Long-term systemic lupus erythematosus disease control after allogeneic bone marrow transplantation.

Systemic lupus erythematosus (SLE), a disorder of the immune system, is potentially curable by allogeneic bone marrow transplantation (alloBMT). Until recently, alloBMT was limited by donor availability and toxicity. Reduced intensity conditioning (RIC) combined with post-transplantation cyclophosphamide (PTCy) has improved the availability and safety of alloBMT permitting its exploration in severe-refractory autoimmune illnesses. We report the six-year follow-up of a young female whose refractory SLE-associated nephrosis resolved after RIC alloBMT with PTCy.

Donor HLA-specific Abs: to BMT or not to BMT?

The engraftment failure associated with Abs to donor-specific HLA (DSA) limits options for sensitized BMT candidates. Fourteen of fifteen patients with no other viable donor options were desensitized and transplanted using a regimen of plasmapheresis and low-dose i.v. Ig modified to accommodate pre-BMT conditioning. DSA levels were assessed by solid-phase immunoassays and cell-based crossmatch tests. DSA levels were monitored throughout desensitization and on day -1 to determine if there was any DSA rebound that would require additional treatment. A mean reduction in DSA level of 64.4% was achieved at the end of desensitization, with a subsequent reduction of 85.5% after transplantation. DSA in 11 patients was reduced to levels considered negative post-BMT, whereas DSA in three patients remained at low levels. All 14 patients achieved donor engraftment by day +60; however, seven patients suffered disease relapses. Four patients experienced mild, grade 1 GVHD. Factors influencing the response to desensitization include initial DSA strength, number, specificity, DSA rebound and a mismatch repeated from a prior transplant. While desensitization should be reserved for patients with limited donor options, careful DSA assessment and monitoring can facilitate successful engraftment after BMT.

High-dose cyclophosphamide for severe systemic lupus erythematosus.

Cytotoxic therapy is a cornerstone for patients with severe systemic lupus erythematosus (SLE). High-dose cyclophosphamide, 200 mg/kg, can induce a complete remission without the need for stem cell rescue in patients with autoimmune illnesses. Here we report on our first four patients treated for severe SLE with this treatment approach. Patients received cyclophosphamide, 200 mg/kg, divided over 4 days. Starting day 10, patients received filgrastim, 5 micrograms/kg/day, until their absolute neutrophil count (ANC) rose to 10.0 x 10(9)/l for two consecutive days. Disease activity as evaluated by scores from the Systemic Lupus Activity Measure-2, the SLE Disease Activity Index and the Responder Index for Lupus Erythematosus were completed before and after high-dose therapy. Before high-dose cyclophosphamide, SLE disease duration ranged from 8 to 21 (mean 12.5) years. Their average disease activity measured by SLAM-2 and SLEDAI was 15.5 (range 11-19) and 23.25 (range 20-26), respectively. At a median of 22 (range 12-39) months of follow-up, mean disease activity measured by SLAM-2 and SLEDAI decreased to 6.25 and 7.75, respectively. All patients experienced febrile neutropenia. No long-term morbidities or mortalities were observed. High dose cyclophosphamide is a therapy capable of decreasing disease severity in poor prognosis SLE patients. Future study is warranted for both refractory patients as well as primary therapy for patients with moderate to severe disease presentations.

High-dose cyclophosphamide without stem-cell rescue for refractory CIDP.

Four patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who were refractory to conventional treatment were treated with high-dose cyclophosphamide (200 mg/kg over 4 days). All improved in functional status and muscle strength. Nerve conduction studies improved in three of four. Other immunomodulatory medications have been discontinued. High-dose cyclophosphamide can be given safely to patients with CIDP and patients with disease persistence after standard therapy may have a response that lasts for over 3 years and results in long-term disease remission.

Philadelphia chromosome-negative engraftment after autologous transplantation with granulocyte-macrophage colony-stimulating factor for chronic myeloid leukemia.

Autologous bone marrow transplantation (BMT) has not been curative in chronic myeloid leukemia (CML), because of the inability to purge CML from the autograft and the absence of the allogeneic T cell-mediated antileukemic activity. However, recent advances demonstrate that normal progenitors can be selected from CML marrows by a variety of techniques, including isolation by their small size. Furthermore, we found that myeloid growth factors have a potent antileukemic effect against CML progenitors in vitro by inducing their terminal differentiation. Based on these data, we initiated a trial of autologous BMT in patients with high-risk CML. Autografts were processed in an attempt to enrich for normal progenitors, first by isolating small cells by counterflow centrifugal elutriation and then incubating them in granulocyte-macrophage colony-stimulating factor (GM-CSF) for 72 hours. After a conditioning regimen of busulfan and cyclophosphamide, all patients received GM-CSF daily for 2 months. The median age of the 13 patients in the trial was 45 years (range 17-56 years). The median duration of disease before BMT was 24 months (range 13-72 months). Eight patients were in chronic phase (CP), and five were in accelerated phase (AP). All patients failed to achieve a cytogenetic response to interferon-alpha and were 100% Philadelphia chromosome (Ph)+ before BMT. There were three transplant-related deaths, all AP patients. All of the remaining 10 patients engrafted with some degree of Ph- hematopoiesis; despite high-risk features, nine patients engrafted 100% Ph-. All patients relapsed cytogenetically at a median of 6 months (range 4-22 months). These results demonstrate that autologous BMT can consistently induce complete Ph- engraftment in CP patients. GM-CSF appears to produce a clinical antileukemic effect against CML after autologous BMT.