James C. Biggs

Bone Marrow Transplantation for Chronic Myelogenous Leukemia in Chronic Phase: Increased Risk for Relapse Associated with T-Cell Depletion

Data on 405 patients with chronic myelogenous leukemia who received bone marrow transplants in chronic phase were analyzed for factors predictive of outcome. The 4-year actuarial probability of relapse was 19% (95% confidence interval [CI], 12% to 28%) and of survival, 55%. In multivariate analyses the probability of relapse was higher for recipients of T-cell-depleted bone marrow compared with recipients of non-T-cell-depleted bone marrow (relative risk, 5.4; P less than 0.0001) and for patients who did not develop chronic graft-versus-host disease (95% CI, 50% to 60%) with patients who did (relative risk, 3.1; P less than 0.01). The probability of survival was lower for patients who developed moderate to severe acute graft-versus-host disease than for patients with no or mild acute graft-versus-host disease (relative risk, 3.7; P less than 0.0001), and in patients aged 20 or older than in younger patients (relative risk, 2.6; P less than 0.0002). Duration of disease before transplant was not associated with outcome. Bone marrow transplantation done in the chronic phase of chronic myelogenous leukemia offers some patients prolonged leukemia-free survival. The T-cell-depleted grafts are associated with an increased probability of relapse.

Risk factors for acute graft‐versus‐host disease

Summary. Acute graft‐versus‐host disease (GvHD) is an important complication of bone marrow transplantation in humans. Risk factors are imprecisely defined and controversial. We analysed data from 2036 recipients of HLA‐identical sibling transplants for leukaemia or aplastic anaemia to identify risk factors for GvHD. Analyses indicate that grading of GvHD can be reproducibly divided into absent or mild versus moderate to severe; 2‐year actuarial probability was 54% (95% confidence interval 52–56%) for absent or mild and 46% (44–48%) for moderate to severe. Factors predictive of development of moderate to severe GvHD include donor/recipient sex‐match (female→male greater than others, relative risk 2.0, P<0.001). This risk was markedly increased if female donors for male recipients were previously pregnant or transfused (relative risk 2.9, P<0.0001). Older patients were at increased risk of GvHD (relative risk 1.6, P<0.001), but the age gradient was modest, even the youngest patients had a substantial risk of GvHD and, if parous or transfused female→male transplants were excluded, age was not a significant risk factor. Cyclosporine or methotrexate were equally effective at preventing GvHD and were superior to no prophylaxis (relative risk 2.3, P<0.01). These data should be useful in estimating the risk of acute GvHD in an individual patient and in designing clinical trials to investigate methods to modify or prevent GvHD.

Cyclosporin A associated nephrotoxicity in the first 100 days after allogeneic bone marrow transplantation: three distinct syndromes.

Summary. Thirty‐six patients received allogeneic (34) or syngeneic (two) bone marrow transplants as treatment for severe aplastic anaemia or acute leukaemia. Nineteen of the allogeneic recipients received methotrexate (MTX) and 15 received cyclosporin A (CyA) as the predominant immunosuppressive agent to minimize graft‐versus‐host disease (GVHD) post transplant. In the first 100 d post transplant renal dysfunction was much less frequent in the MTX recipients than in the CyA recipients who exhibited three distinct syndromes of nephrotoxicity: most commonly, CyA recipients developed asymptomatic azotaemia, proteinuria, urinary casts, impaired urinary concentrating ability and hypertension. Secondly, two CyA recipients developed acute reversible renal failure precipitated by systemic bacterial infection which required dialysis and in which the kidney was the sole target organ; thirdly, two recipients of HLA‐genotypically non‐identical grafts developed a rapidly progressive fatal syndrome with multiple organ involvement including lung, brain and kidney which clinically and histologically resembled thrombotic thrombocytopenic purpura.

