Morris Kletzel

Reduced intensity haemopoietic stem-cell transplantation for treatment of non-malignant diseases in children

BACKGROUND Transplantation of allogeneic haemopoietic stem cells can cure several non-malignant disorders in children. Transplantation with reduced intensity preparation might achieve the same goals but with less toxicity. We undertook a pilot study to determine engraftment rates, kinetics of engraftment, toxicity, and acute graft-versus-host disease (GVHD) associated with a uniform reduced intensity haemopoietic stem-cell transplant (HSCT) regimen for children with non-malignant diseases. METHODS We studied 13 paediatric patients with non-malignant disorders who underwent reduced intensity HSCT at Childrens Memorial Hospital from January, 2000, to February, 2004. Stem-cell sources included unrelated donor, matched-sibling peripheral blood stem cells, and unrelated cord blood. A uniform preparative regimen was used, consisting of fludarabine, busulfan, and anti-thymocyte globulin. Major endpoints were engraftment, transplant-related mortality at day 100, short-term toxicities, and incidence of acute GVHD. RESULTS 72% of evaluable patients achieved full donor engraftment. There was rapid reconstitution of platelets (median 13.5 days) and neutrophils (median 18 days). Short-term toxicities were minimal, as seen by a median length of hospital stay of 7 days (between days 0-100). Incidence of grade II-IV acute GVHD was 8%. Two patients died before day 100 from underlying disease and viral infection, respectively (day 100 transplant-related mortality of 15%). The 1-year overall survival was 84% (95% CI 64-100). Most patients with immunodeficiencies and metabolic disorders had excellent donor engraftment and disease resolution or stabilisation, but most of those with haemoglobinopathies rejected their graft. INTERPRETATION This reduced intensity regimen followed by HSCT provides a good alternative to myeloablative HSCT for children with non-malignant disorders, except for haemoglobinopathies, in which engraftment is poor. Even patients with unrelated donor haemopoietic stem-cell transplants had adequate engraftment with acceptable toxicities.

Treatment of High-Risk Neuroblastoma With Triple-Tandem High-Dose Therapy and Stem-Cell Rescue: Results of the Chicago Pilot II Study

PURPOSE To investigate whether intensive induction therapy followed by triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue and local irradiation will improve event-free survival for patients with high-risk neuroblastoma. PATIENTS AND METHODS From August 1995 to January 2000, 25 consecutive newly diagnosed high-risk neuroblastoma patients and one child with recurrent MYCN-amplified disease were enrolled onto the Chicago Pilot II Protocol. After induction therapy and surgery, peripheral-blood stem cells were mobilized with three cycles of high-dose cyclophosphamide and granulocyte colony-stimulating factor. Patients then underwent triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue followed by radiation to the primary site. RESULTS Twenty-two of the 26 patients successfully completed induction therapy and were eligible for the triple-tandem consolidation high-dose therapy. Sufficient numbers of peripheral-blood stem cells were collected in all but one patient. Seventeen patients were able to complete all three cycles of high-dose therapy and peripheral-blood stem-cell rescue, two patients completed two cycles, and three patients completed one cycle. There was one toxic death, and one patient died from complications of treatment for graft failure. With a median follow-up of 38 months, the 3-year event-free survival and survival rates are 57% +/- 11% and 79% +/- 10%, respectively. CONCLUSION The results of this pilot study demonstrate that it is feasible to intensify consolidation with triple-tandem high-dose chemotherapy and peripheral-blood stem-cell rescue and local irradiation, and suggest that this treatment strategy may lead to improved survival for patients with high-risk neuroblastoma.

Treatment of Wilms tumor relapsing after initial treatment with vincristine, actinomycin D, and doxorubicin. A report from the national Wilms tumor study group

We evaluated the use of alternating cycles of cyclophosphamide/etoposide and carboplatin/etoposide in children entered on National Wilms Tumor Study (NWTS)‐5 who were diagnosed between August 1, 1995 and May 31, 2002 and who relapsed after chemotherapy with vincristine, actinomycin D, and doxorubicin (VAD) and radiation therapy (DD‐4A).

Treatment of Wilms tumor relapsing after initial treatment with vincristine and actinomycin D: A report from the National Wilms Tumor Study Group

NWTS‐5 was a multi‐institutional clinical trial for patients less than 16 years of age at diagnosis with specific renal neoplasms who were diagnosed between August 1, 1995 and May 31, 2002. A uniform approach to the treatment of patients with relapse was employed.

