Biomedical subjects

Brenda M Sandmaier

Publications and source records attributed to Brenda M Sandmaier.

At least 55 records · Page 3Linked to original sources

PubMed2003

Hepatic injury after nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation: a study of 193 patients.

Liver injury is a frequent, serious complication of allogeneic hematopoietic cell transplantation (HCT) following myeloablative preparative regimens. We sought to determine the frequency and severity of hepatic injury after nonmyeloablative conditioning and its relationship to outcomes. One hundred ninety-three consecutive patients who received 2 Gy total body irradiation with or without fludarabine were evaluated for end points related to liver injury. Patients with diseases treatable by HCT who were ineligible for conventional myeloablative allogeneic HCT because of advanced age and/or comorbid conditions were included. Fifty-one patients (26%) developed hyperbilirubinemia of 68.4 microM (4 mg/dL) or greater, most commonly resulting from cholestasis due to graft-versus-host disease (GVHD) or sepsis. Pretransplantation factors associated with liver dysfunction were a diagnosis of aggressive malignancy (hazard ratio [HR] 1.9; P =.04) and the inclusion of fludarabine in the conditioning regimen (HR 1.8; P =.07). Overall survival at 1 year was superior for patients who had maximal serum bilirubin levels in the normal (78%) or minimally elevated (22.23-66.69 microM [1.3-3.9 mg/dL]) ranges (69%) compared with those in the 68.4 to 117.99 microM (4-6.9 mg/dL; 20%), 119.7 to 169.29 microM (7.0-9.9 mg/dL; 17%), and 171.0 microM (10 mg/dL; 19%) or greater groups. In summary, significant jaundice occurred in 26% of patients and was predominantly due to cholestasis resulting from GVHD and/or sepsis. Aggressive malignancies (mainly advanced disease) and later development of jaundice after transplantation predicted inferior survival.

Adolescent↗

PubMed2003

Dog leukocyte antigen nonidentical unrelated canine marrow grafts: enhancement of engraftment by CD4 and CD8 T cells.

BACKGROUND: Previous studies have demonstrated that most marrow grafts from dog leukocyte antigen (DLA)-mismatched unrelated donors were rejected after 9.2 Gy total body irradiation (TBI), and that graft resistance could be overcome by infusing viable peripheral blood mononuclear cells (PBMCs) in addition to marrow. METHODS: To investigate the donor cell populations that facilitate engraftment, we determined the minimal dose of PBMCs required to ensure stable engraftment. Nineteen dogs underwent transplantation with DLA-mismatched unrelated marrow and PBMCs in a dose de-escalation study. In subsequent studies, 12 dogs were given selected CD4 or CD8 cells in addition to marrow. RESULTS: When 3 x 108 PBMC/kg were given in addition to a median of 4 x 108 marrow cells/kg, five of six animals engrafted. At a dose of 1 x 108 PBMC/kg, four of eight animals engrafted, and none of five dogs engrafted at a dose of 3 x 107 PBMC/kg. Accordingly, 12 dogs were given 9.2 Gy TBI, marrow grafts from DLA-mismatched unrelated dogs, and a median of 5.2 x 107 selected CD8 cells/kg or 10.4 x 107 selected CD4 cells/kg corresponding to the number of CD8 or CD4 cells contained in 3 x 108 PBMC/kg. Five of six dogs given CD8 cells and five of six dogs given CD4 cells engrafted. CONCLUSION: Results indicate that at least 3 x 108 unmodified PBMC/kg are needed for stable engraftment of DLA-mismatched unrelated marrow, and that both CD4 and CD8 cell subpopulations are capable of facilitating engraftment.

Animals↗

PubMed2003

Allogeneic hematopoietic stem cell transplantation for myelofibrosis.