Cyclosporine-associated central nervous system toxicity after allogeneic bone marrow transplantation

Five of 64 recipients of HLA-identical sibling marrow allografts who were given cyclosporin (CSP) to minimize graft-versus-host disease posttransplant had a serious neurological illness thought to be due to CSP. Characteristic clinical features included a motor spinal cord syndrome, a cerebellar-like syndrome, and mental confusion. All five recovered when the CSP dose was reduced or the drug was stopped.

HAEMOPOIETIC STEM CELL TRANSPLANTATION FOR AUTOIMMUNE DISEASES

Haemopoietic stem cell transplantation (HSCT) has traditionally been reserved for life-threatening conditions such as acute leukaemia. With time, its safety has improved and its applications have extended to other diseases, such as the haemoglobinopathies, which are not immediately lifethreatening but have significant long-term morbidity and mortality. Autoimmune diseases are rarely life-threatening in the short term although they are a source of considerable disability and in the long term may shorten life. Although various treatments may suppress disease activity, they usually require chronic administration, and often do little to cure the disease or to prevent irreversible end organ damage. The associated economic costs are considerable, both to the individual and to the country. The most prevalent of these conditions, rheumatoid arthritis (RA), which affects 1% of the population, produces significant morbidity with 50% of patients being unable to work 10 years after contracting their disease. Long-term studies indicate that life expectancy in RA is reduced between 5 and 10 years (Markenson, 1991). Modern management of systemic lupus erythematosus (SLE) has improved the 10-year survival to 75% (Ward et al, 1995), although indefinite immunosuppression with its attendant risks is necessary to achieve this outcome in many patients. The vasculitides, such as Wegener’s granulomatosis and microscopic polyangiitis, have an 80% 5-year survival, but recurrent relapse is common (Savage et al, 1997). No satisfactory treatment exists for systemic sclerosis (SSc), which in its diffuse variant has a 5-year mortality of 40%, similar to that of many malignancies (Steen & Medsger, 1991). Multiple sclerosis (MS) has a broad spectrum of severity and prognosis. Its economic consequences are considerable with 75–85% of MS patients unemployed and the total yearly cost of patient care and lost wages in the U.S.A. estimated at almost

Female marrow donors increase the risk of acute graft-versus-host disease: effect of donor age and parity and analysis of cell subpopulations in the donor marrow inoculum

10 billion. Although new therapies seem to offer modest benefits, especially in mild disease, no standard therapy is effective in progressive disease (Andersson et al, 1997). In other autoimmune diseases, such as immune thrombocytopenia (ITP), myasthenia gravis (MG), psoriasis, and inflammatory bowel disease, there are patients who respond poorly to conventional therapy or in whom remission can only be maintained with toxic doses of immunosuppression. Over the last decade there has been a shift in clinical practice to a more aggressive approach to the treatment of systemic autoimmune disease. Multiple immunosuppressive and anti-rheumatic drugs are being given early in the disease with a view to not only suppress the inflammatory component of the condition but also prevent irreversible end organ damage. This approach seems to be advantageous in RA, at least in the short term (Wilske & Healey, 1993). Evidence that HSCT might hold promise for the treatment or possible cure of severe autoimmune diseases has been discussed for a number of years (van Bekkum, 1993; Ikehara, 1994, 1996; Marmont, 1994; Marmont & van Bekkum, 1995; Burt et al, 1995a; Brooks et al, 1995; Hamilton et al, 1995; Snowden et al, 1996; Tyndall & Gratwohl, 1996; van Bekkum et al, 1996; Wicks et al, 1997). Although the risks of allogeneic transplantation remain too high to envisage its routine use for autoimmune disease, advances in autologous stem cell rescue, most notably the use of cytokine-mobilized peripheral blood stem cells (PBSC), have led to a significant reduction in mortality from the procedure (Atkinson et al, 1995), and some centres now have a mortality of <1% (Australian Bone Marrow Transplant Registry, unpublished data). The long-term morbidity of autologous transplantation also appears to be low, with 88% of survivors reporting an above average to excellent quality of life within 12 months of the procedure (Chao et al, 1992). Arguably, the trade-off between benefits and risk has reversed, and it now seems acceptable to commence investigating autologous transplantation as a means of delivering intensive immunomodulation for severe or poor prognosis autoimmune disease. After briefly discussing the nature and pathogenesis of autoimmune disease, this review summarizes the animal and human evidence that has supported the therapeutic potential of high-dose therapy and HSCT. A number of practical issues that are relevant to clinical studies are also discussed.

