[Show abstract][Hide abstract] ABSTRACT: In T-cell-depleted allogeneic bone marrow transplantation (TCD-BMT) using unrelated donors, the role of donor lymphocyte infusion (DLI) for survival and disease control has not been defined. In a study of 116 patients (92 matched, 24 mismatched) who received CD3+ T-cell-depleted marrow graft, sequential infusions of escalated doses of donor T lymphocytes up to 1 x 10(6) CD3+ cells/kg were prospectively investigated. T cells were administered while patients were on cyclosporine, provided >or=grade II acute graft-versus-host-disease (GVHD) had not occurred. Acute GVHD of >or=grade II occurred in 27 of 110 (25%) patients before DLI and in 39 of 79 (49%) patients after DLI. In total, 12 of 27 (44%) patients without DLI and 44 of 72 (61%) patients who received DLI developed chronic GVHD. A total of 19 patients died of GVHD, with 17 of acute and two of chronic GVHD. Overall survival (OS) and event-free survival (EFS) at 5 years were 27 and 21%, respectively. The 2-year incidence of relapse was 14%. In multivariate analysis, only chronic GVHD was a good prognostic factor for both OS: hazard ratio (HR) 1.4, P=0.04, and EFS: HR 1.6, P=0.01. Both acute and chronic GVHD were favorable prognostic factors for relapse probability: HR 1.9 for both, P=0.02, 0.01, respectively. The 1-year cumulative incidence of transplant-related mortality (TRM), excluding cases of GVHD, was 42%. The two most common causes of 1-year non-GVHD death were viral infection (9%) and idiopathic pneumonia syndrome (12%). Although the incidence of relapse was low, the study suggests that the current scheme of DLI in unrelated TCD-BMT would not improve survival unless TRM decreases significantly.
Full-text · Article · Jan 2003 · Bone Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Fifty-two patients with refractory lymphoma were prospectively treated with prophylactic T lymphocyte infusion after T cell-depleted allogeneic bone marrow transplantation, to induce graft-versus-lymphoma effect. Thirty-three patients had related donors; 19 had unrelated donors. After transplantation with marrow that had 0.8 +/- 0.4 x 10(5)CD3(+) cells/kg, T cells up to 1.75 x 10(6) CD3(+) cells/kg were given over 3 months provided > or = grade II acute graft-versus-host disease (GVHD) was not seen. The cumulative incidence of grades II-IV acute GVHD was 69%. Twenty of 32 evaluable patients (63%) developed chronic GVHD. Ten patients (19%) died of GVHD. The Kaplan-Meier 5-year overall survival of all patients was 34%. On multivariate analyses, chronic GVHD was significant for relapse (hazard ratio of 1.7, P < 0.05), and for overall survival (hazard ratio 1.4, P < 0.001). Chemosensitivity was significant for relapse only on univariate analysis. Patients who developed chronic GVHD had 4 years median survival, compared with 9 months in patients without chronic GVHD, P < 0.001. The study shows that patients with chronic GVHD have superior survivals, most probably related to a graft-versus-lymphoma effect, which could be modulated by prophylactic T cell infusion.
Full-text · Article · Apr 2002 · Bone Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Chemosensitive response prior to transplantation has been shown to be most significant for survival post transplant. To estimate toxicity of a dose-intensive regimen that was to improve chemosensitive response rate, 15 patients with primary refractory lymphoma were enrolled in dose escalation of pre-transplant salvage chemotherapy. The first cycle had a fixed dose of ifosfamide 6 g/m2 and mitoxantrone 12 mg/m2, with arabinosyl cytosine (Ara-C) 2 g/m2, and methylprednisolone 2.0 g. Each cycle of the second and third had cisplatin 90 mg/m2, Ara-C 6 g/m2, methylprednisolone 2.0 g, and escalated doses of ifosfamide from 7.5 g/m2 to 15 g/m2 and mitoxantrone from 16 to 28 mg/m2. Blood stem cells were collected before the second cycle and > or = 3 x 10(6) CD34 cells/kg were infused 2 days after the second and third cycles, respectively. The maximum tolerated doses of ifosfamide and mitoxantrone were 11.25 g/m2 and 16 mg/m2, respectively. Acute renal failure and bacterial infection occurred as non-hematologic dose limiting toxicities. Eleven patients completed therapy. Five patients achieved complete remission and five had partial remission. Nine patients received autologous and four received allogeneic transplants. Currently, six are alive without evidence of disease, with a 3-year survival of 40%. Although preliminary, the regimen suggests acceptable toxicity and significant activity that warrants further study.
