Paul L. Weiden

Chronic graft-versus-host syndrome in man : a long-term clinicopathologic study of 20 Seattle patients

This study of chronic graft-versus-host disease (GVHD) describes the clinical, pathologic and laboratory features, and the causes of morbidity and mortality in 20 patients who received allogeneic marrow transplants from HLA identical sibling donors. Chronic GVHD is a pleiotrophic syndrome with variability in the time of onset, organ systems involved and rate of progression. The clinical-pathologic features resemble an overlap of several collagen vascular diseases with frequent involvement of the skin, liver, eyes, mouth, upper respiratory tract, esophagus and less frequent involvement of the serosal surfaces, lower gastrointestinal tract and skeletal muscles. Major causes of morbidity are scleroderma with contractures and ulceration, dry eyes and mouth, pulmonary insufficiency and wasting. Chronic GVHD has features of immune dysregulation with elevated levels of eosinophils, circulating autoantibodies, hypergammaglobulinemia and plasmacytosis of viscera and lymph nodes. In this study, three patients had limited chronic GVHD with relatively favorable prognosis characterized by localized skin involvement and/or hepatic disease without chronic aggressive histology. Most patients, however, had extensive disease with a progressive course. Survival was largely determined by the presence or absence of serious recurrent bacterial infections. The over-all severity of disease was best assessed by using the Karnofsky performance rating.

Antileukemic Effect of Graft-versus-Host Disease in Human Recipients of Allogeneic-Marrow Grafts

To determine whether allogeneic bone-marrow transplantation is associated with a graft-versus-leukemia effect, we examined the relation between relapse of leukemia and graft-versus-host disease in 46 recipients of identical-twin (syngeneic) marrow, 117 recipients of HLA-identical-sibling (allogeneic) marrow with no or minimal graft-versus-host disease, and 79 recipients of allogeneic marrow with moderate to severe or chronic disease. The relative relapse rate was 2.5 times less in allogeneic-marrow recipients with graft-versus-host disease than in recipients without it (P less than 0.01). This apparent antileukemic effect was more marked in patients with lymphoblastic than nonlymphoblastic leukemia, and in those who received transplants during relapse rather than during remission, and was most evident during the first 130 days after transplantation. Survival of all patients was comparable since the lesser probability of recurrent leukemia in patients with graft-versus-host disease was offset by a greater probability of other causes of death.

Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation.

ALLOGENEIC marrow transplantation is being used with increasing frequency in the treatment of acute leukemia.1 2 3 4 Recurrent leukemia is an uncommon cause of therapeutic failure in patients with ...

Marrow transplantation for acute nonlymphoblastic leukemia in first remission.

MARROW transplantation provides the opportunity for aggressive antileukemic therapy without regard to marrow toxicity.1 We have reported the application of this approach combined with intensive che...

Graft-versus-Host Disease as Adoptive Immunotherapy in Patients with Advanced Hematologic Neoplasms

The occurrence of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation for leukemia is thought to decrease the probability of recurrence. To study this effect (called adoptive immunotherapy) we modified the prophylaxis of GVHD in patients with advanced hematologic neoplasms (mostly leukemia) who received bone marrow transplants. Patients under 30 years of age were randomly assigned to one of three regimens of post-transplantation immunosuppression: Group I (n = 44) received a standard course of methotrexate for 102 days after transplantation, Group II (n = 40) received an abbreviated (11-day) course of methotrexate, and Group III (n = 25) received the standard course of methotrexate plus viable buffy-coat cells from the marrow donors. All 109 patients received cyclophosphamide (60 mg per kilogram of body weight on each of two days), total-body irradiation (2.25 Gy daily for seven days), and unmodified marrow from HLA-identical sibling donors. The frequency of GVHD of Grades II through IV was 25 percent in Group I, 59 percent in Group II, and 82 percent in Group III (P = 0.0001). The incidence of chronic GVHD, however, did not differ significantly among the groups (33, 51, and 44 percent, respectively), nor did the five-year probability of recurrence of disease (38, 45, and 33 percent, respectively). However, mortality from causes other than cancer was 34 percent in Group I, 45 percent in Group II, and 64 percent in Group III (I vs. III, P = 0.024); the deaths were due primarily to infections complicating the course of GVHD. With a median follow-up of 5.1 years (range, 3.9 to 7.4), disease-free survival was 41 percent in Group I, 30 percent in Group II, and 24 percent in Group III (the differences were not statistically significant). We conclude that abbreviating methotrexate prophylaxis or infusing donor buffy-coat cells increased the incidence of acute GVHD and related mortality without altering the incidence of chronic GVHD or the recurrence of malignant disease.

