Tae H. Kim

Second neoplasms after acute lymphoblastic leukemia in childhood.

BACKGROUND Effective forms of treatment for acute lymphoblastic leukemia (ALL) in childhood now result in survival rates above 70 percent at five years, but the treatments are potentially carcinogenic. To determine the magnitude of this risk and identify possible risk factors for the development of second neoplasms, we studied a large cohort of children treated for ALL. METHODS AND RESULTS. We undertook a retrospective cohort study of 9720 children who had been given a diagnosis of ALL between June 1972 and August 1988 and had been treated according to the therapeutic protocols of the Childrens Cancer Study Group. The median follow-up was 4.7 years (range, 2 months to 16 years). We found that 43 second neoplasms occurred among the children in the cohort, including 24 neoplasms of the central nervous system, 10 new leukemias and lymphomas, and 9 other neoplasms. This represented a 7-fold excess of all cancers and a 22-fold excess of neoplasms of the central nervous system. The estimated cumulative proportion of children in whom a second neoplasm developed was 2.53 percent 15 years after diagnosis (95 percent confidence limits, 1.74 percent and 3.38 percent). An even higher risk, particularly of central nervous system tumors, was evident in children five years of age or less at the time of the diagnosis of ALL (P = 0.012). All central nervous system neoplasms developed in children who had previously undergone irradiation. There was no association with exposure to cyclophosphamide or anthracyclines. CONCLUSIONS There is a substantial excess of second neoplasms, especially of the central nervous system, among children treated for ALL. Children five years old or younger and those receiving radiation are at higher risk, especially for second tumors arising in the central nervous system.

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.

Thyroid dysfunction among long-term survivors of bone marrow transplantation

Thyroid function studies were followed serially in 27 long-term survivors (median 33 months) of bone marrow transplantation. There were 15 men and 12 women (median age 13 1/12 years, range 11/12 to 22 6/12 years). Aplastic anemia (14 patients) and acute nonlymphocytic leukemia (eight patients) were the major reasons for bone marrow transplantation. Pretransplant conditioning consisted of single-dose irradiation combined with high-dose, short-term chemotherapy in 23 patients, while four patients received a bone marrow transplantation without any radiation therapy. Thyroid dysfunction occurred in 10 of 23 (43 percent) irradiated patients; compensated hypothyroidism (elevated thyroid-stimulating hormone levels only) developed in eight subjects, and two patients had primary thyroid failure (elevated thyroid-stimulating hormone levels and low T4 index). The abnormal thyroid studies were detected a median of 13 months after bone marrow transplantation. The four subjects who underwent transplantation without radiation therapy have remained euthyroid (median follow-up two years). The only variable that appeared to correlate with the subsequent development of impaired thyroid function was the type of graft-versus-host disease prophylaxis employed; the irradiated subjects treated with methotrexate alone had a higher incidence of thyroid dysfunction compared to those treated with methotrexate combined with antithymocyte globulin and prednisone (eight of 12 versus two of 11, p less than 0.05). The high incidence and subtle nature of impaired thyroid function following single-dose irradiation for bone marrow transplantation are discussed.

Radiobiological basis of total body irradiation with different dose rate and fractionation: Repair capacity of hemopoietic cells

Abstract Total body irradiation (TBI) followed by bone marrow transplantation is being used in the treatment of malignant or non-malignant hemopoietic disorders. It has been believed that the ability of hemopoietic cells to repair sublethal radiation damage is negligible. Therefore, several school of investigators suggested that TBI in a single exposure at extremely low dose rate (5 rad/min) over several hours, or in several fractions in 2–3 days, should yield a higher therapeutic gain, as compared with a single exposure at a high dose rate (26 rad/min). We reviewed the existing data in the literature, in particular, the response of hemopoietic cells to fractionated doses of irradiation and found that the repair capacity of both malignant and non-malignant hemopoietic cells might be greather than has been thought. It is concluded that we should not underestimate the ability of hemopoietic cells to repair sublethal radiation damage in using TBI.

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.

Fatal veno-occlusive disease of the liver following high dose chemotherapy, irradiation and bone marrow transplantation

In two patients fatal veno-occlusive disease of the liver developed after bone marrow transplantation for underlying malignancies. Both had received significant pretransplant chemotherapy, including cystosine arabinoside, and total body irradiation. The diagnosis of veno-occlusive disease should be considered in patients in whom hepatomegaly, ascites and deteriorating liver function tests develop after they have received cancer chemotherapy.

A report of the work party: comparison of total body irradiation techniques for bone marrow transplantation

The report presents a survey of total body irradiation techniques for bone marrow transplantation in nine institutions in North America and England. The survey compares their nominal dose, dose rate, point of dose prescription, type of machine used, patients position during treatment, and use of compensators. This experience has emphasized the need for a system of uniform dose reporting and for uniform dose prescription in total body irradiation.

CHANGES IN ACIDITY OF MOUSE TUMOR BY HYPERTHERMIA

The intratissue pH of SCK tumor and leg muscle of unanesthetized mice were determined before, during and after hyperthermia with the use of bulb type pH microelectrodes having pH-sensitive hemisphere 20-40 micron in outer radius. Intratumor pH was heterogeneous throughout tumor (range, 6.60-7.38; average, 6.96), and was more acidic than the intramuscle pH of mouse leg (average, 7.46). Hyperthermia at 43.5 degrees C for 30 min induced a further increase in acidity (decrease in pH of about 0.2 units) in tumor but not in muscle. The heat-induced acidity in tumor lasted for 12 hr following hyperthermia and then recovered to almost control pH value 24 hr after heating. The cause of the increase in acidity in the heated tumors is not clear, but it appears to result from an increase in the contents of acidic metabolites and a sluggish drainage of them due to induced vascular damage. The increased acidity in the heated tumors may inhibit the repair of thermal damage and sensitizes the tumor cells to subsequent heating.

Testicular function following bone marrow transplantation performed during or after puberty

Testicular function was assessed in eight males who had undergone bone marrow transplantation (BMT) during or shortly after puberty. Their ages ranged between 10 years, 10 months and 17 years, 3 months (median, 13 years, 7 months) at the time of BMT, and they were followed 13 to 77 months (median, 36 months) posttransplantation. Therapy for BMT consisted of high‐dose, short‐term chemotherapy either alone (Group I) or in combination with single‐dose irradiation, total lymphoid (Group II) or total body (Group III). Subjects in Group III had all received combination chemotherapy prior to BMT. Hormonal and clinical evidence of germ‐cell dysfunction was common in that 6 patients manifested elevated plasma levels of follicle‐stimulating hormone (FSH), and four subjects were found to have a subnormal testicular volume. Of the six patients with abnormal FSH values, four were followed serially, and all showed normalization over time. Leydig cell function was less impaired in that seven of the eight patients produced normal adult male levels of testosterone, including three subjects with elevated luteinizing hormone (LH) levels. All eight developed normal adult male secondary sexual characteristics. It is concluded that the therapy utilized for BMT causes damage primarily to germinal epithelium which appears amenable to recovery. This may be due, in part, to the use of single dose rather than fractionated radiation.

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.