Cytokine-mobilized allogeneic peripheral blood stem cell transplants in children result in rapid engraftment and a high incidence of chronic GVHD

Between October 1995 and October 1998, 24 children aged 9 months to 17 years (median 11 years) underwent cytokine-mobilized allogeneic peripheral blood stem cell (PBSC) transplantation for treatment of hematological disorders. All of the transplants were the first allogeneic transplant for the recipient. Twenty patients were transplanted for hematological malignancies (ALL = 8, AML = 6, CML = 4, MDS = 2) and four patients were transplanted for non-malignant disease (thalassemia major = 2, Wiskott–Aldrich syndrome = 1, Kostmanns syndrome = 1). Nineteen donors were HLA-identical siblings, four were HLA-matched or single antigen mismatched parents, and one was a syngeneic transplant. Donors aged 8 to 38 years (median 15 years, 14 donors v18 years) received g-csf 10 μg/kg/day subcutaneously beginning 4 days before pbsc collection and were submitted to one to three leukapheresis collections. the median cd34+ cell yield was 7.8 × 106 cells/kg recipient body weight. all patients achieved an anc >0.5 × 109/l after a median of 13 days (range 10–21). Twenty-three patients eventually achieved platelet transfusion independence. One patient died on day 63 without ever achieving platelet transfusion independence. Four patients received platelet transfusions to maintain a platelet count well above 20 × 109/l due to bleeding complications. Of the 19 evaluable patients, the median time to a non-transfused platelet count of 20 × 109/l was 12 days (range 0–44). Ten of 23 at-risk patients developed acute GVHD grades II to IV, with grades III to IV in four patients. Twelve of 19 patients followed for at least 100 days have developed chronic GVHD (extensive = 2, limited = 10) with an actuarial risk of chronic GVHD of 75% at 1 year. The Kaplan–Meier estimate of event-free survival is 65% at 2 years. Four patients died (GVHD = 3, VOD = 1), three patients relapsed, and one patient with thalassemia major had a late graft failure with autologous recovery. Based upon our experience, allogeneic PBSCT is safe for both pediatric donors and recipients and engraftment of neutrophils and platelets is rapid. Bone Marrow Transplantation (2000) 25, 13–18.

Response to Paclitaxel, Topotecan, and Topotecan-Cyclophosphamide in Children With Untreated Disseminated Neuroblastoma Treated in an Upfront Phase II Investigational Window: A Pediatric Oncology Group Study

PURPOSE Most children older than 1 year of age with metastatic neuroblastoma (NB) die despite intensive chemotherapy and bone marrow transplantation. The Pediatric Oncology Group conducted a study of paclitaxel, topotecan, and topotecan-cyclophosphamide (topo-cyclo) in newly diagnosed children with stage IV NB. PATIENTS AND METHODS There were 102 patients enrolled between September 1993 and October 1995; two of them were later shown to be ineligible. Of the remaining 100 patients, the first cohort of 33 patients received paclitaxel 350 mg/m(2) intravenously (IV) over 24 hours every 14 to 21 days; the next 33 patients received topotecan 2 mg/m(2)/d for 5 days IV every 21 days; a third cohort of 34 patients were treated with IV cyclophosphamide 250 mg/m(2) followed by topotecan 0.75 mg/m(2) each day for 5 days every 21 days. Patients were re-evaluated after two courses and then treated with intensive induction therapy and bone marrow transplantation. RESULTS Objective responses (complete response + partial response + mixed response) were documented in 67% of children who received topotecan, 76% after topo-cyclo, and 25% after paclitaxel. Four patients had grade 3 to 4 allergic reactions to paclitaxel; most patients developed grade 3 to 4 marrow suppression after topotecan or topo-cyclo. Neither disease-free survival nor overall survival differed significantly between children who received a phase II agent and those who did not. The 6-year disease-free survival and overall survival rates for all 100 children were 18% +/- 5% and 26% +/- 5%, respectively. CONCLUSION Topotecan and topo-cyclo are active in children with NB, are well tolerated, and should be evaluated further in combination regimens.

Results of little or no treatment for lymphocyte-predominant Hodgkin disease in children and adolescents

Purpose The nodular lymphocyte-predominant form of Hodgkin disease (LPHD) is a distinct clinicopathologic entity with a favorable prognosis. To see if children and adolescents could be spared the adverse sequelae of treatment, the authors adopted a policy of little or no treatment of localized LPHD in 1989. Patients and Methods Presentation, pathology, and outcomes were reviewed for 15 consecutive children and adolescents with LPHD seen at a single institution since 1989. One patient was lost to follow-up and two patients were seen only once in consultation and treated elsewhere. These three cases were excluded, leaving twelve: nine males and three females, ranging in age at diagnosis from 2 to 17 years (median 11). Eleven of the 12 had stage I disease, and 1 had stage II. Six received no treatment following excisional biopsy, while five received a brief treatment with chemotherapy only. One was initially treated with involved field radiotherapy (IFRT) due to an initially imprecise histologic diagnosis of classic Hodgkin disease. Results All patients are alive, without evidence of disease, for periods ranging from 2 to 13+ years after diagnosis (median 6 years). One patient recurred locally with LPHD 6 years after initial brief chemotherapy and was then treated with IFRT, achieving a prolonged second remission. Conclusion Children and adolescents with localized LPHD have an excellent prognosis and may be safely approached either with a wait-and-see attitude of no initial therapy after initial adenectomy or with less aggressive treatments.

