Biomedical subjects

Brenda M Sandmaier

Publications and source records attributed to Brenda M Sandmaier.

60 records · Page 4Linked to original sources

PubMed2002

Related and unrelated nonmyeloablative hematopoietic stem cell transplantation for malignant diseases.

Patients with advanced hematological malignancies ineligible for conventional myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) due to advanced age or medical contraindications were enrolled in multi-center study to investigate the safety and efficacy of nonmyeloablative HSCT using a 2 Gy total body irradi ation (TBI)-based regimen. A total of 192 patients (median age 55) were treated with HLA-matched sibling peripheral blood stem cell (PBSC) grafts, and 63 patients (median age 53) received a 10 of 10 HLA-antigen matched unrelated donor (URD) HSCT (PBSC graft, n = 48; marrow graft, n = 15). Diagnoses included multiple myeloma (n = 61), myelodysplastic syndrome (n = 55), chronic myeloid leukemia (n = 31), non-Hodgkin lymphoma (n = 31), acute myeloid leukemia (n = 28), chronic lymphocytic leukemia (n = 24), Hodgkin Disease (n = 14). The conditioning regimen was fludarabine 30 mg/m2/d x 3 days and 2 Gy TBI. Ninety-five related HSCT patients received 2 Gy TBI without fludarabine. Postgrafting immunosuppression was combined mycophenolate mofetil an cyclosporine. Transplants were well tolerated with a median of 0 days of hospitalization in the first 60 days for eligible patients. For related HSCT recipients, median follow-up was 289 (100-1,188) days. Nonfatal graft rejection occurred in 6.8%. Of those with sustained engraftment, graft-versus-host disease (GVHD) occurred in 49% (33% grade II, 11% grade III, 5% grade IV). Day-100 non-relapse mortality was 6%. Overall, 59% (114/192) of patients were alive. The relapse/disease progression mortality was 18%, and non-relapse mortality was 22%. The projecte 2-year survival and progression-free survival were 50% and 40%. For the URD HSCT recipients, median follow-up was 190 (100-468) days. Graft rejection occurred in 27% (17/63) of patients, mostly in recipients of marrow grafts (9/15). Acute GVHD occurred in 63% (50% grade II, 13% grade III) of 46 engrafted patients. Chronic GVHD requiring therapy occurred in 50% of patients. Of the 63 URD HSCT patients, 54% were alive, 37% in CR, 3% PR, and 14% with disease progression or relapse. Related and unrelated nonmyeloablative HSCT is feasible and potentially curative in patients with advanced hematological malignancies who have no other treatment options.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

Nonmyeloablative hematopoietic cell transplantation: status quo and future perspectives.

In nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT), high-dose cytotoxic therapy as the conceptual basis for treating hematopoietic malignancies has been replaced by graft-versus-tumor effects. The use of potent pre- and postgrafting immunosuppression derived from preclinical studies has allowed omission of myeloablative cytotoxic therapy without compromising hematopoietic donor cell engraftment. This results in a marked reduction in transplant-related toxicities that makes older or medically infirm patients candidates for this treatment option. This patient group is more representative of the population with cancer and would have been ineligible for conventional HSCT. Initial results in patients with a variety of hematologic malignancies have been encouraging with documented sustained cytogenetic and molecular remissions in a substantial number of sometimes heavily pretreated and previously refractory patients. Even though patients with hematologic malignancies will likely require conversion to full donor hematopoiesis for long-term disease control, a state of mixed hematopoietic chimerism might suffice to "cure" the disease phenotypes in various nonmalignant diseases. Strategies aimed at optimizing peritransplant immunosuppression may eventually eliminate the need for pretransplant total body irradiation, which is relevant for minimizing late toxicities. Enhancing graft-versus-tumor effects by virtue of postgrafting vaccination of recipients against tumor-specific antigens may help to use this transplant approach more effectively in the treatment of solid tumors.

Animals↗

PubMed2002

Engraftment of early erythroid progenitors is not delayed after non-myeloablative major ABO-incompatible haematopoietic stem cell transplantation.

We hypothesized that patients undergoing major ABO-incompatible non-myeloablative haematopoietic stem cell transplantation (nm-HSCT) might experience prolonged haemolysis after transplant due to the delayed disappearance of host plasma cells producing anti-donor isohaemagglutinins (HAs). To address this question, we analysed data from 107 consecutive patients transplanted with allogeneic peripheral blood stem cells from human leucocyte antigen-matched (related, n = 84; unrelated, n = 23) donors after non-myeloablative conditioning (200 cGy total body irradiation +/- fludarabine). In total, 23 out of the 107 patients received major or major/minor ABO-incompatible transplants. Red blood cell (RBC) transfusion requirements during the first 120 d post transplant were higher in major ABO-mismatched than in ABO-matched recipients (0.12 vs 0.03 median units RBC concentrate/d, P = 0.04). Two patients developed transient pure red cell aplasia, which had resolved spontaneously by 9 months after transplant. Major ABO incompatibility did not influence rates of engraftment. Patients with sustained engraftment experienced gradual declines of anti-donor HAs, and the estimated median time to reaching IgM and IgG titres of < 1:1 was at least 133 d in evaluable patients, approximately twice longer than reported after myeloablative conditioning. There was a strong correlation between degrees of donor chimaerism in erythroid burst-forming units, granulocyte macrophage colony-forming units and granulocytes, indicating that donor erythroid engraftment, defined by early erythroid progenitors, was as prompt as myeloid engraftment. In conclusion, our data suggest that major ABO-incompatibility is not a barrier to successful non-myeloablative HSCT.

