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PubMed1998

Influence of CD34 cell selection on the incidence of mixed chimaerism and minimal residual disease after allogeneic unrelated donor transplantation.

Marrow transplantation from unrelated donors has been linked with an increased risk of graft-versus-host disease (GVHD). In an attempt to lower the risk of acute GVHD we used CD34 marrow cell selection for T cell depletion. Since T cell depletion has been linked to an increased risk of relapse and an increased risk of marrow failure, we used PCR amplification of minisatellite sequences to investigate donor cell engraftment and RT-PCR amplification of recurrent chromosomal translocations to investigate the residual disease post-transplant. Twenty-three patients who underwent BMT after positive selection of the CD34-positive cell population were studied. Results were then compared with those of 37 patients who underwent transplantation with unmanipulated marrow graft. Among the 23 patients who received CD34+ selected cell grafts, seven (30%) had evidence of full donor engraftment, 14 had evidence of residual recipient cells (61%), one had a non-take, and one autologous bone marrow recovery. Analysis of the chimaerism status post-transplant in 36 patients who received unmanipulated marrow grafts showed that 31 patients (86%) had evidence of full donor engraftment. The difference in the incidence of mixed chimaerism profile between patients who received unmanipulated marrow graft and those receiving CD34+ selected cell grafts was statistically significant (P< 0.01). Nine patients who received CD34+ selected cell grafts could be analysed for the presence of minimal residual disease post-transplant (one with t(9;22) acute lymphoblastic leukaemia and eight with CML). In the patient transplanted for a Ph-positive acute leukaemia, and in two out of the eight patients with CML, the search fora fusion transcript was consistently negative after transplantation. Among the six patients with evidence of residual disease, three patients also had a mixed chimaerism profile and were given donor lymphocyte infusions. Minimal residual disease study was performed post-transplant in 16 patients who received unmanipulated marrow grafts. In 10 of 14 patients with CML, and in two patients with acute leukaemia the search for a fusion transcript was consistently negative after transplantation. The difference in the incidence of minimal residual disease between patients who received an unmanipulated marrow graft and those receiving CD34+ selected cell grafts was not statistically significantly significant, but numbers of patients included in this analysis are still few. In conclusion, our study highlights the strong influence of graft manipulation on the incidence of mixed chimaerism after transplantation from an unrelated donor.

Adolescent↗
PubMed2002

Autologous and allogeneic stem cell transplantation for chronic lymphocytic leukemia.

Allogeneic and autologous stem cell transplantation (SCT) are increasingly considered for treatment of patients with chronic lymphocytic leukemia (CLL). In order to assess the potential therapeutic value of SCT for CLL, the present article aims at answering the following crucial questions: (1) Is SCT a curative treatment? (2) Does SCT improve the prognosis of poor-risk CLL? (3) Do risk factors exist which are useful for defining prognostic groups in terms of feasibility and post-transplant outcome? The efficacy of auto-SCT relies exclusively on the cytotoxic therapy administered. To date, there is only limited hope that autotransplantation can cure the disease. Nevertheless, the results of the published series suggest that auto-SCT is capable of improving the prognosis of CLL with poor-risk features. Well defined favorable conditions for successful autografting are the status of the disease (CR or VGPR) and the number of lines of therapy (<2) before transplantation. The crucial anti-leukemic principle of allo-SCT consists in the immune-mediated GVL effects conferred with the graft. The GVL activity explains that allografting seems to be curative for at least a subset of patients. However, as long as allo-SCT in CLL is still associated with an excessively high treatment-related mortality, only selected patients with advanced poor-risk disease should be considered for allografting. The development of conditioning regimens with reduced intensity may allow extending the indications of allogeneic SCT for CLL in the near future.

Bone Marrow Purging↗
PubMed2000

Permanent alopecia following chemotherapy and bone marrow transplantation.

Alopecia can be a psychologically daunting prospect for people requiring cancer chemotherapy. Fortunately, most patients experience only temporary hair loss. We report the case of a 23-year-old woman with chronic myeloid leukaemia who developed permanent, near-total alopecia of her scalp, eyebrows, eyelashes, axillary and public hair following busulphan and cyclophosphamide chemotherapy which was used as conditioning prior to allogeneic bone marrow transplantation. The histology from a scalp biopsy revealed hair follicle destruction. Topical minoxidil failed to induce significant re-growth.

