Suppression and recovery of immunologic function after bone marrow transplantation.

Infections are common causes of death in patients undergoing bone marrow transplantation for aplastic anemia or leukemia. A better understanding of the immunologic recovery following marrow grafting may lead to clinical trials of which the goals are to improve immunologic reactivity and to decrease infection.

Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia.

PURPOSE: This report describes results of related or unrelated hematopoietic stem-cell transplants in 111 patients with treatment-related leukemia or myelodysplasia performed consecutively at the Fred Hutchinson Cancer Research Center between December 1971 and June 1998, and identifies patient and treatment characteristics associated with survival and relapse. PATIENTS AND METHODS: At transplantation, 56 patients had treatment-related secondary acute myeloid leukemia (AML), 15 had refractory anemia with excess blasts in transition (RAEB-T), 23 had refractory anemia with excess blasts (RAEB), 15 had refractory anemia (RA), and two had refractory anemia with ringed sideroblasts (RARS). Conditioning regimens were total-body irradiation (TBI) and chemotherapy for 60 patients, busulfan (BU) 14 to 16 mg/kg and cyclophosphamide (CY) 120 mg/kg (BUCY) for 27 patients, BU targeted to 600 to 900 ng/mL plasma steady-state concentration with 120 mg/kg CY (BUCY-t) for 22 patients, and miscellaneous chemotherapy for two patients. The donors were HLA-identical or partially identical family members for 69 patients and unrelated donors for 42 patients. RESULTS: The 5-year disease-free survival was 8% for TBI, 19% for BUCY, and 30% for BUCY-t (P =.006). The 5-year cumulative incidence of relapse was 40% for secondary AML, 40% for RAEB-T, 26% for RAEB, and 0% for RA or RARS (P =.0009). The 5-year cumulative incidence of nonrelapse mortality after TBI was 58%; after BUCY, 52%; and after BUCY-t, 42% (P =.02). CONCLUSION: Patients at risk for treatment-related leukemia or myelodysplasia should be followed closely and be considered for stem-cell transplantation early in the course of myelodysplasia using conditioning regimens such as BUCY-t designed to reduce nonrelapse mortality.

Ovarian function following marrow transplantation for aplastic anemia or leukemia.

One hundred eighty-seven women between 13 and 49 years of age had ovarian function evaluated from 1 to 15 years (median, 4) after marrow transplant for aplastic anemia or leukemia. Among 43 women transplanted for aplastic anemia following 200 mg/kg cyclophosphamide (CY), all 27 less than 26 years of age, but only five of 16 greater than 26 years of age recovered normal ovarian function. Nine of the 43 have had 12 pregnancies, resulting in eight live births, and two elective and two spontaneous abortions. All eight children are normal. Nine of 144 women transplanted for leukemia following 120 mg/kg CY and 9.20 to 15.75 Gy total body irradiation (TBI) recovered ovarian function. Two of these nine have had three pregnancies, resulting in two spontaneous and one elective abortion. The probability of having ovarian failure was 0.35 by 7 years for patients receiving CY alone and was 1.00 at 1 year for patients receiving CY plus TBI (P less than .0001). By 7 years after transplant the probabilities of having normal ovarian function were 0.92 after CY alone and 0.24 after CY plus TBI (P less than .0001). Multivariate analysis showed that TBI was the only factor significantly influencing ovarian failure and that both TBI and greater patient age at transplant were significantly associated with a decreased probability of recovering normal ovarian function. These data demonstrate that after high-dose CY, recovery of ovarian function occurs in younger women and in a minority of older women, but after CY and TBI, recovery occurs in only a few younger women and none of the older women.

Autologous marrow transplantation for malignant lymphoma: a report of 101 cases from Seattle.