Prophylactic use of ganciclovir in allogeneic bone marrow transplantation: absence of clinical cytomegalovirus infection

Summary. We evaluated 27 factors for their influence on acute graft‐versus‐host disease (GVHD) in 40 recipients of HLA‐identical sibling marrow transplants. These factors included the doses of mononuclear cell subpopulations present in the donor marrow inoculum quantitated using a panel of monoclonal antibodies. Female donors were associated with increased severity of acute GVHD, and the older the female donor the greater this effect. Increasing donor parity was also associated with an increased risk of acute GVHD. The number of T cells, T cells subsets, natural killer cells and monocytes infused did not influence the incidence or severity of acute GVHD in this study, and we could not explain the influence of female donors and of female donor age on acute GVHD by the cellular content of their marrow inocula. We postulate that non‐HLA histocompatibility antigen disparity is a more important determinant for acute GVHD than the number of infused donor T cells, especially when female donors are used. The association between acute GVHD and increasing parity suggests that some female marrow donors have been pre‐sensitized to their respective recipients by preceding pregnancies.

Oral administration of cyclosporin A for recipients of allogeneic marrow transplants: implications of clinical gut dysfunction

Ganciclovir was given prophylactically to 25 patients receiving allogeneic bone marrow transplants for haematological malignancy. Patients who were seropositive for cytomegalovirus (CMV) pre‐transplant were given ganciclovir both pre‐ and post‐transplant. Those who were CMV seronegative, but who received marrow from a CMV seropositive donor, received ganciclovir post‐transplant. No non‐haemopoietic toxicity was observed. Toxicity was restricted to late reversible haematological toxicity in four of the 19 evaluable patients (one thrombocytopenia, one pancytopenia, two leucopenia). No CMV interstitial pneumonitis (IP) was observed, nor were any other clinically manifest CMV infections detected. Sixteen patients remain alive at > 84 to > 518 d post‐transplant. In a retrospective comparison of 152 recipients of allogeneic transplants for haematological malignancy not given prophylactic ganciclovir, and in whom either the recipient or the donor or both were CMV seropositive, the incidence of all clinically manifest CMV infections was 23% (P= 0·02) and that of CMV IP 17% (P= 0·05). If only patients in the study group and the control group receiving the same cyclosporin/short methotrexate prophylactic immune suppressive regimen, the same prophylactic acyclovir regimen and the same CMV and leucocyte‐filtered blood product transfusion strategy were considered, the incidence of all clinically manifest CMV infections in the control group was 24% (P= 0·01) and that of CMV IP 13% (P= 0·07). Ganciclovir appears to reduce the incidence of CMV infections in allogeneic marrow transplant recipients even in those given immune suppressive regimens associated with adequate control of acute graft‐versus‐host disease.

Serum erythropoietin changes in autologous and allogeneic bone marrow transplant patients

Summary. Cyclosporin A (CyA) was used to minimize graft‐versus‐host disease (GVHD) in 28 recipients of allogeneic marrow transplants. When given orally, the absorption of CyA was markedly dependent on normal gut function. Patients without gut dysfunction showed normal serum concentration‐time curves while those with diarrhoea from any cause (chemo‐radiation enteritis, acute GVHD of the gut, infectious enteritis) showed minimal absorption of the drug. These data indicate the desirability of the intravenous administration of CyA during periods of gut dysfunction in marrow transplant recipients.

Peripheral Blood and Bone Marrow Findings in Patients with Acquired Immune Deficiency Syndrome

Summary. Sequential changes in serum erythropoietin (sEPO) levels were measured by radioimmunoassay in six patients receiving autologous rescue (AR) and 11 patients receiving an allogeneic bone marrow transplant (BMT) for malignant disease.