Adult↗
PubMed2002

Bone marrow transplantation for beta-thalassaemia major by an HLA-mismatched parent.

A six-year-old boy was diagnosed with beta-thalassaemia major during infancy. Since then, he required monthly blood transfusion and irregular iron chelation therapy. He had hepatosplenomegaly and elevated liver enzymes; the serum ferritin was up to 3800 ng/mL. An echocardiogram showed left-ventricular enlargement. His one-antigen-mismatched mother was chosen as a bone marrow donor. He was pretreated with intensive red blood cell transfusion and hydroxyurea for 6 weeks prior to conditioning. The conditioning included total body irradiation (300 cGy), busulfan (14 mg/kg), cyclophosphamide (160 mg/kg) and anti-thymocyte globulin (rabbit; 90 mg/kg). Marrow cell dose was 5.4 x 108/kg. Graft versus host disease (GVHD) prophylaxis included cyclosporine A (CSA) and methylprednisolone. Neutrophil engraftment occurred on day 23. Grade II acute GVHD occurred on day 45. The patient developed complications including septicaemia, haemorrhagic cystitis, intracranial haemorrhage and heart failure. He subsequently recovered from the complications without sequelae. The patient remained transfusion-independent at a follow-up examination after 18 months. This case suggested that a mismatched family member may be considered as a bone marrow donor for beta-thalassaemia major. In places where conventional treatment is not feasible, for example, in China, this approach may be an alternative option. A more intensive immunosuppressive regimen and a higher marrow cell dose may be important for successful engraftment. High-dose anti-thymocyte globulin may also prevent severe GVHD.

Bone Marrow Purging↗
PubMedDate not supplied

Long-time survival after unrelated bone marrow transplantation in children and adolescents and targeted therapy with CD25 blockade to prevent GVHD.

To evaluate longtime survival after matched unrelated donor (MUD) transplantation a group of patients (n = 10) with intensified GVHD prophylaxis were compared to patients receiving matched sibling (MSD) transplantation (n = 10); all transplantations were done between 1989 and 1995 in the same institution. A murine monoclonal antibody against CD25 was assessed in addition to standard GVHD prophylaxis for reducing GVHD in children with advanced leukemia after MUD BMT (group I). We compared the incidence of GVHD, relapse and survival under prophylaxis with either anti-CD25 (group I, n = 10) or MSD BMT without anti-CD25 (group II, n = 10) with respect to known risk factors of transplant related morbidity, mortality and outcome. 3/10 leukemia patients in both groups were in CR3 or in relapse at time of transplant. Whereas incidence of acute GVHD grade III and IV was significantly higher in group I compared to group II (0.4 vs. 0.0), no differences in engraftment, or chronic GVHD were seen between both groups. In addition, overall (0.5 vs. 0.6) and leukemia free survival (0.5 vs. 0.6) was not different after 8 respectively 10 years from transplant. Murine anti-CD25 therapy may have contributed to matching outcome of MUD vs. MSD marrow transplants in children with advanced leukemia. In conclusion, the use of anti-CD25 in modulation of CD25+ regulatory and effector T cells in allo- and leukemia recognition merrits further exploration of its potential to improve both tolerance and leukemia control. Since the outcome of children with leukemia that received intensified GVHD prophylaxis in MUD BMT was similar to children with MSD transplants, MUD BMT has to be considered as an equivalent therapeutic option for patients, who have no HLA-identical sibling donor.

Acute Disease↗
PubMed2001

Pharmacokinetics of CAMPATH-1H in BMT patients.