Fifty-six patients, 10 to 66 years of age, with idiopathic myelofibrosis (IMF) or end-stage polycythemia vera or essential thrombocythemia received allogeneic hematopoietic cell transplants from related (n = 36) or unrelated (n = 20) donors. Forty-four patients were prepared with busulfan plus cyclophosphamide and 12 with total body irradiation plus chemotherapy. The source of stem cells was marrow in 33 and peripheral blood in 23 patients. All but 3 patients achieved engraftment. While 50 patients showed complete donor chimerism, 3 patients were found to be mixed chimeras at 26, 48, and 86 months after transplantation, respectively. Two patients died from relapse/progressive disease, and 18 died from other causes. There are 36 patients surviving at 0.5 to 11.6 (median, 2.8) years, for a 3-year Kaplan-Meier estimate of 58% (CI, 43%-73%). Dupriez score, cytogenetic abnormalities, and degree of marrow fibrosis were the most significant risk factors for posttransplantation mortality. Patients conditioned with a regimen of busulfan targeted to plasma levels of 800 to 900 ng/mL plus cyclophosphamide had a higher probability of survival (76% [CI, 62%-91%]) than other patients. Results with unrelated donors were comparable with those with HLA-identical sibling transplants. Thus, allogeneic hematopoietic cell transplantation offers long-term relapse-free survival for patients with myelofibrosis.

Adolescent↗

PubMed2003

Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma.

The full potential of a graft-versus-myeloma effect after allogeneic hematopoietic cell transplantation (HCT) for patients with multiple myeloma (MM) has not been realized because of excessive early transplantation-related mortality (TRM) with conventional HCT. Autologous HCTs have been characterized by almost universal disease recurrences. The current trial combined autologous HCT with subsequent nonmyeloablative allogeneic HCT to maintain the benefits of both approaches with acceptable toxicity. Fifty-four patients, 52 years of age (median; range, 29-71 years), with previously treated stage II or III MM (52% refractory or relapsed disease) were given melphalan 200 mg/m2 and autologous HC transplants. Regimen-related toxicities after autologous HCT were moderate with a median of 6 days of neutropenia, 7 days of hospitalization, and 1 death from infection. Forty to 229 days later (median, 62 days), 52 patients received a single fraction dose of 2 Gy total body irradiation and HC transplants from HLA-identical siblings with postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). Patients experienced medians of 0 days of hospitalization, neutropenia, and thrombocytopenia. Sustained engraftment was uniform. With a median follow-up of 552 days after allografting, overall survival is 78%. One patient (2%) died before day 100 from disease progression. Thirty-eight percent of patients developed acute graft-versus-host disease (GVHD; grade II in all but 4 cases) and 46% chronic GVHD requiring therapy. Tumor responses occurred slowly. Thus far, 57% of patients have achieved complete remissions and 26% have achieved partial remissions for an overall response of 83%. Despite being evaluated in elderly patients with MM, this 2-step approach has reduced the acute toxicities of allogeneic HCT while achieving potent antitumor activities.

Adult↗

PubMed2003

Risks and outcomes of idiopathic pneumonia syndrome after nonmyeloablative and conventional conditioning regimens for allogeneic hematopoietic stem cell transplantation.

Idiopathic pneumonia syndrome (IPS) is a significant noninfectious complication of hematopoietic stem cell transplantation (HSCT). We compared the incidences and outcomes of IPS among patients who underwent allogeneic HSCT after nonmyeloablative (n = 183) compared with conventional (n = 917) conditioning between December 1997 and December 2001. Patients given nonmyeloablative conditioning were older than those given conventional conditioning (median ages, 53 vs 41 years; P =.001). The cumulative incidence of IPS was significantly lower at 120 days after nonmyeloablative conditioning than conventional conditioning (2.2% vs 8.4%; P =.003). In addition, greater patient age (older than 40 years), diagnosis of acute leukemia or myelodys-plastic syndrome, and severe acute graft-versus-host disease were associated with significantly increased risks for IPS. Among older patients (older than 40 years) given conventional conditioning, high-dose total body irradiation (TBI) was associated with an increased risk for IPS than were non-TBI-based regimens (16% vs 5.8%; P =.001). IPS occurred early after transplantation, progressed rapidly, and was associated with a high mortality rate (75%) despite aggressive support. Initiation of mechanical ventilation and the presence of renal insufficiency at IPS onset were associated with increased risks for death after IPS. These findings support the concept that lung damage from the conditioning regimen plays a crucial role in the development of IPS after HSCT.

Adolescent↗

PubMed2003

HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies.

