Hematopoietic stem cell transplantation using umbilical cord blood progenitors: review of current clinical results.

SUMMARY: Umbilical cord blood (CB) has been rapidly established as an alternative source of stem cells to bone marrow for allogeneic-related and unrelated hematopoietic transplantation. To date, almost 70 000 CB units are available for transplantation and more than 2000 CB transplants (CBT) have been performed, mostly in children, for the treatment of a variety of malignant and nonmalignant conditions. Considerable experience has been rapidly accumulated in this field and many aspects of CBT have been elucidated, while other questions remain unresolved. A concise review of the clinical results achieved after related and unrelated CBT is presented and discussed.

Allogeneic peripheral blood stem cell transplantation (PBSCT) from HLA-identical sibling donors in children with hematological diseases: a single center pilot study.

Between February 1995 and July 1999 25 pediatric patients (8 months to 14 years old) underwent peripheral blood stem cell transplantation (PBSCT) from an HLA-identical sibling donor. Diagnoses included ALL (17), non-ALL (6), and non-malignant disease (2). GVHD prophylaxis consisted of cyclosporine plus methotrexate (15), only cyclosporine (8), cyclosporine plus prednisone (1), or nothing (1). All donors (6 months to 41 years old) received G-CSF at 10 microg/kg/day subcutaneously for 4-5 days and on day 5 underwent large volume leukapheresis. Median number of CD34(+) and CD3(+) cells collected and infused was 6.9 x 10(6) (range 2.5-32.8) and 4.5 x 10(8) (0.5-22.1) per kg of recipient body weight respectively. Median time to achieve ANC >0.5 x 10(9)/l and platelets >20 x 10(9)/l was 10 and 12 days, respectively. Acute GVHD grade > or =II developed in 10 of 24 evaluable patients (42%). Probability of acute GVHD was 62%. Median time to discharge was 25 days (range 14-52). Among 20 evaluable patients, five (25%) developed chronic GVHD at day 100. Probability of chronic GVHD was 29% after 1 year post PBSC. At a median follow-up of 558 (9-2071) days, overall survival for the whole group is 68%. Probabilities of event-free survival, overall survival and relapse for patients with malignant hematological diseases are 53%, 59% and 24% at 5 years, respectively. This study has confirmed the feasibility and safety of mobilization and collection of PBSC products and the applicability of this procedure to the pediatric population, both donors and recipients. Studies including larger numbers of pediatric patients undergoing allogeneic PBSCT are warranted to determine the long-term outcomes of such procedures.

Absence of major histocompatibility class II expression does not impair hematopoiesis in mice.

OBJECTIVE: Major histocompatibility class II (MHC II) molecules are among the earliest antigens to be expressed in hematopoietic progenitor cells; however, the functional role of these molecules in hematopoiesis remains controversial. We examined the role of MHC II antigens during hematopoiesis using a mouse model of MHC II deficiency related to the absence of the critical transcriptional activator, CIITA. METHODS: Sca-1(-), Sca-1(+)lin(+), and Sca-1(+)lin(-) populations of marrow cells from CIITA(-)(/-) and wild-type mice were analyzed by immunofluorescence for MHC II expression. Hematopoietic capacity was assessed in CIITA(-/-) and wild-type mice by CFU-S, CFU-GM, and radiation sensitivity assays. RESULTS: Flow cytometric characteristics of hematopoietic progenitors from CIITA(-/-) and wild-type mice were identical except for the absence of MHC II expression in CIITA null mice. There were no significant differences in capacity for hematopoietic reconstitution and clonogenicity as measured by radiation sensitivity, CFU-S, and CFU-GM assays among CIITA(-/-) and wild-type mice. CONCLUSIONS: These experiments show that downregulation of MHC II gene transcription does not effectively alter normal hematopoiesis, and provide strong evidence that MHC II expression on hematopoietic progenitors is not required for normal hematopoietic development.

Ki-1+ anaplastic large cell lymphoma in a child with unpredictable clinical course.

Ki-1+ anaplastic large cell lymphoma (Ki-1+ ALCL) is a subtype of non-Hodgkin lymphoma (NHL) with defined histopathological characteristics but with highly variable clinical presentation and outcome. Although in most of the patients the disease behaves as an intermediate- or high-grade lymphoma, some patients present with an indolent clinical course. Factors that determine the clinical behavior of this lymphoma have not yet been identified. A case is reported of a 13-year-old girl who initially presented with Ki-1+ ALCL but later developed recurrent localized cutaneous disease and followed a clinical course similar to that of a low-grade lymphoma.

Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease.

BACKGROUND: In a pilot trial we evaluated the toxicity and efficacy of sirolimus (rapamycin) as second-line therapy for the treatment of acute graft-versus-host disease (GVHD) in 21 patients (1-46 years of age) after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: All patients were treated with methylprednisolone at 2 mg/kg/day, but failed to respond satisfactorily. Sirolimus was started 19-78 (median 37) days after HSCT when 10 patients had grade III and 11 had grade IV GVHD. The first four patients received a loading dose (15 mg/m2) of oral sirolimus on day 1 followed by 5 mg/m2/day for 13 days. The next 17 patients received either 5 (n=7) or 4 (n=10) mg/m2/day for 14 days without a loading dose. Eleven patients completed the 14-day sirolimus course. Five patients were treated for 9-13 days, two for 6 days, and three for 1-3 days. RESULTS: Sirolimus was discontinued early in 10 patients because of lack of improvement in GVHD (n=5), myelosuppression (n=2), seizure (n=2), and attending physician preference (n=1). The most common and significant adverse events were thrombocytopenia (n=7) and neutropenia (n=4). Other side effects included increased blood triglycerides (n=8) and cholesterol (n=3). Five patients had evidence of a hemolytic uremic syndrome concurrently with or after sirolimus treatment. Eighteen of the 21 patients received 6 or more doses of sirolimus and 12 responded, 5 with complete and 7 with partial responses. Six of the 12 responders (28% of all patients enrolled) and 1 nonresponder are currently alive at 400-907 days after HSCT, 3 with chronic GVHD. Fourteen of the 21 patients (66%) died 40-263 days after transplant. CONCLUSION: These data suggest that sirolimus has activity in the treatment of steroid-refractory acute GVHD. However, there was considerable toxicity and further dose optimization studies seem warranted.