Lauren Harrison

Advanced Stage, Increased Lactate Dehydrogenase, and Primary Site, but Not Adolescent Age (≥ 15 Years), Are Associated With an Increased Risk of Treatment Failure in Children and Adolescents With Mature B-Cell Non-Hodgkin's Lymphoma: Results of the FAB LMB 96 Study

PURPOSE Adolescents (age 15 to 21 years) compared with younger children with mature B-cell non-Hodgkins lymphoma (NHL) have been historically considered to have an inferior prognosis. We therefore analyzed the impact of age and other diagnostic factors on the risk of treatment failure in children and adolescents treated on the French-American-British Mature B-Cell Lymphoma 96 (FAB LMB 96) trial. PATIENTS AND METHODS Patients were divided by risk: group A (limited), group B (intermediate), and group C (advanced), as previously described. Prognostic factors analyzed for event-free survival (EFS) included age (< 15 v ≥ 15 years), stage (I/II v III/IV), primary site, lactate dehydrogenase (LDH), bone marrow/CNS (BM/CNS) involvement, and histology (diffuse large B-cell lymphoma v mediastinal B-cell lymphoma v Burkitt lymphoma or Burkitt-like lymphoma). RESULTS The 3-year EFS for the whole cohort was 88% ± 1%. Age was not associated as a risk factor for increased treatment failure in either univariate analysis (P = .15) or multivariate analysis (P = .58). Increased LDH (≥ 2 × upper limit of normal [ULN] v < 2 × ULN), primary site, and BM-positive/CNS-positive disease were all independent risk factors associated with a significant increase in treatment failure rate (relative risk, 2.0; P < .001, P < .012, and P < .001, respectively). CONCLUSION LDH level at diagnosis, mediastinal disease, and combined BM-positive/CNS-positive involvement are independent risk factors in children with mature B-cell NHL. Future studies should be developed to identify specific therapeutic strategies (immunotherapy) to overcome these risk factors and to identify the biologic basis associated with these prognostic factors in children with mature B-cell NHL.

Rituximab and FAB/LMB 96 chemotherapy in children with Stage III/IV B-cell non-Hodgkin lymphoma: a Children’s Oncology Group report

Rituximab and FAB/LMB 96 chemotherapy in children with Stage III/IV B-cell non-Hodgkin lymphoma: a Children’s Oncology Group report

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.

Rituximab with chemotherapy in children and adolescents with central nervous system and/or bone marrow-positive Burkitt lymphoma/leukaemia: a Children's Oncology Group Report

Children and adolescents with Burkitt Lymphoma (BL) and combined central nervous system (CNS) and bone marrow involvement still have a poor prognosis with chemotherapy alone. We therefore investigated in children and adolescents with bone marrow (≥25% blasts) and/or CNS‐positive Burkitt lymphoma the chemoimmunotherapy combination of rituximab (375 mg/m2) and the standard chemotherapy arm of our previously reported French‐American‐British (FAB) Lymphome Malins de Burkitt (LMB) 96 trial. Central pathological and cytogenetic characterization was also performed. There were 40 evaluable patients with Burkitt histology (25 with leukaemia and 15 with CNS disease ± leukaemia). The chemoimmunotherapy regimen was well tolerated. The incidence of grade III/IV mucositis during induction cycles with combined chemotherapy and rituximab was 31% and 26%, respectively. The 3‐year event‐free survival (EFS)/overall survival (OS) was 90% (95% confidence interval [CI], 76–96%) in the entire cohort and 93% (95% CI, 61–99%) in patients with CNS disease. Based on the results of this trial, an international randomized study of FAB/LMB 96 chemotherapy ± rituximab for high‐risk patients is currently under investigation.