A hematopoietic cell transplantation (HCT) approach was developed for elderly or ill patients with hematologic malignancies that employed nonmyeloablative conditioning to avoid common regimen-related toxicities and relied on graft-versus-tumor effects for control of malignancy. Eighty-nine patients, median age 53 years, were given fludarabine (90 mg/m2) and 2 Gy total body irradiation. Marrow (n = 18) or granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral blood mononuclear cells (G-PBMCs; n = 71) were transplanted from unrelated donors matched for human leukocyte antigen A (HLA-A), -B, -C antigens and -DRB1 and -DQB1 alleles. Postgrafting immunosuppression included mycophenolate mofetil and cyclosporine. Donor T-cell chimerism was higher for G-PBMCs compared with marrow recipients. Durable engraftment was observed in 85% of G-PBMCs and 56% of marrow recipients. Cumulative probabilities of grade II, III, and IV acute graft-versus-host disease (GVHD) were 42%, 8%, and 2%, respectively. Nonrelapse mortality at day 100 and at 1 year was 11% and 16%, respectively. One-year overall survivals and progression-free survivals were 52% and 38%, respectively. G-PBMC recipients had improved survival (57% vs 33%) and progression-free survival (44% vs 17%) compared with marrow recipients. HLA-matched unrelated donor HCT after nonmyeloablative conditioning is feasible in patients ineligible for conventional HCT. G-PBMCs conferred higher donor T-cell chimerism, greater durable engraftment, and better progression-free and overall survivals compared with marrow.

Adolescent↗

PubMed2003

Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning.

The incidence of invasive mold infections has increased during the 1990s among patients undergoing allogeneic hematopoietic stem cell transplantation (HCT) after myeloablative conditioning. In this study, we determined risk factors for invasive mold infection and mold infection-related death among 163 patients undergoing allogeneic HCT with nonmyeloablative conditioning. The cumulative incidence rates of proven or probable invasive fungal infections, invasive mold infections, invasive aspergillosis, and invasive candidiasis during the first year after allogeneic HCT with nonmyeloablative conditioning were 19%, 15%, 14%, and 5%, respectively, which were similar to those after conventional myeloablative HCT. Invasive mold infections occurred late after nonmyeloablative conditioning (median, day 107), with primary risk factors including severe acute graft-versus-host disease (GVHD), chronic extensive GVHD, and cytomegalovirus (CMV) disease. The 1-year survival after diagnosis of mold infections was 32%. High-dose corticosteroid therapy at diagnosis of mold infection was associated with an increased risk for mold infection-related death. Overall, nonrelapse mortality was estimated at 22% (36 patients) after nonmyeloablative conditioning, of which 39% (14 patients) were mold infection-related (9% of the overall mortality). More effective strategies are needed to prevent invasive mold infections, which currently account for a notable proportion of nonrelapse mortality after nonmyeloablative allogeneic HCT.

Adolescent↗

PubMed2003

Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation.

It is unknown whether the severity, timing, and quality of graft-versus-host disease (GVHD) may be different after nonmyeloablative as compared with myeloablative hematopoietic stem cell transplantation (HSCT). Therefore, GVHD incidence, morbidity of skin, liver, and gut, requirements for immunosuppressive therapy, and survival were retrospectively analyzed in 44 patients who underwent nonablative HSCT and 52 who underwent ablative HSCT (median ages, 56 and 54 years, respectively). The nonablative transplantation regimen consisted of low-dose total body irradiation (TBI), preceded in some patients by fludarabine administration and followed in all patients by immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). Those who underwent myeloablative HSCT were prepared with different TBI- and non-TBI-containing regimens and received CSP plus methotrexate or MMF for GVHD prophylaxis. The cumulative incidence of grades II-IV acute GVHD was lower after nonablative transplantation (64% vs 85%; P =.001), but there were no differences in the cumulative incidence of chronic GVHD requiring treatment (73% vs 71%; P =.96). Nonablative transplantation was associated with the delayed initiation of steroid treatment for GVHD (0.95 months vs 3.0 months; P <.001) and with the use of fewer systemic immunosuppressants in the first 3 months after transplantation (P </=.04). This corresponded to more prevalent skin and more severe gut morbidity 6 to 12 months after nonablative transplantation. Our results show that nonablative HSCT is associated with a syndrome of acute GVHD occurring after day 100 in many patients. This "late-onset acute GVHD" should be taken into consideration in the design of prospective studies comparing GVHD resulting from the two types of transplantation procedures.

Aged↗

PubMed2003

Selective T-cell ablation with bismuth-213-labeled anti-TCRalphabeta as nonmyeloablative conditioning for allogeneic canine marrow transplantation.

