One hundred nine patients with hematologic malignancies, undergoing bone marrow transplants (BMT) from unrelated donors, were randomized in 2 consecutive trials to receive or not to receive antithymocyte globulin (ATG) in the conditioning regimen, as follows: (A) 54 patients (median age, 28 years; 39% with advanced disease) were randomized to no ATG (n ‫؍‬ 25) versus 7.5 mg/kg rabbit ATG (Thymoglobulin; Sangstat, Lyon, France) (n ‫؍‬ 29) ; (B) 55 patients (median age, 31 years, 71% with advanced disease) were randomized to no ATG (n ‫؍‬ 28) versus 15 mg/kg rabbit ATG (n ‫؍‬ 27). Grade III-IV graft-versus-host disease (GVHD) was diagnosed in 36% versus 41% (P ‫؍‬ .8) in the first and in 50% versus 11% (P ‫؍‬ .001) in the second trial. Transplant-related mortality (TRM), relapse, and actuarial 3-year survival rates were comparable in both trials. In fact, despite the reduction of GVHD in the second trial, a higher risk for lethal infections (30% vs 7%; P ‫؍‬ .02) was seen in the arm given 15 mg/kg ATG. Extensive chronic GVHD developed overall more frequently in patients given no ATG (62% vs 39%; P ‫؍‬ .04), as confirmed by multivariate analysis (P ‫؍‬ .03). Time to 50 ؋ 10 9 /L platelets was comparable in the first trial (21 vs 24 days; P ‫؍‬ .3) and delayed in the ATG arm in the second trial (23 vs 38 days; P ‫؍‬ .02). These trials suggest that (1) 15 mg/kg ATG before BMT significantly reduces the risk for grade III-IV acute GVHD, (2) this does not translate to a reduction in TRM because of the increased risk for infections, and (3) though survival is unchanged, extensive chronic GVHD is significantly reduced in patients receiving ATG. (Blood. 2001;98:2942-2947)

Among patients with newly diagnosed myeloma, survival in recipients of a hematopoietic stem-cell autograft followed by a stem-cell allograft from an HLA-identical sibling is superior to that in recipients of tandem stem-cell autografts. (ClinicalTrials.gov number, NCT00415987 [ClinicalTrials.gov].).

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The full potential of a graft-versus-myeloma effect after allogeneic hemato-poietic cell transplantation (HCT) for patients with multiple myeloma (MM) has not been realized because of excessive early transplantation-related mortality (TRM) with conventional HCT. Autolo-gous HCTs have been characterized by almost universal disease recurrences. The current trial combined autologous HCT with subsequent nonmyeloablative alloge-neic 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 melpha-lan 200 mg/m 2 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 immunosup-pression with mycophenolate mofetil (MMF) and cyclosporine (CSP). Patients experienced medians of 0 days of hospitalization , neutropenia, and thrombocytope-nia. 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. (Blood. 2003;102:3447-3454) Introduction High-dose therapy with autologous hematopoietic cell transplanta-tion (HCT) for advanced-stage myeloma in patients younger than 65 years of age has survival advantages compared with conventional therapy. 1,2 In the Intergroupe Francais du Myélome (IFM) 90 trial, the complete remission (CR) rate was higher and the 7-year event-free survival (EFS) 16% and overall survival (OS) 43% compared with 8% and 25% with conventional chemotherapy, respectively. 1,3 The use of tandem autografts is also superior to standard chemotherapy 4 and may be better than a single autograft. Recent data from the IFM94 trial, published in abstract form, comparing single dose of 140 mg/m 2 melphalan (Mel 140) plus total body irradiation (TBI; 8 Gy) versus tandem Mel 140 followed by Mel 140 TBI (8 Gy) in 399 patients found a similar CR rate of 34% versus 35% but 7-year EFS of 10% versus 20% and 7-year OS of 21% versus 42% favoring the tandem transplant arm. 3 Despite high response rates and relatively low transplantation-related mortality (TRM) of less than 10%, fewer than 30% of patients remain in remission 3 to 7 years later. 5-13 The high ...

