N. K. C. Ramsay

Cytomegalovirus pneumonia after bone marrow transplantation. Risk factors and response to therapy.

Cytomegalovirus pneumonia complicated bone marrow transplantation in 75 (63 allogeneic and 12 autologous) of 1136 recipients (Kaplan-Meier incidence 8.8%). CMV pneumonia occurred more frequently in allogeneic (12.4%) than autologous recipients (3.3%). Increased risk for CMV pneumonia was observed in allogeneic recipients who were seropositive (relative risk = 2.9), older age (RR = 1.4 per decade), those conditioned with total-body irradiation (RR = 2.7), who received antithymocyte globulin (RR = 2.9) or T cell-depleted marrow (RR = 2.7) or who had CMV viruria (RR = 4.0) or viremia (RR = 5.9). Autologous recipients were also at increased risk if they were seropositive (RR = 6.1), or developed viruria (RR = 7.0) or viremia (RR = 15.4). Thirteen of 14 untreated patients died without improvement. Prognosis was poor in patients who were ventilator-dependent at initiation of therapy (median survival 17 days), with only 1 long-term survivor. In contrast, patients ventilator-independent at initiation of therapy with ganciclovir and immunoglobulin (n = 22) had a median survival of > 274 days, with 9 long-term survivors. Ganciclovir alone or acyclovir with immunoglobulin in ventilator-independent patients was less effective (median survivals 80 and 10 days, respectively). Overall, 10 of 75 patients were surviving 10-73 months (median 47) from diagnosis; 9 of these were ventilator-independent at initiation of therapy and received ganciclovir with immunoglobulin. CMV pneumonia was less common, but was severe in autologous recipients, with only 2 of 12 surviving. CMV pneumonia remains a prominent cause of death following BMT. Early therapy with ganciclovir and immunoglobulin before respiratory failure supervenes may improve survival.

PRETREATMENT OF DONOR BONE MARROW WITH MONOCLONAL ANTIBODY OKT3 FOR PREVENTION OF ACUTE GRAFT-VERSUS-HOST DISEASE IN ALLOGENEIC HISTOCOMPATIBLE BONE-MARROW TRANSPLANTATION

Ten consecutive patients undergoing transplantation of bone marrow from histocompatible siblings for treatment of haematological malignancy took part in a pilot study to test the safety of in-vitro treatment of donor bone marrow with monoclonal antibody OKT3. Three male and seven female patients aged 7-34 years received concentrated bone marrow buffy-coat cells which had been incubated with OKT3 before infusion. In-vitro studies confirmed that almost all immunocompetent T lymphocytes in the bone-marrow samples were coated with OKT3 at the time of infusion. In vitro, neonatal rabbit complement inhibited the proliferation of bone-marrow T lymphocytes in samples preincubated with OKT3 to less than 4% of the mitogenic responses of the untreated bone marrow. In contrast, fresh autologous complement did not effectively lyse OKT3-treated bone-marrow cells. Infusion of OKT3-treated bone marrow was safely accomplished, and engraftment was achieved in all patients (mean 23 days). Nine of ten patients survived for more than 100 days after bone-marrow transplantation, but significant acute graft-versus-host disease (GvHD) requiring treatment with steroids developed in five of the ten. This finding suggests that further modifications for bone-marrow pretreatment will be needed to achieve effective prophylaxis against acute GvHD in histocompatible bone-marrow transplantation.

Allogeneic bone marrow transplantation for acute lymphoblastic leukemia in remission: prolonged survival associated with acute graft-versus-host disease.

Forty remission patients with high-risk acute lymphoblastic leukemia (ALL) underwent matched allogenic bone marrow transplantation (BMT) following preparation with cyclophosphamide and fractionated total body irradiation (TBI). As of March 1987, the median follow-up is more than 3 1/2 years. Thirteen patients are alive (11 relapse free) between 2 and 4 1/2 years post-BMT. Neither age, sex, remission number, prior extramedullary leukemia, nor WBC at diagnosis of ALL was statistically significant as a predictor of relapse-free survival. The development of acute graft-v-host disease (GVHD) in 17 patients was found, with time-dependent Cox regression analysis, to be associated with a significant reduction in post-BMT relapse risk (P = .04) and improved disease-free survival (P = .11). A prospective, randomized trial of maintenance chemotherapy with oral methotrexate and mercaptopurine did not demonstrate improvement in relapse risk or survival for those assigned maintenance chemotherapy (P = .7). These results suggest that allogeneic BMT can result in extended relapse-free survival for some patients with high-risk ALL. More effective preparative chemoradiotherapy and exploitation of the apparent graft-v-leukemia effect may be useful in future trials.

