Infections after CD34-selected or unmanipulated autologous hematopoietic stem cell transplantation

Immune reconstitution may be delayed after CD34-selected compared with unmanipulated autologous peripheral blood stem cell transplantation (PBSCT), resulting in a theoretically increased risk of infections. In a case-control matched study we compared the incidence of infection in 25 recipients of CD34-selected PBSC (CD34 group) and 75 recipients of unmanipulated PBSC (PBSC group) transplants. The population included 52 males and 48 females suffering from non-Hodgkin's lymphoma (n = 32), Hodgkin's disease (n = 8), multiple myeloma (n = 40) or breast cancer (n = 20). Neutrophil engraftment was comparable in the two groups. The actuarial incidence of infection was similar in the two groups (56% vs. 49% at day 30, and 70% vs. 64% at 1 yr respectively). The proportion of patients with 1, 2 or 3 infections, the number of infectious event per patient (1.32 vs. 1.04; NS), the number of infections before day 15 or 30, between days 31 and 100 or after day 100, the risk of varicella-zoster virus or cytomegalovirus infection or disease, or the use of antibiotic or antifungal therapy, were not increased in the CD34 compared with the PBSC group. The main agents responsible for infection were bacteria, particularly gram-positive cocci, in both groups. Bacteremia accounted for 33% of all infectious events in the CD34 group vs. 16% in the PBSC group (P < 0.05). Fungal infections were rare. In conclusion, our results do not support the notion that CD34-selection of the graft is associated with an increased rate of infection after autologous PBSC transplantation. The role of extended infection prophylaxis should be evaluated.     

Long-term follow-up of fertility and pregnancy in autoimmune diseases after autologous haematopoietic stem cell transplantation

Issues of fertility and pregnancy require special attention in the long-term care of patients with autoimmune diseases (AD), who are candidates for haematopoietic stem cell transplantation (HSCT). In this single-centre observational study, we report fertility status and pregnancy outcomes in 15 patients (11 female and 4 male) after immunoablation with cyclophosphamide, antithymocyte globulin and autologous CD34⁺—selected HSCT for severe, refractory AD. The median follow-up after HSCT was 12 years (range 2–16 years). Impaired fertility was observed in six patients (five females and one male) before HSCT based on sexual hormone measurements. Higher age and cumulative cyclophosphamide dosage before HSCT correlated with fertility impairment. Median serum level of follicle-stimulating hormone (FSH) was significantly higher in female patients at 1 year after HSCT compared to baseline values, but premature ovarian failure developed in only one patient. Four women had five pregnancies and six healthy offsprings during follow-up, and no miscarriages were observed. The mothers were in treatment-free remissions during conception. No peripartal flare of their AD occurred. Although AD patients undergoing HSCT are at risk of developing infertility, pre-HSCT treatment and patients’ age seem to have higher impact on long-term fertility status than HSCT itself. HSCT offers the opportunity to conceive during treatment-free remissions with favourable pregnancy outcomes.     

Management of autoimmune diseases after haematopoietic stem cell transplantation

Autologous and allogeneic haematopoietic stem cell transplantation (HSCT) is an option for the treatment of malignant and non-malignant diseases, including the severe autoimmune diseases. Intriguingly, the 'new' autoimmunity developing after transplantation is a constantly recognized phenomenon, which has to be differentiated from original disease relapse, toxicity, infection and graft-versus-host disease. The reported autoimmune diseases occurring in this setting are mainly antibody-associated and organ-specific, with scarce evidence in support for specific treatment options. This review focuses on current concepts on the pathogenesis, the available data on incidence, risk factors, manifestations and treatment of post-HSCT autoimmune diseases.     