Two major immunologic barriers, the host-versus-graft (HVG) and graft-versus-host (GVH) reactions, have to be overcome for successful allogeneic hematopoietic cell transplantation. T cells were shown to be primarily involved in these barriers in the major histocompatibility complex identical setting. We hypothesized that selective ablation of T cells using radioimmunotherapy together with postgrafting immunosuppression would suffice to ensure stable allogeneic engraftment. We had described a canine model of nonmyeloablative marrow transplantation in which host immune reactions were impaired by a single dose of 200 cGy total body irradiation (TBI), and both GVH and residual HVG reactions were controlled by postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). Here, we substituted the alpha-emitter bismuth-213 (213Bi) linked to a monoclonal antibody (mAb) against T-cell receptor (TCR) alphabeta, using the metal-binding chelate diethylenetriaminepentaacetic acid (DTPA) derivative cyclohexyl-(CHX)-A", for 200 cGy TBI. Biodistribution studies using a gamma-emitting indium-111-labeled anti-TCRalphabeta mAb showed uptake primarily in blood, marrow, lymph nodes, spleen, and liver. Four dogs were treated with 0.13 to 0.46 mg/kg TCRalphabeta mAb labeled with 3.7 to 5.6 mCi/kg (137-207 MBq/kg) 213Bi. The treatment was administered in 6 injections on days -3 and -2 followed by transplantation of dog leukocyte antigen-identical marrow on day 0 and postgrafting immunosuppression with MMF/CSP. The therapy was well tolerated except for elevations of transaminases that were transient in all but one of the dogs. No other organ toxicities or signs of graft-versus-host disease were noted. The dogs had prompt allogeneic hematopoietic engraftment and achieved stable mixed donor-host hematopoietic chimerism with donor contributions ranging from 5% to 55% after more than 30 weeks of follow up.

Animals↗

PubMed2003

Dog leukocyte antigen-haploidentical stem cell allografts after anti-CD44 therapy and reduced-intensity conditioning in a preclinical canine model.

OBJECTIVE: We previously described a nonmyeloablative hematopoietic stem cell transplantation regimen in dog leukocyte antigen (DLA)-identical littermate recipients consisting of low-dose total body irradiation (TBI) before and mycophenolate mofetil (MMF)/cyclosporine (CSP) given after transplant to control both graft-vs-host and residual host-vs-graft reactions. In this study, we sought to develop a reduced-intensity regimen to achieve engraftment across major histocompatibility complex barriers in DLA-haploidentical littermate recipients. MATERIALS AND METHODS: We tested a regimen of 450-cGy TBI with or without postgrafting MMF/CSP for 28 and 35 days, respectively, and with the administration of monoclonal antibody (mAb) S5 (anti-CD44), at a dose of 0.2 mg/kg/day from days -7 through -2, prior to receiving TBI. RESULTS: One of six dogs conditioned with 450-cGy TBI alone achieved engraftment of granulocyte colony-stimulating factor-mobilized peripheral blood stem cells. Three of six dogs achieved sustained donor cell engraftment using 450-cGy TBI and posttransplantation MMF/CSP. None of three dogs given mAb S5 followed by 450-cGy TBI showed signs of donor cell engraftment. However, when S5 mAb pretreatment was added to 450-cGy TBI and postgrafting MMF/CSP, 10 of 12 dogs achieved sustained engraftment (p = 0.008 or 0.007 vs 450-cGy alone or to S5 + 450-cGy TBI without MMF/CSP, respectively), with only three dogs developing severe graft-vs-host disease on this short regimen of immunosuppression. CONCLUSION: These results show that engraftment across a DLA haplotype-mismatched barrier can be achieved after reduced-intensity conditioning when mAb S5 directed at CD44 is added to this regimen.

Animals↗

PubMed2003

Relapse or progression after hematopoietic cell transplantation using nonmyeloablative conditioning: effect of interventions on outcome.

