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Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors.

Sixty-one evaluable patients, 19 with advanced aplastic anemia and 42 with end stage hematological malignancies, were conditioned for marrow grafting with total body irradiation or cyclophosphamide, or a combination of both. Marrow graft donors were siblings matched at the HL-A region and nonreactive in mixed leukocyte culture. All patients received methotrexate postgrafting to modify anticipated graft-versus-host disease (GVHD). Forty-three of the 61 patients developed clinically recognizable GVHD. In seven GVHD was limited to the skin. In the remaining patients, skin involvement was more severe and was followed by gastrointestinal involvement manifested by anorexia, nausea, diarrhea, abdominal pain, and malabsorption and/or liver involvement manifested by hepatomegaly, rises in serum glutamic oxaloacetic acid transaminase, and bilirubin. The severity of GVHD showed no correlation with the underlying disease, the conditioning regimen, or the day of onset after grafting. Fourteen of 25 patients without GVHD or with only skin involvement are alive. By contrast, only 5 of 36 with severe GVHD are alive. Twenty-six of the 36 patients with severe GVHD succumbed to infection, whereas only 4 of 25 without GVHD or with only skin involvement did so. The results show that despite histocompatibility matching and methotrexate therapy, GVHD remains a serious and often fatal complication of marrow transplantation.

Methotrexate and Cyclosporine Compared with Cyclosporine Alone for Prophylaxis of Acute Graft versus Host Disease after Marrow Transplantation for Leukemia

We treated 93 patients who had acute nonlymphoblastic leukemia in the first remission or chronic myelocytic leukemia in the chronic phase (median age, 30 years) with high-dose cyclophosphamide and fractionated total-body irradiation, followed by infusion of marrow from an HLA-identical sibling. To evaluate postgrafting prophylaxis for graft versus host disease, we studied these patients in a sequential, prospective, randomized trial that compared the effect of a combination of methotrexate and cyclosporine (n = 43) with that of cyclosporine alone (n = 50). All patients had evidence of sustained engraftment. A significant reduction in the cumulative incidence of grades II to IV acute graft versus host disease was observed in the patients who received both methotrexate and cyclosporine (33 percent), as compared with those who were given cyclosporine alone (54 percent) (P = 0.014). Seven patients who received cyclosporine alone acquired grade IV acute graft versus host disease, as compared with none who received both methotrexate and cyclosporine. Thirty-five of the 43 patients given both methotrexate and cyclosporine and 31 of the 50 patients given cyclosporine are alive as of this writing, at 4 months to 2 years (median, 15 months); the actuarial survival rates in the two groups at 1.5 years were 80 percent and 55 percent, respectively (P = 0.042). We conclude that the combination of methotrexate and cyclosporine is superior to cyclosporine alone in the prevention of acute graft versus host disease after marrow transplantation for leukemia, and that this therapy may have a beneficial effect on long-term survival.

Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation : a cohort study of 355 patients