BACKGROUND: CAMPATH-1 (CD52)Abs are used in stem-cell transplantation for prevention of GvHD and rejection. The humanized Ab CAMPATH1H has recently replaced the rat Ab CAMPATH-1G. There was a concern whether it might have a longer half-life in vivo and, possibly, cause prolonged immunosuppression post-transplant. METHODS: Serum samples were collected pre- and post-transplant from patients receiving CAMPATH-1H at 10 mg/day according to two protocols: (A) from Day -5 to Day +4 (total dose, 100 mg), (B) from Day -10 to Day -6 (total dose, 50 mg). The Ab concentrations were measured using an immunofluorescence assay. RESULTS: Lymphocytes were substantially depleted by the second day of treatment and were below 0.1 x 10(9)/L by the day of transplant and for at least 1 month post-transplant. By Day 90 there was a greater recovery in Group B, to a median of 0.32 x 10(9)/L compared with 0.25 x 10(9)/L in Group A. By Day 180, both groups had recovered to approx 0.52 x 10(9)/L. Serum concentrations of CAMPATH-1H on the day of transplant were well above the level necessary for opsonization of lymphocytes. The peak Ab concentration was 6.1 micro g/mL in Group A and 2.5 micro g/mL in Group B. CAMPATH-1H could be detected in Group A for 23 days post-transplant, significantly longer than in Group B (11 days). The terminal half-life in the two groups was similar (range 15-21 days) and contrasts with the half-life of < 1 day previously estimated for CAMPATH-1G. There were no cases of graft failure and the incidence of GvHD was similar in the two groups. DISCUSSION: The humanized Ab CAMPATH-1H appears to persist in the circulation for longer than the original rat Ab CAMPATH-1G. This might contribute to delayed lymphocyte recovery and prohibit the use of early donor-lymphocyte infusions. A short course of treatment given early pre-transplant is likely to be preferable to the extended course given both pre- and post-transplant.

Adult↗
PubMed2001

Complement-mediated T-cell depletion of bone marrow: comparison of T10B9.1A-31 and Muromonab-Orthoclone OKT3.

BACKGROUND: T10B9.1A-31 (T(10)B(9)) and Muromonab-Orthoclone OKT3 (OKT3) are both murine MAb with a narrow specificity for T lymphocytes. Over the past 10 years, we have used each for T-cell depletion (TCD) of BM. In this report we describe similarities and differences using these antibodies, as well as their effects on patient outcome. METHODS: We compared BM mononuclear cells (BMMC) prepared using a Cobe Spectra apheresis machine with density gradient (DG) separation to remove RBC and enrich for CD34(+) cells prior to TCD. FACS and limiting dilution assays (LDA) were used to measure the efficiency of TCD, the subsets of cells removed and CD34 content. Univariate statistics were used to assess graft outcome, including GvHD, graft failure, post-transplant lymphoproliferative disease (PTLD), relapse, DFS, and TRM. RESULTS: BMMC preparation on the Cobe Spectra resulted in superior recovery of CD34(+) cells. However, this method could not be used with OKT3 due to inhibition of T-cell lysis. Optimal TCD required two rounds of complement at room temperature for OKT3, compared with one or two rounds for T(10)B(9). TCR(gamma delta)(+) T-cells, but not natural killer cells, were spared to a greater degree with T(10)B(9). Further T-cell loss occurred during culture with T(10)B(9) but not with OKT3. Overall efficiency of TCD was superior using T(10)B(9). The risk of acute GvHD was higher with OKT3-mediated TCD, independent of T-cell content, and may have led to a higher incidence of PTLD. A decreased risk of relapse for patients with high-risk disease was seen with OKT3-treated grafts, but engraftment, TRM and DFS did not significantly differ. DISCUSSION: TCD using OKT3 results in higher T-cell content and higher rates of acute GvHD and PTLD compared with T(10)B(9). Cobe Spectra cannot be used for BMMC processing with OKT3, fewer CD34(+) are therefore infused. Technical, as well as biological, differences between narrow specificity MAbs can affect graft outcome.

Animals↗
PubMed1999

Differential effects of IL-2 incubation on hematopoietic potential of autologous bone marrow and mobilized PBSC from patients with hematologic malignancies.