Autologous stem cell transplantation in autoimmune diseases

Since 1996, approximately 1,000 patients have received an autologous hematopoietic stem cell transplant (HSCT) as treatment for a severe autoimmune disease (AD). The European Group for Blood and Marrow Transplantation (EBMT)/European League Against Rheumatism (EULAR) Autoimmune Disease Working Party have registered more than 800 patients and works in close collaboration with networks in the United States where several hundred more AD patients have been similarly transplanted. The majority of ADs were multiple sclerosis (MS), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), juvenile idiopathic arthritis, and immune cytopenias. Many patients have experienced long-term disease-free remissions and immune reconstitution studies have shown in some cases that a "resetting" of autoimmunity is possible. The initially high treatment-related mortality (TRM) is reduced significantly in the later years, and the phase I/II experience is now being verified in several international prospective randomized clinical trials. In addition, the past several years have seen a growing interest in the role and potential therapeutic application of mesenchymal stem cells (MSC) in the immunomodulation of AD, as in the early experience with acute-graft-versus host disease (GvHD).     

Experimental basis for the treatment of autoimmune diseases with autologous hematopoietic stem cell transplantation

Preclinical research with autologous bone marrow transplantation has been performed in two models of autoimmune disease using Buffalo rats. In this strain, adjuvant arthritis develops as a chronic progressive systemic type of arthritis and experimental allergic encephalomyelitis as a chronic remitting relapsing disease. In these models, the influence of various treatment parameters was studied, among them the conditioning regimen, the composition of the graft and the effect of reimmunization of cured animals. Continued research in animal models is recommended to solve problems that have emerged from the experience with several hundreds of severely ill autoimmune patients treated thus far with autologous stem cells.     

Immune reconstitution after purified autologous and allogeneic blood stem cell transplantation compared with unmanipulated bone marrow transplantation in children

Immune reconstitution is critical for the long-term success of haematopoietic stem cell transplantation (HSCT). We prospectively analysed immune reconstitution parameters after transplantation of autologous (group 1; n = 10) and allogeneic (group 2; n = 12) highly purified CD34+ peripheral blood stem cells (PBSC) and unmanipulated allogeneic bone marrow (BM) (group 3; n = 9) in children. Median follow-up after HSCT was 56 (group 1), 61 (group 2), and 40.5 months (group 3). Median CD34-cell dose transplanted in the three groups was 9.4 x 10(6)/kg, 20.3 x 10(6)/kg, and 4.25 x 10(6)/kg recipient's body weight (BW) respectively. Complete haematopoietic engraftment was seen in all patients without any significant differences between the three groups. T-cell reconstitution at 6 months was significantly delayed in autologous peripheral blood stem cell transplantation (PBSCT) compared with allogeneic BM transplantation (P < 0.028) and allogeneic PBSCT (P < 0.034). At 3 months after transplantation numbers of CD56+/3- natural killer cells were higher in the allogeneic PBSC group (P < 0.01) compared with the BM group. The numbers of proven bacterial and viral infections were equally distributed between the three groups. In conclusion, recipients of allogeneic highly purified CD34+ PBSC or unmanipulated BM have higher lymphocyte subset counts at 6 months after transplantation than recipients of autologous CD34-selected PBSC. Infection rates and outcome, however, were not significantly different.     

Autologous hematopoietic stem cell transplantation in autoimmune diseases

The term 'autoimmune diseases' encompasses a spectrum of diseases whose clinical manifestations and, possibly, biological features vary widely. The results of conventional treatment are considered unsatisfactory in aggressive forms, with subsets of patients having short life expectancies. Relying on wide experimental evidence and more feeble clinical data, some research groups have used autologous hematopoietic stem cell transplantation (HSCT) in the most disabling autoimmune diseases with the aim of resetting the patient's immune system. Immunoablative conditioning regimens are preferred over their myeloablative counterparts, and some form of in vivo and/or ex vivo T-cell depletion is generally adopted. Despite 15 years' experience, published controlled clinical trials are still lacking, with the evidence so far available coming from pilot studies and registry surveys. In multiple sclerosis, clinical improvement, or at least lasting disease stabilization, can be achieved in the majority of the patients; nevertheless, the worst results are observed in patients with progressive disease, where no benefit can be expected from conventional therapy. Concerning rheumatologic diseases, wide experience has been acquired in systemic sclerosis, with long-term improvements in cutaneous disease being frequently reported, although visceral involvement remains unchanged at best. Autografting has proved to be barely effective in rheumatoid arthritis and quite toxic in juvenile idiopathic arthritis, whereas it leads to clinical remission and the reversal of visceral impairment in the majority of patients with systemic lupus erythematosus. A promising indication is Crohn's disease, in which long-term endoscopic remission is frequently observed. Growing experience with autologous HCST in autoimmune diseases has progressively reduced concerns about transplant-related mortality and secondary myelodysplasia/leukemia. Therefore, a sustained complete remission seems to be within the reach of autografting in some autoimmune diseases; in others, the indications, risks and benefits of autografting need to be better defined. Consequently, the search for new drugs should also be encouraged.     