An increased frequency of 13q deletions detected by fluorescence in situ hybridization and its impact on survival in children and adolescents with Burkitt lymphoma: results from the Children’s Oncology Group study CCG-5961

Burkitt lymphoma (BL), an aggressive B‐cell malignancy, is often curable with short intensive treatment regiments. Nearly all BLs contain rearrangements of the MYC/8q24 region; however, recent cytogenetic studies suggest that certain secondary chromosomal aberrations in BL correlate with an adverse prognosis. In this multi‐centre study, the frequency and impact on clinical outcome of del(13q) and +7 in addition to MYC rearrangements as detected by fluorescence in situ hybridization (FISH) in children and adolescents with intermediate and high‐risk BL registered on Children’s Cancer Group study CCG‐5961 were investigated. Analysis with 13q14.3 and 13q34 loci specific probes demonstrated deletions of 13q in 38/90 (42%) cases. The loss of either 13q14.3 or 13q34 alone occurred in 14% and 8% respectively, while 20% exhibited loss of both regions. Gain of chromosome 7 was observed in 7/68 (10%) cases and MYC rearrangements were detected in 84/90 (93%). Prognostic analysis controlling for known risk factors demonstrated that patients exhibiting loss of 13q, particularly 13q14.3, had a significant decrease in 5‐year overall survival (77% vs. 95%, P = 0·012). These observations indicate that del(13q) occurs in childhood BL at frequencies higher than previously detected by classical cytogenetics and underscores the importance of molecular cytogenetics in risk stratification.

Outcome and pathologic classification of children and adolescents with mediastinal large B-cell lymphoma treated with FAB/LMB96 mature B-NHL therapy

Mediastinal large B-cell lymphoma (MLBL) represents 2% of mature B-cell non-Hodgkin lymphoma in patients ≤ 18 years of age. We analyzed data from childhood and adolescent patients with stage III MLBL (n = 42) and non-MLBL DLBCL (n = 69) treated with Group B therapy in the French-American-British/Lymphome Malins de Burkitt (FAB/LMB) 96 study. MLBL patients had a male/female 26/16; median age, 15.7 years (range, 12.5-19.7); and LDH < 2 versus ≥ 2 × the upper limit of normal, 23:19. Six MLBL patients (14%) had < a 20% response to initial COP (cyclophosphamide, vincristine, and prednisone) therapy. Central pathology revealed approximately 50% with classical features of primary MLBL. Five-year event-free survival for the stage III MLBL and non-MLBL DLBCL groups was 66% (95% confidence interval [CI], 49%-78%) and 85% (95% CI, 71%-92%), respectively (P < .001; 14%). The 5-year overall survival in the 42 MLBL patients was 73% (95% CI, 56%-84%). We conclude that MLBL in adolescent patients is associated with significantly inferior event-free survival compared with stage III non-MLBL DLBCL and can be of multiple histologies. Alternate treatment strategies should be investigated in the future taking into account both adult MLBL approaches and more recent biologic findings in adult MLBL.

A comparison of immune reconstitution and graft-versus-host disease following myeloablative conditioning versus reduced toxicity conditioning and umbilical cord blood transplantation in paediatric recipients

Immune reconstitution appears to be delayed following myeloablative conditioning (MAC) and umbilical cord blood transplantation (UCBT) in paediatric recipients. Although reduced toxicity conditioning (RTC) versus MAC prior to allogeneic stem cell transplantation is associated with decreased transplant‐related mortality, the effects of RTC versus MAC prior to UCBT on immune reconstitution and risk of graft‐versus‐host disease (GVHD) are unknown. In 88 consecutive paediatric recipients of UCBT, we assessed immune cell recovery and immunoglobulin reconstitution at days +100, 180 and 365 and analysed risk factors associated with acute and chronic GVHD. Immune cell subset recovery, immunoglobulin reconstitution, and the incidence of opportunistic infections did not differ significantly between MAC versus RTC groups. In a Cox model, MAC versus RTC recipients had significantly higher risk of grade II–IV acute GVHD [Hazard Ratio (HR) 6·1, P = 0·002] as did recipients of 4/6 vs. 5–6/6 HLA‐matched UCBT (HR 3·1, P = 0·03), who also had significantly increased risk of chronic GVHD (HR 18·5, P = 0·04). In multivariate analyses, MAC versus RTC was furthermore associated with significantly increased transplant‐related (Odds Ratio 26·8, P = 0·008) and overall mortality (HR = 4·1, P = 0·0001). The use of adoptive cellular immunotherapy to accelerate immune reconstitution and prevent and treat opportunistic infections and malignant relapse following UCBT warrants further investigation.

