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Reduced-intensity allogeneic stem cell transplantation as salvage treatment for patients with indolent lymphoma or CLL after failure of autologous SCT

Bone Marrow Transplantation volume 26, pages 1361–1362 (2000)Cite this article

Autologous stem cell transplantation (SCT) is an effective therapy for poor-risk indolent lymphomas, such as follicular lymphoma (FL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL). Since autologous SCT is, however, in most instances not curative in these diseases, most patients will ultimately relapse and require effective salvage treatment.12 Due to its inherent graft-versus-lymphoma (GVL) activity, which has proven efficacy in indolent lymphoma, allogeneic SCT appears to be the most promising approach for rescuing patients who failed autologous SCT. Unfortunately, allogeneic transplantation after standard myeloablative conditioning has been associated with an extraordinarily high treatment-related mortality in patients with low-grade lymphoma.3 Based on the encouraging experiences with reduced-intensity conditioning for allografting of patients with resistant lymphoma reported by the MD Anderson and Jerusalem groups,45 we have developed a fludarabine-based preparative regimen for salvage allo-SCT in patients with low-grade lymphoma who failed autologous transplantation. Seven patients with resistant indolent lymphoid neoplasms (MCL = 2, CLL = 2, FL = 1, multiple myeloma = 1, angioimmunoblastic lymphoma with dysproteinemia (AILD) = 1) were eligible. Median age was 51 (35–54) years. Previous therapy consisted of five (2–7) regimens; autologous SCT had failed in five patients due to relapse and in two patients due to unsuccessful mobilization. Performance status was ECOG 0–1 in five patients but worse in the remaining two. Five patients were in second or subsequent remission and two patients were refractory at time of allo-transplant. Conditioning regimen was given from day −7 to day −3 and consisted of fludarabine 30 mg/m2/day (= 150 mg/m2 total dose) and cyclophosphamide 500 mg/m2/day (= 2500 mg/m2 total dose). G-CSF-mobilized PBSC were obtained from HLA-identical sibling donors in six cases and from an unrelated donor in the remaining patient. GVHD prophylaxis was performed with CsA (day −1 to day +100) and mini-MTX (methotrexate 10 mg/m2 on days +1, +3, and +6). Unfractionated peripheral blood nucleated cells were used for monitoring chimerism by XY-FISH in case of sex mismatch (n = 2) or by multiplex PCR utilizing primers amplifying the repeat units of microsatellite loci. In the patients with CLL, residual disease was assessed by flow cytometry (gating for CD19-positive CD20-dim CD5-positive lymphocyte events) and PCR (consensus primer amplification of IgH gene rearrangements) as previously described.6

With 4.6 × 106/kg CD34+ cells (1.2–6.5) infused, all recipients showed prompt neutrophil recovery (>0.5 × 109/l neutrophils reached on day +13 (5–18)). The median number of platelet units tranfused was 0 (0–63). With a median duration of mucositis, parenteral nutrition and neutropenic fever of 0 (0–5), 0 (0–14) and 0 (0–10) days, respectively, the general non-hematological toxicity was very low. However, severe early toxicity occurred in two patients with MCL relapse after previous autologous SCT using a total body irradiation-containing regimen. Both entered conditioning for allogeneic transplantation with a performance status of ECOG >1. The first of these, who had lymphoma infiltration of the spleen, experienced splenic rupture on day 10 and needed splenectomy. The course was further complicated by development of grade IV acute intestinal GVHD, CMV viremia, severe hemorrhagic cystitis and unexplained hemiparesis and coma, which lead to death on day +57. Also the second patient with MCL showed neurotoxicity which presented as general dysesthesia, tremor, and disturbance of vigilance. After withdrawal of cyclosporine, neurological symptoms resolved, but the patient developed grade III acute intestinal GVHD which was subsequently complicated by fatal CMV pneumonia (day +82). In three of the remaining five patients, cessation of cyclosporine was followed by extensive chronic GVHD requiring renewed immunosuppressive treatment. Although donor chimerism was complete at day +30 in four patients, initial hematopoietic recovery was partially autologous in the remaining three. Nevertheless, after stopping cyclosporine, complete chimerism was also established in these individuals at days +180, +182, and +305, respectively. An interesting course was observed in the patient with multiple myeloma, who had been pretreated with radiotherapy and six cycles of the VAD regimen (vincristin, doxorubicine, dexamethasone) for relapsing disseminated osteolytic lesions and had no autograft available. This patient had only 22% donor chimerism at day +120 when cyclosporine was withdrawn. About 1 month later, he developed pancytopenia which was associated with an increase of donor chimerism to 93%, suggesting that donor T cells were suppressing hematopoiesis which had been mainly autologous at this time. A single boost of donor-derived PBSC without further conditioning at day +255 led to prompt and durable hematopoietic normalisation.

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  1. Departments of Internal Medicine II and BMT Unit, University of Kiel, Chemnitzstr 33, Kiel, 24116, Germany

    P Dreger, B Glass, B Seyfarth, A Humpe, A Claviez, N von Neuhoff, M Suttorp, R Schoch & N Schmitz

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Dreger, P., Glass, B., Seyfarth, B. et al. Reduced-intensity allogeneic stem cell transplantation as salvage treatment for patients with indolent lymphoma or CLL after failure of autologous SCT. Bone Marrow Transplant 26, 1361–1362 (2000). https://doi.org/10.1038/sj.bmt.1702722

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