OBJECTIVE: This study analyzes the effect of interventions aimed at reinducing remissions in patients with relapse or progression of malignant disease following allogeneic hematopoietic cell transplantation (HCT) using nonmyeloablative conditioning. METHODS: We performed a retrospective analysis of 81 instances of relapse or progression occurring among 224 patients given HCT as treatment of their hematologic malignancies. All patients received conditioning with 2 Gy total-body irradiation with or without fludarabine and with postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. RESULTS: Overall survival of patients after relapse or progression was 36%. Fifteen of the 81 patients were given no interventions. Three of these 15 (20%) patients are alive with disease while 12 died with disease progression. Sixty-six patients (81%) received interventions, including withdrawal of immunosuppression (n=32), donor lymphocyte infusions (n=13), or chemotherapy (n=21). Twenty of the 66 (30%) are alive, 5 in complete remission, 4 in partial remission, 1 with stable and 10 with progressive disease. The overall response rate to intervention was 27%. Forty-six (70%) of the patients given interventions died, mainly due to relapse/progression. Patients not receiving interventions had a 1-year survival estimate of 15% compared to 41% in patients given interventions. Factors associated with survival in patients given intervention were disease response (p=0.002), disease category (p=0.001), and time to relapse from transplantation (p=0.0005). CONCLUSIONS: While the overall prognosis of patients relapsing or progressing after nonmyeloablative HCT is poor, interventions such as the combined use of immunotherapy and chemotherapy can improve patient survival.

Adolescent↗

PubMed2003

Non-myeloablative allografting from human leucocyte antigen-identical sibling donors for treatment of acute myeloid leukaemia in first complete remission.

Many patients with acute myeloid leukaemia (AML) in first complete remission (CR1) are ineligible for allogeneic transplantation as a result of age or medical problems other than leukaemia. Eighteen patients (median age 59 years, range 36-73 years) with de novo (n = 13) and secondary (n = 5) AML in morphological CR1, who were not candidates for conventional allografting, received non-myeloablative peripheral blood stem cell transplants from human leucocyte antigen identical sibling donors after conditioning with 2 Gy total body irradiation (TBI; n = 10) or 2 Gy TBI and 90 mg/m2 of fludarabine (n = 8). Postgrafting immunosuppression was with cyclosporine and mycophenolate mofetil. Two rejections were observed in patients not given fludarabine and one died with relapse. Overall, 10 patients died between 77 and 841 d, seven from relapse and three from non-relapse mortality (NRM). Day +100 NRM was 0% with a 1-year estimated NRM of 17%[95% confidence interval (CI) 0-35%]. The median follow-up among the eight survivors was 766 d (range, 188-1141 d). Seven of these eight survivors remain in complete remission (CR). One-year estimates of overall and progression-free survivals were 54% (95% CI 31-78%) and 42% (95% CI 19-66%) respectively. While follow-up is short, this analysis demonstrates that the procedure is sufficiently safe to be studied in a wider group of patients.

Acute Disease↗

PubMed2003

Impact of unrelated donor status on the incidence and outcome of cytomegalovirus infections after non-myeloablative allogeneic stem cell transplantation.

Little is known about the impact of cytomegalovirus (CMV) infections that occur after human leucocyte antigen (HLA)-matched unrelated donor (MUD) non-myleoablative haematopoietic stem cell transplantation (HCT). We analysed the incidence, onset and outcomes of CMV infections in 59 recipients of MUD and in 109 recipients of HLA-matched related donor (MRD) allogeneic HCT following non-myeloablative conditioning containing 2 Gy total body irradiation and fludarabine. In CMV seropositive recipients, antigenaemia occurred in 68% (MUD) and in 49% (MRD, P = 0.08); there were no differences in the maximum levels of CMV antigenaemia and the time to cessation with antiviral therapy. CMV viraemia by culture was more common in MUD compared with MRD HCT recipients in univariate analysis (26% vs. 6%, P = 0.01), however, this difference was not detectable after controlling for other factors. The rates of CMV disease in the first 100 d were similar in MUD (9%) and MRD (5%) HCT recipients. CMV disease tended to occur earlier in the MUD compared with the MRD recipients (median day 41 vs. day 80). Beyond day 100, rates of CMV disease remained similar in both cohorts (cumulative incidence: MUD 21% and MRD 14%). The 30-d and 1-year survivals after CMV disease diagnosis were not significantly different in both groups. Thus, there appeared to be a trend toward increased CMV reactivation in MUD compared with MRD non-myeloablative allogeneic HCT recipients; however, these differences did not reach statistical significance in this cohort and preemptive therapy was similarly effective in preventing CMV diseases.