Cyclosporin A and methotrexate in canine marrow transplantation: engraftment, graft-versus-host disease, and induction of intolerance.

We examined the effect of methotrexate (MTX) and cyclosporin A (Cy A) on engraftment, graft-versus-host disease (GVHD), and the induction of tolerance in dogs prepared for marrow transplantation by 9 Gy of total body irradiation and grafted with bone marrow and buffy coat cells. Nineteen dogs were given grafts from DLA-identical littermates followed by immunosuppression with Cy A for 25 or 100 days. All had sustained engraftment, and 12 became healthy long-term chimeras. Sixty dogs were given grafts from DLA-nonidentical unrelated donors. Among nine given MTX only post-grafting, one rejected the graft and eight died with GVHD. Among 18 dogs given Cy A only postgrafting, eight failed to achieve engraftment, seven died of various causes, and three died with GVHD. Thirty-four dogs were given both MTX and Cy A in various regimens postgrafting. The only long-term survivors were 4 of 10 dogs given MTX on days 1, 3, 6, and 11 and Cy A from days 0 through 100. Two have chronic GVHD. We conclude that Cy A can induce graft-host tolerance across minor, but not major, histocompatibility differences. The combination of MTX early after transplantation with Cy A prevents failure of engraftment of histoincompatible marrow and some recipients become long-term survivors.

Antihuman thymocyte globulin for prophylaxis of graft-versus-host disease. A randomized trial in patients with leukemia treated with HLA-identical sibling marrow grafts.

SUMMARY Patients with hematological malignancies undergoing allogeneic marrow transplantation from HLA-identical siblings were entered into a randomized study to determine whether the prophylactic administration of horse anti-human thymocyte globulin (ATG) would decrease the incidence or severity of graft-versus-host disease (GVHD). Patients were conditioned with high-dose cyclophosphamide and total body irradiation before grafting and received methotrexate after grafting. When marrow engraftment was documented (median 16.5 days after transplantation), patients were randomized either to receive or not to receive horse ATG, 7 mg/kg, i.v., every other day for six doses. Twenty-nine patients received ATG and 27 patients did not. Both groups were comparable with respect to diagnoses, disease status, age, sex, donor-recipient sex match, and supportive care. Administration of ATG was associated with fever and chills in most patients, but was otherwise well tolerated. Patients receiving ATG had no delay in recovery of peripheral granulocyte or platelet counts, did not require increased platelet support, and did not have more infectious complications. No significant difference in either incidence or severity of GVHD was noted between patients receiving and those not receiving prophylactic ATG, although GVHD, if it developed, tended to be less severe among patients receiving ATG. Survival and causes of death were also comparable between groups. Thus, administration of horse ATG after documentation of marrow engraftment in recipients of HLA-identical allogeneic marrow grafts had neither significant toxicity nor beneficial effect.

Canine Cyclic Neutropenia: A STEM CELL DEFECT

Two normal collie dogs were given 1,200 R total body irradiation followed by successful marrow grafts from their grey collie littermates with cyclic hematopoiesis. During observation periods of 97 and 41 days after grafting, both previously normal recipients showed regular cyclic fluctuations of their granulocyte and reticulocyte counts similar to those observed in their donors. These findings suggest that canine cyclic neutropenia is due to a defect in the marrow stem cell.