Survival after bone marrow transplantation depends on recovery from the effects of cytoreductive therapy, successful engraftment, prevention of infections and graft-versus-host disease, and eradication of the underlying disease [1]. Liver damage, a common complication of cytoreductive therapy, develops in 20% to 40% of patients who undergo bone marrow transplantation for malignancy [2-5]. The most prominent site of liver damage after cytoreductive therapy is the terminal hepatic venule [6, 7]. In addition to causing vascular changes, cytoreductive therapy may result in necrosis of hepatocytes in zone 3 of the liver acinus, engorgement of sinusoids with hepatocytes and red blood cells, and perivenular fibrosis [3, 6, 7]. The clinical syndrome resulting from this hepatic damage is commonly called veno-occlusive disease of the liver (VOD). In 1980, we reported that patients receiving high-dose cytoreductive therapy had a higher incidence of VOD than did those receiving low-dose therapy [7]. In recent years, the trend has been to give even greater doses of cytoreductive therapy to patients at increased risk for relapse of malignancy after marrow grafting [5, 8-10]. High-dose regimens reduce the incidence of tumor relapse but are associated with liver, renal, cardiac, and pulmonary complications [8-12]. Our clinical impression is that the current incidence of VOD at our institution is much higher than the 21% rate we reported 9 years ago [2] and that more patients have severe liver disease. Factors other than high-dose cytoreductive therapy must be involved in the pathogenesis of VOD, because not all patients receiving identical high-dose regimens develop this complication. In three studies, patients with hepatitis at the time of cytoreductive therapy were significantly more likely to develop VOD than patients with normal serum liver enzyme levels [2-4]. Other factors that have been reported to increase the risk for VOD include increasing age, certain diagnoses, estrogen-progestin therapy, amphotericin therapy during cytoreductive therapy, methotrexate therapy after transplantation, and seropositivity for cytomegalovirus [2-5, 13, 14]. In addition to increases in cytoreductive therapy dosing, several other changes in the technique of bone marrow grafting occurred in the last decade: These include the use of cyclosporine for graft-versus-host disease prophylaxis; the more extensive use of antibiotics, antifungal agents, and antiviral drugs during periods of profound immunodeficiency; and the wider use of bone marrow from unrelated and HLA-mismatched donors [15-17]. To determine the incidence of VOD after bone marrow transplantation, we prospectively followed 355 consecutive patients who underwent transplantation in Seattle, Washington. We were particularly interested in analyzing risk factors for VOD in order to explain the apparent increased incidence and severity of this complication. We also examined the relation between VOD and the failure of other organs because we have noted that multiorgan failure tends to follow the development of liver disease. Methods Patient Selection We evaluated all patients referred to the Fred Hutchinson Cancer Research Center for bone marrow transplantation between August 1987 and August 1988. Three hundred and sixty patients received cytoreductive therapy in preparation for bone marrow grafting. Five patients who died before bone marrow infusion were excluded from the analysis. Thus, 355 patients were prospectively studied for the development of liver toxicity and organ failure in the early post-transplant period. Four patients received a second marrow graft within the year, but only data from the first transplant were analyzed. Underlying diseases for which transplantation was done included acute myelocytic leukemia (n = 98), acute lymphocytic leukemia (n = 61), chronic myelogenous leukemia (n = 94), lymphoma (n = 65), other malignant conditions (n = 16), and other hematologic disorders (n = 21). Bone Marrow Transplant Techniques The methods used at our institution have been previously reported [8, 9, 15, 18]. Briefly, patients receive chemotherapy or chemoradiation therapy before infusion of bone marrow. By convention, the day of bone marrow infusion is considered day zero and all post-transplant events are dated from this day. Patients who receive allogeneic marrow are given prophylactic therapy, usually with cyclosporine and methotrexate, for graft-versus-host disease [15]. Definition of Veno-occlusive Disease A diagnosis of VOD was made according to the criterion we proposed in 1984, that is, the occurrence of two of the following events within 20 days of transplantation: hyperbilirubinemia (total serum bilirubin > 34.2 mol/L [2 mg/dL]), hepatomegaly or right upper quadrant pain of liver origin, and sudden weight gain (> 2% of baseline body weight) because of fluid accumulation [2, 19]. No other explanation for these signs and symptoms could be present at the time of diagnosis. Patients were classified as having liver disease of uncertain cause if liver disease developed that could be explained by graft-versus-host disease, sepsis syndrome (fever and hypotension), cardiac failure, or tumor infiltration. Patients who developed both mild hyperbilirubinemia (total serum bilirubin < 34.2 mol/L [2 mg/dL]) and weight gain below the threshold criterion of 2% were also placed in the uncertain cause category. Patients who died before day 5 were also classified as having disease of uncertain cause because they did not live long enough for liver disease to become clinically apparent. Patients were classified as showing no liver disease if no liver abnormalities were observed within 20 days of marrow infusion. Clinical Course and Outcome of Veno-occlusive Disease Patients who met criteria for the diagnosis of VOD were evaluated for severity as follows: Patients were classified as having mild disease if they showed no apparent adverse effect from liver disease; required no medications for diuresis of excessive fluid or for hepatic pain; and had completely reversible signs, symptoms, and laboratory abnormalities. Patients were classified as having moderate VOD if they had an adverse effect from liver disease; required sodium restriction and diuretics to minimize signs of fluid excess (edema, ascites, cardiopulmonary congestion) or medication to alleviate pain from hepatomegaly; and eventually showed a complete resolution of all signs of liver damage (a return of weight to baseline, a decrease in liver size, and a decrease in total serum bilirubin to < 34.2 mol/L [2 mg/dL]). Patients were classified as having severe VOD if they showed an adverse effect from liver disease, and signs, symptoms, and laboratory values did not resolve before day 100 or the patient died, whichever occurred first. Death was not a requirement for assignment to the severe VOD category. Risk Factors for the Development of Veno-occlusive Disease Appendix Table 1 summarizes all risk factors analyzed for the development of VOD. Appendix Table 1. Individual Risk Factors Analyzed for the Development of Veno-occlusive Disease of the Liver One of us reviewed referral correspondence and interviewed and examined each patient at his or her arrival to the center. Medications given before the start of cytoreductive therapy were recorded. Then, starting with day 1 of cytoreductive therapy, each patients signs, symptoms, medications, laboratory and radiologic results, and clinical findings were noted on a daily basis until day 20 after transplantation. We analyzed three categories of factors that could be related to the development of VOD: pretransplant factors, transplant decision factors, and clinical course factors. Pretransplant factors were those present before the start of cytoreductive therapy. Included in this category were demographic variables and variables derived from a detailed medical history, including information about individual chemotherapy agents as well as combination chemotherapy delivered before patients arrived at our center. Transplant decision factors were those decided on for each patient before the start of cytoreductive therapy. Such factors included the dose and type of cytoreductive therapy, the type of transplant, and the HLA match between donor and recipient. The dose rate of total body irradiation for most patients (271 of 277) was 6 to 7 cGy/min using opposing cobalt sources. Six patients received total body irradiation at 12 cGy/min using a linear accelerator. For patients receiving a total body irradiation dose of more than 12 Gy, we analyzed whether radiation delivered in divided daily doses (fractionated) or in multiple doses per day (hyperfractionated) had an effect on the incidence of VOD. Clinical course factors were those occurring after the start of cytoreductive therapy but before the clinical appearance of liver disease. Such factors included all medications received by each patient and the occurrence of fever. Evaluation of Renal, Cardiac, Pulmonary and Neurologic Events Organ dysfunction was scored on a daily basis (to day 20 after transplantation). We noted the day of onset of organ dysfunction and its severity, using the following definitions: Renal insufficiency was defined by a doubling of the baseline creatinine level (that is, the lowest serum level 1 to 3 days before bone marrow infusion). Renal failure was defined by a creatinine level of 265 mol/L (3 mg/dL), a blood urea nitrogen level 28.6 mmol/L (80 mg/dL), or the need for hemodialysis. Cardiac failure was defined by radiographic evidence of an increased cardiac size or the development of pulmonary vascular congestion that was not present at baseline. Pleural effusions were defined by radiographic evidence in the pleural space, and pulmonary infiltrates by radiographic evidence of diffuse interstitial infiltrates that were not present at baseline. The need for oxygen support was based on documentation of hypoxemia by arteri

Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers.

BACKGROUND In recipients of allogeneic hematopoietic-cell transplants, peripheral-blood cells mobilized with the use of filgrastim (recombinant granulocyte colony-stimulating factor) engraft more rapidly than bone marrow. However, the relative effects of these techniques on the rates of acute and chronic graft-versus-host disease, overall survival, and disease-free survival have not been determined in randomized studies. METHODS Between March 1996 and July 1999, 172 patients (12 to 55 years of age) with hematologic cancer were randomly assigned to receive either bone marrow or filgrastim-mobilized peripheral-blood cells from HLA-identical relatives for hematopoietic rescue after the treatment of hematologic cancer with high doses of chemotherapy, with or without radiation. RESULTS The recovery of both neutrophils and platelets was faster with peripheral-blood cells than with marrow (P<0.001 for both comparisons). The cumulative incidence of grade II, III, or IV acute graft-versus-host disease at 100 days was 64 percent with peripheral-blood cells and 57 percent with marrow (hazard ratio, 1.21; 95 percent confidence interval, 0.81 to 1.81; P=0.35). The cumulative incidence of chronic graft-versus-host disease was 46 percent with peripheral-blood cells and 35 percent with marrow (hazard ratio, 1.16; 95 percent confidence interval, 0.71 to 1.90; P=0.54). The estimated overall probability of survival at two years was 66 percent with peripheral-blood cells and 54 percent with marrow (hazard ratio for death, 0.62; 95 percent confidence interval, 0.38 to 1.02; P=0.06). The rate of disease-free survival at two years was 65 percent with peripheral-blood cells and 45 percent with marrow (hazard ratio for relapse or death, 0.60; 95 percent confidence interval, 0.38 to 0.95; P=0.03). CONCLUSIONS In patients given high-dose chemotherapy, with or without radiation, for the treatment of hematologic cancer, allogeneic peripheral-blood cells used for hematopoietic rescue restore blood counts faster than allogeneic bone marrow, without increasing the risk of graft-versus-host disease.

