Conditioning with purine analogs leads to good engraftment rates of immunodepleted grafts for aplastic anemia.

Immunodepletion with alemtuzumab is an effective strategy for preventing graft-versus-host disease after allogeneic stem cell transplantation (SCT), but it may be associated with graft failure. We tested the effectiveness of a purine analog-based reduced-intensity conditioning combination in patients undergoing allogeneic SCT for bone marrow aplasia. Patients with severe marrow aplasia who had a tissue-compatible sibling donor were conditioned with fludarabine 30 mg/m(2) for 5 days and cyclophosphamide 120 mg/kg. Stem cells from HLA-identical sibling donors were mobilized with filgrastim, and the harvested blood concentrates were incubated ex vivo with alemtuzumab. After graft infusion, patients received therapeutic doses of cyclosporine up to day 90. The primary objective of this study was to examine the proportion of patients who achieved engraftment and overall survival. Secondary objectives were the rates of graft-versus-host disease, posttransplantation infections, and graft failure. The study group comprised 30 patients who received a total of 31 cytokine-mobilized blood stem cell transplantations. The median CD34(+) cell dose infused was 4.99 × 10(6)/kg. All patients engrafted at a median of 12 days post-SCT. Two patients exhibited delayed graft failure, at 3 months and 7 months post-SCT, and required retransplantation or donor lymphocyte infusion to reestablish full-donor chimerism. At a median of 1,560 days post-SCT, all patients survived and were transfusion-free. We confirm that the combination of purine analog and cyclophosphamide is adequate for engraftment of grafts immunodepleted with alemtuzumab. This strategy is associated with excellent outcomes.

Is there a role for autologous stem cell transplantation for patients with acute myelogenous leukemia? A retrospective analysis.

For patients with acute myelogenous leukemia (AML) who are unable to secure an acceptable HLA donor, the role of autologous stem cell transplantation (auto-SCT) has remained controversial. Its effectiveness remains unclear as, when analyzed on intention-to-treat strategies, a significant number do not undergo the procedure, whereas others seem to fail therapy from pretransplant recurrences. To improve our counseling to our patients on these 2 therapeutic options, we compared the outcome of patients in first remission of AML who actually underwent autologous or allogeneic transplantation. The choice for the type of graft was based on availability of HLA identical siblings. Patients received myeloablative conditioning followed by allogeneic or autologous cytokine mobilized peripheral blood stem cell transplantation. For prophylaxis of graft-versus-host disease (GVHD), grafts were incubated ex vivo with anti-CD52 antibodies and patients were prescribed cyclosporin until day 90. Patients were stratified by clinical and laboratory factors as well as cytogenetic risk. The endpoints were treatment-related mortality (TRM), disease-free survival (DFS), and overall survival (OS). The median presentation age for both transplant groups was 35 (14-60) years. Of the 112 consecutive patients achieving remission, autologous or allogeneic grafts were transplanted to 43 and 32 patients, respectively. There was no significant difference in the presentation clinical features, laboratory parameters, marrow morphology, or proportion of low and intermediate cytogenetic risk for both transplant options. Treatment mortality as well as relapse rate was similar (14% and 15%; 39% and 27%, respectively). At a median of 1609 and 1819 posttransplant days, 56% and 63% in each group survived. In univariate analysis performance status, cytogenetic risk, morphologic features of dysplasia, blast count, and lactate dehydrogenase (LDH) were significant factors for survival. Although for the entire group there was no difference in survival between both modalities, all patients with unfavorable cytogenetics receiving an autologous graft died of disease recurrence (3-year survival 35% versus 0%; P = .05). We conclude that patients with AML who have low or intermediate cytogenetic risk undergoing myeloablative conditioning followed by autologous or allogeneic T cell-depleted stem cell transplantation appeared to have similar outcome. However, those with unfavorable karyotype are unlikely to be cured with autologous grafts and are candidates for experimental modalities.

Combined submyeloablative and myeloablative dose intense melphalan results in satisfactory responses with acceptable toxicity in patients with multiple myeloma.

