David D. Hurd

Allogeneic bone marrow transplantation for acute lymphoblastic leukemia in remission: prolonged survival associated with acute graft-versus-host disease.

Forty remission patients with high-risk acute lymphoblastic leukemia (ALL) underwent matched allogenic bone marrow transplantation (BMT) following preparation with cyclophosphamide and fractionated total body irradiation (TBI). As of March 1987, the median follow-up is more than 3 1/2 years. Thirteen patients are alive (11 relapse free) between 2 and 4 1/2 years post-BMT. Neither age, sex, remission number, prior extramedullary leukemia, nor WBC at diagnosis of ALL was statistically significant as a predictor of relapse-free survival. The development of acute graft-v-host disease (GVHD) in 17 patients was found, with time-dependent Cox regression analysis, to be associated with a significant reduction in post-BMT relapse risk (P = .04) and improved disease-free survival (P = .11). A prospective, randomized trial of maintenance chemotherapy with oral methotrexate and mercaptopurine did not demonstrate improvement in relapse risk or survival for those assigned maintenance chemotherapy (P = .7). These results suggest that allogeneic BMT can result in extended relapse-free survival for some patients with high-risk ALL. More effective preparative chemoradiotherapy and exploitation of the apparent graft-v-leukemia effect may be useful in future trials.

SUCCESSFUL ALLOGENEIC BONE-MARROW TRANSPLANTATION FOR PATIENTS IN THE ACCELERATED PHASE OF CHRONIC GRANULOCYTIC LEUKAEMIA

Nine patients underwent allogeneic bone-marrow transplantation as treatment for chronic granulocytic leukaemia (CGL) during the accelerated phase, a point in the course of the disease when it has progressed beyond the stable chronic phase but before the onset of blast crisis. After bone-marrow transplantation, haematological and cytogenetic studies showed ablation of all evidence of leukaemia, successful engraftment, and persistence of normal haemopoiesis in all patients. In one patient severe myelofibrosis and osteosclerosis disappeared after bone-marrow transplantation. Two patients have died of complications related to graft-versus-host disease (GvHD) but with no evidence of CGL. In one patient haematological and cytogenetic evidence of recurrent disease developed after bone-marrow transplantation, and she survives in chronic phase. Six patients are free of disability, do not require transfusions, possess normal marrow chromosomes, and have persistent clinical and haematological evidence of complete remission from CGL. Intervention with allogeneic bone-marrow transplantation during the accelerated phase of CGL can eradicate the disease and can provide normal haemopoiesis with acceptably low early morbidity and mortality. The long-term efficacy of bone-marrow transplantation as treatment for CGL, and the most effective timing of the transplantation with regard to the course of disease have yet to be determined.

Comparison of two total body irradiation regimens in allogeneic bone marrow transplantation for acute non-lymphoblastic leukemia in first remission.

Between November 1976 and December 1987, 84 patients with newly diagnosed acute non-lymphoblastic leukemia who had achieved complete remission underwent non T-cell depleted allogeneic bone marrow transplantation from Human Leukocyte Antigen-Mixed Lymphocyte Culture (HLA-MLC) matched sibling donors. The first 36 patients (November 1976-June 1983) were prepared with cyclophosphamide, 60 mg/kg/day, IV for 2 days and single fraction total body irradiation with 750 cGy at a dose rate of 26 cGy/minute (Group I). The next 48 patients (July 1983-December 1987) were prepared with similar chemotherapy, but received hyperfractionated total body irradiation with total 1320 cGy, 165 cGy twice a day at a dose rate of 10 cGy/minute (Group II). Patient characteristics between these two groups are similar except for the significantly older age distribution in Group II. Median follow-up of Groups I and II are 8 years and 11 months and 2 years and 3 months, respectively. The Kaplan-Meier relapse-free survival, survival, and relapse rates at 3 years are 56, 58, and 19% in Group I and 69 (p = 0.22), 77 (p = 0.07), and 10% (p = 0.37) in Group II. There is no difference in the incidence of interstitial pneumonitis, viral or idiopathic, engraftment rate, or incidence of graft versus host disease (GVHD) between these two groups. The fractionated total body irradiation treated group had significantly less nausea and vomiting. Multivariate analysis shows that total body irradiation regimen is not a significant factor in regard to relapse rate, relapse-free survival, and survival.

Invasive scopulariopsis in the immunocompromised host

Opportunistic infections with fungal organisms have been well described in patients undergoing intensive chemotherapy and bone marrow transplantation. In two patients, invasive infections with the saprophyte Scopulariopsis developed either following intensive chemotherapy or bone marrow transplant. Fungal disease persisted in both patients despite resection of the primary focus and prolonged treatment with the usual antifungal agents, and contributed to the death of one patient.

Extramedullary presentation of the blast crisis of chronic myelogenous leukaemia

Summary. We report the clinical histories and a multiparameter pathological study of the extramedullary lesions of seven patients with chronic myelogenous leukaemia in whom the initial clinical presentation of blast crisis (BC) was in an extramedullary site (lymph nodes in six, mandibular mass in one). Bone marrow BC was demonstrated simultaneously or within a few months in four patients. Three patients received chemotherapy only, four underwent bone marrow transplant. Six patients died within 1 year from diagnosis of extramedullary BC, one is alive without disease. The longest survivals (12 +, 12, 11 months) were those of patients who never developed bone marrow BC and were recipients of bone marrow transplant.

Autologous bone marrow transplantation in non-Hodgkin's lymphoma: monoclonal antibodies plus complement for ex vivo marrow treatment.