Regimen-related toxicity in patients undergoing bone marrow transplantation.

Bone marrow transplantation is associated with significant morbidity and mortality, some of which is due to high-dose chemoradiotherapy. In order to quantitate toxicity that was felt to be due to the preparative regimen (termed regimen-related toxicity [RRT]), a system was developed in which toxicities were graded from 0 (none) to 4 (fatal). One hundred ninety-five patients who underwent marrow transplantation for leukemia were studied retrospectively to determine whether toxicities that were clinically felt to be due to the preparative regimen were influenced by other factors such as disease status, graft-versus-host disease (GVHD) prophylaxis, and allogenicity. All patients developed grade I toxicity in at least one organ, and 30 developed grades III-IV (life-threatening or fatal) RRT. RRT was more common in relapsed patients v remission patients (P = .04), in those receiving 15.75 Gy total body irradiation (TBI) v 12.0 Gy TBI (P = .028), and in those receiving allogeneic marrow v autologous marrow (P = .0029). Autologous marrow recipients did not develop grades III-IV toxicity in this study. A multivariate analysis controlling for autologous marrow grafting showed that the dose of TBI was the only statistically significant predictor of grades III-IV RRT. Those patients who developed grade III RRT were unlikely to survive 100 days from transplant, though not all deaths could be attributed to RRT. Patients who developed grade II toxicity in three or more organs were more likely to die within 100 days than those developing grade II toxicity in two or less organs (P = .0027). This system was generally able to distinguish RRT from other toxicities observed in marrow recipients.

Marrow Transplantation from Related Donors Other Than HLA-Identical Siblings

Marrow transplantation has generally been limited to patients with a sibling who is genotypically identical for HLA. In a study of the acceptable limits of HLA incompatibility, 105 consecutive patients with hematologic cancers who received marrow grafts from haploidentical donors (study group) were compared with 728 similar patients concurrently receiving grafts from HLA genotypically identical siblings (control group). The unshared haplotypes differed variably: 12 were phenotypically but not genotypically identical for HLA-A, HLA-B, and HLA-D; 63 differed at one locus (A, B, or D); 24 at two loci; and 6 at three. A higher proportion of study patients had delayed engraftment, granulocytopenia, or graft rejection. Acute graft versus host disease occurred earlier and with greater frequency in study patients. The risk of the disease did not correlate with disparity for Class I (A or B) versus Class II (D-region) loci. Thus, incompatibility for HLA has an important effect on the course after clinical marrow transplantation. In spite of these complications, there was no statistically significant difference in the survival of the study patients and control patients who received their transplants during remission.

