Cyclosporin A is associated with faster engraftment and less mucositis than methotrexate after allogeneic bone marrow transplantation

S ummary . Thirty-eight patients with severe aplastic anaemia or acute leukaemia received HLA-identical sibling marrow transplants. Seventeen were treated with methotrexate and 21 with cyclosporin A (CyA) to minimize graft-versus-host disease post transplant. Marrow engraftment was more rapid and oropharyngeal mucositis less severe in those receiving CyA. This resulted in a shorter period of neutropenia and thrombocytopenia, fewer platelet and granulocyte transfusions and less fever. These benefits have to be weighed against the increased nephrotoxicity of CyA.     

Cyclosporin in bone marrow transplantation

Cyclosporin, the first truly selective immunosuppressive agent, has a useful role in HLA-identical sibling bone marrow transplantation for haematological malignancy and severe aplastic anaemia. Specifically, it has been shown to minimise graft-versus-host disease, particularly when used in combination with methotrexate, and to reduce the risk of marrow graft rejection. Its mode of action, pharmacology, clinical utility and toxicology in the marrow transplant setting are described.     

Resolution of immune haemolytic anaemia with allogeneic bone marrow transplantation after an unsuccessful autograft

Autologous transplantation of lymphocyte-depleted peripheral blood stem cells (PBSC) has been proposed for treatment of patients with severe autoimmune disease. However, several patients have been reported to achieve only transient remissions. We report on a child with thalassaemia intermedia and immune-mediated haemolytic anaemia, given an autologous lymphocyte-depleted PBSC transplant, who relapsed 7 weeks after transplant. A complete remission, lasting 18 months to date, was obtained with allogeneic bone marrow transplantation (BMT) from an HLA-matched unrelated donor. This experience indicates that, in selected cases, allogeneic BMT may be the treatment of choice for life-threatening autoimmune disease. A graft-versus-autoimmunity effect may favour the eradication of the recipient autoaggressive lymphocytes.     

Transplantation of ABO-incompatible bone marrow and peripheral blood stem cell components

Hemolysis may occur during infusion of an ABO-incompatible HSC component if the recipient has isoagglutinins directed against donor red blood cells, or later as a result of the production by donor lymphocytes of isoagglutinins directed against recipient ABO-antigens. Peripheral blood stem cell (PBSC) components collected by apheresis contain few red cells but considerably greater numbers of lymphocytes than marrow. We reviewed the transplant courses of 158 recipients of marrow (n = 90) or PBSC (n = 68) from HLA-identical, ABO-incompatible sibling donors. No patient experienced immediate or delayed hemolysis attributable to the ABO incompatibility. Recipients of minor ABO-incompatible red cell-replete marrow required fewer red cell transfusions during the first week after transplantation than recipients of PBSC or marrows depleted of red cells; the red cell transfusion requirements for the following 3 weeks did not differ. The maximum level of bilirubin did not differ for patients classified by ABO incompatibility or source of HSC. The development of positive antiglobulin tests occurred for eight marrow recipients from a separate group of 22 patients (17 marrow, five PBSC) for whom this testing was performed. None of these patients developed overt hemolysis. These data indicate that hemolysis complicating ABO-incompatible transplantation is not common after either marrow or PBSC transplantation. Bone Marrow Transplantation (2000) 26, 749-757.     

Late graft rejection and second infusion of bone marrow in children with aplastic anaemia

Late graft rejection following allogeneic bone marrow transplantation (BMT) for aplastic anaemia is a significant clinical problem and is associated with a high risk of mortality. We report two children with severe aplastic anaemia (SAA) who developed very late graft rejection 2 years and 4 months and 10 years respectively after allogeneic BMT from HLA-identical siblings. Following a second BMT from their initial donors, engraftment has been sustained in both cases. The patients are alive with full donor chimaerism, 18 and 19 years from initial transplant. These cases illustrate that graft failure can be an extremely late event after allogeneic BMT for SAA, and that long-term sustained engraftment can be achieved in these patients with second BMT from the original donors.     

