M E Nesbit

PRESYMPTOMATIC CENTRAL NERVOUS SYSTEM THERAPY IN PREVIOUSLY UNTREATED CHILDHOOD ACUTE LYMPHOBLASTIC LEUKAEMIA: COMPARISON OF 1800 RAD AND 2400 RAD: A Report for Children's Cancer Study Group

The Childrens Cancer Study Group has organised two therapeutic clinical trials designed to evaluate the efficacy of various types and doses of CNS prophylaxis in the treatment of childhood acute lymphoblastic leukaemia. Of 478 previously untreated patients who subsequently achieved an initial marrow remission, 299 were randomised to receive 2400 rad craniospinal radiation therapy (RT) or 2400 rad cranial RT plus intrathecal methotrexate (i.t. MTX) while the remaining 179 patients were randomised between the same two regimens using a radiation dose of 1800 rad. All patients received identical induction and maintenance chemotherapy. Comparison of the two studies indicated that reduction of the dose of CNS radiation from 2400 rad to 1800 rad did not result in a significant increase in the frequency of CNS relapse, bone marrow relapse, or death. Moreover, no significant differences were observed when analyses were done within prognostic risk groups. Randomised trials with RT doses lower than 1800 rad or with i.t. chemotherapy alone should be considered to determine the most effective and least toxic forms of CNS prophylaxis.

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.

Effects of radiation on ovarian function in long-term survivors of childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group.

The Childrens Cancer Study Group has assessed serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and pubertal development in 97 long-term female survivors of childhood acute lymphoblastic leukemia (ALL). All patients received identical induction and maintenance therapy with either 18 or 24 Gy of radiation therapy (RT) to one of the following fields: cranial, craniospinal, or craniospinal plus 12 Gy abdominal RT including the ovaries. Thirty-six percent (35 patients) were found to have above normal levels of FSH and/or LH. The percentages of elevated values for RT fields were 93% for craniospinal plus abdominal RT, 49% for craniospinal RT, and 9% for cranial RT (P less than .001). A dose-response relationship was observed between 18 Gy and 24 Gy in females receiving only craniospinal RT (P = .01). Craniospinal plus abdominal RT and abnormal FSH/LH levels were significantly associated with lack of pubertal development and delayed onset of menses. Duration of maintenance chemotherapy was not associated with abnormal gonadotropin levels or the development of secondary sexual characteristics. Additional follow-up of this cohort is needed to establish the ultimate pubertal development and fertility of these patients.

Intraocular retinoblastoma group V: an analysis of prognostic factors.

A retrospective analysis of the University of Minnesota (Minneapolis) experience with retinoblastoma is presented. Seventy-five patients were diagnosed with retinoblastoma between 1958 and 1983, of which 53 (71%) had at least one Reese-Ellsworth group V eye. Nineteen group V patients and one group II patient developed extraocular disease recurrence. The cumulative actuarial rate of recurrence at 12 years was 36% for patients with group V disease. The median time from diagnosis to recurrence for unilateral patients was seven months and for bilateral patients 28 months (P = .001). Patients developing extraocular disease had a 10-year actuarial survival rate postrecurrence of 34%. The four long-term survivors of extraocular recurrences had had isolated orbital or local soft tissue recurrences only. Features of group V patients associated with extraocular recurrences were identified by univariate life table analyses. Clinical poor-risk factors included the nongenetic form of the disease (P = .03) and male sex (P = .02). Pathologic poor risk factors included rubeosis (P = .01), undifferentiated histology (P = .03), large tumor size (P = .05), and intraocular extension to the anterior segment (P = .02), retinal pigment epithelium (P = .03), choroid (P less than .001), and optic nerve beyond the lamina cribrosa (P = .02). Treatment-associated poor-risk factors included an optic nerve length of less than 5 mm removed at enucleation (P = .003). Multivariate life table analyses demonstrated the following parameters to be independent poor-prognostic factors: optic nerve length of less than 5 mm removed at enucleation (P = .001), optic nerve involvement (P = .004), and large tumor size (P = .01). These results will help to identify patients with retinoblastoma who are at greatest risk for extraocular recurrence.

EFFECT OF ISOLATED CENTRAL NERVOUS SYSTEM LEUKAEMIA ON BONE MARROW REMISSION AND SURVIVAL IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKAEMIA: A Report for Children's Cancer Study Group

The Childrens Cancer Study Group investigated the relative efficacies of four treatments directed at the central nervous system (CNS) and other sanctuary areas in 724 children with acute lymphoblastic leukaemia (ALL). The results show that CNS relapse rates are lower in patients receiving effective treatment before CNS symptoms arise, but the bone marrow relapse rate was not significantly affected by prophylactic therapy. In patients with an initial white blood count of 50000/microliter or more, multiple CNS relapses resulted in a lower survival rate. The data from the group receiving the least effective CNS prophylaxis indicate that CNS leukaemia is not necessarily followed by bone marrow relapse and death. These observations suggest that reseeding of the bone marrow by leukaemic cells from the CNS is not a major factor in the evolution of ALL. CNS prophylaxis is of value in averting the CNS complications of ALL and those associated with its therapy, but the improved survival in childhood ALL during the past decade is probably not due to the successful prevention of CNS leukaemia. Improvements in survival are probably the result of more effective systemic chemotherapy and better general management.

Long-term evaluation of a CNS prophylaxis trial--treatment comparisons and outcome after CNS relapse in childhood ALL: a report from the Childrens Cancer Study Group.