BONE MARROW TRANSPLANTS FROM UNRELATED DONORS FOR PATIENTS WITH CHRONIC MYELOID LEUKEMIA

BACKGROUND Chronic myeloid leukemia can be cured by marrow transplantation from an HLA-identical sibling donor. The use of transplants from unrelated donors is an option for the 70 percent of patients without an HLA-identical sibling, but the morbidity and mortality associated with such transplants have been cause for concern. We analyzed the safety and efficacy of transplants from unrelated donors for the treatment of chronic myeloid leukemia and identified variables that predict a favorable outcome. METHODS Between May 1985 and December 1994, 196 patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase received marrow transplants from unrelated donors. RESULTS The median follow-up was 5 years (range, 1.2 to 10.1). Graft failure occurred in 5 percent of patients who could be evaluated. Acute graft-versus-host disease of grade III or IV severity was observed in 35 percent of patients who received HLA-matched transplants, and the estimated cumulative incidence of relapse at five years was 10 percent. The Kaplan-Meier estimate of survival at five years was 57 percent. Survival was adversely affected by an interval from diagnosis to transplantation of one year or more, an HLA-DRB1 mismatch, a high body-weight index, and an age of more than 50 years. Survival was improved by the prophylactic use of fluconazole and ganciclovir. The Kaplan-Meier estimate of survival at five years was 74 percent (95 percent confidence interval, 62 to 86 percent) for patients who were 50 years of age or younger who received a transplant from an HLA-matched donor within one year after diagnosis. CONCLUSIONS Transplantation of marrow from an HLA-matched, unrelated donor is safe and effective therapy for selected patients with chronic myeloid leukemia.

Effect of HLA Compatibility on Engraftment of Bone Marrow Transplants in Patients with Leukemia or Lymphoma

We analyzed the relevance of HLA compatibility to sustained marrow engraftment in 269 patients with hematologic neoplasms who underwent bone marrow transplantations. Each patient received marrow from a family member who shared one HLA haplotype with the patient but differed to a variable degree for the HLA-A, B, and D antigens of the haplotype not shared. These 269 patients were compared with 930 patients who received marrow from siblings with identical HLA genotypes. All patients were treated with cyclophosphamide and total-body irradiation followed by the infusion of unmodified donor marrow cells. The rate of graft failure was 12.3 percent among the recipients of marrow from a donor with only one identical haplotype, as compared with 2.0 percent among recipients of marrow from a sibling with the same HLA genotype (both haplotypes inherited from the same parents) (P less than 0.0001). The incidence of graft failure correlated with the degree of donor HLA incompatibility. Graft failure occurred in 3 of 43 transplants (7 percent) from donors who were phenotypically HLA-matched with their recipient (haplotypes similar, but not inherited from the same parents), in 11 of 121 donors (9 percent) incompatible for one HLA locus, in 18 of 86 (21 percent) incompatible for two loci, and in 1 of 19 (5 percent) incompatible for three loci (P = 0.028). In a multivariate binary logistic regression analysis, independent risk factors associated with graft failure were donor incompatibility for HLA-B and D (relative risk = 2.1; 95 percent confidence interval, 1.7 to 2.5; P = 0.0004) and a positive crossmatch for anti-donor lymphocytotoxic antibody (relative risk = 2.3; 95 percent confidence interval, 1.8 to 2.8; P = 0.0038). Residual host lymphocytes were detected in 11 of 14 patients with graft failure, suggesting that the mechanism for graft failure could be host-mediated immune rejection. We conclude that donor HLA incompatibility and prior alloimmunization are significant risk factors for graft failure, and that a more effective immunosuppressive regimen than those currently used is needed for consistent achievement of sustained engraftment of marrow transplanted from donors who are not HLA-identical siblings.

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...

Marrow Transplantation for the Treatment of Chronic Myelogenous Leukemia

One hundred ninety-eight patients with chronic myelogenous leukemia received marrow transplants after intensive chemotherapy and total body irradiation. Multivariate analysis showed disease status at time of transplantation to be the most powerful predictor of survival. The probability of long-term survival for allogeneic graft recipients was 49% for 67 patients in the first chronic phase, 58% for 12 in the second chronic phase, 15% for 46 in the accelerated phase, and 14% for 42 in the blastic phase. The major cause of death was interstitial pneumonia for patients in the chronic phase, and relapse for those in the blastic or accelerated phases. Factors favoring survival were early transplantation, age less than 30 years, and absence of severe graft-versus-host disease. Splenectomy or spleen size did not influence survival. For recipients of syngeneic grafts survival probability was 87% for 16 patients in the chronic phase, 27% for 7 in the accelerated phase, and 12% for 8 in the blastic phase. Of the 198 patients, 71 are alive without Philadelphia chromosomes 1 to 9 years after receiving their graft. All but 4 long-term disease-free survivors have Karnofsky performance scores of 80% or better.