Between October 1979 and January 1988, 101 patients with malignant lymphoma who failed initial induction treatment or relapsed received high-dose combination chemotherapy or chemoradiotherapy followed by infusion of autologous bone marrow. Twenty-eight of the 101 patients survive, 18 of whom are disease-free for a median of 26 (range, 12 to 66) months. The 5-year actuarial probabilities of survival, event-free survival (EFS), and relapse from transplantation were 20%, 11%, and 84%, respectively. Multivariate analysis showed that the likelihood of EFS was decreased among patients transplanted with a Karnofsky score of less than 80%. Recurrent lymphoma after transplant was the most important cause of treatment failure with 36 of 62 relapses occurring within 100 days from marrow infusion. Early, but not late relapse, was more frequent in patients transplanted for advanced lymphoma, and both early and late relapses were increased among patients with impaired pretransplant clinical performance or high-grade histology of lymphoma. Ten patients who relapsed post-transplant are alive, seven in remission. Further improvement of these results will require earlier transplantation, improved preparative regimens, or early posttransplant therapy.

New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia.

PURPOSE: To determine the incidence of and risk factors for second malignancies after allogeneic bone marrow transplantation (BMT) for childhood leukemia. PATIENTS AND METHODS: We studied a cohort of 3, 182 children diagnosed with acute leukemia before the age of 17 years who received allogeneic BMT between 1964 and 1992 at 235 centers. Observed second cancers were compared with expected cancers in an age- and sex-matched general population. Risks factors were evaluated using Poisson regression. RESULTS: Twenty-five solid tumors and 20 posttransplant lymphoproliferative disorders (PTLDs) were observed compared with 1.0 case expected (P <.001). Cumulative risk of solid cancers increased sharply to 11.0% (95% confidence interval, 2.3% to 19.8%) at 15 years and was highest among children at ages younger than 5 years at transplantation. Thyroid and brain cancers (n = 14) accounted for most of the strong age trend; many of these patients received cranial irradiation before BMT. Multivariate analyses showed increased solid tumor risks associated with high-dose total-body irradiation (relative risk [RR] = 3.1) and younger age at transplantation (RR = 3.7), whereas chronic graft-versus-host disease was associated with a decreased risk (RR = 0.2). Risk factors for PTLD included chronic graft-versus-host disease (RR = 6.5), unrelated or HLA-disparate related donor (RR = 7. 5), T-cell-depleted graft (RR = 4.8), and antithymocyte globulin therapy (RR = 3.1). CONCLUSION: Long-term survivors of BMT for childhood leukemia have an increased risk of solid cancers and PTLDs, related to both transplant therapy and treatment given before BMT. Transplant recipients, especially those given radiation, should be monitored closely for second cancers.

Recurrence of acute leukemia more than two years after allogeneic marrow grafting.

The records of 232 patients with acute leukemia in continuous complete remission at two years after a marrow graft from genotypically or phenotypically HLA-identical family member were reviewed. With a followup time of 2-14.2 years, 17 patients have developed recurrent leukemia 2.0-6.3 years after grafting. No relapses have occurred beyond 6.3 years. Actuarial analysis shows a low but significant risk of recurrence of leukemia more than two years after grafting. These data suggest that the majority of the disease-free patients have had their original leukemic clone eliminated. It is important to study the leukemic cells in patients who suffer a relapse more than two years after grafting to determine whether the leukemia is of host or donor origin.

Marrow transplantation for treatment of pregnancy-associated aplastic anemia.

This report describes the results of marrow transplantation in four patients with aplastic anemia during the last trimester of their pregnancies. All patients were treated with supportive care until delivery. Because of persistent severe aplasia, marrow transplantation was then performed 1.6-11.0 months postpartum. Marrow donors were HLA-identical siblings. Although all were at increased risk for graft rejection because of their pregnancies as well as their long transfusion histories, two patients were successfully engrafted and now survive 12 and 95 months after transplant. The other two patients rejected their grafts despite attempts at second or third marrow infusions. Both died of infectious complications, 42 and 111 days after transplant.

Treatment of aplastic anemia with antithymocyte globulin, high-dose corticosteroids, and androgens.

