Philip B. McGlave

Analysis of 462 Transplantations from Unrelated Donors Facilitated by the National Marrow Donor Program

BACKGROUND AND METHODS Allogeneic bone marrow transplantation is curative in a substantial number of patients with hematologic cancers, marrow-failure disorders, immunodeficiency syndromes, and certain metabolic diseases. Unfortunately, only 25 to 30 percent of potential recipients have HLA-identical siblings who can act as donors. In 1986 the National Marrow Donor Program was created in the United States to facilitate the finding and procurement of suitable marrow from unrelated donors for patients lacking related donors. RESULTS During the first four years of the program, 462 patients with acquired and congenital lymphohematopoietic disorders or metabolic diseases received marrow transplants from unrelated donors. The probability of engraftment by 100 days after transplantation was 94 percent, although 8 percent of patients later had secondary graft failure. The probability of grade II, III, or IV acute graft-versus-host disease was 64 percent, and the probability of chronic graft-versus-host disease at one year was 55 percent. The rate of disease-free survival at two years among patients with leukemia and good prognostic factors was 40 percent and among patients at higher risk, 19 percent. Twenty-nine percent of the patients with aplastic anemia were alive at two years, and the rate of two-year disease-free survival among patients with myelodysplasia was 18 percent. For patients with congenital immunologic or nonimmunologic disorders, the probability of survival was 52 percent. CONCLUSIONS The National Marrow Donor Program has benefited a substantial number of patients in need of marrow transplants from closely HLA-matched unrelated donors and has facilitated the recruitment of unrelated donors into the donor pool and the access to suitable marrow.

Relapse risk after umbilical cord blood transplantation: enhanced graft-versus-leukemia effect in recipients of 2 units

Umbilical cord blood (UCB) transplantation is potentially curative for acute leukemia. This analysis was performed to identify risk factors associated with leukemia relapse following myeloablative UCB transplantation. Acute leukemia patients (n = 177; 88 with acute lymphoblastic leukemia and 89 with acute myeloid leukemia) were treated at a single center. Patients received a UCB graft composed of either 1 (47%) or 2 (53%) partially human leukocyte antigen (HLA)-matched unit(s). Conditioning was with cyclophosphamide and total body irradiation with or without fludarabine. The incidence of relapse was 26% (95% confidence interval [CI], 19%-33%). In multivariate analysis, relapse was higher in advanced disease patients (> or = third complete remission [CR3]; relative risk [RR], 3.6; P < .01), with a trend toward less relapse in recipients of 2 UCB units (RR = 0.6; P = .07). However, relapse was lower for CR1-2 patients who received 2 UCB units (RR 0.5; P < .03). Leukemia-free survival was 40% (95% CI, 30%-51%) and 51% (95% CI, 41%-62%) for single- and double-unit recipients, respectively (P = .35). Although it is known that transplantation in CR1 and CR2 is associated with less relapse risk, this analysis reveals an enhanced graft-versus-leukemia effect in acute leukemia patients after transplantation with 2 partially HLA-matched UCB units. This trial was registered at http://clinicaltrials.gov as NCT00309842.

Risk Factors For Acute Graft-versus-host Disease In Histocompatible Donor Bone Marrow Transplantation

We have analyzed factors associated with acute graft-versus-host disease following allogeneic bone marrow transplantation in 469 patients with histocompatible sibling donors between 1979 and 1987. Overall, 46±5% (95% confidence interval) developed clinical grade II-IV acute GVHD following transplantation. In univariate analysis, patient or donor age ≥18 years was significantly associated with increased GVHD risks (≥18, 63± 6% grade II-IV GVHD vs. <18,27±6%, P<.0001), without incremental risk in older adults. Univariate analysis showed that donor:recipient sex match and female: female transplants were associated with less-frequent GVHD. More frequent GVHD was associated with chronic myelogenous leukemia, cytomegalovirus seropositivity, and prior donor alloimmunity (pregnancy or transfusion). Additionally, the allele HLA-A26 was associated with increased risk of GVHD (72%, P=.005) while HLA-DR3 was associated with less GVHD (31%, P=.03). Stepwise multivariate analysis confirmed the increased GVHD risks associated with older recipient age, HLA-A26 and donor:recipient gender (not female: female) and the protective effect of HLA-DR3. Similar results were found using the different analytic technique of recursive partition analysis, which identified within the adult population the lowest GVHD risk in female recipients with nonalloimmunized female donors (20%), while other gender combinations had 68% acute GVHD, regardless of donor alloimmunity. In children (<18 years), lower GVHD risk accompanied donor:recipient sex-matched (18%) versus mismatched (33%) BMT. Clinical trials undertaken to lessen the hazards of GVHD must be designed with appropriate attention to these reproducibly identified clinical variables associated with different GVHD risks.

