Elaine S. Jaffe

New Malignant Diseases After Allogeneic Marrow Transplantation for Childhood Acute Leukemia

PURPOSEnTo determine the incidence of and risk factors for second malignancies after allogeneic bone marrow transplantation (BMT) for childhood leukemia.nnnPATIENTS AND METHODSnWe studied a cohort of 3, 182 children diagnosed with acute leukemia before the age of 17 years who received allogeneic BMT between 1964 and 1992 at 235 centers. Observed second cancers were compared with expected cancers in an age- and sex-matched general population. Risks factors were evaluated using Poisson regression.nnnRESULTSnTwenty-five solid tumors and 20 posttransplant lymphoproliferative disorders (PTLDs) were observed compared with 1.0 case expected (P <.001). Cumulative risk of solid cancers increased sharply to 11.0% (95% confidence interval, 2.3% to 19.8%) at 15 years and was highest among children at ages younger than 5 years at transplantation. Thyroid and brain cancers (n = 14) accounted for most of the strong age trend; many of these patients received cranial irradiation before BMT. Multivariate analyses showed increased solid tumor risks associated with high-dose total-body irradiation (relative risk [RR] = 3.1) and younger age at transplantation (RR = 3.7), whereas chronic graft-versus-host disease was associated with a decreased risk (RR = 0.2). Risk factors for PTLD included chronic graft-versus-host disease (RR = 6.5), unrelated or HLA-disparate related donor (RR = 7. 5), T-cell-depleted graft (RR = 4.8), and antithymocyte globulin therapy (RR = 3.1).nnnCONCLUSIONnLong-term survivors of BMT for childhood leukemia have an increased risk of solid cancers and PTLDs, related to both transplant therapy and treatment given before BMT. Transplant recipients, especially those given radiation, should be monitored closely for second cancers.

Increased Incidence of Hodgkin's Disease After Allogeneic Bone Marrow Transplantation

PURPOSEnImmune dysregulation associated with allogeneic bone marrow transplantation (BMT) is linked to an increased risk of posttransplant lymphoproliferative disorders (PTLD); however, reports of Hodgkins disease (HD) after transplantation are rare.nnnPATIENTS AND METHODSnWe evaluated the risk of HD among 18,531 persons receiving allogeneic BMT between 1964 and 1992 at 235 centers. The number of HD cases was compared with that expected in the general population. Risk factors were identified using Poisson regression and a nested case-control study.nnnRESULTSnRisk of HD was increased in the postBMT population compared with the general population with an observed-to-expected incidence ratio (O/E) of 6.2 (observed cases, n = 8; 95% confidence interval [CI], 2.7 to 12). A significantly increased risk of HD remained after excluding two human immunodeficiency virus-positive patients (observed cases, n = 6; O/E = 4.7, 95% CI, 1.7 to 10.3). Mixed cellularity subtype predominated (five of eight cases, 63%). Five of six assessable cases contained Epstein-Barr virus (EBV) genome. Posttransplant HD differed from PTLD by later onset (> 2.5 years) and lack of association with established risk factors (such as T-cell depletion and HLA disparity). Patients with HD were more likely than matched controls to have had grade 2 to 4 acute graft-versus-host disease (GVHD), required therapy for chronic GVHD, or both (P =.002), although analysis included small numbers of patients.nnnCONCLUSIONnThe increased incidence of HD among BMT recipients adds support to current theories which link overstimulation of cell-mediated immunity and exposure to EBV with various subtypes of HD. The long latency of HD after transplant and lack of association with risk factors for PTLD is noteworthy and should be explored further for possible insights into pathogenesis.

Phase II and dose-escalation with or without granulocyte colony-stimulating factor study of 9-aminocamptothecin in relapsed and refractory lymphomas.