Late onset transfusion-dependent anaemia with thrombocytopenia secondary to marrow fibrosis and hypoplasia associated with chronic graft-versus-host disease

Late onset transfusion-dependent anaemia is very rare in the presence of sustained engraftment after HLA-identical sibling bone marrow transplantation. The only previously described consistent cause is pyridoxine-responsive sideroblastic anaemia. We describe here a second cause, marrow hypoplasia and fibrosis, occurring in association with extensive chronic graft-versus-host disease (GVHD). A 20-year-old Caucasian male who received cyclophosphamide and fractionated total body irradiation followed by an unmanipulated HLA-identical sibling marrow transplant from his sister for acute nonlymphoblastic leukaemia in first remission developed chronic GVHD of the skin and mouth at day 101 post-transplant. At day 689 post-transplant, he developed leuco-erythroblastic anaemia with thrombocytopenia, due to patchy marrow hypoplasia and fibrosis. Between days 689 and 1987 post-transplant he received 71 units of packed red cells, requiring transfusion approximately monthly. He remains well although still on prednisone for chronic GVHD of skin and is receiving desferrioxamine 4 g five nights/week i.v. as prophylaxis for iron overload.     

The helper T lymphocyte precursor (HTLp) frequency does not predict outcome after HLA-identical sibling donor G-CSF-mobilised peripheral blood stem cell transplantation

Here, we report the first study assessing the helper T lymphocyte precursor (HTLp) frequency as a predictor of outcome in patients undergoing allogeneic PBSC transplantation. The HTLp assay uses limiting dilution analysis to measure the frequency, in PBMCs from the donor, of T lymphocytes capable of producing IL-2 in response to histocompatibility antigenic differences on PBMCs from the recipient. This assay has shown promise as a functional histocompatibility assessment used to predict the risk of recipients of HLA-matched donor bone marrow developing severe acute GVHD: the higher the HTLp frequency, the greater the significance of any histoincompatibility, and the greater the risk of severe acute GVHD. In the current report, the HTLp frequency was measured in 28 HLA-identical sibling pairs who subsequently underwent allogeneic PBSC transplantation for haematological malignancies. The HTLp frequency did not predict for acute GVHD (P = 0.38), chronic GVHD (P = 0.95), transplant-related mortality (P = 0.79), relapse (P = 0.39) or overall survival (P = 0.84). Converting the HTLp frequency to HTLp infused per kilogram of recipient body weight also did not predict for any of the outcome measures. We conclude that, although the HTLp assay may be useful for patients undergoing BMT, it does not predict for outcome after HLA-identical sibling donor G-CSF-mobilised PBSC transplantation.     

Ecstasy-induced very severe aplastic anaemia complicated by invasive pulmonary mucormycosis treated with allogeneic peripheral blood progenitor cell transplant

Very severe aplastic anaemia (vSAA) is rare. We report a case of Ecstasy-induced very severe aplastic anaemia which did not respond to immunosuppressive therapy, developing invasive pulmonary mucormycosis. The patient underwent an HLA-identical sibling peripheral blood progenitor cell transplant (PBPCT) with rapid neutrophil engraftment. During engraftment he developed life-threatening adult respiratory distress syndrome (ARDS). This case serves to illustrate a novel aetiology of vSAA where the infective complications responded to prompt haematopoietic engraftment.     

Unrelated volunteer bone marrow transplantation: initial experience at St Vincent's Hospital, Sydney