Adult↗

PubMed2003

Allografting after nonmyeloablative conditioning as a treatment after a failed conventional hematopoietic cell transplant.

Outcomes with conventional allogeneic hematopoietic cell transplantation (HCT) after failed HCT are typically poor. To reduce transplantation-related mortality (TRM), 55 patients (median age, 43 years; range, 18-69 years) who had failed conventional autologous (n = 49), allogeneic (n = 4), or syngeneic (n = 2) HCT received human leukocyte antigen-matched related (n = 31) or unrelated (n = 24) donor allografts after nonmyeloablative conditioning with 2 Gy of total body irradiation or 2 Gy of total body irradiation and 90 mg/m(2) of fludarabine. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. One rejection occurred. Thirty-three patients died a median of 127 days (range, 7-834 days) after HCT: 21 of relapse, 11 of TRM, and 1 of suicide. The TRM rate on day 100 was 11% with an estimated 1-year TRM rate of 20% (95% confidence interval [CI], 9% to 31%). The median follow-up among the 22 survivors is 368 days (range, 173-796 days). Seventeen of 22 survivors are progression-free. One-year estimates of overall and progression-free survival rates are 49% (95% CI, 35% to 62%) and 28% (95% CI, 16% to 41%), respectively. Untreated disease at the time of allografting after nonmyeloablative conditioning increased the risk of death (hazard ratio = 2.4; P =.04). Although the length of follow-up is still short, it appears that encouraging outcomes can be achieved with nonmyeloablative conditioning in patients expected to have poor outcomes with conventional allografting.

Adolescent↗

PubMed2003

The role of cancer vaccines following autologous stem cell rescue in breast and ovarian cancer patients: experience with the STn-KLH vaccine (Theratope).

The success of high-dose chemotherapy followed by autologous stem-cell rescue as treatment for breast and ovarian cancer is limited by a high incidence of relapse. After autologous transplantation, patients are likely to have a low tumor burden and thus would be more likely to respond immunologically to a cancer vaccine. Sialyl-Tn (STn) is a carbohydrate associated with the MUC1 mucin on breast and ovarian cancer and is an ideal candidate for vaccine immunotherapy. Sialyl-Tn-keyhole limpet hemocyanin (STn-KLH) vaccine (Theratope) incorporates a synthetic STn antigen that mimics the unique tumor-associated STn carbohydrate and is designed to stimulate tumor antigen-specific immune responses in patients with mucin-expressing tumors. Between 1995 and 2000, 70 patients (16 with stage II/III breast cancer, 17 with stage III/IV ovarian cancer, and 37 with stage IV breast cancer) were treated with 2 different formulations of STn-KLH. Toxicity, outcome, and immune response data are reported. STn-KLH was well-tolerated with minimal toxicity. The most common side effects were indurations and erythema at the sites of injections. Humoral and cellular responses were elicited in the majority of patients. Overall, these data indicate that post-autologous transplant patients are able to mount an effective immune response to vaccine immunotherapy with minimal side effects, and that vaccine immunotherapy may be a useful addition to high-dose chemotherapy regimens.

Antigens, Tumor-Associated, Carbohydrate↗

PubMed2002

Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases.

Toxicities of high-dose conditioning regimens have limited the use of conventional unrelated donor hematopoietic cell transplantation (HCT) to younger, medically fit patients. Based on preclinical studies, an HCT approach has been developed for elderly or medically infirm patients with HLA-matched or mismatched unrelated donors. In this study, 52 patients with hematological diseases were included. Most (88%) had preceding unsuccessful conventional HCT or refractory/advanced disease. Patients were treated with fludarabine 30 mg/m(2)/d from days -4 to -2, 2 Gy total body irradiation on day 0, cyclosporine at 6.25 mg/kg twice daily from day -3, and mycophenolate mofetil at 15 mg/kg twice daily from day 0. Durable donor chimerism was attained in 88% of the patients. By day 28, a median of 100% of CD56(+) cells were of donor origin. Granulocyte and T-cell donor chimerism increased to medians of 100% on day 56 and day 180 (range, 55%-100%), respectively. Acute GVHD, grade II, was seen in 42% (CI, 29%-56%); grade III in 8% (CI, 0%-15%); and grade IV in 13% (CI, 4%-23%) of patients; it was fatal in 9%. The 100-day transplantation-related mortality was 11%. Complete remissions, including molecular remissions, were seen in 45% of patients with measurable disease before transplantation. Mortality from disease progression was 27% at one year. With a median follow-up of 19 months, 18 of the 52 patients (35%) were alive and 25% were in remission. HCT from HLA-matched or mismatched unrelated donors can be performed with a reduced intensity conditioning regimen in patients ineligible for conventional HCT.