Rasburicase in the prevention of laboratory/clinical tumour lysis syndrome in children with advanced mature B-NHL: a Children's Oncology Group Report

Laboratory (LTLS) and clinical (CTLS) tumour lysis syndrome (TLS) are frequent complications in newly diagnosed children with advanced mature B cell non‐Hodgkin lymphoma (B‐NHL). Rasburicase, compared to allopurinol, results in more rapid reduction of uric acid in paediatric patients at risk for TLS. However, the safety and efficacy of rasburicase for the treatment or or prevention of TLS has not been prospectively evaluated. Children with newly diagnosed stage III‐IV, bone marrow+ and/or central nervous system+ mature B‐NHL received hydration and rasburicase prior to cytoreductive therapy. Rasburicase was safe and well‐tolerated and there were no grade III–IV toxicities probably or directly related to rasburicase. Patients with an initial lactate dehydrogenase ≥2× upper limit of normal had a significantly elevated uric acid level (P = 0·005), increased incidence of TLS (P−0·005) and lower glomerular filtration rate (GFR; P < 0·001). Following rasburicase, there was only a 9% and 5% incidence of LTLS and CTLS, respectively. Furthermore, there was a significant improvement in estimated GFR from Day 0 to Day 7 following rasburicase (P = 0·0007) and only 1·3% of patients required new onset renal assisted support after rasburicase administration. A TLS strategy incorporating rasburicase prior to cytoreductive chemotherapy proved safe and effective in preventing new onset renal failure and was associated with a significant improvement in GFR.

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

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 one 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.

A Phase I Study of 90Yttrium-Ibritumomab-Tiuxetan in Children and Adolescents with Relapsed/Refractory CD20-Positive Non–Hodgkin's Lymphoma: A Children's Oncology Group Study

Purpose: The prognosis for children with recurrent CD20+ non–Hodgkins lymphoma is dismal. A radiolabeled anti-CD20 antibody, 90yttrium-ibritumomab-tiuxetan (90Y-IT), is Food and Drug Administration approved for adults with recurrent indolent CD20+ B cell–non–Hodgkins lymphoma. There is no data on the safety and feasibility of 90Y-IT in refractory childhood CD20+ lymphoma. Experimental Design: Children and adolescents with refractory/relapsed CD20+ lymphoma were eligible for this phase I radioimmunotherapy study. Patients (n = 5) received rituximab (250 mg/m2 i.v.) on days 0 and 7 and indium-111 ibritumomab-tiuxetan (5 mCi i.v.) on day 0. Dosimetry studies were done on days 0, 1, 3, and 6. Immediately after rituximab on day 7, patients received 90Y-IT if dosimetry studies showed <2000 cGy exposure to all solid organs and <300 cGy to marrow, as well as 0.4 mCi/kg in patients with good marrow reserve (n = 3) and 0.1 mCi/kg in patients with poor marrow reserve (after bone marrow transplant; n = 2). Results: No patients experienced nonhematologic or hematologic dose-limiting toxicity. Human antimurine antibody/human antichimeric antibody incidence was 0%. One patient experienced grade II infusion–related chills associated with rituximab. The following are the means of organ radiation exposure (cGy): kidneys 341 (112-515), liver 345 (83-798), lungs 309 (155-519), marrow 46 (20-78), spleen 565 (161-816), and total body 42 (14-68). Conclusions: Based on these findings, an expanded investigator-initiated limited institutional phase II study has been designed to further evaluate the safety, tolerability, and response rate with 90Y-IT dose stratification based on marrow reserve.