Background: Only 30% of patients with leukaemia have an HLA-compatible family member able to act as a marrow donor. The recent development of volunteer bone marrow donor registries has supplied HLA-matched donors for a number of such individuals. Aims: To define the problem and outcome of the first cohort of patients given HLA-matched unrelated volunteer bone marrow transplants at St Vincent's Hospital, Sydney. Methods: Post transplant outcome of patients with advanced leukaemia given HLA-identical unrelated donor marrow transplants was compared to that of patients transplanted concurrently from HLA-identical sibling donors, in terms of survival, leukaemia-free survival, incidence and severity of acute graft-versus-host disease (GVHD), duration of neutropenia, incidence of infection and duration of transplant hospitalisation. Results: Sixteen patients with advanced leukaemia and without a histocompatible family member donor received unrelated donor bone marrow transplants. Actuarial survival at two years post transplant was 30%. Actuarial survival of 23 recipients of HLA-identical sibling bone marrow transplants with advanced leukaemia transplanted during the same time period was 17% (not significant). Actuarial disease free survival at two years was 30% and 13% respectively. Three of five long term survivors of the unrelated transplants had chronic myeloid leukaemia in blastic transformation at the time of transplant; thus blastic transformation should not preclude consideration of unrelated marrow transplantation. Recipients of unrelated allografts had a higher incidence of acute GVHD which occurred earlier and with greater severity than in recipients of sibling allografts, a longer duration of post transplant neutropenia (24 days to reach 0.5 × 10⁹/L versus 19.5, p= 0.07), a higher frequency of infection in the first 100 days post transplant (p= 0.0004) and a longer duration of transplant hospitalisation (p= 0.04). Transplant-related complications were the commonest cause of death in the unrelated donor recipients, while leukaemic recurrence was the commonest single cause of death in the HLA-identical sibling recipients. Improvements are needed in prophylaxis of infection and in prevention and treatment of acute GVHD in recipients of unrelated donor transplants. Nevertheless, this modality provides curative treatment for patients with otherwise incurable haematological malignancies and should no longer be considered experimental. (Aust NZ J Med 1993; 23: 450–457.)     

Allogeneic stem cell transplant from HLA-identical sibling for chronic granulomatous disease and review of the literature

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by an abnormal function of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the phagocytic cells, which results in an increased susceptibility to severe bacterial and fungal infections. We report on a 12-year-old boy with X-linked CGD who was successfully treated with allogeneic bone marrow transplantation from an HLA-identical sibling following a conditioning regimen consisting of busulphan (BU, 16 mg/kg) and cyclophosphamide (CY, 200 mg/kg). At >2 years from transplant, the boy is in excellent clinical and hematological condition with full chimerism. Our patient is the 24th case of CGD transplanted from an HLA-identical sibling. A review of the literature revealed that 20 of 24 CGD patients are alive and disease free 1-7 years after transplant. Most of these patients were conditioned with the BUCY combination, which should be considered the recommended regimen.     

One-year cyclosporine prophylaxis reduces the risk of developing extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation

BACKGROUND AND OBJECTIVES: Chronic graft-versus-host disease (GVHD) remains the most common late complication of allogeneic stem cell transplantation, producing significant long-term morbidity and contributing to a substantial risk of late mortality. Chronic GVHD may be more common, more protracted and less responsive to current treatments after peripheral-blood stem cell (PBSC) transplantation than after bone marrow transplantation. The purpose of this retrospective cohort study was to determine whether the hazard of extensive chronic GVHD after allogeneic PBSC transplantation could be decreased by prolonging cyclosporine A (CsA) prophylaxis over 12 months. DESIGN AND METHODS: Fifty-seven consecutive patients with hematologic malignancies who had received a PBSC transplant from an HLA-identical sibling were evaluable for chronic GVHD. All patients began CsA tapering at day 50 but 2 different durations of immunosuppression were used: the first 36 patients were allocated to receive a 6-month course with tapering by 5% at weekly intervals (group A), while the following 21 received a 12-month course with tapering by 5% every 2 weeks (group B). RESULTS: The cumulative incidence of extensive chronic GVHD at 2 years was 69% (95% CI, 53-85%) for group A and 25% (95% CI, 3-47%) for group B with a significantly lower hazard in group B than in group A (HR=0.2; 95% CI, 0.07-0.57; p=0.0009). In multivariate analysis, the 12-month CsA tapering schedule was associated with a significantly decreased risk of extensive chronic GVHD (HR=0.2; 95% CI, 0.06-0.66; p=0.008). The hazard of transplant-related mortality, relapse and failure to survive in remission was not significantly different among the 2 groups. INTERPRETATION AND CONCLUSIONS: One-year CsA prophylaxis seems to be more effective than the standard six-month CsA regimen at preventing extensive chronic GVHD after PBSC transplant from an HLA-identical sibling. Conclusive assessment of the benefits of such prolonged immunosuppression, in terms of better quality of life and minor morbidity, requires both long-term follow-up to evaluate the rates of relapse and secondary tumors and a randomized setting.     