Impaired lymphocyte transformation in intestinal lymphangiectasia: evidence for at least two functionally distinct lymphocyte populations in man

Intestinal lymphangiectasia is a disease characterized by hypoproteinemia and edema resulting from protein-losing gastroenteropathy secondary to abnormal intestinal lymphatics. Immunologic abnormalities associated with this disease include hypogammaglobulinemia, lymphocytopenia, skin anergy, and impaired allograft rejection. In the present study, the in vitro blastogenic transformation of lymphocytes from 12 patients with intestinal lymphangiectasia was assessed in order to gain insight into the mechanism of the cellular immune defect in this disease. Peripheral blood lymphocytes from patients with intestinal lymphagiectasia showed impaired in vitro transformation to nonspecific mitogens, specific antigens, and allogeneic cells when compared to equal numbers of cells from normal individuals. Patients with the most deficient in vitro reactivity tended to have the lowest serum albumin concentration and the lowest absolute lymphocyte count. Lymphocytes obtained from chylous effusions in each of the four patients studied transformed more vigorously than peripheral blood cells from the same patients. These results may be explained by the loss of recirculating, long-lived lymphocytes into the gastrointestinal tract, resulting in a relative depletion of the population of lymphocytes necessary for in vitro blast transformation. This disease thus represents a clinical analogue of animals with experimental thoracic duct drainage, and provides evidence for the existence, in man, of two functionally distinct lymphocyte populations. In addition, these findings establish a new mechanism of impaired delayed hypersensitivity and defective in vitro lymphocyte transformation, i.e. the gastrointestinal loss and consequent depletion of the long-lived, recirculating population of lymphocytes from the peripheral lymphocyte pool.

Pretargeted radioimmunotherapy (PRIT™) for treatment of non-Hodgkin's lymphoma (NHL)

Pretargeted radioimmunotherapy (PRIT) was first investigated in a series of phase I and phase II studies in patients with adenocarcinoma using a pancarcinoma antibody, NR-LU-10. The principles and schema developed were then applied to an initial study in patients with non-Hodgkins lymphoma (NHL). The PRIT approach used is a multi-step delivery system in which an antibody is used to target streptavidin to a tumor-associated antigen receptor, and subsequently, biotin is used to target the 90Y radioisotope to the tumor localized streptavidin. In the NHL study, a chimeric, IgG1, anti-CD20 antibody (Rituximab) was conjugated to streptavidin (SA) and administered to patients. Thirty-four hours later, a clearing agent, synthetic biotin-N-acetyl-galactosamine, was administered to remove non-localized conjugate from the circulation. Finally, a DOTA-biotin ligand, labeled with 111In for imaging and/or 90Y for therapy was administered. Ten patients with relapsed or refractory NHL were studied, and seven received 30 or 50 mCi/m(2) 90Y DOTA-biotin. Preliminary studies using 186Re labeled conjugate confirmed that it localized to tumor and that the clearing agent removed >95% of the conjugate from the circulation. Radiolabeled biotin localized well to tumor. Unbound radiobiotin was rapidly excreted from the whole body and normal organs. The mean tumor dose calculated was 29+/-23 cGy/mCi 90Y, and the mean tumor to whole body dose ratio was 38:1. Only grade I/II non-hematologic toxicity was observed. Hematologic toxicity was also not severe; i.e. five of the seven patients who received 30 or 50 mCi/m(2) of 90Y-DOTA-biotin experienced only transient grade III (but no grade IV) hematologic toxicity. Although six of 10 patients developed humoral immune responses to the streptavidin, these were delayed and transient and hence may not preclude retreatment. Six of seven patients who received 30 or 50mCi/m(2) 90Y achieved objective tumor regression, including three complete and one partial response. The estimate of tumor to whole body dose ratio (38:1) achieved with PRIT in these NHL patients is higher than that achieved in other studies using conventional RIT. Toxicity was mild and tumor response encouraging. PRIT clearly deserves additional study in patients with NHL.