Purpose We reported encouraging early results of allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning in 64 patients who had advanced chronic lymphocytic leukemia (CLL). Here, we have extended the follow-up to a median of 5 years and have included data on an additional 18 patients. Patients and Methods Eighty-two patients, age 42 to 72 years, who had fludarabine-refractory CLL were conditioned with 2 Gy total-body irradiation alone or combined with fludarabine followed by HCT from related (n = 52) or unrelated (n = 30) donors. Results Complete remission (CR) and partial remission were achieved in 55% and 15% of patients, respectively. Higher CR rates were noted after unrelated HCT (67% v 48%). The 5-year incidences of nonrelapse mortality (NRM), progression/relapse, overall survival, and progression-free survival were 23%, 38%, 50%, and 39%, respectively. Among 25 patients initially reported in CR, 8% relapsed and 8% died as a result of NRM, whereas 84% have remained alive and in CR. Among 14 responding patients who were tested and who had molecular eradication of their disease, two died as a result of NRM, two relapsed, and 10 have remained negative. At 5 years, 76% of living patients were entirely well, whereas 24% continued to receive immunosuppression for chronic graft-versus-host disease; the median performance status in each group was 100% and 90%, respectively. Lymphadenopathy ≥ 5 cm, but not cytogenetic abnormalities at HCT, predicted relapse. In a risk-stratification model, patients who had lymphadenopathy less than 5 cm and no comorbidities had a 5-year OS of 71%. Conclusion Nonmyeloablative HCT resulted in a median survival of 5 years for patients who had fludarabine-refractory CLL with sustained remissions and in the continued resolution of chronic graft-versus-host disease in surviving patients.

We compared the outcome of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) for patients with relapsed or refractory Hodgkin lymphoma (HL) based on donor cell source. Ninety patients with HL were treated with nonmyeloablative conditioning followed by HCT from HLA-matched related, n = 38, unrelated, n = 24, or HLA-haploidentical related, n = 28 donors. Patients were heavily pretreated with a median of 5 regimens and most patients had failed autologous HCT (92%) and local radiation therapy (83%). With a median follow-up of 25 months, 2-year overall survivals, progression-free survivals (OS)/(PFS), and incidences of relapsed/progressive disease were 53%, 23%, and 56% (HLA-matched related), 58%, 29%, and 63% (unrelated), and 58%, 51%, and 40% (HLA-haploidentical related), respectively. Nonrelapse mortality (NRM) was significantly lower for HLA-haploidentical related (P =.02) recipients compared to HLA-matched related recipients. There were also significantly decreased risks of relapse for HLA-haploidentical related recipients compared to HLA-matched related (P = .01) and unrelated (P = .03) recipients. The incidences of acute grades III–IV and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 16%/50% (HLA-matched related), 8%/63% (unrelated), and 11%/35% (HLA-haploidentical related). These data suggested that salvage allogeneic HCTusing nonmyeloablative conditioning provided antitumor activity in patients with advanced HL; however, disease relapse/progression continued to be major problems. Importantly, alternative donor stem cell sources are a viable option.

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This is an update of a randomized study on antithymocyte globulin (ATG; Thymoglobulin) before transplantation in patients undergoing unmanipulated marrow transplantation from unrelated donors. The median follow-up for surviving patients is 5.7 years. At last follow-up, chronic graft-versus-host disease (GVHD) was scored in 60% of non-ATG and in 37% of ATG patients (P=.05), and extensive chronic GVHD was present in 41% and 15%, respectively (P=.01). Chronic lung dysfunction was diagnosed in 51% versus 19% of patients (P=.005). Forced vital capacity decreased significantly with time in non-ATG patients (P=.005), but not in patients who received ATG (P=.30). The proportion of patients with Karnofsky scores of >or=90% at 4 years was 57% versus 89% in non-ATG versus ATG patients (P=.03). The actuarial 6-year survival for all patients randomized was 31% versus 44% (non-ATG versus ATG; P=.80). The cumulative incidence of transplant-related mortality was 51% versus 41% (P=.70) and of relapse was 32% versus 40% (P=.90). For patients who survived 1 year, transplant-related mortality was 25% versus 3% (P=.03), and actuarial survival was 58% versus 85% (P=.09). In conclusion, the addition of ATG to cyclosporine/methotrexate provides significant protection against extensive chronic GVHD and chronic lung dysfunction, reduces late transplant mortality, and improves quality of life in patients undergoing unrelated donor transplantation.