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Purpose: The objective of this randomized trial was to assess the efficacy and safety of rituximab as in vivo purging before transplantation and as maintenance treatment immediately after high-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT) in patients with relapsed follicular lymphoma (FL)., Patients and Methods: Patients with relapsed FL who achieved either complete or very good partial remission with salvage chemotherapy were randomly assigned using a factorial design to rituximab purging (P+; 375 mg/m(2) once per week for 4 weeks) or observation (NP) before HDC-ASCT and to maintenance rituximab (M+; 375 mg/m(2) once every 2 months for four infusions) or observation (NM)., Results: From October 1999 to April 2006, 280 patients were enrolled. The median age was 51 years (range, 26 to 70 years), and baseline characteristics were well balanced between groups. On average, patients were 44 months (range, 3 to 464 months) from diagnosis, with 79% having received two lines and 15% three lines of prior therapy. Median follow-up was 8.3 years. In contrast to purging, 10-year progression-free survival (PFS) was 48% for P+ and 42% for NP groups (hazard ratio [HR], 0.80; 95% CI, 0.58 to 1.11; P = .18); maintenance had a significant effect on PFS (10-year PFS, 54% for M+ and 37% for NM; HR, 0.66; 95% CI, 0.47 to 0.91; P = .012). Overall survival (OS) was not improved by either rituximab purging or maintenance., Conclusion: Rituximab maintenance after HDC-ASCT is safe and significantly prolongs PFS but not OS in patients undergoing transplantation for relapsed FL. Pretransplantation rituximab in vivo purging, even in rituximab-naive patients, failed to improve PFS or OS.

Purpose: Although high-dose chemotherapy supported by autologous peripheral-blood progenitor-cell (PBPC) transplantation improves response rates and survival for patients with multiple myeloma, all patients eventually develop progressive disease after transplantation. It has been hypothesized that depletion of malignant plasma cells from autografts may improve outcome by reducing infused cells contributing to relapse., Patients and Methods: A randomized phase III study using the CEPRATE SC System (Cellpro, Bothell, WA) to enrich CD34(+) autograft cells and passively purge malignant plasma cells was completed in 190 myeloma patients randomized to receive an autograft of CD34-selected or unselected PBPCs., Results: After CD34 selection, tumor burden was reduced by 1.6 to 6.0 logs (median, 3.1), with 54% of CD34-enriched products having no detectable tumor. Median time to count recovery, number of transfusions, transplantation-related mortality, and days in hospital were equivalent between the two transplantation arms. With a median follow-up of 37 months, 33 patients (36%) in the selected and 34 patients (35%) in the unselected arm had died (P =.784). Median overall survival in the selected arm was reached at 50 months and is not reached at this time in the unselected arm (P =.78). Median disease-free survival was 100 versus 104 weeks (P =.82), with 67% of patients in the selected arm and 66% of patients in the unselected arm relapsing., Conclusion: This phase III trial demonstrates that although CD34 selection significantly reduces myeloma cell contamination in PBPC collections, no improvement in disease-free or overall survival was achieved.

Purpose: To improve autologous leukapheresis strategies in high-risk neuroblastoma (NB) patients with extensive bone marrow involvement at diagnosis., Patients and Methods: Anti-G(D2) immunocytochemistry (sensitivity, 1 in 10(5) to 10(6) leukocytes) was used to evaluate blood and bone marrow disease at diagnosis and during the recovery phase of the first six chemotherapy cycles in 57 patients with stage 4 NB and bone marrow disease at diagnosis. A total of 42 leukapheresis samples from the same patients were evaluated with immunocytology, and in 24 of these patients, an anti-G(D2) immunomagnetic enrichment step was used to enhance tumor-cell detection., Results: Tumor cytoreduction was much faster in blood compared with bone marrow (3.2 logs after the first cycle and 2.1 logs after the first two cycles, respectively). Bone marrow disease was often detectable throughout induction, with a trend to plateau after the fourth cycle. By direct anti-G(D2) immunocytology, a positive leukapheresis sample was obtained in 7% of patients after either the fifth or sixth cycle; when NB cell immunomagnetic enrichment was applied, 25% of patients had a positive leukapheresis sample (sensitivity, 1 in 10(7) to 10(8) leukocytes)., Conclusion: Standard chemotherapy seems to deliver most of its in vivo purging effect within the first four cycles. In patients with overt marrow disease at diagnosis, postponing hematopoietic stem-cell collection beyond this point may not be justified. Tumor-cell clearance in blood seems to be quite rapid, and earlier collections via peripheral-blood leukapheresis might be feasible. Immunomagnetically enhanced NB cell detection can be highly sensitive and can indicate whether ex vivo purging should be considered.

