Alexander Fefer

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.

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.

Hickman catheter infections in patients with malignancies.

The infectious complications associated with implantation of 1,088 Hickman catheters (HCs) in 992 patients reported in 18 published series are presented (including data on 129 previously unreported HCs from our own institution). HCs allow reliable long-term venous access (mean, 92.4 days) with low complication and infection rates (0.30 and 0.14 cases per 100 catheter days, respectively). Exit site infections were the most common form of infection encountered (45.5%), followed by septicemia alone (30.8%), tunnel infections (20.3%), and septic thrombophlebitis (3.5%). Staphylococcus epidermidis (54.1%) and S. aureus (20.0%) were the most common pathogens responsible for catheter infections. HC infections were associated with a low mortality rate (maximum rate of 0.5%). Risk factor analysis of 129 HCs demonstrated that catheter thrombosis was the major risk factor associated with development of catheter infection. Presence of fever, distant infection, neutropenia or antibiotic administration on the day of catheter insertion was not significantly associated with HC infection in this series (although there was a trend suggesting an increased risk of infection of HCs inserted during febrile episodes). Based on observations at our institution and from a review of the literature, tentative recommendations for management of the various types of HC infections are outlined.

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.

Treatment of malignant lymphoma in 100 patients with chemotherapy, total body irradiation, and marrow transplantation.

Between July 1970 and January 1985, 100 patients with malignant lymphoma were treated with high-dose chemoradiotherapy and bone marrow transplantation. Twenty-eight of the 100 are alive and the actuarial probability of disease-free survival 5 years from transplantation is 22%. The most common reason for treatment failure was disease recurrence, with an actuarial probability of 60%. A proportional hazards regression analysis showed that the likelihood of disease-free survival was less in those patients transplanted in resistant relapse and in those previously treated with chest radiotherapy. Neither disease histology (Hodgkins disease, high-grade lymphoma or intermediate-grade lymphoma), nor source of marrow (syngeneic, allogeneic, or autologous) significantly influenced either disease-free survival or probability of relapse. The use of high-dose chemoradiotherapy and marrow transplantation appears to offer a better chance for long-term survival than any other form of therapy for young patients with disseminated malignant lymphoma whose disease has progressed after initial combination chemotherapy. The best results with marrow transplantation were obtained in patients transplanted in early relapse or second remission who had not received prior chest radiotherapy.

Marrow transplantation for acute nonlymphoblastic leukemia in first remission using fractionated or single-dose irradiation

Abstract Fifty-three patients with acute nonlymphoblastic leukemia in first remission were treated with cyclophosphamide, total body irradiation and marrow transplantation. Twenty-seven patients received 1000 rad in one exposure and 12 are living in remission 6–29 months later. Twenty-six received 200 rad on each of 6 days and 18 are living in remission after 4–27 months. Kaplan-Meier analysis shows a survival advantage for the fractionated regimen (p = 0.05).

Marrow Transplantation in Thirty Untransfused Patients with Severe Aplastic Anemia

Thirty patients with severe aplastic anemia had no transfusions of blood products until just before marrow transplantation from HLA-identical family members. They were conditioned for grafting with cyclophosphamide, 50 mg/kg body weight on each of 4 successive days. All 30 had prompt initial marrow engraftment, which was sustained in 27. Twenty-five of the 30 are alive between 9 to 84 (median, 19.5) months. The actuarial projection of survival for 2 to 6 years is 75%. Twenty of the 25 surviving patients have no problems. Five have chronic graft-versus-host disease, resolving in two and active in three. Five patients died with infection or hemorrhage, four of whom had graft-versus-host disease. These data show that early transplantation should be carried out before transfusions are given for any patient with severe aplastic anemia who has an HLA-identical family member. If sensitization to minor transplantation antigens contained in blood products is avoided, the incidence of marrow-graft rejection will decrease, and survival will improve.

High‐dose cyclophosphamide therapy for malignant disease. Toxicity, tumor response, and the effects of stored autologous marrow

Twenty‐five patients with disseminated malignant disease received single or multiple courses of cyclophosphamide (CY) 60 to 120 mg/kg. Stored autologous marrow was infused following 120 mg/kg of CY in 6 instances. One patient received 240 mg/kg of CY over a 4‐day period followed by autologous marrow infusion. Patients receiving 60 mg/kg showed a moderate leukopenia (mean nadir of 500/mm3), anemia (mean hematocrit decline of 8.2 vol%) and variable thrombocytopenia that ranged from no change to 34,000/mm3 with a mean nadir of 127,000/mm3. Increasing the dose to 120 mg/kg produced leukopenia to below 500 cells/mm3 with a mean nadir of 120 cells/mm3. Thrombocytopenia was severe with a mean nadir of 37,000/mm3. Hematocrit values in this group fell by 15.2 vol%. Infectious complications occurred following 1 of 10 courses at 60 mg/kg and 18 of 35 courses at 120 mg/kg. In the latter group, there were 7 episodes of septicemia including one death from pseudomonas septicemia. A second patient, with cerebral metastases, died of a CNS hemorrhage. The patient receiving 240 mg/kg died as a consequence of myocardial necrosis. The infusion of autologous marrow had no apparent effect on hemopoietic recovery or infectious complications. Of the responding patients, 3 had ovarian carcinoma, 3 had testicular tumors, 1 had adenocarcinoma of the bowel, and 1 had an undifferentiated malignancy.

Subcutaneous granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome: toxicity, pharmacokinetics, and hematological effects.

The toxicity, pharmacokinetics, and hematologic effects of granulocyte-macrophage colony-stimulating (GM-CSF) were studied in a phase I/II trial of 16 patients with myelodysplastic syndrome (MDS). The GM-CSF was administered subcutaneously (SC) daily so as to achieve prolonged blood levels and to establish an outpatient treatment regimen. Four dose levels were administered for ten days: 0.3 microgram/kg/d (three patients), 1.0 microgram/kg/d (three), 3.0 micrograms/kg/d (four), and 10.0 micrograms/kg/d (six). The most common toxicities were fever and a flu-like syndrome, which were dose-dependent. The maximum-tolerated dose was 10.0 micrograms/kg/d, which induced severe rigors (two patients), fever greater than 40 degrees C (one), severe bronchospasm (one), and WBC 60,000 (one). In one patient, refractory anemia with excess blasts in transformation (RAEB-T) progressed to acute nonlymphocytic leukemia after two doses of GM-CSF, and the patient died of leukemia that did not respond to chemotherapy. After doses of 3.0 and 10.0 micrograms/kg, serum GM-CSF levels peaked at 3.8 to 6.3 hours, and persisted for 14 and 24 hours, respectively. Circulating granulocytes (neutrophils and bands) increased in a dose-dependent manner, as 11 of 13 patients who received greater than or equal to 1.0 microgram/kg/d responded with a two- to 194-fold increase. Although the neutrophils usually returned to pretreatment levels shortly after stopping GM-CSF, two patients continue to exhibit an elevation of neutrophils for 6 months. Dose-related increases in circulating monocytes and eosinophils were also noted. Transient increases in platelet and reticulocyte counts were observed in two and three patients, respectively. Five of the 16 patients later received maintenance GM-CSF at 3 micrograms/kg/d for 2 to 9 weeks. All showed a dramatic increase in neutrophils after 2 weeks. Thereafter, despite continued therapy, the neutrophil count in four patients declined markedly. In conclusion, GM-CSF is well tolerated by the SC route and induces striking, but usually temporary, improvement in the neutropenia of MDS. Larger prospective phase III trials will determine the duration of hematologic responses and the impact on infection, morbidity, and mortality.