HIGH INCIDENCE OF EARLY LEUKEMIC RELAPSE IN PATIENTS GIVEN CYCLOSPORIN AND T CELL DEPLETED HLA-IDENTICAL SIBLING MARROW TRANSPLANTS FOR ACUTE LEUKEMIA IN FIRST REMISSION*

:Twelve patients with acute nonlymphoblastic leukemia (ANL, n = 6) or acute lymphoblastic leukemia (ALL, n = 6) in first complete remission received cyclophosphamide 120 mg/kg and total body irradiation (TBI) 12 Gy followed by HLA-identical sibling marrow that had been depleted of T cells by incubation with anti-CD2 (with or without anti-CD8) monoclonal antibody and rabbit complement. These 12 patients were compared historically to 25 patients with ANL (n = 15) or ALL (n = 10) in first remission given cyclophosphamide 120 mg/kg and TBI 12 Gy followed by non-T cell depleted HLA-identical sibling marrow for parameters of relapse and survival. Thirty-six of the 37 patients received cyclosporin as post transplant prophylaxis for graft-versus-host disease (GVHD). All surviving patients have been followed for a minimum of one year from transplant. The actuarial rate of leukemic relapse in the T-depleted group was 62% compared to 37% in the non-depleted group (p< 0.02). Additionally, relapse occurred significantly earlier post transplant in the T-depleted recipients (p = 0.012). Actuarial survival at two years post transplant was 24% for the T-depleted recipients and 41 % at six years post transplant for the non-depleted recipients (not significant, p = 0.37). We have previously shown that GVHD is less severe in patients given T cell depleted transplants. Taken together, these findings suggest that (under the protocol conditions used) a graft-versus-leukemia effect is not separable from a GVHD effect in man. More effective anti-leukemia therapy must be devised before the benefit of T cell depletion can be applied to patients with ANL or ALL receiving HLA-identical sibling marrow transplants in first remission. (Aust NZ J Med 1988; 18: 587–593).     

Intensification of GVHD prophylaxis with low-dose ATG-F before allogeneic PBSC transplantation from HLA-identical siblings in adult patients with hematological malignancies: results from a retrospective analysis

Several studies have shown that chronic GVHD (cGVHD) is more frequent in patients receiving transplants from PBSC than in those receiving BM. In the setting of PBSC-unrelated transplants, the addition of anti-T-cell globulin (ATG) has shown a significant decrease in incidence/severity of cGVHD, without an increase in relapses or infections. However, no prospective data are yet available in the sibling setting. We retrospectively analyzed the effects of intensification of standard GVHD prophylaxis (CsA+MTX) by the addition of low-dose ATG in 245 patients receiving a transplant from HLA-identical sibling. From 1996 to 2001, patients received PBSC as the preferred source (group 2), and then ATG was added before transplant (group 3) because of a high cGVHD rate. Patients receiving BM in the same time period were analyzed as a control group (group 1). The incidence of grade III-IV acute GVHD and cGVHD was not significantly different in the three groups, but extensive cGVHD was highest in group 2 (38%) compared with group 3 (21%) or group 1 (28%; P=0.03). OS, TRM and time to relapse/progression were similar in the three groups. Our analysis shows that adding ATG to PBSC sibling allogeneic transplants can lower cGVHD, without an increase of relapse. Further prospective studies are needed to confirm these findings.     

Marrow transplantation for Fanconi anaemia: conditioning with reduced doses of cyclophosphamide without radiation

Nine patients with Fanconi anaemia (FA) were conditioned for HLA-identical sibling bone marrow transplant (BMT) with reduced dose of cyclophosphamide (Cy) without radiation or antithymocyte globulin (ATG). The total dose of Cy was 140 mg/kg ( n =2) or 120 mg/kg ( n =7). The median patient age was 8 years (range 4–19). Graft-versus-host disease (GVHD) prophylaxis was with methotrexate and cyclosporine ( n =8) or cyclosporine alone ( n =1). All patients had sustained engraftment and two developed grade ≥II acute GVHD. Cy toxicity included grade ≥2 mucositis seen in all evaluable patients and haemorrhagic cystitis in two patients. The Kaplan-Meier survival estimate is 89% with a median follow-up of 285 d (range 56–528).
For the purpose of comparison, this report also reviews and updates long-term follow-up data on 32 previously reported FA patients conditioned with 140–200 mg Cy/kg without radiation.
The lowest dose of Cy (without radiation or ATG) after which HLA-identical sibling marrow transplant can be successfully performed in FA patients has yet to be determined, but it appears that uniform and sustained engraftment can be achieved with a Cy dose of as low as 120 mg/kg.     