Preview · Article · Apr 2002 · Bone Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: The use of allogeneic stem cell transplantation is usually restricted to patients (pts) younger than 55 years of age due to the excessive transplant related mortality (TRM) observed in older pts. The low risk of TRM from non-myeloablative transplants makes the procedure applicable to older pts. Here we report 9 pts with a median age of 61 years (range 57 to 67) who underwent conditioning with fludarabine 25mg/m2x3 days and cyclophosphamide 750mg/nvx 3days followed by PBCT from a G-CSF stimulated HLA identical sibling donor. As GVHD prophylaxis 6 pts received cyclosporin (CSA) and mini-dose methotrexate, 2 pts CSA and mycophenolate mofetyl and 1 pt CSA and prednisone. CSA was given until day 60 then tappered off if no GVHD occured. All pts received low dose amphotericin B at 0.3mg/Kg as antifungal prophylaxis during neutropenia, CMV prophylaxis with gancyclovir and PCP prophylaxis. Diagnosis included secondary AML in 2 pts, multiple myeloma in 1 pt. CML in accelerated phase in Ipt, AL amyloid in 1 pt, mantle cell lymphoma in Ipt, secondary MDS in Ipt, NK leukemia in 1 pt and chronic myelomonocytic leukemia in another. There were 3 females and 6 males. Two pts had previous transplants (1 allogeneic and ! autologous). Only one pt was in CR at time of therapy. Median transplant dose was 5.2x10" CD34+cells/Kg and 2.2x10" CD3+cells/Kg. Severe mucositis and VOD did not occur. The pt with amyloid experienced acute renal failure requiring dialysis. Hématologie nadirs were brief with a median time to ANC>0.5xlO /L of 10 days (range 7 to 17) and a platlet count > 20xlO'/L of 11 days (range 6 to 13). Six pts experienced grade III-1V acute GVHD. GVHD contributed to the death of 3 pts. One pt has chronic GVHD. Seven pts survived more than 28 days. Two early deaths were caused by disseminated aspergillosis in 1 pt and engraftment syndrome in another. One pt with multiple myeloma died of disease progression . Three pts are alive at +15, +12, +6 months. All are in CR. We conclude that this approach seems feasible in an older population. Modifications are needed to reduce the incidence of GVHD.
[Show abstract][Hide abstract] ABSTRACT: Adenovirus infection is a major cause of mortality after BMT. Currently, no effective therapy is known. Cidofovir is a nucleoside analogue with broad in vitro antiviral activity. Recent reports suggest cidofovir may be active against Adenovirus. We treated six consecutive severely immunosuppressed patients with Adenoviral infection following allogeneic stem cell transplantation with cidofovir. Patients had clinically symptomatic cystitis or enterocolitis at the time of the initial culture/biopsy. With treatment all became culture negative and clinical symptoms regressed. Patients had either allogeneic marrow (1 related, 2 unrelated) or related allogeneic peripheral stem cell transplant (2 nonmyeloablative, 1 myeloablative) at the age of 22-57 years (median 47). Adenovirus was cultured from stool in 1, urine in 2, both stool and urine in 1 and colon biopsy in 2 cases. Cidofovir was given intravenously at 5mg/kg weekly for 2-4 weeks. Dose adjustments are made according to the renal function (Brody et al. Clin Pharmacol Ther. 1999. 65:21-8). AU patients received probenecid and saline hydration with each dose of cidofovir. Adenovirus culture became negative after 1 -4 doses (median 2). Three patients had transient renal toxicity attributed at least in part to Cidofovir. One developed neutropenia and progressive renal failure, eventually requiring hemodialysis as his overall condition deteriorated. A second patient had rise in creatinine to 5.4mg/dl following a third dose but subsequently returned to normal. A third patient with hemorrhagic cystitis was felt to have transient renal failure due to obstructive uropathy. Dose reduction was made in 5 cases according to pre-existing (3 cases) or worsening (2cases) renal function. Four of them were able to continue the treatment without worsening of renal failure. Conclusion: Cidofovir is effective against Adenovirus infection in stem cell transplant patients. Renal toxicity can be managed using published dose reduction guidelines. Source of Cidofovir dose / # doses Pre-Crt Maximum Response by Pt# Viral Isolate (mg/kg) (mg/dl) Post-Crt # of dose 1 Stool 3 / #4 doses 2.0 2.6 Cleared #4 2 Urine + Stool 5 / #3 doses 1.0 5.4 Cleared #3 3 Urine 5/#!, 1 / #1, 2 / #1 1.3 4.0 Cleared#1 4 GI Biopsy 0.5 / #1, 1.5 / #3 3.9(onHD) 4.1 Cleared#1 5 Urine 5/#l, 1.5/#! 1.3 5.5 Cleared#2 6 GI Biopsy l/#l,2/#3 2.4 2.2 Cleared #4.