A total of 46 patients with aplastic anemia (34 severe; 12 moderate) were treated with antihuman thymocyte globulin (ATG), high-dose methylprednisolone, and oxymetholone. Early symptoms of ATG toxicity included fever, rash, and bronchospasm. Signs of serum sickness also developed in 23 patients. Complications associated with high doses of steroids were hyperglycemia, hypertension, fluid retention, gastrointestinal hemorrhage, and aseptic necrosis of the hip. Other morbidity possible associated with steroid administration included seizures, arrhythmias, and headache with papilledema. Studies of elevated liver function necessitated discontinuation of androgen therapy in eight patients. A complete or partial hematological response was noted in 19 patients (41%). Of these, three have had recurrent cytopenias, of whom one has developed a myelodysplastic syndrome. There are currently 34 patients surviving, and 12 who have died. Actuarial survival at three years is 65%. These response and survival data are comparable to those of previous trials using ATG and androgens without high-dose steroids. A prospective, randomized trial is needed to determine whether the addition of high-dose corticosteroids to ATG does significantly increase the rate and frequency of response in order to justify the toxicity of this additional immunosuppressive therapy in the treatment of aplastic anemia.

Autologous marrow recovery and sensitization to non-HLA antigens after HLA-identical marrow transplantation for aplastic anemia.

One hundred seventy-five patients with severe aplastic anemia were treated by high-dose cyclophosphamide and HLA-A, -B, and -D-identical sibling marrow transplants. Thirty-eight patients rejected their grafts. Four of the 38 showed autologous marrow recovery as determined by blood genetic markers. The remarkable feature of one case following autologous marrow recovery was the presence of unidirectional proliferative and cytotoxic responses of circulating host lymphocytes to marrow donor lymphocytes in mixed lymphocyte culture and cell-mediated lympholysis. Presumably these responses were the result of in vivo sensitization to those non-HLA antigens for which donor and recipient differed.

Recovery from aplastic anemia following attempted marrow transplantation.

A 23-year-old man with severe idiopathic aplastic anemia was prepared for marrow transplantation by the administration of cyclophosphamide (CY) 50 mg/kg on each of 4 days. He then received an intravenous infusion of 9.5 x 10(9) marrow cells from an HL-A matched and mixed leukocyte culture non-reactive sister. The graft was successfully established as shown by cytogenetic studies but was rejected after approximately 4 weeks. In preparation for a second transplant he was given procarbazine 12.5 mg/kg and goat antihuman thymocyte globulin (ATG) 7 mg/kg administered on alternate days for a total of 4 doses of each agent. At the end of this therapy his white blood cell count was noted to be going up and the second transplant was not carried out. Complete hematologic recovery of host type marrow ensued and persists now 20 months later. The various pathophysiologic mechanisms that may be involved are discussed.

An unusual case of a brain abscess arising from an odontogenic infection.

A brain abscess that originates from an odontogenic infection, although rare, can at times be difficult to diagnose, especially in the context of pain and trismus. We report a rare case of odontogenic infection as a result of an infected maxillary third molar, causing an infratemporal and temporalis collection, resulting in a brain abscess with concurrent cerebritis. This is a clinical case review documenting an uncommon but potentially fatal complication.

Myasthenia gravis after allogeneic bone marrow transplantation: relationship to chronic graft-versus-host disease.

Three patients with chronic graft-versus-host disease (GVHD) developed myasthenia gravis (MG) 762 to 1,180 days after allogeneic bone marrow transplantation. Symptoms of MG were observed after taper or discontinuation of immunosuppressive treatment of chronic GVHD. All patients developed antibodies to acetylcholine receptor, and one had antibody formation to striated muscle. One patient died of complications of treatment of MG. The severity of disease underscores the importance of the differential diagnosis and the need for prompt therapy of this late complication after human bone marrow transplantation.

Treatment of acute graft-versus-host disease after allogeneic marrow transplantation. Randomized study comparing corticosteroids and cyclosporine.

