Changes in endogenous TPO levels during mobilization chemotherapy are predictive of CD34+ megakaryocyte progenitor yield and identify patients at risk of delayed platelet engraftment post-PBPC transplant.

Patients with delayed platelet recovery post-PBPC transplant (PBPCT) are a high-risk group for thrombocytopenic bleeding and platelet transfusion dependence. Total CD34+ cell dosage has been proposed as the most important factor influencing the rate of platelet recovery. To achieve the shortest time to platelet engraftment, a minimum leukapheresis target of 10x10(6) CD34+ cells/kg was established for 30 patients. Of the 29 evaluable patients, 62% had rapid (group I: time to platelets >20x10(9)/l < or =10 days and 50x10(9)/l < or =14 days) platelet recoveries while 38% had delayed (group II: 20x10(9)/l >10 days and 50x10(9)/l >14 days) recoveries. Groups I and II were compared for: (1) pretreatment variables; (2) mobilizing capability of CD34+ cells and subsets including megakaryocyte (Mk) progenitors; (3) infused dose of these cells at transplant; (4) changes in endogenous levels of Mpl ligand (or TPO) during mobilization and myeloablative chemotherapy. Group II patients received significantly more platelet transfusions (6 vs. 2.1, P = 0.002) post-PBPCT, had a higher proportion of patients with a prior history of BM disease (64% vs. 6%, P = 0.001), and showed a reduced ability to mobilize differentiated (CD34+/38+, CD34+/DR+) and Mk progenitors (CD34+/42a+, CD34+/61+). Only the number of Mk progenitors reinfused at transplant was significantly different between the groups (group II vs. group I: CD34+/42a+ = 1.02 vs. 2.56x10(6)/kg, P = 0.013; CD34+/61+ = 1.12 vs. 2.70x10(6)/kg, P = 0.015). The ability to mobilize Mk progenitors correlated with percentage changes in endogenous levels of TPO from baseline to platelet nadir during mobilization chemotherapy (CD34+/42a+: r = 0.684, P = 0.007; CD34+/61+: r = 0.684, P = 0.007), with group II patients experiencing lower percentage changes. An inverse trend but no correlation was observed between serial TPO levels and platelet counts. TPO levels remained elevated in group II patients throughout a prolonged period of thrombocytopenia (median days to 50x10(9)/l = 25 vs. 11 for group I), indicating that delayed engraftment was not due to a deficiency of TPO but to a lack of Mk progenitor target cells. Our results show that the number of reinfused Mk progenitors is a better predictor of platelet engraftment than total CD34+ cell dosage. Small changes in endogenous TPO levels during mobilization predict for low Mk progenitor yields.

Modelling cure rates using the Gompertz model with covariate information.

We extend the modified Gompertz hazard function, first used by Cantor and Shuster for estimation of cure rates from pediatric clinical trials, by including covariate effects. The extended model provides a convenient method for estimation of the cure rate as a function of treatments and covariates.

Lymphocyte predominant Hodgkin disease: clinico-pathologic features and results of treatment--the Pediatric Oncology Group experience.

PURPOSE: In this report, the Pediatric Oncology Group (POG) experience with lymphocyte predominant Hodgkin Disease (LPHD) in children is reviewed. MATERIALS AND METHODS: From 1984-1993, the POG conducted 3 clinical trials for advanced stage HD and 2 for early stage HD. There were 26 cases of LPHD in 613 patients in these trials. Patients' ages ranged from 3.1-17.8 years (mean of 12.9 years). There was a marked male predominance. RESULTS: Histologic subtypes were 17 nodular, 8 diffuse pattern; 1 was indeterminant. The sites involved at diagnosis were primarily the peripheral lymph nodes. Fourteen patients had stage (S) I disease; 9 had SII; 3 had SIII; there was no SIV disease. Only 4 of 26 patients had B symptoms. All 26 patients achieved complete remission, 10 with radiotherapy, 6 with chemotherapy and 10 with combined modality therapy. Treatment was not uniform since patients were registered on different protocols. Event-free survival after 5 years was 86.5 percent. Two patients developed and succumbed to large cell, T-cell type, non-Hodgkin lymphoma (NHL). CONCLUSIONS: Optimal treatment for LPHD should focus on efforts to limit the risk of second malignancy.

Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin's disease in pediatric patients: a Pediatric Oncology Group study.

PURPOSE: To determine whether the addition of low-dose total-nodal irradiation (TNI) in pediatric patients with advanced-stage Hodgkin's disease who have received eight cycles of alternating mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) will improve the event-free survival (EFS) and overall survival (OS) when compared with patients who have received chemotherapy only. PATIENTS AND METHODS: At diagnosis, 183 children and adolescents with stages IIB, IIIA2, IIIB, and IV Hodgkin's disease were randomized to receive eight cycles of alternating MOPP-ABVD with or without low-dose TNI. RESULTS: Of 183 patients, four were rendered ineligible before treatment was initiated. One hundred sixty-one of 179 patients (90%) were in complete remission (CR) at the completion of eight cycles of alternating MOPP-ABVD; 81 were in the chemotherapy-only group and proceeded to observation off therapy, whereas 80 of 161 were to receive combined modality therapy (CMT). Nine of 80 patients randomized at the time of diagnosis to receive CMT did not receive radiation (RT) because of a protocol violation, but were monitored for EFS and OS and included in all analyses. The estimated EFS and OS rates at 5 years for the 179 eligible patients are 79% and 92%, respectively. The actuarial EFS at 5 years was 80% for patients who received CMT and 79% for patients who received MOPP-ABVD only. The OS for the former group is estimated to be 87% and for the latter patients 96%. Age < or = 13 years of age at diagnosis and the attainment of a clinical CR after three cycles of chemotherapy were associated with a statistically significant improved EFS. CONCLUSION: Our results indicate that after the delivery of eight cycles of MOPP-ABVD, the addition of low-dose RT does not improve the estimated EFS or OS in pediatric patients with advanced-stage Hodgkin's disease.

Meta-analysis and prospective meta-analysis in childhood leukemia clinical research.

In this paper, we consider the role of meta-analysis and 'prospective meta-analysis' studies in childhood acute lymphocytic leukemia (ALL). In this issue, Valsecchi and Masera [1] give a thoughtful discourse, generally favorable to this approach. This article presents the opposite point of view. The aims of our article are to present the implications in clinical, rather than biostatistical terms, and to provide an extensive literature review of the subject of meta-analysis. We conclude that treatment assessments, resulting from meta-analysis of closed studies (retrospective) should be met with healthy skepticism. Trials requiring international resources should be true intergroup trials with a single coordinating center, rather than prospective meta-analysis, unless it is a question grafted onto each group's own research agenda. For example, each group might ask its own systemic control question, but a CNS protection question is asked collectively.