Bone mineral density in patients undergoing bone marrow transplantation for myeloid malignancies

Bone mineral density (BMD) was measured in 23 patients who had undergone bone marrow transplantation (BMT) at the University of Minnesota for myeloid leukemia. The median age at BMT was 22 years (range 3–53) and the median age at assessment of BMD was 27 years (range 4–56). Total body BMD was measured a median of 2 years (range 1–10) after BMT using Dual Photon X-ray Absorptiometry (DEXA). BMD was measured in g/cm2, with results expressed as percent of normal values and as Z (standard deviation) scores. Patients were categorized into two groups (pediatric and adult) according to age at BMT (⩽18 years vs >18 years). Total body BMD of patients in the pediatric age group was significantly decreased (median Z-score −0.5) compared to the adult population (median Z-score 0.0, P = 0.03). No association was observed between BMD and time elapsed since BMT, type of conditioning regimen, gonadal function, steroid intake or graft-versus-host disease. Investigation of decreased BMD in children with AML following BMT is needed to determine the metabolic basis, long-term implications, appropriate preventive measures and potential interventions.

Biphenotypic leukemia." Immunologic and morphologic evidence for a common lymphoid-myeloid progenitor in humans

A 5-year-old white girl had a white blood cell count of 80,000/cu mm and 82% lymphoblasts in the peripheral blood. Acute lymphocytic leukemia (ALL) was diagnosed, defined by typical morphology (FAB-L1), a positive reaction for terminal deoxynucleotidyl transferase (TdT) and characteristic surface antigens detected with lymphoid monoclonal antibodies. The patients peripheral lymphoblast count fell rapidly with ALL therapy, but the WBC count began to rise unexpectedly on the sixth day of treatment, with 84% myeloblasts and monocytoid blasts. Malignant cells in the bone marrow showed FAB-M4 morphology and were no longer reactive with antibodies directed against TdT or common ALL antigen. However, the myeloblasts continued to react with some of the same monoclonal antibodies as the original leukemia cells, and in addition expressed new determinants detected by monoclonal antibody TA-1 and peanut agglutinin. The rapid dynamic evolution of the malignancy during the course of induction chemotherapy favors the existence of a stem cell capable of differentiation into both lymphoid and myeloid clones that are both independently and selectively sensitive to specific chemotherapeutic regimens.

BONE-MARROW TRANSPLANTATION IN HIGH-RISK ACUTE LYMPHOBLASTIC LEUKAEMIA IN FIRST AND SECOND REMISSION

Bone-marrow transplantation has been used in patients with acute lymphoblastic leukaemia (ALL) thought to be at high risk of relapse if managed with chemotherapy. Data from 444 ALL patients with one or more high-risk features at diagnosis were analysed to evaluate outcome after HLA-identical bone-marrow transplantation during first or during second remission. The 4-year actuarial probability of leukaemia-free survival was 45% (95% confidence interval 36-54%) for transplants in first remission compared with 22% (15-29%) for those in second remission (p less than 0.0002). The 4-year probabilities of relapse were 26% (14-38%) and 56% (45-67%) respectively (p less than 0.0001). For high-risk ALL, transplantation in first remission had clearly superior results to transplantation in second remission. Further studies are needed to determine whether patients with high-risk ALL should receive transplants during first remission or should initially receive chemotherapy, with transplantation being reserved for patients who relapse.

SCLERODERMATOUS GRAFT-VERSUS-HOST DISEASE LIMITED TO AN AREA OF MEASLES EXANTHEM

A female patient with severe idiopathic aplastic anaemia received a successful bone-marrow transplant from her HLA-identical, mixed-lymphocyte-culture-compatible, brother. 8 months after transplantation she had localised cutaneous measles. Chronic sclerodermatous changes developed which were indistinguishable from chronic graft-versus-host disease and were limited to the areas of the original exanthem. Interaction between viral infection and minor histocompatibility differences probably resulted in graft-versus-host disease in this patient.