Dendritic cell recovery after autologous stem cell transplantation

There is persistent immunosuppression not only in allogeneic but also in autologous stem cell transplantation because humoral and cellular immunity may take a year or more to return to normal, with increased risk of infectious complications. This immune defect may also involve antigen presentation, in particular dendritic cell (DC) function. We evaluated DC subset reconstitution in 58 patients who underwent bone marrow (BM) or peripheral blood (PB) autologous haematopoietic stem cell transplantation (HSCT). In all patients DC type 1 (DC1) and DC type 2 (DC2) were already significantly lower than in normal individuals before conditioning therapy (DC1/microl 3.1 +/- 1.0, DC2/microl 3.0 +/- 1.1). On day 0 and day +7 the mean DC1 and DC2 numbers were very low in both groups. Patients who received unmanipulated marrow or peripheral blood stem cells reached pre-conditioning levels of DC1 and DC2 cells on day +20. In patients receiving selected CD34 cells, DC increased slowly and pre-transplant counts were observed only on day +60. Nearly 'normal' levels of DC1 and DC2 could be observed in the first group from day +180, and were maintained thereafter; in CD34(+) selected patients DC1 and DC2 counts remained lower than normal. Our data emphasise that circulating antigen presenting cells (APC) recover quickly. It remains to be determined if DC frequency in PB reflects their tissue function. The relatively low incidence of infections in patients undergoing autologous transplantation, despite defective lymphocyte reconstitution, could be related to functionally efficient DC.     

Autologous hematopoietic stem cell transplantation for autoimmune diseases

Experimental data and early phase I/II studies suggest that high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) can arrest progression of severe autoimmune diseases. We have evaluated the toxicity and disease response in 473 patients with severe autoimmune disease treated with autologous HSCT between 1995 and 2003, from 110 centers participating in the European Group for Blood and Marrow Transplantation (EBMT) autoimmune disease working party database. Survival, transplant-related mortality, treatment response and disease progression were assessed. In all, 420 patients (89%; 86+/-4% at 3 years, median follow-up 20 months) were alive, 53 (11%) had died from transplant-related mortality (N=31; 7+/-3% at 3 years) or disease progression (N=22; 9+/-4% at 3 years). Of 370 patients, 299 evaluable for response (81%) showed a treatment response, which was sustained in 213 (71% of responders). Response was associated with disease (P<0.001), was better in patients who received cyclophosphamide during mobilization (relative risk (RR)3.28 (1.57-6.83)) and was worse with increasing age (>40 years, RR0.29 (0.11-0.82)). Disease progression was associated with disease (P<0.001) and conditioning intensity (high intensity, RR1; intermediate intensity, RR1.81 (0.96-3.42)); low intensity, RR2.34 (1.074-5.11)). These data from the collective EBMT experience support the hypothesis that autologous HSCT can alter disease progression in severe autoimmune disease.     

Autologous hematopoietic stem cell transplantation for autoimmune diseases

Ten years have passed since the first published consensus statement on the use of hematopoietic stem cell transplantation (HSCT) in the treatment of severe autoimmune disease (AD) appeared. During that time, around 700 patients suffering from severe AD have undergone HSCT in the frame of phase I/II clinical trials from over 20 countries including the US. The majority have received an autologous HSCT using one of a limited number of regimens, consistent with the original consensus statement. Long-term drug-free remissions, remission then relapse, no response and treatment-related mortality (TRM) were seen in all the subgroups of AD. An overall TRM of 7% was observed, with marked variation between ADs, i.e. 11% in systemic lupus erythematosus (SLE) and only 1 patient in rheumatoid arthritis (RA). Phase III prospective, comparative randomized trials are running or being planned in multiple sclerosis (MS), systemic sclerosis (SSc), SLE and RA. Basic science programs are also being undertaken to study the immunological mechanisms underlying the clinical events observed.     