ABO Blood-Group System↗

PubMed2002

Hematopoietic stem cell transplantation for advanced myelodysplastic syndrome after conditioning with busulfan and fractionated total body irradiation is associated with low relapse rate but considerable nonrelapse mortality.

The objectives of this study were to develop transplantation regimens for patients with advanced myelodysplastic syndrome (MDS) that would be associated with low transplantation-related mortality and improved relapse-free survival. Sixty patients with advanced MDS or acute myeloid leukemia evolving from MDS (sAML), 12 to 62 years old (median, 40 years), were conditioned with busulfan (7 mg/kg) and TBI (6 x 200 cGy) (BU/TBI) and received transplants from related (n = 20) or unrelated donors (n = 40). By French-American-British (FAB) criteria, 21 patients had refractory anemia with excess blasts (RAEB), 16 had RAEB in transformation (RAEB-T), 15 had sAML, and 8 had chronic myelomonocytic leukemia (CMML). By International Prognostic Scoring System (IPSS) criteria, 1 patient had low, 10 had intermediate-1, 13 had intermediate-2, and 31 had high-risk MDS (5 patients had proliferative CMML). All evaluable patients achieved sustained engraftment. The cumulative incidence (CI) of acute GVHD grades II to IV was 83% with unrelated donors and 85% with related donors. The CI of relapse was 25% at 3 years. The incidence of nonrelapse mortality (NRM) at 100 days was 38%. The Kaplan-Meier estimate of survival was 26% at 3 years. Major causes of death were relapse, organ failure, GVHD, and infection. In multivariate analysis, improved relapse-free survival was associated with good cytogenetic risk (P = .002) and shorter disease duration (P = .004). NRM was increased with longer disease duration (P = .0002), positive cytomegalovirus serology (P = .02), and male sex (P = .02). Relapse was associated with poor cytogenetic risk (P = .0004). Thus, BU/TBI conditioning as used in this trial was associated with relapse rates comparable to those observed with a previously used more intensive regimen combining BU/TBI with cyclophosphamide. However, despite the omission of cyclophosphamide, transplantation-related morbidity and mortality were considerable, particularly with transplants from unrelated donors. Future trials should explore the efficacy and tolerability of reduced-intensity conditioning regimens.

Adolescent↗

PubMed2002

Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study.

Infections contribute significantly to morbidity and mortality after myeloablative allogeneic hematopoietic stem cell transplantation (HSCT). Whether recipients of nonmyeloablative HSCT have different posttransplantation infection risk was unknown. We therefore analyzed the incidence and risk of bacteremia during the first 100 days and of fungal infection during the first 365 days posttransplantation for 56 consecutive patients with hematological malignant disease who received nonmyeloablative HSCT (case patients). We compared the results with those among 112 control patients who received conventional myeloablative HSCT during the same years (January 1997-April 2000). Control patients were matched (2:1) for cytomegalovirus (CMV) risk group, HSC source, donor type, age, and underlying disease. Most donors (93%) were HLA-matched and related. Case patients had shorter periods of neutropenia (absolute neutrophil count, <100/mm3) than did control patients (median, 0 days; range, 0-11 versus 9 days; range, 4-25; P < .0001). This finding was associated with fewer episodes of bacteremia during the first 30 days (9% versus 27%; P = .01) and a trend to fewer episodes of bacteremia during the first 100 days posttransplantation (27% versus 41%, P = .07). Overall survival was significantly improved in case patients compared with control patients (day 100, 93% versus 81%; P = .04). During the first year posttransplantation, invasive aspergillosis occurred at a similar rate (case patients, 15%; control patients, 9%; P value not significant). Multivariate risk factor analyses identified neutropenia and CMV disease as the major factors associated with bacteremia and aspergillosis, respectively. We conclude that shorter periods of severe neutropenia in nonmyeloablative HSCT are associated with decreased risk of early bacteremia, although risk of fungal infection late after HSCT persists. This risk is an important consideration for the future development of preventive strategies.

Adult↗

PubMed2002

Non-myeloablative transplantation.

The concept of utilizing enhanced immunosuppression rather than myeloablative cytotoxic conditioning has allowed the engraftment of allogeneic stem cells from related and unrelated donors with lower early transplant-related mortality (TRM) and morbidity. This approach shifts tumor eradication to the graft-vs-host immune response directed against minor histocompatibility antigens expressed on tumor cells. This is not without risk, as the long-term effects of graft-versus-host disease (GVHD), it's treatment, or resulting complications and immunodeficiency may be life threatening. However, this approach does allow the application of a potentially curative procedure to elderly or medically infirm patients who would not tolerate high-dose conditioning regimens. Section I, by Dr. Sandmaier, describes the current use of nonmyeloablative regimens and matched related or unrelated donors for the treatment of patients with CLL, CML, acute leukemia, MDS, lymphoma, and myeloma. In Section II, Dr. Maloney discusses the use of cytoreductive autologous followed by planned non-myeloablative allografts as treatment for patients with myeloma or NHL. This tandem transplant approach has a lower TRM than conventional high dose allografting. The nonmyeloablative allograft may allow the graft-versus-tumor (GVT) immune response to eradicate the minimal residual disease that causes nearly all patients with low-grade NHL or myeloma to relapse following autologous transplantation. In Section III, Dr. Mackinnon discusses the risks and benefits of T cell depletion strategies to prevent acute GVHD, while retaining GVT activity by planned donor lymphocyte infusions. Finally, in Section IV, Dr. Shizuru discusses the relationship between GVHD and GVT activity. Future studies, employing a greater understanding of these issues and the separation of GVHD from GVT activity by immunization or T cell cloning, may allow nonmyeloablative allogeneic transplantation to be safer and more effective.

Alemtuzumab↗