Seventy-seven patients (age 12 to 46 years) who underwent allogeneic marrow transplantation for hematologic malignancy or aplastic anemia and who had grade II to IV acute graft-versus-host disease despite methotrexate prophylaxis were randomly assigned to receive methylprednisolone 2 mg/kg per day intravenously (n = 39) or cyclosporine (n = 38) either 12 to 15 mg/kg per day orally or 3 to 5 mg/kg per day intravenously. In both groups, clinical and histologic evidence of graft-versus-host disease was detected at medians of 16 and 25 days, respectively. Drugs were given for a minimum of 14 days unless significant deterioration occurred. If graft-versus-host disease did not improve with this therapy, treatment with a second agent was initiated. Treatment responses were scored after reviewing clinical and laboratory data collected before, during, and after the 14-day treatment period. Possible scores were as follows: -1, worse; 0, no change; + 1, improvement in one organ system (skin, liver, gut) with no deterioration in the other two; +2, complete resolution of all involved systems. The median response score among 39 methylprednisolone-treated patients was 0. Sixteen patients (41 percent) showed response to treatment, 11 with partial and five with complete response. The median response score among 38 cyclosporine-treated patients was +1. Twenty-three patients (61 percent) showed response to treatment, 15 with partial and eight with complete response (p = 0.039). Twenty patients receiving methylprednisolone and 18 receiving cyclosporine required additional therapy. The incidence of chronic graft-versus-host disease was similar in both groups. It developed in all nonresponding patients at risk who had received secondary therapy. Among responding patients (scores +1 or +2) who were not given additional treatment, chronic graft-versus-host disease developed in eight of 11 (72 percent) receiving methylprednisolone and five of ten (50 percent) receiving cyclosporine. Survival beyond 17 months was similar in the two groups (28 percent and 24 percent, respectively). These data suggest that cyclosporine is a useful agent for the treatment of acute graft-versus-host disease, comparable in its efficacy to methylprednisolone.

Cataracts after total body irradiation and marrow transplantation: a sparing effect of dose fractionation.

We examined 277 patients, who have been followed for 1 to 12 years after marrow transplantation, for cataract development. In preparation for transplantation, 96 patients with aplastic anemia were conditioned with chemotherapy only, usually cyclophosphamide 50 mg/kg X 4 intravenously, while 181 patients (two with aplastic anemia and 179 with a hematologic malignancy) were conditioned with a regimen of total body irradiation (TBI) and chemotherapy. TBI was delivered from two opposing 60Co sources at an exposure rate of 4 to 8 cGy/min, either as a single dose of 10 Gy (105 patients) or in fractions (76 patients), usually at increments of 2 to 2.25 Gy/day for 6 to 7 days for cumulative doses of 12 to 15.75 Gy. To date, 86 patients have developed cataracts. Kaplan-Meier product limit estimates of the incidence of cataracts for patients given chemotherapy only and no TBI, single-dose TBI, and fractionated TBI are 19, 80, and 18%, respectively. On the basis of proportional hazards regression analyses, patients given single-dose TBI had a relative risk of developing cataracts that was 4.7-fold higher than in patients given fractionated TBI or chemotherapy only (p less than 0.00005), suggesting a significant sparing effect with use of TBI dose fractionation. Addition significant risk factors included the chronic use of steroids posttransplant (highly associated with the presence of chronic graft-versus-host disease), and the diagnoses of acute lymphoblastic or chronic myelogenous leukemia.

Cataracts after bone marrow transplantation: long-term follow-up of adults treated with fractionated total body irradiation.