PURPOSE Patients with non-Hodgkins lymphoma who fail to achieve a complete remission or who relapse are rarely cured with conventional therapies. For this group of patients, intensive therapy and bone marrow rescue may be curative. Our goal was to assess the effects of autologous transplantation in patients with B-cell lymphomas and a poor prognosis. To avoid occult or overt contamination with lymphoma, monoclonal antibodies BA-1, BA-2, and BA-3 were used for ex vivo marrow treatment. PATIENTS AND METHODS Seventeen patients underwent intensive therapy and autologous bone marrow transplant using the aforementioned marrow. Ten of the 17 patients (Group I) had disease that was in complete or partial remission. The other seven patients either had disease that was not responsive to treatment or had bone marrow transplant as their initial therapy at relapse. RESULTS The ex vivo treatment did not adversely affect engraftment. For those patients who could be evaluated, the median time to white cell engraftment was 24 days; the median durations of red cell and platelet support were 24 and 29 days, respectively. Eleven of the 17 patients had complete remissions at the evaluation 28 days after transplant. Three patients subsequently experienced a relapse, three died while their disease was in complete remission, and five are alive and disease-free 405 to 1,674 days after transplant. Group I patients had an estimated 40 percent disease-free survival rate at three years compared with 0 percent for Group II patients (p less than 0.01). CONCLUSION Our data support autologous bone marrow transplantation as an important treatment modality for the non-Hodgkins lymphomas. With the current preparative regimens available, however, its use should be limited to patients with disease that is still responding to conventional therapies.

Severe Delayed Hemolytic Transfusion Reaction Complicating an ABO‐Incompatible Bone Marrow Transplantation

Abstract. A 26‐year‐old, blood group O bone marrow transplant recipient experienced a severe, delayed hemolytic transfusion reaction 6 days following transplantation of marrow from his HLA‐mixed lymphocyte culture ‐ identical, blood group AB sister. The patients pretransplant serum contained both anti‐A (IgG titer = 1:128; IgM = 1:32) and anti‐B (IgG = 1:16; IgM = 1:64) which was reduced by a two‐plasma volume plasma exchange followed by transfusion of four units of incompatible, donor type red cells. The patient experienced no immediate adverse reaction. On the 6th posttransplant day, he became acutely dyspneic. His hematocrit dropped to 18%; the direct antiglobulin test was positive for IgG and complement; anti‐A and anti‐B were eluted from his red cells. His peripheral blood smear demonstrated extensive agglutination resembling a mixed field reaction. This case demonstrates that significant morbidity may be associated with major ABO‐incompatible bone marrow transplantation, that the transfusion of incompatible red cells should be undertaken with extreme caution, and that efforts should be continued to develop methods of pretransplant in vitro red cell removal from the infused bone marrow.

Reversal of severe bone marrow fibrosis and osteosclerosis following allogeneic bone marrow transplantation for chronic granulocytic leukaemia.

Summary. Severe marrow fibrosis and osteosclerosis gradually disappeared after a 33‐year‐old woman received an allogeneic bone marrow transplantation (BMT) as experimental treatment for chronic granulocytic leukaemia. Serial biopsies demonstrate gradual resolution of dense reticulin fibrosis, collagen fibrosis and osteosclerosis, and restoration of normal marrow architecture after transplantation. These changes correspond with histological and cytogenetic evidence of normal marrow engraftment and sustained complete remission from chronic granulocytic leukaemia. In this case severe marrow infiltration with reticulin and collagen fibrosis as well as severe derangement of marrow architecture and obliteration of the medullary cavity by osteosclerosis was an entirely reversible process after allogeneic bone marrow transplantation, and did not prevent successful engraftment, haemopoietic and cytogenetic reconstitution and complete remission from chronic granulocytic leukaemia.

Central nervous system involvement in acute nonlymphocytic leukemia: A prospective study of adults in remission

To identify adults with acute nonlymphocytic leukemia at risk for the development of central nervous system involvement, we performed periodic cerebrospinal fluid examinations on patients in remission. Among 58 consecutive patients monitored during first remission, central nervous system leukemia developed in nine (16 percent). Four patients, including one who was symptomatic, had central nervous system leukemia detected simultaneously with marrow relapse. Five additional patients were asymptomatic and continue to have bone marrow remission. Following central nervous system and systemic treatment, two of these five patients have never had relapse, and three had relapse in the bone marrow five, 10, and 21 months later. Factors at diagnosis associated with the subsequent development of central nervous system leukemia were elevated leukocyte count, serum lysozyme and lactate dehydrogenase, extramedullary infiltration including splenomegaly, and monocytic (FAB M4 or M5a) morphology. In six of 17 patients (35 percent) with monocytic morphology, central nervous system leukemia developed compared with only three of 41 patients (7 percent) with other subtypes (p = 0.02). Discriminant analysis identified leukocyte count, splenomegaly, and M4 or M5a morphology as the most important risk factors and led to a mathematical formula that correctly identified 90 percent of the patients. Although the risk of central nervous system leukemia in adults with acute nonlymphocytic leukemia is too low to justify routine prophylaxis, those patients recognized to be at a greater risk should receive prophylaxis or be monitored closely with periodic lumbar punctures.

15; 17 Translocation in Acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is a relatively rare subtype of leukemia that has been reported to be associated with a specific chromosome abnormality, t(15;17). It has been suggested that this translocation may have a geographical distribution and its presence may signify a poorer prognosis. In this present series of 14 patients with APL, 9 patients (64%) had the t(15;17) and 5 did not; however, no significant differences in clinical features or outcome could be found between those who did and those who did not express the translocation. When ethnic backgrounds were explored, no differences were found. More cases of the t(15;17) were found in recent years (7 of 8 patients studied since 1978 compared to 2 of 6 before 1978). This corresponded to changes made in our cytogenetic techniques suggesting that the finding of the t(15;17) may be a function of technique, rather than a real difference in disease entities, and all patients with APL may have the t(15;17) when appropriately studied.