Adult↗

PubMed2002

Bismuth 213-labeled anti-CD45 radioimmunoconjugate to condition dogs for nonmyeloablative allogeneic marrow grafts.

To lower treatment-related mortality and toxicity of conventional marrow transplantation, a nonmyeloablative regimen using 200 cGy total-body irradiation (TBI) and mycophenolate mofetil (MMF) combined with cyclosporine (CSP) for postgrafting immunosuppression was developed. To circumvent possible toxic effects of external-beam gamma irradiation, strategies for targeted radiation therapy were investigated. We tested whether the short-lived (half-life, 46 minutes) alpha-emitter bismuth 213 ((213)Bi) conjugated to an anti-CD45 monoclonal antibody (mAb) could replace 200 cGy TBI and selectively target hematopoietic tissues in a canine model of nonmyeloablative DLA-identical marrow transplantation. Biodistribution studies using iodine 123-labeled anti-CD45 mAb showed uptake in blood, marrow, lymph nodes, spleen, and liver. In a dose-escalation study, 7 dogs treated with the (213)Bi-anti-CD45 conjugate ((213)Bi dose, 0.1-5.9 mCi/kg [3.7-218 MBq/kg]) without marrow grafts had no toxic effects other than a mild, reversible suppression of blood counts. On the basis of these studies, 3 dogs were treated with 0.5 mg/kg (213)Bi-labeled anti-CD45 mAb ((213)Bi doses, 3.6, 4.6, and 8.8 mCi/kg [133, 170, and 326 MBq/kg]) given in 6 injections 3 and 2 days before grafting of marrow from DLA-identical littermates. The dogs also received MMF (10 mg/kg subcutaneously twice daily the day of transplantation until day 27 afterward) and CSP (15 mg/kg orally twice daily the day before transplantation until 35 days afterward). The therapy was well tolerated except for transient elevations in levels of transaminases in 3 dogs, followed by, in one dog, ascites. All dogs had prompt engraftment and achieved stable mixed hematopoietic chimerism, with donor contributions ranging from 30% to 70% after more than 27 weeks of follow-up. These results will form the basis for additional studies in animals and later the design of clinical trials using (213)Bi as a nonmyeloablative conditioning regimen with minimal toxicity.

Animals↗

PubMed2002

Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study.

Nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly being explored as therapy in patients who are not eligible for conventional myeloablative HSCT. Whether these transplants are associated with reduced risk of transplantation-related infections is unknown. We analyzed the incidence of posttransplantation cytomegalovirus (CMV) infections in 56 consecutive mycophenolate mofetil (MMF) patients with hematologic malignancies who underwent nonmyeloablative HSCT (TBI, 2Gy, day 0; MMF/cyclosporine after transplantation). In addition, 18 of 56 patients received 30 mg/m(2)/d fludarabine on days -4 to -2. Most donors were HLA matched and related (93%). Each case patient was matched to 2 controls who were treated by conventional HSCT during the same time period (January 1997 through April 2000). Matching criteria included CMV risk group, HSC source, donor type, age, and underlying diseases. No CMV disease occurred in the low (donor and recipient serologically negative) and intermediate (donor serologically positive and recipient negative) CMV risk groups during the first 100 days. Among cases at high risk for CMV (seropositive recipients), trends to less CMV antigenemia (P =.11), viremia (P =.16), and disease (P =.08) compared with controls were observed; all severe manifestations combined (CMV viremia and disease) were significantly reduced among cases (P =.01). However, by day 365, the overall incidence of CMV disease became similar in both groups. The onset of CMV disease was significantly delayed among case patients compared with controls (median, 130 days versus 52 days; P =.02). It was concluded that CMV disease was significantly delayed in nonmyeloablative cases, but that the overall 1-year incidence was similar to myeloablative HSCT patients. Therefore, nonmyeloablative HSCT patients should receive CMV surveillance beyond day 100 and pre-emptive ganciclovir treatment similar to that of myeloablative HSCT patients.

Adult↗