A Randomized Study of the Prevention of Acute Graft-versus-Host Disease

Acute graft-versus-host disease is a major problem in allogeneic bone-marrow transplantation. We performed a randomized study to compare the effectiveness of two regimens in the prevention of acute graft-versus-host disease. Thirty-five patients received methotrexate alone, and 32 received methotrexate, antithymocyte globulin, and prednisone. Of the patients who received methotrexate alone, 48 per cent had acute graft-versus-host disease, as compared with 21 per cent of those who received methotrexate, antithymocyte globulin, and prednisone (P = 0.01). The age of the recipient was a significant factor in the development of acute graft-versus-host disease: Older patients had a higher incidence of the disease (P = 0.001). We conclude that the combination of methotrexate, antithymocyte globulin, and prednisone significantly decreased the incidence of acute graft-versus-host disease and should be used to prevent this disorder in patients receiving allogeneic marrow transplants.

Mechanisms underlying abnormal trafficking of malignant progenitors in chronic myelogenous leukemia. Decreased adhesion to stroma and fibronectin but increased adhesion to the basement membrane components laminin and collagen type IV.

We studied the adhesion of primitive and committed progenitors from chronic myelogenous leukemia (CML) and normal bone marrow to stroma and to several extracellular matrix components. In contrast to benign primitive progenitors from CML or normal bone marrow, Ph1-positive primitive progenitors from CML bone marrow fail to adhere to normal stromal layers and to fibronectin and its proteolytic fragments, but do adhere to collagen type IV, an extracellular matrix component of basement membranes. Similarly, multilineage colony-forming unit (CFU-MIX) progenitors from CML bone marrow do not adhere to fibronectin or its adhesion promoting fragments but adhere to collagen type IV. Unlike committed progenitors from normal bone marrow, CML single-lineage burst-forming units-erythroid and granulocyte/macrophage colony-forming units fail to adhere to fibronectin or its components but do adhere to both collagen type IV and laminin. Evaluation of adhesion receptor expression demonstrates that fibronectin receptors (alpha 4, alpha 5, and beta 1) are equally present on progenitors from normal and CML bone marrow. However, a fraction of CML progenitors express alpha 2 and alpha 6 receptors, associated with laminin and collagens, whereas these receptors are absent from normal progenitors. These observations indicate that the premature release of malignant Ph1-positive progenitors into the circulation may be caused by loss of adhesive interactions with stroma and/or fibronectin and acquisition of adhesive interactions with basement membrane components. Further study of the altered function of cell-surface adhesion receptors characteristic of the malignant clone in CML may lead to a better understanding of the mechanisms underlying both abnormal expansion and abnormal circulation of malignant progenitors in CML.

Respiratory syncytial virus-Induced acute lung injury in adult patients with bone marrow transplants: A clinical approach and review of the literature

Acute lung injury induced by respiratory syncytial virus (RSV) is a major cause of morbidity and mortality in patients who have undergone bone marrow transplantation. Twenty-nine of the 74 patients who received bone marrow transplants at the University of Minnesota during a 1-year period developed evidence of acute lung injury, and RSV was identified as the cause in 8. We discuss the clinical course of these 8 patients and offer a clinical approach to RSV infection occurring after bone marrow transplantation. We also review the immune response to infection with RSV and relate this information to the nature and degree of immunosuppression present in patients undergoing this type of transplantation. We found bronchoalveolar lavage with rapid antigen detection to be particularly useful for the prompt diagnosis of this serious infection. The virus was obtained from the lower respiratory tract of each patient and was identified in lavage effluent by culture and by antigen detection (ELISA). The mean time to a positive culture was 6 days, while detection of antigens of respiratory syncytial virus by ELISA was completed within 18 hours in all cases. The clinical progression of the illness in immunocompromised patients appears to be the same as in non-immunocompromised persons: upper respiratory tract infection and illness precede lower respiratory tract infection and acute lung injury. Seven of our 8 patients had upper respiratory tract symptoms or abnormal sinus radiographs, and upper respiratory specimens (cultures and ELISA from nasopharynx, throat, and sputum) were positive in 5 of 8 patients. Six patients developed RSV-induced lung injury before marrow engraftment; 4 of them had respiratory failure requiring mechanical ventilation and died, including 3 in whom RSV was eliminated from the lower respiratory tract following treatment with ribavirin aerosol. Two additional pre-engraftment patients had only relatively mild lung injury 4 days after beginning treatment with ribavirin for RSV infection in the upper respiratory tract. Their recovery suggests that early treatment may ameliorate RSV-induced lung injury. The remaining 2 patients developed lung injury after marrow engraftment. Both of these patients had clear chest radiographs, responded clinically to ribavirin, and survived. RSV is a potentially treatable cause of life-threatening lung injury, if the physician is aggressive in identifying the virus in the upper respiratory tract before evidence of lung injury appears. Rapid detection methods are essential when bone marrow transplant patients have fever along with signs, symptoms, or radiographic indications of nasal or sinus disorders.(ABSTRACT TRUNCATED AT 400 WORDS)