PURPOSE: To determine the risk of, and risk factors for, developing cataracts after bone marrow transplantation. METHODS AND MATERIALS: Four hundred and ninety-two adults who underwent bone marrow transplantation in Seattle were followed for 2 to 18 (median, 6) years. Before transplantation, patients received a preparative regimen of chemotherapy plus total body irradiation (TBI) (n = 407) or chemotherapy alone, without TBI (n = 85). TBI was administered in a single dose of 10 Gy (n = 74) or in fractionated doses totaling 12-15.75 Gy (n = 333). The risk of cataracts was determined for groups of patients with respect to the type of preparative regimen received and other pretransplant and posttransplant variables. RESULTS: One hundred and fifty-nine patients (32%) developed cataracts between 0.5 to 11 (median, 2.3) years after transplantation. The probability of cataracts at 11 years after transplantation was 85%, 50%, 34%, and 19% for patients receiving 10 Gy of single-dose TBI, > 12 Gy fractionated TBI, 12 Gy fractionated TBI, and no TBI, respectively (p < 0.0001). Among those developing cataracts, the severity was greater in patients after single-dose TBI (59% probability of surgical extraction) than after > 12 Gy fractionated TBI, 12 Gy fractionated TBI, or no TBI (33%, 22% and 23%, respectively). Patients given corticosteroids after transplant had a higher probability of cataracts (45%) than those without steroids (38%) (p < 0.0001). In a proportional hazards regression model, the variables that were correlated with an increased probability of cataracts were single-dose TBI (relative risk (RR) = 2.46) and steroid therapy (RR = 2.34), while a decreased probability of cataracts was correlated with a nonTBI preparative regimen (RR = 0.41). The yearly hazard of developing cataracts in recipients of single-dose TBI was highest during the third year after transplantation, while in recipients of fractionated TBI, the hazard was distributed among years one through seven. The probability of cataracts in all groups reached a plateau at 7 years after transplantation, after which the development of cataracts was extremely unlikely. CONCLUSION: TBI is the major risk factor for developing cataracts after BMT. Single-dose TBI results in the highest risk of cataracts. However, the risk of cataracts in recipients of fractionated-TBI is significantly higher than in patients who receive no TBI. In addition to TBI, steroid therapy is an independent risk factor for cataracts after BMT.

Marrow transplantation following escalating doses of fractionated total body irradiation and cyclophosphamide--a phase I trial.

Thirty-six patients with advanced hematologic malignancy were entered into a Phase I study designed to define the maximum tolerated dose of unshielded total body irradiation delivered from dual 60 Cobalt sources at an exposure rate of 8 cGy/min and given in fractions twice daily for total doses ranging from 12 Gy to 17 Gy. All patients received cyclophosphamide, 120 mg/kg administered over 2 days before total body irradiation. Allogeneic marrow was infused from HLA-identical siblings (n = 29) or one locus HLA incompatible family members (n = 3); three patients received cryopreserved autologous marrow and one patient received syngeneic marrow. The maximum tolerated dose of total body irradiation given as 2 Gy fractions twice a day was 16 Gy. One of eight patients receiving 12 Gy, none of four receiving 14 Gy, three of 20 receiving 16 Gy, and two of four receiving 17 Gy developed severe (Grade 3-4) regimen-related toxicity. The primary dose limiting toxicity was pneumonitis, followed by veno-occlusive disease of the liver, renal impairment, and mucositis. Five patients (14%) are alive, four disease-free 798-1522 days posttransplant. Twenty (56%) relapsed posttransplant. Further investigation of regimens containing 16 Gy of hyperfractionated total body irradiation is warranted to assess anti-tumor efficacy.

Antigen-specific antibody responses of lymphocytes to tetanus toxoid after human marrow transplantation.

