Charles G. Craddock

CYTOMEGALOVIRUS SEROPOSITIVITY ADVERSELY INFLUENCES OUTCOME AFTER T-DEPLETED UNRELATED DONOR TRANSPLANT IN PATIENTS WITH CHRONIC MYELOID LEUKAEMIA: THE CASE FOR TAILORED GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS

Graft‐versus‐host disease (GVHD) remains a major cause of morbidity and mortality after haematopoietic stem cell transplantation from matched unrelated donors (MUD). The role of T‐cell depletion (TCD) as a strategy to prevent GVHD is controversial because of the associated increased risk of leukaemic relapse, graft failure and delayed immune reconstitution. The demonstration that donor lymphocyte infusion (DLI) is effective salvage therapy if patients relapse after transplantation for chronic myeloid leukaemia (CML) prompted us to examine the proposal that TCD may be a form of GVHD prophylaxis particularly suited to this disease in patients undergoing MUD transplantation. We analysed the outcome of 106 consecutive patients with CML in first chronic phase who underwent MUD transplantation. Patients were conditioned with cyclophosphamide and total body irradiation (TBI), and received in vivo TCD, using CD52 monoclonal antibody, as GVHD prophylaxis. Donor lymphocytes were infused at the time of leukaemic relapse. The projected survival at 5 years for all patients was 52·6%. The probability of developing severe acute GVHD (grade 3 or 4) was 14·5%. The only significant predictor of overall survival in univariate and multivariate analysis was patient cytomegalovirus (CMV) serostatus: in CMV‐negative patients survival at 5 years was 60% vs. 42% in CMV‐positive patients (P = 0·006). The use of TCD was associated with an increased risk of relapse (62% probability at 5 years after transplant), but 80% of patients who received DLI achieved molecular remission that was durable in all but two cases. In vivo TCD, in conjunction with DLI at relapse, is a valuable GVHD prophylactic regimen in CMV‐seronegative recipients of MUD allografts, but in CMV‐seropositive patients this approach is associated with an increased non‐relapse mortality. Consequently, GVHD prophylactic regimens in MUD transplantation should be tailored according to the patient and donor pretransplant characteristics.

Immunoglobulin Synthesis in Vitro by Splenic Tissue in Idiopathic Thrombocytopenic Purpura

Abstract Experimental and clinical observations suggest that platelet destruction in idiopathic thrombocytopenic purpura (ITP) is due to the production of an antibody against autologous platelets. The origin of antibody synthesis is unknown although the spleen has been considered one likely possibility. When we determined immunoglobulin (Ig) synthesis in vitro by human splenic tissue, mean Ig production by spleens from patients with ITP was five times greater than that of unstimulated control tissue, but was similar to the degree of Ig synthesis by control tissue after in vitro antigenic stimulation. Immunoglobulins produced by one ITP spleen showed binding to autologous and homologous platelets. These data suggest that the spleen in ITP is involved in a humoral response to some antigen. Whether this increased Ig production is directed toward platelet-associated antigens cannot be definitely stated although preliminary findings are suggestive.

Treatment of relapse after allogeneic bone marrow transplantation with reduced intensity conditioning (FLAG ± Ida) and second allogeneic stem cell transplant

Acute leukaemias in relapse after allogeneic stem cell transplantation (SCT) respond poorly to donor leucocyte infusions (DLI) compared with chronic myeloid leukaemia (CML), at least in part because of faster disease kinetics. Fludarabine‐containing ‘non‐myeloablative’ chemotherapy followed by further allo SCT may offer more rapid and effective disease control. We report 14 patients with relapse after allo SCT for acute leukaemia [seven acute myeloid leukaemia (AML), five acute lymphoblastic leukaemia (ALL)] or refractory anaemia with excess blasts in transformation (RAEB‐t, n = 2) treated with fludarabine, high‐dose cytosine arabinoside (ara‐C) and granulocyte colony‐simulating factor (G‐CSF) with (n = 10) or without (n = 2) idarubicin (FLAG ± Ida) or DaunoXome (FLAG‐X) (n = 2) and second allo SCT from the original donor. Donors were fully human leucocyte antigen (HLA) ‐matched in 13 cases with a single class A mismatch in one. Actuarial overall survival was 60% and disease‐free survival was 26% at 58 months. Remissions after the second SCT were longer than those after the first bone marrow transplantation (BMT) in eight of the 13 assessable patients to date. Haematopoietic recovery was rapid. Transplants were well tolerated with no treatment‐related deaths. The major complication was graft‐versus‐host disease (GvHD, acute  grade II−2 cases, chronic – eight cases, two limited, six extensive) although there have been no deaths attributable to this. FLAG ± Ida and second allo SCT is a safe and useful approach and may be more effective than DLI in the treatment of acute leukaemias relapsing after conventional allo SCT.

