Failure of sustained engraftment after non-myeloablative conditioning with low-dose TBI and T cell-reduced allogeneic peripheral stem cell transplantation

Abstract

Summary:We investigated whether a T cell-reduced allogeneic stem cell transplant (SCT) with minimal conditioning and subsequent donor lymphocyte infusions (DLI) could reduce the incidence and severity of GVHD while retaining stable engraftment. Five patients with hematological malignancies (three MM, one CLL, one ChediakHigashi syndrome) were conditioned with TBI (200 cGy). One patient additionally received fludarabine (120 mg/m 2 ). CsA and mofetyl-mycophenolate (MMF) were administered to prevent GVHD. All patients were grafted with Ͼ3 ؋ 10 6 /kg highly purified CD34 + cells together with 2 ؋ 10 6 /kg CD3 + cells (three patients) or 1 ؋ 10 5 /kg CD3 + cells (two patients). Quick hematopoietic recovery and initial mixed donor chimerism was observed. Treatment-related toxicity was minimal in all but one patient who died of treatment-refractory GVHD on day 112. The four other patients only achieved partial donor T cell chimerism. BM and PBMC donor chimerism was lost between day 40 and 209 despite DLI. Three patients are alive with disease and one is in CR. We conclude that T cell-reduced SCT using 200 cGy as the conditioning regimen does not result in stable hematopoietic engraftment. Predominant donor T cell chimerism is not a prerequisite for initial allogeneic hematopoietic proliferation. However for sustained long-term engraftment it is of major importance. Bone Marrow Transplantation (2001) 28, 157-161. Keywords: non-myeloablative; fludarabine; T cell depletion; multiple myeloma; allogeneic stem cell transplantation; chimerism analysisIn conventional allogeneic SCT, myeloablative conditioning therapy serves the purpose of eradicating the underlying disease and ensuring engraftment of donor hematopoiesis. Treatment-related toxicity and GVHD remain the major post-transplantation complications resulting in high morbidity and mortality. Allogeneic SCT with reduced intensity conditioning regimens are increasingly used in order to decrease the procedure-related complications in patients not eligible for standard SCT because of age, comorbidities or prior excessive therapies. 1,2 Storb and colleagues [3][4][5] showed in a canine model that stable engraftment can be reached with minimal myelosuppressive conditioning regimens and minimal treatment-related toxicities. In addition, they provided evidence that a state of mixed donor-recipient chimerism is connected with a reduced incidence of GVHD. 5,6 However, an ongoing clinical trial revealed a 36% acute GVHD rate in this setting in spite of intensive prophylactic immunosuppression. 1 One way to circumvent the problems of GVHD is T cell depletion of the donor stem cell product. However, these allografts are more likely to be rejected and the graft-versus-leukemia potential is reduced. 7-9 DLI subsequent to establishment of donor chimerism represents one possibility to immunologically eradicate the underlying disease. We report on the results of a pilot trial which combines the 200 cGy conditioning with transplantation of T cell-reduced grafts followed by prophylactic ...

Normal hematopoiesis is maintained by activated bone marrow CD4+ T cells

“…57 Similar results were found in human studies with patients under nonmyeloablative regimen, that is, T-cell donor chimerism higher than 90% is required for donor cell engraftment to occur. 58,59 Our work suggests an additional role for CD4 ϩ T cell on BM engraftment, not only promoting rejection of the few host cells left after the conditioning regimen, but also allowing efficient HSC differentiation and reconstitution of the peripheral pool of mature granulocytes ( Figure 7).…”

High stem cell dose will not compensate for T cell depletion in allogeneic non-myeloablative stem cell transplantation

“…11 Other groups have reported high graft failure rates in small series of patients with malignancy undergoing T celldepleted NST. 29,30 The close association of stable engraftment and tumor response with acute GVHD has been described by us and others. 31 Apparently, patients with malignancy undergoing NST do require some, hopefully manageable degree, of GVHD.…”

Low T-cell chimerism is not followed by graft rejection after nonmyeloablative stem cell transplantation (NMSCT) with CD34-selected PBSC

“…One out of six patients (17%) experienced grade X2 acute GVHD only after abrupt cyclosporin discontinuation and a interferon therapy for life-threatening tumor progression. T-cell chimerism was 23% (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) on day 28, 32% (10-35) on day 100, 78% (49-95) on day 180 and 99.5% (99-100) on day 365. Three out of four patients who had measurable disease before the transplant experienced a complete response.…”

“…Two previous preliminary reports have studied the feasibility of NMSCT with CD34-selected PBSC after a nonmyeloablative conditioning regimen combining 2 Gy TBI and fludarabine 21,22 (Table 2). Four out of five patients reported by Kreiter et al rejected their transplant 37-210 days after NMSCT.…”

“…Kreiter et al 21 Gorner et al 22 Baron NMSCT with CD34-selected PBSC patients treated. Unfortunately, the follow-up of their patients was quite short and the authors did not report the evolution of T cell chimerism.…”