T cell depletion with anti-cd5 immunotoxin in histocompatible bone marrow transplantation: The correlation between residual CD5 negative T cells and subsequent graft-versus-host disease

Twenty-nine patients with advanced leukemias (median age 34 years) received histocompatible sibling marrow that had been depleted of T cells by ex vivo incubation with anti-CD5 monoclonal antibody-ricin immunotoxin (T101-R) for the purpose of graft-versus-host disease prophylaxis. Donor cell engraftment was documented in 28/29 patients by DNA restriction fragment length polymorphisms. In this pilot study the dose of T101-R incubated with donor marrow was increased in a stepwise manner from 300 ng (10 patients) to 600 ng (5 patients) to 1000 ng immunotoxin (IT)/10(7) bone marrow mononuclear cells (14 patients) in an attempt to achieve more effective GvHD prophylaxis. A statistically significant reduction in acute GvHD was achieved for patients receiving marrow pretreated with 1000 ng of immunotoxin (34%) compared to recipients of BM treated with 300 ng immunotoxin (100%, P = 0.0004). T-depleted marrow samples were evaluated for residual T cell activity using several in vitro assays including proliferation to the purified mitogen PHA (HA-17) and in mixed lymphocyte culture (MLC), T cell cytotoxicity, a limiting dilution assay for detecting precursors of proliferating T cells (LDApPTL), and phenotypic analysis of viable T cells expanded in 16-day culture with interleukin 2. The extent of T cell depletion determined by LDA assay varied widely at each immunotoxin concentration used. Thus, there was no correlation between the dose of T cells infused and subsequent GvHD. Phenotyping of lymphocytes recovered from immunotoxin-treated marrow demonstrated that residual T cells were CD5 negative in all cases tested. The only in vitro parameter that predicted subsequent acute or chronic GvHD was the demonstration of viable CD5 negative lymphocytes with T cell phenotype (CD2, CD3, and/or CD7 positive) after 16-day culture with IL-2 of the T-depleted bone marrow. We observed that such CD5 negative cells expressing other T cell markers have cytotoxic function and speculate that these cells may be capable of mediating GvHD in allogeneic transplantation.

Graft-versus-leukemia is sufficient to induce remission in juvenile myelomonocytic leukemia

It has been unclear whether a graft-versus-leukemia (GVL) effect assists in the control of juvenile myelomonocytic leukemia (JMML) following allogeneic bone marrow transplant. We describe a patient with JMML who relapsed early after an unrelated donor transplant, and following withdrawal of immunosuppression developed graft-versus-host disease (GVHD). Associated with GVHD the proportion of donor cells measured by variable nucleotide tandem repeat (VNTR) analysis increased, and peripheral blasts and cutaneous disease were eliminated. These findings strongly suggest that GVL has a role in the control of JMML.

Allogeneic bone marrow transplantation with related donors other than HLA MLC-matched siblings, and the use of antithymocyte globulin, prednisone, and methotrexate for prophylaxis of graft-versus-host disease

Fifteen patients ranging in age from 1-29 years (median age 9 years) had bone marrow transplantations (BMT) from related donors other than HLA mixed lymphocyte culture (MLC) identical siblings. Donors were selected on the basis of HLA similarity and low reactivity in the MLC. Posttransplant immunosuppression consisting of methotrexate (MTX), antithymocyte globulin (ATG), and prednisone was used in an effort to decrease graft-versus-host disease (GVHD). Seven children were treated for aplastic anemia, 7 for hematologic malignancy, and 1 for osteopetrosis. Primary engraftment failure contributed to death in 3 patients, all of whom had aplastic anemia. Nine of 12 engrafted patients developed moderate-to-severe acute graft-versus-host disease. Of the 15 patients, 7 developed interstitial pneumonitis. Three patients demonstrated mixed chimerism (at or beyond 3 months posttransplant). Two of the seven patients treated for aplastic anemia are currently alive six months and more than five years posttransplant; the latter patient has chronic GVHD. Four of the seven patients treated for hematologic malignancy are currently alive more than 500 days posttransplantation. Three have chronic GVHD. Analysis of patient outcome according to the degree of similarity in histocompatibility testing revealed that patients with low reactivity in the MLC (less than 5% relative response in both directions) had a better prognosis (5/6, 83% long-term survival) than patients with maximum donor vs. recipient mixed lymphocyte culture relative response greater than 5% (1/9, 12% long-term survival), P = .016.