Bone marrow transplantation for patients with myelodysplasia. Pretreatment variables and outcome.

STUDY OBJECTIVE: To determine the efficacy of allogeneic bone marrow transplantation for severe myelodysplasia, and to identify variables predictive of outcome. DESIGN: Case series study. SETTING: A referral-based bone marrow transplant center. PATIENTS: Consecutive series of 59 patients with myelodysplasia or closely related disorders and either life-threatening cytopenia or a progressive increase in marrow blast percentage. INTERVENTION: Patients were treated with high-dose cyclophosphamide and total body irradiation followed by allogeneic bone marrow transplantation from either an HLA-identical (n = 45) or HLA-partially matched (n = 14) donor. MEASUREMENTS AND MAIN RESULTS: The product-limit estimate for disease-free survival 3 years after transplant is 45% (95% CI, 32% to 59%). The commonest causes of death after transplant were disease recurrence, interstitial pneumonia, and graft-versus-host disease, accounting for eight deaths each. In a univariate analysis, younger patients, those with shorter disease duration, and those whose disease was characterized by an abnormal cytogenetic karyotype had better survival and disease-free survival than the group as a whole. In a multivariate analysis, younger age and abnormal karyotype were independent predictors of improved disease-free survival and overall survival. Patients who received transplants when they had fewer blasts in their bone marrow had a decreased chance for disease recurrence when compared with patients with excess blasts. CONCLUSIONS: Bone marrow transplantation offers a potential cure for many patients with myelodysplasia. Best results can be expected in younger patients who receive transplants relatively early in their disease course.

Host metaphases after chemoradiotherapy and allogeneic bone marrow transplantation for acute nonlymphoblastic leukemia.

The post-transplant cytogenetic data were reviewed for 191 recipients of sex-mismatched marrow after conditioning with chemoradiotherapy as treatment for acute nonlymphoblastic leukemia. Host metaphases were detected transiently in unstimulated marrow from 12/184 patients and in PHA-stimulated peripheral blood from 18/140 patients during the first 100 days after transplantation. Of the 14 patients with HM who survived more than 150 days, five have relapsed, and nine are alive and in remission 509-1783 days after detection of HM. There was no significant correlation between transient detection of HM and pretransplant remission status, HLA matching, radiation regimen or graft-vs-host disease. We conclude that transient detection of HM by conventional cytogenetics is not related to any single peritransplant parameter and does not predict relapse.

Clonal cytogenetic abnormalities in patients with otherwise typical aplastic anemia.

Between June 1981 and August 1986, 183 patients with the referring diagnosis of aplastic anemia were evaluated with cytogenetic studies and marrow biopsies. Seven patients (4%) on biopsy were found to have myelodysplasia. Seven of the 176 patients (4%) with marrow biopsies that confirmed the pathologic diagnosis of severe aplastic anemia were found to have clonal cytogenetic abnormalities in unstimulated marrow samples. Among the 169 patients with typical aplastic anemia and no cytogenetic abnormalities, 5 (3%) subsequently developed either myelodysplasia or leukemia. Two of three patients with pathologically confirmed aplastic anemia and clonal cytogenetic abnormalities, who were not transplanted, developed myelodysplasia. These results demonstrate that approximately 4% of patients with aplastic anemia have clonal cytogenetic abnormalities of marrow cells, and that while all patients with aplastic anemia may have some risk of developing leukemia, those with a cytogenetic abnormality have an especially high risk.

Treatment of preleukemic syndromes with marrow transplantation.

Thirty patients with advanced preleukemic syndromes were treated with marrow transplantation. Most cases were diagnosed by the presence of peripheral pancytopenia and a diagnostic marrow examination but in 6 of the 30 patients pretransplant chromosome studies were instrumental in establishing the diagnosis. Three patients prepared for transplantation with cyclophosphamide alone recurred with their disease within 6 months of transplantation. The other 27 patients were treated with cyclophosphamide and total body irradiation. Twenty of these 27 patients had preleukemia not associated with prior therapy or severe marrow fibrosis. Thirteen of these 20 are alive and well 9 to 56 months from transplant and 7 died, 4 of interstitial pneumonia, 2 of candida septicemia, and 1 of disseminated zoster. There have been no disease recurrences in this group. The remaining preleukemic patients, which include 3 patients transplanted for preleukemia secondary to prior therapy and 4 patients transplanted for preleukemia associated with severe marrow fibrosis, have all died. Major problems in these patients included disease recurrence (2 cases) and, in those with severe marrow fibrosis, graft failure (2 cases). These results suggest that for patients with life-threatening pancytopenia due to spontaneous preleukemia without severe marrow fibrosis, marrow transplantation can prolong disease-free survival and may result in cure of the disease.