We studied in patients with multiple myeloma (MM) the efficacy, cost-effectiveness, and toxicity of a strategy of submyeloablative doses of Mel and stem cell support in the ambulatory setting, followed by a standard myeloablative dose transplant. Patients with recently diagnosed symptomatic MM received dexamethazone to induce clinical response. Cytokine mobilized peripheral blood progenitor cells (PBPC) were split into 2 aliquots and cryopreserved. Patients then received Mel 100 mg/m(2) (Mel100) and infusion of the first PBPC aliquot in an ambulatory facility. Individuals received standard neutropenia prophylaxis and no growth factor support, but were seen regularly at the clinic until recovery. The cost of this step was calculated in a cohort of 23 patients where information for the expenditure was available. Six months later patients were conditioned in the hospital with Mel 200 mg/m(2) (Mel 200) followed by nfusion of the second aliquot. This study tested the cost, effectiveness, and the toxicity of out-patient-based transplantation, as well as the rate of response (complete remission [CR], very good partial remission [VGPR], partial remission [PR], and stable disease [SD]) and overall survival (OS) of this strategy. Twenty-six female and 16 male patients, with a median age of 53 years (range: 33-68 years) and median Salmon & Durie clinical disease stage III (range: II-III) were studied. The paraprotein was IgA in 17%, IgG in 52%, and light chains in 26%. The median harvested CD34(+) x 10(6) cells/kg was 12.03 (2.25-55.4). The median interval between the 2 transplant procedures was 239 (105-376) days. The median Karnofsky presentation score was 40%, but improved to 80% after the Mel 100 and was 90% following Mel 200. Subsequent to MEL 100 response was complete (CR) in 7 and it was VGPR in 9. Mel 100 grade 3-4 toxicity was mainly hematologic, but 15 (36%) required hospital admission for a median of 5 days. The median cost of MEL100 and corresponding supportive therapy was U.S. $2,142.35. In addition, the total median cost of those who needed admission to hospital was U.S. $6,042.78. Thus, pooling costs from patients who needed or did not need admissions the average cost of this strategy was U.S. $3,546.50 per patient. Among Mel 200 patients, except for hematologic toxicity, no patient had greater than grade 2 side effects. On completion of the program, 20 (48%) patients achieved CR, a further 14 (33%) had VGPR, whereas 6 had PR. At a median follow-up of 659 days there were 8 deaths, 1 (2%) was related to the treatment procedures and 6 from disease progression; thus, the 1000 days OS was 73%. Significant adverse factors included older age, lower presentation Hb, and lower Karnofsky %. Nonparametric testing confirmed that good performance scores and VGPR or CR were associated with more favorable outcome. Importantly, these satisfactory results were obtained in the absence of the new biologic cell modifiers. Mel 100 was well tolerated in the outpatient setting and the overall strategy seems to be effective in inducing durable responses with acceptable toxicity.

In stem cell transplantation, by limiting the morbidity of graft-versus-host disease tolerance to myeloablative conditioning is improved.

Myeloablative conditioning followed by T-cell depletion of grafts and reduced intensity conditioning (RIC) has both been shown to decrease treatment related mortality (TRM). However in RIC the incidence of graft vs. host disease (GvHD) is high and patients with aggressive diseases tend to relapse. Following myeloablative conditioning, patients with chemotherapy-responsive hematological malignancies underwent transplantation from HLA identical siblings. GvHD prophylaxis was by ex viva T-cell depletion with alemtuzumab. The outcome of these patients was analysed. At transplantation, the median age of 81 consecutive individuals was 45 years (range 15-60). GvHD was seen in 10% and was commonly associated with infections resulting in one and 3 year TRM of 15 and 20.5%. Fifteen patients relapsed, 10 who had myeloproliferative syndromes or lymphoma and two with myeloma responded to DLI. For the whole group, median follow up is 777 (range 7-2702) days and 73% remain disease free. Cox regression analysis for survival showed that only occurrence of GvHD was a significant adverse factor. Age order than median was not associated with worse outcome. By reducing the incidence and severity of GvHD, T-cell depletion of grafts leads to greater tolerance to myeloablative chemotherapy, resulting in acceptable TRM. This strategy should be compared with the RIC approaches.

Allogeneic stem cell transplantation with T cell-depleted grafts for lymphoproliferative malignancies.

In non-Hodgkin lymphoma allogeneic stem cell transplantation (SCT) can be curative, but with standard dose conditioning patients may have substantial morbidity and mortality from graft-versus-host disease (GVHD); for aggressive malignancies, reduced intensity conditioning may result in higher recurrence. Patients with advanced follicular lymphoma (n = 12), transformed B cell malignancy (n = 11), and non-CD30+T cell lymphomas (n = 17) responsive to chemotherapy who had an HLA-identical sibling were offered T cell depleted (CAMPATH-1 G or H antibodies) SCT. Conditioning was with ablative doses of chemotherapy or radiotherapy. Before SCT, patients with follicular lymphoma had a median of 3 treatment courses, and those with transformed B cell and those diagnosed with T cell non-Hodgkin lymphoma had 2 (range, 1-3). At SCT the median age was 46 years (range, 21-59 years) and the number of CD34+ cells infused was 2.85 x 10(6)/kg. All patients showed engraftment but 7 patients (17.5%) developed GVHD. In total 12 subjects expired of transplant-related causes (n = 6) or from disease recurrence. One-year transplant-related mortality was 15%. There was no difference in survival across diagnostic groups. At a median of 1051 days, 70% survived and 68% are without disease. By reducing the incidence and severity of GVHD, patients can tolerate myeloablative doses of chemotherapy satisfactorily. This has resulted in low treatment-related mortality and adequate protection from disease recurrence.