PURPOSEnTo assess the efficacy and maximum dose-intensity of a new topoisomerase I (topo I)-targeting agent, 9-aminocamptothecin (9-AC), in patients with relapsed or refractory lymphomas.nnnPATIENTS AND METHODSnEligible patients had measurable disease and were considered incurable. 9-AC was infused over 72 hours at an initial dose rate of 40 microg/m2/h every 3 weeks with subsequent intrapatient escalations or reductions in 10-microg/m2/h increments based on toxicity. To assess the impact of granulocyte-colony stimulating factor (G-CSF) on dose-intensity, the first 16 patients received no G-CSF and the subsequent 29 patients received G-CSF on all cycles.nnnRESULTSnForty-five patients received a total of 142 cycles of 9-AC. The patients median age was 55 years, 73% had stage IV disease, and histologies included indolent and aggressive non-Hodgkins lymphoma (NHL) in 33% and 58% of patients, respectively, and Hodgkins lymphoma in 9%. Patients had received a median of two prior chemotherapy regimens, and 67% of patients had chemotherapy-sensitive disease. Of 40 assessable patients, 10 (25%) achieved a partial response (PR). Chemotherapy-sensitive patients had a 32% response rate compared with 8% in chemotherapy-resistant patients. With a median follow-up duration of 35 months, the median event-free survival (EFS) and overall survival times were 1.5 and 12.5 months, respectively, and the median duration of response was 5 months (range, 1 to 10). G-CSF significantly reduced the incidence of neutropenia and diarrhea, but did not permit a significant increase in dose-intensity.nnnCONCLUSIONn9-AC had a reasonable response rate of 25% in heavily pretreated patients. The low response rate in patients with chemotherapy-resistant disease suggests that there is cross-resistance between 9-AC and standard chemotherapy. However, there was no association between 9-AC response and the number of prior regimens. Due to dose-limiting thrombocytopenia, G-CSF support did not increase dose-intensity, although individual patients benefited from the use of G-CSF.

Phase II study of EPOCH infusional chemotherapy in relapsed or refractory Hodgkin's lymphoma (HL). A report on toxicity, efficacy and prognostic indicators of outcome

6598 Background: In relapsed/refractory HL, an effective and well tolerated salvage regimen has important roles both prior to autologous stem cell transplant (SCT) and as palliative therapy in patients (pts) who are ineligible for or have failed SCT.nnnMETHODSnEligible pts had relapsed/refractory HL and adequate organ function unless due to HL. Pts received fixed dose EPOCH chemotherapy (etoposide 200 mg/m2, vincristine 1.6 mg/m2 (no cap) and doxorubicin 40 mg/m2 CIVI x 96-hrs D1-4; cyclophosphamide 750 mg/m2 IV D5 and prednisone 60 mg/m2 qd D1-6 ) with G-CSF q21 days until disease progression or stabilization over ≥ 2 cycles.nnnRESULTSnOf 54 pts, median (range) age was 31 yrs (19-64), 35 (66%) were male, stage was III in 11(21%) and IV in 30(56%), and 29 (55%) had B symptoms. Histology included nodular sclerosis 34 (64%), mixed cellularity 3 (25%), and lymphocyte depleted 5 (9%) classical HL, and nodular lymphocyte predominant HL 1 (2%). 24 (45%) pts had had ≥ 2 prior regimens, 27 (51%) pts received chemotherapy within the previous 10 mos, and 40 (75%) pts had responded to their last treatment. Over 202 cycles, toxicities included fever and neutropenia on 9 (4%), grade (gr) 4 neutropenia on 31 (15%), gr 4 thrombocytopenia on 20 (10%), and ≥ gr 2 gastrointestinal toxicity on 20 (10%) cycles; ≥ gr 2 cardiotoxicity occurred in 2 (4%) and ≥ gr 2 neurotoxicity in 11 (20%) pts. There was one treatment related death. 45 (84%) pts responded with 23 (44%) CR and 21 (40%) PR. With a median follow-up of 68 mos, the median progression-free (PFS) and overall survivals (OS) are 10 and 40 mos, and at 68 mos median follow-up, PFS and OS are 21% and 41%. Among 33 pts who underwent SCT, median PFS is 15 mos and OS has not been reached. Multivariate analysis revealed that the no. of prior drugs and response to the preceding regimen significantly influenced OS and PFS; in addition PFS was significantly influenced by performance status and mos since previous chemotherapy.nnnCONCLUSIONSnEPOCH is well tolerated and has a high response rate in relapsed/refractory HL. It should be considered as salvage therapy prior to SCT or for palliation in incurable HL. No significant financial relationships to disclose.