Purpose: The role for high-dose therapy and autologous stem-cell transplantation in mantle-cell lymphoma (MCL) is unknown. We retrospectively analyzed patients with chemosensitive disease who underwent high-dose chemoradiotherapy and anti-B-cell monoclonal antibody-purged autologous bone marrow transplantation (ABMT) for MCL in first remission, as well as following relapse from conventional therapy., Patients and Methods: Between August 1985 and April 1996, 28 patients underwent ABMT using a uniform ablative regimen with cyclophosphamide and total-body irradiation (TBI) and a bone marrow-purging regimen. Re-review of original tissue demonstrated that all patients had morphologic, phenotypic, and genotypic characteristics of MCL. MCL was the original diagnosis in 21 patients, whereas seven patients had a prior diagnosis of diffuse small cleaved-cell lymphoma., Results: Twenty patients received multiple regimens before ABMT, while eight underwent ABMT in first complete remission (CR)/partial remission (PR) following CHOP induction. At bone marrow harvest, only 18% of patients were in CR and overt BM infiltration was present in 57%. Following cyclophosphamide/TBI, no treatment-related deaths were seen. Nineteen of 28 patients have relapsed at a median time of 21 months (range, 3 to 70). Of eight patients transplanted in first CR/PR, five have relapsed. Nine patients are in continuous CR with a median follow-up time of 24 months (range, 10 to 135). Disease-free survival (DFS) and overall survival (OS) are estimated to be 31% and 62% at 4 years, respectively., Conclusion: ABMT using cyclophosphamide/TBI conditioning may at best be effective in only a small fraction of patients with relapsed MCL. The lack of plateau with a median follow-up time of 24 months suggests cure may not be achievable. The role of this therapy in patients in first remission requires more study using better induction therapy to enhance the CR rate before ABMT.

Purpose: To evaluate the following prospectively in poor-risk neuroblastoma (NBL) patients: (1) the feasibility and efficacy of in vivo purging of bone marrow; and (2) the outcome after autologous bone marrow transplantation (ABMT) when immunologically tumor-free, unpurged autografts were used., Patients and Methods: Twenty-three children with poor-risk NBL were evaluated during induction chemotherapy by repeat bone marrow examinations, including aspirate, biopsy, and an immunofluorescence method using the anti-GD2 monoclonal antibody 3A7. Nineteen patients completed the program with surgery with or without local irradiation followed by ABMT., Results: Autologous bone marrow grafts, both immunologically and cytologically clean, were obtained and used in 19 of 23 children. The overall 4-year disease-free survival of the 19 grafted children was 53%, with a toxic death rate of 16% and a posttransplant relapse rate of 37%. According to the in vivo purging efficacy of the 18 children with initial marrow disease, the following three groups were formed: patients with (1) perfect in vivo purging (n = 5); (2) eventually successful in vivo purging (n = 8); and (3) unsuccesful in vivo purging (n = 5). The 4-year DFS was 100%, 67%, and 0%, respectively (P < 0.001). The five patients with unsuccessful in vivo purging failed because of resistant/progressive bulky disease., Conclusion: In patients with poor-risk NBL, in vivo purging of bone marrow by conventional chemotherapy is feasible, can be monitored, and the purging efficacy during the first 3 months after diagnosis is a strong prognostic factor reflecting tumor responsiveness to therapy. Autografting with immunologically clean, unpurged marrows gives a DFS well comparable to previous studies using ex vivo purging.

Purpose: To evaluate in a prospective study the efficacy of autologous bone marrow transplantation (BMT) in adult patients with acute myelogenous leukemia (AML) in first remission, using a single course of high-dose Cytarabine (HD Ara-C) consolidation therapy as in vivo purging., Patients and Methods: Sixty consecutive adult patients with AML in first complete remission (CR) were treated with HD Ara-C consolidation therapy as a method of in vivo purging before marrow collection. High-dose therapy consisted of fractionated total-body irradiation (FTBI) 12 Gy, intravenous etoposide 60 mg/kg, and cyclophosphamide 75 mg/kg, followed by reinfusion of cryopreserved marrow., Results: Sixty patients underwent consolidation treatment with HD Ara-C with the intent to treat with autologous BMT. Sixteen patients were unable to proceed to autologous BMT (10 patients relapsed, one died of sepsis, one developed cerebellar toxicity, two had inadequate blood counts, and two refused). Forty-four patients underwent autologous BMT and have a median follow-up time of 37 months (range, 14.7 to 68.7) for patients who are alive with no relapse. The cumulative probability of disease-free survival (DFS) at 24 months in the intent-to-treat group is 49% (95% confidence interval [CI], 37% to 62%) and in those who actually underwent autologous BMT is 61% (95% CI, 46% to 74%). The probability of relapse was 44% (95% CI, 31% to 58%) and 33% (95% CI, 20% to 49%) for the intent-to-treat and autologous BMT patients, respectively., Conclusion: This approach offers a relatively high DFS rate to adult patients with AML in first CR. The results of this study are similar to those achieved with allogeneic BMT.

