Summary

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.

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.

Purpose

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).

Results

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).

Conclusion

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.

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.

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.

Purpose

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.

Results

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.

Conclusions

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.

Background

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.

Methods

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.

Results

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).

Conclusions

CCG-5941 demonstrated efficacy similar to previously reported regimens but with significant hematologic toxicity.

Background

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).

Methods

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.

Results

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.

Conclusions

The combination of rituximab and ICE chemotherapy was associated with an encouraging objective response rate and an acceptable toxicity profile.

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.

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.

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.