A COMPARATIVE STUDY OF T-CELL DEPLETED AND NON-DEPLETED MARROW TRANSPLANTATION FOR HEMATOLOGICAL MALIGNANCY

Sixteen patients with hematological malignancy received cyclophosphamide (120 mg/kg), fractionated total body irradiation (12 Gy), oral cyclosporin, and an HLA-identical sibling marrow transplant depleted of T cells by incubation with the monoclonal antibody anti-HuLy-m1 (CD2) and rabbit complement with (five patients) or without (11 patients) anti-HuLy-m8 (CD8). These 16 patients were compared historically to 84 patients with hematological malignancy receiving cyclophosphamide (120 mg/kg), fractionated total body irradiation (12 or 14 Gy), oral cyclosporin, and unmanipulated HLA-identical sibling marrow, for parameters of engraftment and graft-versus-host disease (GVHD). Graft failure occurred in one of the 16 T-cell depleted recipients and in one of the 84 non-depleted recipients. Engraftment was slightly but significantly slower in the T-cell depleted group and bacterial infections significantly more, frequent and severe than in the unmanipulated group. There was a suggestion that the severity of acute GVHD was reduced in those receiving T depleted marrow. Randomized trials will be necessary to determine if marrow T-cell depletion results in superior long-term leukemia-free survival.     

Bone marrow transplantation for severe aplastic anemia: the Barcelona Hospital Clinic experience

BACKGROUND AND OBJECTIVE: The outcome of patients with severe aplastic anemia (SAA) has improved considerably over the last decades. Bone marrow transplantation (BMT) is the treatment of choice in young patients who have an HLA-identical sibling donor. This study analyzes the outcome and factors related to survival in patients with SAA receiving BMT in our institution. DESIGN AND METHODS: Between March 1978 and December 1996, 49 consecutive patients received an HLA-identical sibling marrow transplant for SAA. Median age was 21 years (range, 4 to 47) and 15 (31%) were women. Median interval from diagnosis to transplant was 2.6 months (range, 0.5 to 159). Between 1978 and 1982 all patients were conditioned with cyclophosphamide (CY) alone and received methotrexate (MTX) until day 102 as graft-versus-host disease (GvHD) prophylaxis. From 1983 most patients received CY and thoraco-abdominal irradiation (TAI) as the conditioning regimen and cyclosporin A (CSA) as GvHD prophylaxis. RESULTS: Survival probability at 10 years was 55 +/- 7% with a median follow-up for the surviving patients of 8.5 years. The incidences of graft failure, grade II to IV acute GvHD, and chronic GvHD were 21%, 39.5% and 31%, respectively. In multivariate analysis three factors adversely influenced survival: a) age > or = 30 years (p = 0.05); b) > or = 10 transfusion units pre-BMT (p = 0.008); and c) use of long course MTX for GvHD prophylaxis (p = 0.01). One case of squamous-cell carcinoma occurred in a TAI-treated patient 13 years post-transplantation. INTERPRETATION AND CONCLUSIONS: BMT is effective in young patients with SAA who have an HLA-identical sibling donor, particularly if minimally transfused pre-transplant. The introduction of TAI and CSA to our preparative regimen has led to a remarkably increased survival.     