Culturing of hematopoietic progenitor cells for 24 h with IL-2 generates cytotoxic effector cells that mediate in vitro and possibly in vivo antitumor activity. We examined the effect of IL-2 incubation on progenitor cells from 24 patients with hematologic malignancies using paired autologous bone marrow (ABM) and PBSC to determine differences in hematopoietic potential. Cells were cryopreserved and stored in liquid nitrogen until conditioning therapy was completed. After thawing, cells were incubated with IL-2 for 24 h at 37 degrees C. Paired samples of ABM and PBSC from the same patient were analyzed for nucleated and mononuclear cell number, CD34 antigen expression, and colony-forming unit (CFU) activity before and after IL-2 incubation. There was a significant decrease in the average number of mononuclear cells (MNC) (x10(8)/kg) (<0.001) and CD34+ cells (x10(6)/kg) (0.006) from both ABM and PBSC after 24 h IL-2 culture (ABM MNC: 0.6+/-0.1 vs. 0.4+/-0.0, p = <0.001; PBSC MNC: 4.4+/-0.5 vs. 3.7+/-0.4, p = 0.03; ABM CD34+: 2.4+/-0.5 vs. 1.3+/-0.3, p = <0.001; PBSC CD34+: 6.6+/-1.8 vs. 5.0+/-1.2, p = 0.05). However, whereas ABM CFU/10(5) MNC plated (269.3+/-47.2 vs. 385.6+/-70.6) were significantly increased (p = 0.005), there was no change in PBSC CFU (271.0+/-47.2 vs. 257.3+/-48.5). The mean plating efficiency (%) of ABM CD34+ cells was markedly increased after IL-2 incubation (10.1+/-3.3 vs. 19.0+/-7.2, p = 0.04), although it was lower than that of PBSC CD34+ cells, which did not change significantly in culture (29.4+/-5.5 vs. 36.0+/-6.5). Additional work is in progress to determine the cause and significance of the enhanced plating efficiency of the ABM progenitor cells.

Adult↗
PubMed1999

Bone marrow processing for transplantation using the COBE spectra cell separator.

BM processing, volume reduction, and granulocyte and erythrocyte depletion are important considerations for minimizing the side effects of graft administration and bypassing ABO incompatibility in allogeneic BMT. We used the COBE Spectra cell separator for BM processing in 33 patients suffering from hematologic malignancy and solid tumor (median age 39 years). We processed 42 BM harvests with the aim of maximizing recovery of mononuclear cells (MNC). BM was collected from the posterior iliac crest under general anesthesia. The mean volume of collected BM before filtration was 1,303 ml, and the mean number of collected total nucleated cells (TNC) was 2.61 x 10(8)/kg. The BM processing resulted in a mean recovery of 35.8% (10.1%-78.3%) TNC, 22.3% (1.1%-75.7%) of granulocytes, 78.8% (34.3%-135.2%) of MNC, 77.2% (8.3%-260.0%) of CD34+ cells, and 153.3% (32.9%-464.0%) of colony-forming units (CFU-GM) in the final product. A mean of 98.2% (94.5%-99.5%) of RBC was removed, with a mean of 13.3 ml (5.1-26.2 ml) of RBC in the final product. BM processing using the COBE Spectra cell separator proved to be fast, safe, and effective. However, the reasons for the very wide range of recovery of harvested CD34+ cells and CFU-GM need to be further investigated.

Adult↗
PubMed1992

Autologous graft engineering.

Autologous transplantation of bone marrow or peripheral blood stem cell preparations is now a widely used form of rescue from the myeloablative effects of high-dose therapy for malignant disease. The success of this procedure is affected by numerous factors associated both with management of the patient and the quality of the graft. In this review, approaches are described to maximize the success and utility of this therapeutic approach.

Biomedical Engineering↗
PubMed1993

ISHAGE bone marrow processing survey: report on an international information gathering process. International Society for Hematotherapy Graft Engineering.

Significant amounts of information are currently available within the database generated by the responses to the Bone Marrow Processing Survey. As additional Surveys are returned, the data will continue to be entered into a Lotus spreadsheet, until a more sophisticated database with a programmed interface becomes available. The readership is encouraged to enter or edit the databank by returning a completed or amended Survey to the Society. Copies of the form are available from the Society or can be found in the first issue of the Journal of Hematotherapy.