Mixed hematologic chimerism after allogeneic marrow transplantation for severe aplastic anemia is associated with a higher risk of graft rejection and a lessened incidence of acute graft-versus-host disease.

Ninety-six patients with severe aplastic anemia who received a sex-mismatched, HLA-identical allogeneic sibling marrow transplant had sequential cytogenetic analyses performed to determine the incidence and implications of posttransplant mixed hematologic chimerism. Of the 96 patients, 56 (58.3%) became mixed chimeras with coexisting host and donor cells detected in peripheral blood or marrow 14 days or later after transplant, and 40 patients (41.7%) were complete chimeras with 100% donor-type hematopoietic cells. The incidence of mixed chimerism was independent of prior blood production transfusions and infusion of donor buffy coat. The rejection rate was significantly increased in the mixed chimeric group, particularly in patients not receiving buffy coat (14 of 36 rejecting), although overall, the majority (69.7%) retained their first graft. Rejection was seen almost exclusively in patients exposed to multiple transfusions before transplantation. If patients who reject their first graft are censored, the overall incidence of grades II through IV acute graft-v-host disease (GVHD) was significantly reduced in those with mixed chimerism. Transfused patients with mixed chimerism in particular were less likely to develop grades II through IV acute GVHD. The incidence of chronic GVHD was similar in the two groups and did not significantly influence survival. In this study, mixed chimerism persisted for up to 395 days posttransplant, either the first graft being rejected or, more commonly, hematopoiesis reverting to 100% donor-type cells. Mixed lymphohematopoietic chimerism may persist in patients with aplastic anemia who have received matched allogeneic marrow transplants for significant periods before hematopoiesis reverts to donor cell type.

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.

Cellular interactions in marrow-grafted patients. II. Normal monocyte antigen-presenting and defective T-cell-proliferative functions early after grafting and during chronic graft-versus-host disease.

The proliferation of T cells of marrow donor origin in response to Escherichia coli, an ubiquitous antigen, presented by circulating monocytes of marrow donor origin was investigated in 30 human allogeneic marrow transplant recipients. Compared with cells from healthy marrow donors, T cell proliferation was found to be deficient in all recipients studied 36-71 days after grafting, regardless of the presence or absence of acute graft-versus-host disease and in most patients with chronic graft-versus-host disease studied 118-1804 days postgrafting . In contrast, lymphocytes from most long-term patients without chronic graft-versus-host disease studied 363-2673 days had immune reactivity comparable to that of lymphocytes from their marrow donors. Results of cell-mixing experiments showed that (1) monocytes from most marrow recipients were capable of presenting antigens to normal T cells of marrow donors, and (2) T cells from short-term patients and from long-term patients with active chronic graft-versus-host disease were not induced to proliferate by E-coli-pulsed monocytes from the marrow donors. This inability of T cells to proliferate was likely the result of ineffective interactions among T cell subsets.

Allogeneic marrow transplantation in the treatment of preleukemia.

Ten patients with preleukemia and life-threatening pancytopenia were treated with marrow transplantation. In all ten cases allogeneic marrow was successfully engrafted. In three patients prepared for transplantation with cyclophosphamide alone, the abnormal cell clone either persisted or reemerged within 6 months of transplantation. The other seven patients were treated with cyclophosphamide plus total body irradiation before transplantation and six of the seven are alive and well without evidence of disease from 7 to 25 months after transplantation. These results suggest that cyclophosphamide alone before marrow transplantation is incapable of eradicating the abnormal clone. Cyclophosphamide combined with total body irradiation appears more effective, although more time is needed for full evaluation of results. This experience also emphasizes the importance of performing chromosome studies before transplantation for pancytopenic states in order to identify cases of preleukemia.

Long-term stable hematopoietic chimerism following marrow transplantation for acute lymphoblastic leukemia: a case report with in vitro marrow culture studies.

This article describes the course of a patient who received an allogeneic marrow graft from his HLA-identical sister for acute lymphoblastic leukemia in second remission. In the second month after grafting, marrow aspirates showed the presence of 7%-10% lymphoblasts. In addition, cytogenetic examination indicated the persistence of host cells. Thereafter, the patient had morphologically normal marrow examinations, with no evidence for recurrent leukemia. In addition, stable hematopoietic chimerism in both the lymphoid and myeloid cell lines has persisted for over 5 yr. Between 20% and 50% of phytohemagglutinin-stimulated peripheral blood mononuclear cells were host-derived on repeated studies. A marrow sample 4 yr after transplantation was established in long-term culture and produced 2% host granulocyte-macrophage colonies at its inception, but 24% host colonies by week 4. Despite this persistent chimerism, no in vitro or in vivo abnormalities of hematopoiesis have been detected.