Histological recurrence of autoimmune liver diseases after living-donor liver transplantation

Background:  The effects of living donor liver transplantation (LDLT) on the recurrence of autoimmune liver diseases have not been well documented. Genetic similarities may be beneficial to avoid severe rejection but may facilitate the recurrence of autoimmune diseases. Because familial occurrence of autoimmune liver diseases has been documented, there is a possibility that candidates for living-related donors may have the same disease as that of the recipients.
Method:  Between November 1994 and June 2004, 50 patients with primary biliary cirrhosis (PBC) (16-non-blood-relative donors and 34 blood-relative donors), and 28 patients with primary sclerosing cholangitis (PSC) underwent LDLT in Kyoto University Hospital.
Results:  Among 35 patients with PBC who survived more than 1 year, 10 patients (29%) showed recurrent PBC, and nine of 10 patients with recurrent PBC (90%) were associated with blood-relative donors (mean follow-up period, 30 months; range, 2–68). Two recipients had donors with some clinical or histological characteristics of PBC, and their grafts developedrecurrent PBC. Cirrhosis or graft failure was not observed in any patients with recurrent PBC. For PSC patients who survived more than 1 year after LDLT, 13 of 22 (59%) showed PSC-compatible histology and radiological findings (mean follow-up period, 31 months; range, 22–71), and five died or underwent retransplantation. Human leukocyte antigen-DR15 was positively associated with susceptibility to PSC with ulcerative colitis. One donor was revealed to have retroperitoneal fibrosis without evidence of sclerosing cholangitis.
Conclusions:  Blood-relative donors may be associated with susceptibility to recurrent autoimmune diseases. Recurrence of PSC, but not PBC, adversely affected the outcome of LDLT. Caution should be taken as blood-relative donors can be at risk of autoimmune liver diseases.     

Treatment of autoimmune diseases by hematopoietic stem cell transplantation

Remarkable advances have been made in bone marrow transplantation (BMT), which now has become a powerful strategy for the treatment of leukemia, aplastic anemia, congenital immunodeficiency disorders, and autoimmune diseases. Using various animal models, allogeneic BMT has been found to be useful in the treatment of autoimmune diseases. In MRL/lpr mice, which are radiosensitive (<8.5 Gy) and are an animal model for autoimmune disorders, conventional BMT resulted in only transient effects; the manifestations of the autoimmune diseases recurred 3 months after BMT. However, the combination of BMT plus bone grafts (to recruit donor stromal cells) was capable of preventing the recurrence of autoimmune diseases in MRL/lpr mice. This strategy was found to be ineffective in the treatment of MRL/lpr mice that had developed autoimmune diseases, because these mice were more sensitive to the effects of radiation after the onset of lupus nephritis due to uremic enterocolitis. We have recently discovered a safer strategy for treatment of autoimmune diseases, which includes fractionated irradiation (5.5 Gy x 2) (day -1) followed by portal venous injection (day 0) plus intravenous injection (day 5) of donor unfractionated bone marrow cells. We successfully treated autoimmune diseases in MRL/lpr mice using this strategy; 100% of MRL/lpr mice treated in this fashion survive >1 year after treatment. We identified the mechanisms underlying the components of this approach and have found that stromal cells play a crucial role in successful BMT. In this review, the conditions essential for successful allogeneic BMT are discussed.     

Treatment of refractory autoimmune diseases with autologous stem cell transplantation: focus on juvenile idiopathic arthritis

Autologous stem cell transplantation (ASCT) can be performed in a variety of refractory autoimmune diseases. A retrospective multicenter analysis is presented to evaluate safety and efficacy of ASCT for refractory juvenile idiopathic arthritis. In all, 18 of the 34 patients (53%) with a follow-up of 12 to 60 months achieved a drug-free complete remission. There were three cases (9%) of transplant-related mortality and two cases of disease-related mortality (6%). Infectious complications were seen frequently. We propose adjustments in future protocols to reduce this mortality in this high-risk patient group.     