Blood Transfusion, Autologous↗
PubMed1993

Phototherapy, photochemotherapy, and bone marrow transplantation.

Recent preclinical and clinical investigations indicate that phototherapy and photochemotherapy may have applications that go far beyond their "traditional" roles in the treatment of skin disorders, selected solid tumors, and neonatal hyperbilirubinemia. Bone marrow transplantation is one area that may benefit substantially from these new developments. This review focuses on new applications of phototherapy and photochemotherapy that pertain to the inactivation of tumor cells in autologous bone marrow grafts, the prevention and treatment of acute and chronic graft-versus-host disease, the prevention of transfusion-induced allosensitization and graft rejection, and the inactivation of pathogenic viruses and parasites in bone marrow grafts and blood products.

Animals↗
PubMed1994

CAMPATH-1 monoclonal antibodies in bone marrow transplantation.

CAMPATH-1 (CDw52) antibodies recognize a very small lipid-anchored glycoprotein that is expressed on the surface of human lymphocytes. They are remarkably lytic with human complement. In addition, CAMPATH-1G (rat IgG2b) and CAMPATH-1H (human IgG1) bind to human Fc receptors and are very effective for cell lysis in vivo. CAMPATH-1M (rat IgM) and CAMPATH-1G have been used to control GVHD and graft rejection in bone marrow transplantation by depletion of the T cells of the donor and recipient. Depletion of donor T cells alone gave excellent control of GVHD but up to 20% of the patients transplanted from HLA-matched siblings, and 51% of those transplanted from nonsibling donors, experienced graft failure caused by immunological rejection. Graft rejection could be partly overcome by additional immunosuppression either with CsA or total lymphoid irradiation (TLI). More effective was the use of CAMPATH-1G in vivo to deplete residual host lymphocytes. Preliminary results from current protocols of antibody depletion give two year actuarial leukemia-free survival as good as or better than similar studies with conventional GVHD prophylaxis, as well as a decreased morbidity from chronic GVHD, although engraftment was delayed by about 5 days. We propose that prophylactic T cell depletion with CAMPATH-1 antibodies is a simple and valid alternative to drug-based immunosuppression that may be particularly applicable to patients with acute leukemia or nonmalignant diseases transplanted from HLA-matched siblings as well as any patients transplanted from unrelated donors. Future developments of antibody-based immunosuppression may allow the extension of marrow transplantation for tolerance induction to organ transplants or in autoimmune diseases.

Amino Acid Sequence↗
PubMed1994

Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for follicular lymphoma.

Since June 1985, 121 patients with follicular lymphoma aged 24-61 years (median 43) have received myeloablative therapy (cyclophosphamide: 60 mg/kg x 2, + total body irradiation: 200 cGy x 6) with autologous bone marrow transplantation (CY+TBI+ABMT) as consolidation of 2nd or subsequent remission. The marrow mononuclear cell fraction was treated in vitro with anti-CD20 alone and baby rabbit complement at St. Bartholomew's Hospital (SBH) and with the addition of anti-B5 and anti-CD10 at the Dana Farber Cancer Institute (DFCI) prior to reinfusion. There were 4 treatment related deaths, (nonengraftment 1, haemorrhage 1, systemic fungal infection 1, veno-occlusive disease 1). The median time for neutrophil recovery (> 0.5 x 10(9)/1) was 26 days (range 10 to 59 days), and for platelets (> 20 x 10(9)/1), 30 days (range 12 to 73 days). One patient did not engraft and 7 have had delayed recovery of red cells and platelets (> 3 months). Two other patients have subsequently developed acute myelogenous leukaemia and 5, evidence of myelodyplasia. Seventy-one patients continue in unmaintained remission between 3 months and 7 years, with a median follow up of 2.5 years. Forty-three have developed recurrent lymphoma; 98 remain alive. Freedom from progression was the same, irrespective of whether patients received CY + TBI + ABMT whilst in a complete or partial remission and did not depend on the specific remission in which treatment was given (2nd: 90 patients vs. > 2nd: 31 patients).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