The current status of children with acute lymphoblastic leukemia (ALL) who had developed CNS disease while being treated on protocol CCG-101 was investigated. Seven hundred thirty-six eligible patients were entered into the study between June 1972 and July 1974. All children who were greater than 18 months of age were eligible for randomization to a CNS prophylaxis trial for which one regimen gave only a short course of intrathecal methotrexate (IT MTX) as prophylaxis. All other regimens included radiation therapy as prophylaxis. Current follow-up (median, greater than 10 years) shows no significant difference by standard life-table analysis for ultimate survival, although a substantial excess of CNS episodes occurred on the IT MTX regimen. Of the 675 patients who completed induction therapy and achieved remission in the study, 100 (14.8%) developed CNS disease as the first evidence of relapse. Fifty-five of these 100 had no subsequent CNS episodes. Only 17 of these 55 patients are surviving without further relapses since the CNS episode. The median time to isolated CNS relapse was 457 days. Time to the initial CNS relapse was found to be the most important factor for predicting outcome. Thirty-five of the 55 patients with isolated relapse subsequently relapsed in the bone marrow, and of these, 32 have died. Twenty patients of the 100 with CNS disease as the first evidence of relapse developed two episodes of CNS involvement and 17 of these 20 patients subsequently relapsed in the bone marrow; only one patient survived. Twenty-five patients of the 100 have shown a pattern of chronic CNS disease with multiple CNS relapses. The overall disease-free survival for the 100 patients who developed one or more relapse was only 16%. These data demonstrate that the occurrence of a CNS relapse is an indicator of poor subsequent outcome. Comparison of results of groups receiving different CNS prophylaxis required careful consideration of the entire pattern of relapses and mortality.

SCLERODERMATOUS GRAFT-VERSUS-HOST DISEASE LIMITED TO AN AREA OF MEASLES EXANTHEM

A female patient with severe idiopathic aplastic anaemia received a successful bone-marrow transplant from her HLA-identical, mixed-lymphocyte-culture-compatible, brother. 8 months after transplantation she had localised cutaneous measles. Chronic sclerodermatous changes developed which were indistinguishable from chronic graft-versus-host disease and were limited to the areas of the original exanthem. Interaction between viral infection and minor histocompatibility differences probably resulted in graft-versus-host disease in this patient.

Randomized study of 3 years versus 5 years of chemotherapy in childhood acute lymphoblastic leukemia.

Between 1972 and 1975 the Childrens Cancer Study Group conducted two clinical trials for the treatment of newly diagnosed patients with acute lymphoblastic leukemia. Upon achieving 3 yr of continuous complete remission, 316 children and young adults were randomly allocated either to discontinue chemotherapy or to continue chemotherapy for an additional 24 mo. With a median follow-up from the time of randomization of 50 mo, those patients who received 3 yr of therapy have demonstrated a statistically non-significant yet higher incidence of bone marrow relapse as compared to those patients treated for 5 yr (p = 0.09). However, the proportion of patients surviving 5 yr from randomization is 93% for the 3-yr treatment group and 89% for the 5-yr treatment group (p = 0.27). No significant difference was observed between the randomized groups for the occurrence of testicular relapse (p = 0.12), central nervous system relapse (p = 0.17), or first occurrence of relapse or death (p = 0.24). The relapse-free survival of patients treated for 5 yr as compared to those treated for 3 yr was not significantly higher in males (81% versus 75%, p = 0.14) or females (89% versus 89%, p = 0.95). This randomized study did not demonstrate a significant difference between treatment for either 3 or 5 yr.

Successful reinduction of patients with acute lymphoblastic leukemia who relapse following bone marrow transplantation.

At the present time, there is limited information on the outcome of patients with acute lymphoblastic leukemia (ALL) who relapse after bone marrow transplantation (BMT). Intuitively, it might be expected that leukemia recurring after BMT would be refractory to further treatment. In an attempt to improve survival in patients with ALL who relapse after BMT, we used standard chemotherapy for reinduction and maintenance. Of 65 patients who relapsed following allogeneic, autologous, or syngeneic BMT, 12 elected to receive no further chemotherapy, and their median survival from relapse was 36 days (range 13 to 167 days). The 53 patients who received therapy had a significantly longer median survival of 168 days (range 18 days to 4.7 years). With multidrug induction regimens there were 29 of 52 (56%) complete remissions. Six patients are currently alive, with two off therapy. In the patients who received therapy, the following factors were independent predictors of prolonged survival: longer time from BMT to relapse; younger age at diagnosis; and the use of a preparative regimen containing fractionated total body irradiation. In conclusion, leukemia recurring after BMT remains sensitive to standard therapy in many patients. We recommend that patients with ALL who relapse after BMT receive reinduction and maintenance therapy as additional good quality survival time is achieved in patients who attain a remission.

Combined Immunosuppression Using Cyclophosphamide Plus Total Lymphoid Irradiation in Preparation for Allogeneic Marrow Transplantation in Humans

Cellular engineering using allogeneic bone marrow offers an attractive form of therapy for a variety of human immunologic and hematologic disorders. The full potential of allogeneic marrow transplantation is yet to be realized, in large part due to problems associated with graft rejection and graft versus host disease [1–5]. Graft rejection (GR) continues to provide formidable obstacles to allogeneic marrow grafting when cyclophosphamide (CY) alone or CY in combination with other agents is used for pretransplant immunosuppression [1–5]. Graft versus host disease (GVHD) has been reported to occur following all immunosuppression combinations including CY and total body irradiation, reported to date [1–5]. In the present studies, we have attempted to reduce the incidence of GR and GVHD in man using new combinations of CY irradiation, or more recently, CY combined with total lymphoid irradiation. Results to date are the subject of this report.