled, of whom 20 were eligible and evaluable. Although hematologic toxicities were common, only one patient was removed from study due to prolonged myelosuppression. Toxicities related to infusions of rituximab were frequent but manageable. Of the 6 eligible patients with diffuse large B-cell lymphoma, 3 achieved complete remission (CR), 1 had stable disease (SD), and 2 had progressive disease (PD). Of the 14 eligible patients with Burkitt lymphoma and B-ALL, there were 4 complete responses (CR), 5 partial responses (PR), 1 SD and 4 with PD. Thus the CR/PR rate for the entire group was 12/20 (60%). Following completion of protocol therapy 6 patients were able to proceed to consolidation with high-dose therapy and stem cell rescue.
The combination of rituximab and ICE chemotherapy was associated with an encouraging objective response rate and an acceptable toxicity profile.
PMCID: PMC2728935  PMID: 18816698
Non-Hodgkin's Lymphoma; Large Cell Lymphoma; Burkitt's Lymphoma; Chemotherapy
22.  The Israel Penn International Transplant Tumor Registry 
The Israel Penn International Transplant Tumor Registry is literally the world’s premier repository of information on patients who have developed malignancies after organ transplants. The administrators of the Registry not only collect information but also provide consulting services based on the accumulated knowledge that the Registry contains. By creating a secure Web-based front end, we have made it possible for the Registry to keep pace with its burgeoning international caseload.
PMCID: PMC1480060  PMID: 14728556

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