In vitro IgG anti-tetanus toxoid (IgG anti-TT) antibody produced by peripheral blood lymphocytes (PBL) from 16 normal subjects (9 marrow donors and 7 random healthy subjects) and 17 marrow graft recipients from 45-1058 days postgrafting was measured with an enzyme-linked immunosorbent assay (ELISA). PBL from 11 of 13 seropositive (anti-TT greater than or equal to 1:1024) normal subjects produced IgG anti-TT in vitro, whereas the PBL from the 3 seronegative (IgG anti-TT less than 1:1024) normal subjects did not. In our normal subjects, there was a high correlation between seropositivity and in vitro IgG anti-TT production (P = .0048, chi 2, two-tailed). PBL from only one of 13 seropositive marrow graft recipients produced in vitro IgG anti-TT antibody. B and T cell functions of 8 marrow graft recipients were assessed by coculturing their T and B cells with those from their HLA-identical marrow donors. One short-term patient and 7 long-term patients (4 with and 3 without chronic graft-versus-host disease) were studied. Recipient B cells failed to produce antibody in the presence of donor T cells in 7 of these 8 cases. However, T cells from long-term survivors provided helper activity to immune donor B cells in 7 of 9 evaluable cases. TT-specific helper T cell activity was present in most seropositive long-term recipients, and B cells from marrow recipients failed to produce specific antibody in the presence of normal donor TT-specific helper T cells. These results, TT-specific T cell helper activity, and normal circulating serum IgG anti-TT antibody levels in marrow graft recipients without postgrafting TT boosters suggest that specific immunity had been transferred from the marrow donor to the marrow recipient.

Regulation of immunoglobulin production after human marrow grafting. The role of helper and suppressor T cells in acute graft-versus-host disease.

The effect of acute graft-versus host disease (GVHD) on T4 and T8 lymphocyte regulation of in vitro immunoglobulin production was explored. The peripheral blood lymphocytes from 20 patients were studied sequentially in the first 100 days after sibling bone marrow grafting for hematologic malignancy or aplastic anemia. T and non-T lymphocytes were prepared from peripheral blood by Ficoll-Hypaque density gradient centrifugation and sheep erythrocyte rosetting. T cells were enriched for T4 or T8 cells and cocultured for six days with pokeweed mitogen and autologous non-T or T and non-T cells from unrelated normal individuals. Immunoglobulin production was assessed using a reverse hemolytic plaque assay. All three patients without acute GVHD had failure of non-T cells to secrete immunoglobulin, one had failure of helper T cell activity, and 2 developed suppressor T cells. Similarly, all six patients studied sequentially after the development of GVHD had non-T-cell failure, five developed helper T cell failure, and five had suppressor T cells. These data suggest no difference in lymphocyte function before or after the development of acute GVHD. When the T cells of these patients were split into T4 and T8 subpopulations and studied for immunoglobulin production there was helper T cell failure in 4 of 9 tests with enriched T4 populations. Five of 9 tests with T8 enriched populations showed suppressor activity. Suppressor T cell function was also seen in 4 of 9 tests with with T4-enriched populations. These data show that T cell function does not necessarily correlate with the surface phenotype during the first 100 days after grafting. A role for cytomegalovirus (CMV) infection in bringing out suppressor activity is suggested, because among patients without GVHD, 6 of 8 tests in CMV-positive patients showed suppressor cells compared with none of 4 tests in patients without CMV infection.

Association of interstitial pneumonia and diminished in vitro lymphocyte blastogenesis in human marrow graft recipients.

The lymphocyte responses of 51 human marrow graft recipients were tested in vitro 18 to 45 days after marrow grafting by stimulation with lymphocytes from unrelated individuals or phytohemagglutinin (PHA). Fourteen of the 51 patients subsequently developed interstitial pneumonia (IP). The relative responses of the lymphocytes of patients who developed IP were significantly lower than those of individuals not developing IP (P less than 0.01 for allogeneic cells, P = 0.02 for PHA). These nonspecific in vitro tests of cell-mediated immunity are of value in identifying patients at risk of developing IP.

Immunoglobulin production of donor origin after marrow transplantation for acute leukemia or aplastic anemia.

Four patients with acute leukemia and one with aplastic anemia were not transfused within 90 days before marrow transplantation from the HLA-identical sibling. When studied 4 to 12 1/2 months after transplantation their immunoglobulin allotypes were those of their donors.