Clinical impact and prognostic value of metaiodobenzylguanidine imaging in children with metastatic neuroblastoma.

PURPOSE The clinical value of metaiodobenzylguanidine (mIBG) scintigraphy in patients with disseminated neuroblastoma (NB) at the time of diagnosis and after induction chemotherapy was evaluated. PATIENTS AND METHODS The medical records and imaging studies of 30 patients with stage 4 NB who underwent mIBG scintigraphy and 99mTc hydroxy methylene diphosphonate bone scintigraphy at the time of diagnosis were reviewed. Scores were calculated for the mIBG and bone scintigrams, and outcome according to the initial and follow-up imaging studies was determined. RESULTS Discrepancies between bone scintigraphy and mIBG osteomedullary localization were seen in six patients. For the entire cohort, 2-year event-free survival did not significantly differ for the group of patients with initial mIBG or bone scintigraphy scores > or = 10 compared to those with scores < 10 (P = 0.23 and 0.61, respectively). However, for patients older than 1 year, a trend associating worse outcome with mIBG scores > or = 10 at diagnosis was seen (P = 0.08). A trend correlating abnormal mIBG scintigraphy after induction therapy and poor outcome was also observed (P = 0.09). Outcome did not correlate with the results of the bone scintigram studies performed after induction chemotherapy (P = 0.68). CONCLUSION Because a discordance between mIBG and bone scintigraphy results were seen in a subset of stage 4 NB patients, both imaging studies should be performed at the time of diagnosis. mIBG imaging studies performed at the time of diagnosis and after induction chemotherapy may be of prognostic value, particularly in stage 4 patients older than 1 year.

High WT1 gene expression before haematopoietic stem cell transplant in children with acute myeloid leukaemia predicts poor event-free survival.

WT1 gene expression has been proposed as a useful marker of minimal residual disease in leukaemia. Its utility in paediatric haematopoietic stem cell transplantation (HSCT) has not been studied. We studied the prognostic value of WT1 expression in peripheral blood prior to HSCT in 36 children with acute myeloid leukaemia (AML). Samples were obtained 2 weeks pre‐transplant to determine the level of WT1 expression. WT1 expression was normalized using K562 cells as a control and a relative value of 0·5 was chosen as the cut‐off point between high and low WT1 expression. The median level of pre‐transplant WT1 expression in the 36 patients was 0·09 (range 0·0001–11·0), with 11patients having WT1 ≥ 0·5 and 25, WT1 < 0·5. After HSCT, 76% of patients with high pre‐transplant WT1 expression relapsed, in contrast to 0% of the patients with low WT1 expression. Those with high WT1 expression had significantly lower 5‐year event‐free survival (EFS) (18%, 95% CI 0–40%) as compared to those with low WT1 expression (68%, 95% CI 50–86%, P = 0·007). Multivariate analysis showed that pre‐transplant WT1 level is the only significant prognostic factor for the difference in EFS. Our finding suggests that elevated WT1 gene expression before HSCT in paediatric AML predicts relapse and poor long‐term EFS. A larger prospective study is warranted to compare the value of high WT1 expression and other markers of minimal residue disease in predicting clinical outcomes after HSCT.

Eosinophilia correlates with the presence or development of chronic graft-versus-host disease in children

Finding predictors of chronic graft-versus-host disease (cGVHD) in children would be extremely useful. Because of recent data suggesting that cGVHD may be a Th-2-mediated process, a theoretical foundation linking eosinophilia and cGVHD exists. While an association between eosinophilia and cGVHD has been described in adults, it has never been described in children. We studied 53 patients that received allogeneic hematopoietic stem cell transplants (SCT) between 1999 and 2002. Ten (19%) of these patients developed eosinophilia (absolute eosinophil count (AEC) > 500× 106/L) after day 100. Of these ten, eight either had or later developed cGVHD. We conclude that following the peripheral eosinophil count in children post-SCT is useful, and a rise in the AEC may herald the development of cGVHD. Taking the AEC into account with other risk factors (such as previous grade II-IV acute GVHD, human leukocyte antigen (HLA)-mismatch, and unrelated donor (URD) transplant) may improve our ability to predict cGVHD.