K. Downs

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

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.

The toxicity of busulphan and cyclophosphamide as the preparative regimen for bone marrow transplantation

Summary. The toxicity of the conditioning regimen of high dose busulphan (Bu) (16 mg/kg) and cyclophosphamide (Cy) (120 mg/kg) has been compared to cyclophosphamide (Cy) (120 mg/kg) and fractionated total body irradiation (TBI) 12‐14 Gy. Since 1985, 67 patients have received conditioning of Bu and Cy for HLA‐identical sibling bone marrow transplants. 166 patients have received Cy and TBI since 1981.

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

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. 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.

A comparison of the pattern of interstitial pneumonitis following allogeneic bone marrow transplantation before and after the introduction of prophylactic ganciclovir therapy in 1989

A comparison was made of the pattern of interstitial pneumonitis (IP) following allogeneic bone marrow transplantation before and after the introduction of ganciclovir prophylaxis to minimize the risk of cytomegalovirus (CMV) disease in the St Vincent’s Hospital bone marrow transplant program in 1989. A total of 456 recipients of allogeneic transplants were included. 280 received no prophylactic ganciclovir while 176 received prophylactic ganciclovir. The overall incidence of interstitial pneumonitis dropped from 19.6 to 12.5% (P = 0.03) and this was primarily due to a reduction in the incidence of CMV-IP which fell from 12.9 to 1.7% (P < 0.0005). the incidence of idiopathic ip was not different between the two groups (6.3 vs 3.2%), nor was the incidence of Pneumocystis carinii pneumonia (2.9 and 0.6%). Prophylactic ganciclovir has thus had a significant impact in reducing both the overall incidence of IP and specifically cytomegalovirus IP in allogeneic marrow transplant recipients. The most common form of IP in patients given prophylactic ganciclovir is now idiopathic interstitial pneumonitis.

Radiation-free preparation for allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia.

PURPOSE The study was undertaken to investigate the effectiveness of allogeneic bone marrow transplantation from HLA-identical siblings after preparation with busulfan and cyclophosphamide in adults with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Thirty-nine patients aged 15 to 42 years underwent transplantation at three different centers from November 1984 through November 1990. All patients received 16 mg/kg busulfan and 120 mg/kg cyclophosphamide as preparative therapy. Cyclosporine plus methotrexate or cyclosporine plus corticosteroids with or without methotrexate were given for prevention of graft-versus-host disease (GVHD). RESULTS Twelve patients died of treatment-related complications, 12 patients relapsed, and 15 patients are leukemia-free survivors. For 27 patients in group 1 (first remission, second remission, first relapse), the estimated leukemia-free survival (LFS) rate is 42.3% (95% confidence interval [CI], 22.9% to 71.7%) at 3 years. For 12 patients with more advanced disease (group 2), the 1-year LFS rate is 13.5% (95% CI, 0% to 37.1%). Chronic GVHD occurred at an estimated incidence of 63.3% and developed significantly more frequently among patients who received corticosteroids for prevention of acute GVHD. Chronic GVHD was associated with a significantly lower incidence of relapse and with improved LFS rates. CONCLUSION LFS rate in this study is comparable to that obtained with radiation-containing regimens; however, the effectiveness of this preparative regimen in ALL requires further study.

Lenograstim administration to HLA-identical donor-recipient pairs to accelerate marrow recovery post-transplant

In an attempt to accelerate marrow recovery after HLA-identical sibling bone marrow transplantation, the donors of 12 patients with haematological malignancy were given recombinant human granulocyte colony-stimulating factor (rHuG-CSF; lenograstim; Granocyte) 5 μ g/kg/day for seven doses prior to marrow harvest. All 12 recipients also received lenograstim 5 μ g/kg/day from the day of transplant until their neutrophil count was 1.0 × 109/l. In addition to lenograstim post-transplant and lenograstim-stimulated donor bone marrow the first six recipients also received donor peripheral blood stem cells that had been enriched for CD34+ stem/progenitor cells and T cell depleted on an immune absorption column (cohort 1). The second six patients (cohort 2) received lenograstim post-transplant and lenograstim-stimulated donor marrow only. All 12 patients showed a marked elevation of their circulating white blood cell count (predominantly neutrophils) on day 1 post-transplant. Compared to carefully matched historical control patients the rate of neutrophil engraftment was significantly accelerated in both patient cohorts and platelet engraftment was accelerated in cohort 2.

INFLUENCE OF UNDERLYING DISEASE AND DONOR SEX ON THE INCIDENCE OF GRAFT-VERSUS-HOST DISEASE IN ALLOGENEIC BONE MARROW TRANSPLANTATION

tion occurring in vivo. Hossfeld et a1 ( 198 5) described a case in which an abnormal karyotype persisted in a patient with AML following treatment with ARA-C. In this case, however, the conclusions were based on a single karyotypic analysis carried out only 6 weeks after initiating treatment and, as it showed a significant number of previously undetected normal metaphases in addition to the abnormal clone of cell, the observations are difficult to interpret. The follow-up was also limited in the patient in the series reported by Griffin et a1 (1 9 8 5 ) who appeared to retain an abnormal chromosomal marker (trisomy 8) after responding to treatment with lowdose AKA-C. Nevertheless, it is likely that in many, perhaps most, patients ARA-C exerts its therapeutic effects via a direct cytotoxic mechanism. Several studies have found a higher incidence of significant myelosuppression following low-dose ARA-C (Griffin et a/. 1985) than had been initially reported. even when used in ‘very-low-dose’ regimens of 3 mg/m2 per day (Worsley et a/ . 1986). In addition, there is direct evidence from isoenzyme typing (Mittermuller et a/. 1986) and cytogenetic analyses (Tagawa et a/. 1985: Griffin r t a/ , 1985) consistent with a predominantly cytotoxic mode of action. Unfortunately, it does not seem possible to predict which groups of patients will respond to AKA-C in a manner similar to that observed in our patient, although it is interesting that the small numbers of cases described with hypoplastic acute leukaemia treated with low-dose ARA-C do appear to respond well to this form of therapy.