Allogeneic stem cell transplantation in patients with non-Hodgkin lymphoma who experienced relapse or progression after autologous stem cell transplantation

There are few treatment options for patients with non-Hodgkin lymphoma (NHL) who experienced progression after high-dose chemotherapy (HDC) with autologous stem cell transplantation (auto-SCT). The role of allogeneic stem cell transplantation (allo-SCT) in these patients has not been clarified yet. In this study, we report clinical outcomes of allo-SCT in patients with NHL who experienced progression after HDC with auto-SCT. Patients were enrolled from seven hospitals in Korea. A total of 38 patients were included: 18 patients (47.4%) underwent myeloablative conditioning and 20 patients (52.6%) reduced intensity conditioning. Overall response rate was 73.3%. Median event-free survival was 6.3 months. Median overall survival (OS) was 19.0 months. Estimated 5-year survival rate was 35.0%. Acute graft-versus-host disease developed in 13 patients (34.2%). Transplant-related mortality (TRM) was 21.1% (eight patients). Ann Arbor stage (p=0.022), performance status (p<0.001), and baseline serum albumin level (p=0.010) were significant risk factors for OS. Performance status (p=0.022) was a significant risk factor for TRM. Eight patients with persistent or progressive disease received donor lymphocyte infusion, and two of them achieved complete remission. In conclusion, despite high TRM, allo-SCT is a viable option for patients with NHL who underwent progression after HDC with auto-SCT.     

Early lymphocyte recovery predicts superior survival after autologous hematopoietic stem cell transplantation in multiple myeloma or non-Hodgkin lymphoma

Autologous stem cell transplantation (ASCT) improves survival in patients with previously untreated multiple myeloma (MM) and relapsed, chemotherapy-sensitive, aggressive non-Hodgkin lymphoma (NHL). Lower relapse rates seen in allogeneic stem cell transplantation have been related to early absolute lymphocyte count (ALC) recovery as a manifestation of early graft-verus-tumor effect. In ASCT, the relation between ALC recovery and clinical outcomes in MM and NHL was not previously described. This is a retrospective study of patients with MM and NHL who underwent ASCT at the Mayo Clinic between 1987 and 1999. The ALC threshold was determined at 500 cells/microL on day 15 after ASCT. The study identified 126 patients with MM and 104 patients with NHL. The median overall survival (OS) and progression-free survival (PFS) times for patients with MM were significantly longer in patients with an ALC of 500 cells/microL or more than patients with an ALC of fewer than 500 cells/microL (33 vs 12 months, P <.0001; 16 vs 8 months, P <.0003, respectively). For patients with NHL, the median OS and PFS times were significantly longer in patients with an ALC of 500 cells/microL or more versus those with fewer than 500 cells/microL (not reached vs 6 months, P <.0001; not reached vs 4 months, P <.0001, respectively). Multivariate analysis demonstrated day 15 ALC to be an independent prognostic indicator for OS and PFS rates for both groups of patients. In conclusion, ALC is correlated with clinical outcome and requires further study. (Blood. 2001;98:579-585)     

Autoimmune thrombocytopenic purpura after autologous stem cell transplantation

The pathogenesis of thrombocytopenia occurring after autologous stem cell transplantation (ASCT) remains unclear. Six cases of classical peripheral thrombocytopenia that developed after ASCT for non-Hodgkin's lymphoma (NHL) are presented. Resolution of this complication was obtained by usual treatment such as steroids, splenectomy or progressively resolved without specific treatment. Five out of six patients have been followed for more than 5 years after hematopoietic transplantation and are still alive in complete remission despite poor prognostic factors at diagnosis. Several arguments suggest that this phenomenon represents autoimmune thrombocytopenia and may be the consequence of an altered immune balance. Consequently, development of autoimmune reactions after bone marrow transplantation might be associated with an antitumoral effect (graft-versus-lymphoma effect).