Survival of patients with chronic myelogenous leukaemia relapsing after bone marrow transplantation: comparison with patients receiving conventional chemotherapy

Treatment with busulphan and/or hydroxyurea rarely produces remission in patients with chronic myelogenous leukaemia (CML) in chronic phase. HLA-identical sibling transplants almost always produce remission, and only about 20% of patients relapse post-transplant. The increased anti-leukaemic efficacy of transplants results from intensive pretransplant treatment and immune-mediated anti-leukaemia effects. We studied 433 patients surviving  2 years after diagnosis of CML to determine if patients who have relapsed after a transplant in chronic phase have longer survival from diagnosis than comparable subjects receiving chemotherapy. The chemotherapy cohort included 344 adults < 50 years of age treated on consecutive trials of the Italian Cooperative Study Group on CML between 1973 and 1986. The transplant cohort included 89 patients reported to the International Bone Marrow Transplant Registry who relapsed after an HLA-identical sibling bone marrow transplant carried out between 1978 and 1992. Survivals in the two groups were compared using Cox proportional hazards regression to adjust for prognostic variables. Median survival was 65 months in the chemotherapy cohort and 86 months in the transplant cohort. The 7-year probability (95% confidence interval) of survival was 34% (28–39%) in the chemotherapy cohort and 57% (43–70%) in the transplant cohort ( P =0.003). There was no difference in survival of patients relapsing after T-cell depleted and non-T-cell-depleted transplants. We conclude that patients who relapse after an HLA-identical sibling bone marrow transplant for CML in chronic phase have longer survival from diagnosis than comparable patients receiving chemotherapy. This effect is most likely to be the result of intensive chemotherapy and/or radiation given for pretransplant conditioning.     

Successful haematopoietic stem cell transplantation from a matched unrelated donor following three graft failures from HLA-mismatched related donors

Graft rejection and graft failure are serious complications after allogeneic stem cell transplantation (SCT). We report a patient with CML in first chronic phase who finally engrafted with a transplant from an HLA-identical unrelated donor after graft failures from two related HLA-mismatched sibling donors. After failure of one BM and two PBSC grafts from two 1 HLA-antigen mismatched related donors, the patient was finally successfully transplanted from a subsequently identified HLA-identical unrelated donor (donor 3). At 5 years post transplant, the patient is in complete cytogenetic and molecular remission.     

Bone marrow transplants for paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare clonal haematological disorder characterized by intravascular haemolysis and increased risk of thrombosis. PNH is associated with bone marrow failure syndromes including aplastic anaemia, myelodysplasia and leukaemia. Bone marrow transplants are sometimes used to treat PNH, but small series and reporting biases make assessment of transplant outcome difficult. The outcome of 57 consecutive allogeneic bone marrow transplants for PNH reported to the International Bone Marrow Transplant Registry (IBMTR) between 1978 and 1995 was analysed. The 2-year probability of survival in 48 recipients of HLA-identical sibling transplants was 56% (95% confidence interval 49-63%). Two recipients of identical twin transplants remain alive 8 and 12 years after treatment. One of seven recipients of alternative donor allogeneic transplants is alive 5 years after transplant. The most common causes of treatment failure were graft failure and infections. Our results indicate that bone marrow transplantation can restore normal bone marrow function in about 50% of PNH patients.     

Treatment of severe aplastic anemia

A total of 100 patients with severe aplastic anemia were treated and evaluated in a prospective study at our hospital between January 1976 and October 1983: 28 patients had an HLA-identical sibling donor and were treated with bone marrow transplantation, and 72 patients without an HLA-identical sibling donor were given antilymphocyte globulin followed by oral low-dose androgen therapy. At 1 1/2-9 years after treatment, 13 patients (46%) survive in the transplant group and 45 patients (75%) survive in the second group. All except one in the second group have self-sustaining hematopoiesis without need for transfusions. There is one major difference between the two therapies. Marrow transplantation restores bone marrow function completely and no late hematologic complications have been seen in this group. The majority of patients treated with antilymphocyte globulin in contrast have residual abnormalities of hematopoiesis: macrocytosis, mild granulocytopenia, and mild thrombopenia. Relapse (11 of 72 patients) and clonal hematologic disorders, such as paroxysmal nocturnal hemoglobinuria (four patients) and leukemia (one patient) can occur years after complete bone marrow reconstitution with antilymphocyte globulin. These late disorders are of concern. Despite this, we conclude that antilymphocyte globulin treatment is an effective therapy with low early mortality and morbidity and a high chance for a long, sustained remission. Results are better or at least equivalent to bone marrow transplantation and patients with donors should be given the option of transplant or antilymphocyte globulin.