Treatment of chronic granulocytic leukemia with chemoradiotherapy and transplantation of marrow from identical twins.

Twelve patients in the chronic phase of Ph1 (Philadelphia)-positive chronic granulocytic leukemia (CGL) received chemoradiotherapy and marrow from their normal, identical twins. All had a complete remission, with disappearance of all Ph1-positive cells. One patient died of pneumonitis while in remission. Three had a cytogenetic relapse 22 to 30 months after grafting; only one of these three entered blast crisis and died. Eight remain in complete remission 21 to 65 months (median, 30) after transplantation. Thus, the Ph1-positive clone can be ablated and blast crisis delayed or prevented. Of 10 patients with CGL who received transplants during the terminal phase, eight died soon after, one is in complete remission 11 months after receiving a second graft, and one remains in complete remission 71 months after transplantation. This experience suggests to us that every patient with CGL and an identical twin should receive a marrow graft, preferably in the chronic phase. On the basis of our results, trials of allogeneic-marrow transplantation for CGL seem justified.

The incidence of recurrence of leukemia in donor cells after allogeneic bone marrow transplantation.

A total of 243 patients with acute leukemia received a marrow graft from a donor of the opposite sex. Seventy-five patients subsequently relapsed, and specimens of the recurrent leukemia cells were available for cytogenetic analysis in 54. Three relapses were in donor-type cells. Four patients whose relapses were in host-type cells showed a cytogenic abnormality that differed from the original leukemic clone. We conclude that a 'new' leukemia in donor cells, and possibly in host cells, constitutes a small but significant fraction of recurrent leukemia after marrow grafting.

Disappearance of Ph1-positive cells in four patients with chronic granulocytic leukemia after chemotherapy, irradiation and marrow transplantation from an identical twin.

Four patients (21, 41, 13 and 38 years of age) with a history of chronic granulocytic leukemia for 12, 10, 11, and 106 months, respectively, were treated with dimethyl busulfan, cyclophosphamide, 920 rads of total-body irradiation and intravenous marrow infusion from normal, genetically identical twins. Serial chromosome analyses were performed on marrow aspirates cultured without mitotic stimulants. No Ph1-positive cells were detected in the marrows from the normal twins, whereas just before therapy, all 100 metaphases examined from each patient were Ph1-positive. Chromosome analyses were performed three to five times per patient after transplantation, and not a single Ph1-positive cell was detected. The patients remain hematologically normal 22, 23, 26 and 31 months after transplantation. The results show that the Ph1-positive clone can be eradicated by vigorous therapy and that the marrow in chronic granulocytic leukemia can be repopulated by stem cells from normal twins.

Treatment of chronic granulocytic leukemia by chemotherapy, total body irradiation and allogeneic bone marrow transplantation.

Fourteen patients with chronic granulocytic leukemia received bone marrow grafts from HLA identical siblings. Ten patients were in blast crisis prior to grafting, three were in an accelerated phase of their disease, and one was aplastic secondary to chemotherapy. Prior to transplant all patients were conditioned with chemotherapy including cyclophosphamide plus 1,000 rad of total body irradiation. Ten patients achieved engraftment while four died 1 to 26 days after marrow infusion without functioning grafts. Two patients received a second infusion of donor marrow because of delayed engraftment. Neither marrow cell dose nor presence of myelofibrosis correlated with successful engraftment. Three out of ten engrafted patients developed graft-versus-host disease. Interstitial pneumonia occurred in seven patients. The immediate cause of death was bacterial septicemia in six patients. All evidence of leukemia disappeared in nine out of ten evaluable patients. The median survival was 43 days. One patient had a complete remission of 16 months duration.

Direct evidence for a bone marrow origin of the alveolar macrophage in man.

Alveolar macrophages were obtained from 23 patients who had received marrow transplants for hematologic disorders. The presence of a Y body in macrophages of male origin was demonstrated by fluorescence microscopy. In those patients with a marrow donor of opposite sex the alveolar macrophages were shown to be of donor origin. The disappearance with time of host macrophages indicates a life-span, under the conditions, of approximately 81 days.