Purpose: Acute and chronic graft-versus-host disease (GVHD) continues to be the major causes of morbidity and mortality after allogeneic bone marrow transplantation (BMT). In this study, we have evaluated the clinical effects of selective in vitro T-cell depletion of donor allogeneic bone marrow by using a single monoclonal antibody ([MoAb] anti-T12, CD6) and rabbit complement. This antibody recognizes mature T cells, but not other cellular elements such as natural-killer (NK) cells, B cells, and myeloid precursors., Patients and Methods: From August 1983 to April 1991, 112 consecutive adult patients with hematologic malignancies underwent BMT with bone marrow from HLA-identical sibling donors. Marrow was harvested and depleted of mature T lymphocytes ex vivo by the use of three rounds of incubation with an anti-T12 antibody and rabbit complement. The preparative regimen consisted of cyclophosphamide and fractionated total body irradiation (TBI) in 108 patients. No patients received prophylactic immune suppression post-BMT. Purgation by anti-T12 was used as the only method for the prevention of GVHD., Results: Twenty patients (18%) developed acute GVHD (grade 2 to 4); only eight patients developed chronic GVHD. The incidence of GVHD did not increase significantly with age. Only three of 112 patients (2.7%) exhibited acute graft failure. One patient developed late graft failure that was associated with cytomegalovirus (CMV) infection. Within the subset of 50 patients who had not previously undergone unsuccessful conventional therapy (acute leukemia in first remission or chronic myelogenous leukemia [CML] in stable phase), we estimated by the Kaplan-Meier method that the probability of disease-free survival was 50% at 3 years post-BMT, with a median follow-up of 44 months. The treatment-related mortality rate in this group was only 14% and was independent of patient age., Conclusions: We conclude that selective in vitro T-cell depletion with an anti-T12 monoclonal antibody effectively reduces the incidence of both acute and chronic GVHD after allogeneic BMT without compromising engraftment. Moreover, depletion of CD6-positive cells from donor marrow obviates the need to administer immune suppressive medications to the majority of patients. This approach reduces the morbidity and mortality of allogeneic BMT and permits the BMT of older patients.

In a phase I clinical trial of autologous bone marrow transplantation, we determined the feasibility of ex vivo purging with high concentrations of pharmacologics in combination. Light-density cells isolated from the grafts of 26 patients with acute leukemia or lymphoblastic lymphoma were treated with 4-hydroperoxycyclophosphamide (4-HC; 30 to 60 micrograms/mL), vincristine (Vcr; 1.5 to 3.0 micrograms/mL), and methylprednisolone sodium succinate (MP; 5 mg/mL). All patients received marrow-lethal induction therapy followed by infusion of the treated grafts. Three patients died of transplant-related complications before achieving peripheral blood recovery of greater than 0.5 x 10(9) granulocytes per liter. All other patients achieved this parameter of engraftment at a median of 35 days after marrow infusion. The median time to last platelet transfusion was 45 days. These durations of aplasia were similar to those experienced by other patients receiving density-gradient separated grafts treated with 60 micrograms/mL of 4-HC as a single agent. No patient required infusion of untreated reserve marrow because of engraftment failure. The colony-forming unit-granulocyte macrophage (CFU-GM) content of the grafts after purging predicted these parameters of engraftment. Colony-forming unit-leukemia (CFU-L) cultured from the grafts of 12 of the patients treated for acute lymphoblastic leukemia (ALL) were considerably more sensitive to the combination regimen than to 4-HC alone; the sensitivity of CFU-GM from these patients did not differ between the two regimens. The results of this trial indicate the feasibility of treating autologous bone marrow grafts with high concentrations of pharmacologics in combination. The use of combinations may increase the efficacy of ex vivo purging without increasing the toxicity to normal hematopoietic cells.