In Vitro Splenic IgG Synthesis in Hodgkin's Disease

Abstract Experimental and clinical observations suggest increased lymphoid reactivity in Hodgkins disease. Since thymus-dependent lymphocyte function is often depressed whereas serum antibody responses appear normal, in vitro splenic IgG synthesis was studied to assess B lymphocyte activity. Increased total splenic IgG synthesis occurred in 20 of 22 patients with Hodgkins disease. Mean IgG production by uninvolved and lightly involved spleens of the patients was five and 11 times normal, whereas heavily involved spleens averaged twice normal levels. Unstimulated IgG synthesis by uninvolved and lightly involved spleens of patients was similar to that of normal spleens after secondary antigenic stimulation, suggesting an in vitro response to an in vivo antigenic challenge. When IgG produced in culture by spleens affected by Hodgkins disease was incubated with homologous lymphocytes, highly significant IgG binding levels were found. These data suggest that the spleen in Hodgkins disease responds with a h...

Molecular studies in patients with chronic myeloid leukaemia in remission 5 years after allogeneic stem cell transplant define the risk of subsequent relapse

We identified 103 consecutive patients who, 5 years after allogeneic transplantation for chronic myeloid leukaemia (CML), were in molecular remission (MR). The 103 patients were divided into three groups on the basis of reverse transcription–polymerase chain reaction (RT–PCR) studies for BCR‐ABL transcripts in the first 5 years post transplant: Group A comprised 63 patients who had been continuously PCR negative; Group B comprised 20 patients with one or more positive PCR result but only at a low level; and Group C comprised 20 patients who had fulfilled the criteria for molecular relapse, been treated with donor lymphocyte infusions (DLI) and had thereafter regained complete MR within the 5‐year post‐transplant period. The median follow‐up for all 103 patients was 8·4 years from transplant (range 5–17·6 years). In group A only one patient relapsed at 9·2 years. In group B eight patients (40%) relapsed: six at molecular, one at cytogenetic and one haematological levels. The actuarial probabilities of survival at 10 years for patients in Groups A, B and C were 97·4%, 92·9% and 100% respectively; the probabilities of relapse were 3%, 54% and 0% respectively. We conclude that molecular studies during the first 5 years post transplant can help to predict long‐term leukaemia‐free survival and, possibly, cure of CML.

A comparison of prophylactic vs pre-emptive ganciclovir to prevent cytomegalovirus disease after T-depleted volunteer unrelated donor bone marrow transplantation

The prophylactic and pre-emptive use of ganciclovir (GCV) both reduce significantly the incidence of CMV disease after sibling BMT but it is unclear which of these strategies is best for volunteer unrelated donor (VUD) BMT patients. We reviewed 49 consecutive patients, who received a T-depleted VUD BMT (from March 1990 to March 1996) for the treatment of CML in chronic phase, and were CMV seropositive before transplant or had a CMV seropositive donor. Patients were conditioned with cyclophosphamide (120 mg/kg for 2 days) and total body irradiation (13.2–14.4 Gy). Prophylaxis for GVHD was cyclosporin A and methotrexate with ex vivo or in vivo T cell depletion. Twenty-seven patients received pre-emptive GCV if CMV infection was detected by short-term culture before day +120 post BMT. Twenty-two patients received prophylactic GCV from engraftment until day +120 post BMT. The probabilities of CMV infection and disease occurring by 1 year post-BMT were greater in the pre-emptive GCV group than in the prophylactic GCV group (73.8% and 64.0% vs 53.1% and 30.0%, respectively; P = 0.04 and 0.07). The incidence of death from CMV disease was similar in both groups (3/12 (25%) vs 3/10 (30%), respectively) and there was no difference in 1 year survival (55.6% vs 54.2%, respectively). New strategies are urgently required for the prevention of CMV disease after T-depleted VUD BMT.

Diseases of Cellular Immunity

Abstract Cellular immune reactions are mediated by lymphocytes and their products, the cellular mediators. Although it is convenient to consider cellular immunity and antibody immunity as separate,...

THE DYNAMICS OF LEUKOPENIA AND LEUKOCYTOSIS

Excerpt Many features of the physiology of leukocytes are controversial. The origin of certain cells—for example, the monocyte and the plasma cell—is disputed. The functions of many of the cell spe...

Granulocytes in Human Disease

Abstract The neutrophilic granulocyte develops from a committed hemopoietic stem cell under hormonal and microenvironmental influences. By the promyelocyte stage it begins to develop its arsenal of...

Antisera to neutrophils, lymph node cells, and thymus cells of the guinea pig: hematological effects and antibody localization.

SUMMARY The hematological and the immunological studies of antincutrophilicserum(ANS),and antilymphocytic serum(ALS) show remarkable agreement. Thus,ANS produces its significant effects on stabs and neytrophils whereas ATS has a distinct effect on stabs and neutriphils and, also a very distinct effect on the lymphcyts. ALS produces a significant reduction in blood and marrow neutrophils. Precipitating antibodies to neutrophil antigens are present in both ANS and ATS. No precipitating antibodies have been demonstrable in and about Hassalls corpuseles by immunofluorescent technique. The findings may be of importance in the interpretation of certain experimental results dealing with immunosuppression by means of antisera for white blood cells.