ALLOGENEIC BONE-MARROW TRANSPLANTATION FOR CHRONIC MYELOGENOUS LEUKAEMIA

In 117 patients with chronic myelogenous leukaemia (CML) treatment with a combination of high-dose chemoradiotherapy plus transplantation of allogeneic bone-marrow from HLA-identical, mixed-lymphocyte-culture-identical siblings resulted in an actuarial probability of 3-year survival of 63 +/- 16% (95% confidence interval) for 39 patients transplanted in chronic phases; 36 +/- 14% for 56 transplanted in accelerated phase; and 12 +/- 15% for 22 transplanted during blast crisis. Irrespective of disease status at the time of transplantation, and in contrast to chemotherapy, a plateau-effect was observed in the survival curves starting 14 to 19 months after transplantation. The actuarial probability of recurrent or persistent leukaemia at 3 years was 7 +/- 9% for patients transplanted in chronic phase, 41 +/- 19% for accelerated phase, and 41 +/- 39% for blastic phase. All relapses occurred within 18 months of transplantation. This study demonstrates that long-term disease-free survival in CML can be achieved with bone-marrow transplantation. Best results were obtained in patients transplanted during chronic phase of the disease.

Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein

Haploidentical natural killer (NK) cell infusions can induce remissions in some patients with acute myeloid leukemia (AML) but regulatory T-cell (Treg) suppression may reduce efficacy. We treated 57 refractory AML patients with lymphodepleting cyclophosphamide and fludarabine followed by NK cell infusion and interleukin (IL)-2 administration. In 42 patients, donor NK cell expansion was detected in 10%, whereas in 15 patients receiving host Treg depletion with the IL-2-diphtheria fusion protein (IL2DT), the rate was 27%, with a median absolute count of 1000 NK cells/μL blood. IL2DT was associated with improved complete remission rates at day 28 (53% vs 21%; P = .02) and disease-free survival at 6 months (33% vs 5%; P < .01). In the IL2DT cohort, NK cell expansion correlated with higher postchemotherapy serum IL-15 levels (P = .002), effective peripheral blood Treg depletion (<5%) at day 7 (P < .01), and decreased IL-35 levels at day 14 (P = .02). In vitro assays demonstrated that Tregs cocultured with NK cells inhibit their proliferation by competition for IL-2 but not for IL-15. Together with our clinical observations, this supports the need to optimize the in vivo cytokine milieu where adoptively transferred NK cells compete with other lymphocytes to improve clinical efficacy in patients with refractory AML. This study is registered at clinicaltrials.gov, identifiers: NCT00274846 and NCT01106950.

Interferon-alpha restores normal adhesion of chronic myelogenous leukemia hematopoietic progenitors to bone marrow stroma by correcting impaired beta 1 integrin receptor function

Treatment of chronic myelogenous leukemia (CML) with interferon-alpha frequently results in normalization of peripheral blood counts and, in up to 20% of patients, reestablishment of normal hematopoiesis. We hypothesize that interferon-alpha may restore normal adhesive interactions between CML progenitors and the bone marrow microenvironment and restore normal growth regulatory effects resulting from these progenitor-stroma interactions. We demonstrate that treatment with interferon-alpha induces a significant, dose-dependent increase in the adhesion of primitive long-term culture initiating cells and committed colony-forming cells (CFC) from CML bone marrow to normal stroma. Adhesion of CFC seen after interferon-alpha treatment could be inhibited by blocking antibodies directed at the alpha 4, alpha 5, and beta 1 integrins and vascular cell adhesion molecule, but not CD44 or intracellular adhesion molecule, suggesting that interferon-alpha induces normalization of progenitor-stroma interactions in CML. Because FACS analysis showed that the level of alpha 4, alpha 5, and beta 1 integrin expression after interferon-alpha treatment is unchanged, this suggests that interferon-alpha may restore normal beta 1 integrin function. Normalization of interactions between CML progenitors and the bone marrow microenvironment may then result in the restoration of normal regulation of CML progenitor proliferation, and explain, at least in part, the therapeutic efficacy of interferon-alpha in CML.

Depressed Mood and Other Variables Related to Bone Marrow Transplantation Survival in Acute Leukemia

Routine psychiatric evaluations of 100 adult patients undergoing allogeneic bone marrow transplantation for acute leukemia were reviewed to examine the possible relationship of psychiatric and psychosocial factors to duration of survival following the procedure. Three variables were found to independently affect outcome: illness status (first remission vs. other status), presence of depressed mood, and the extent of perceived social support. Patients transplanted while in their first remission had significantly improved survival; patients with depressed mood, regardless of specific psychiatric diagnosis, had poorer outcomes; and patients with a high level of perceived social support had improved survival. The possible mechanisms by which these variables affect outcome are discussed.