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We examined the results of stopping therapy in children with acute lymphocytic leukemia. Of 639 patients in eight consecutive "total therapy" studies, 278 (44 per cent) had all treatment stopped, usually after 2 1/2 years of complete remission. About one fifth (55 of 278) of this group have relapsed, mainly in the bone marrow. The relapse rate for the first year off therapy was higher than that for the next three years (0.16 vs. 0.04, P less than 0.01). The life-table estimates of the four-year relapse rates were 0.24 for all patients and 0.22 for patients receiving adequate central-nervous system prophylaxis. Boys had a higher relapse rate than girls (0.33 vs. 0.15 P less than 0.01). None of the 79 patients who remained in complete remission for at least four years off therapy have yet relapsed. Acute lymphocytic leukemia appears curable in over one third of all newly diagnosed patients who receive treatment for approximately 2 1/2 years.

Ninety-seven children with either acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) received HLA-identical bone marrow transplants from sibling donors, after preparation with 1320 cGy of hyperfractionated total-body irradiation and high-dose cyclophosphamide. Kaplan-Meier product-limit estimates (means +/- SE) of disease-free survival at five years among patients with ALL in second remission, third remission, and fourth remission or relapse were 64 +/- 9, 42 +/- 14, and 23 +/- 11 percent, respectively, with probabilities of relapse of 13 +/- 7, 25 +/- 13, and 64 +/- 16 percent. Among patients with AML in first remission, second remission, and third remission or relapse, five-year disease-free survival estimates were 66 +/- 10, 75 +/- 15, and 33 +/- 19 percent, with respective relapse probabilities of 0, 13 +/- 12, and 67 +/- 19 percent. The most frequent cause of death in patients in early remission (ALL in second or third remission or AML in first or second remission) was bacterial sepsis, fungal sepsis, or both, most often in the presence of acute or chronic graft-versus-host disease. Among patients with ALL who received transplants while in second remission, the duration of the initial remission had no effect on the probability of relapse after transplantation. The only pretransplantation factor that significantly affected outcome was the disease status at the time of transplantation; patients in early remission had better disease-free survival. We conclude that transplantation after preparation with hyperfractionated total-body irradiation and cyclophosphamide is an effective mode of therapy in children with refractory forms of acute leukemia.

Chemoradiotherapy and transplantation of bone marrow from matched sibling donors have been useful for the treatment of acute lymphoblastic leukemia in patients with a poor prognosis but are not available to some two thirds of patients who do not have a matched allogeneic donor. We undertook this study to compare autologous and allogeneic marrow transplantation in the treatment of such cases. We treated 91 patients with high-dose chemoradiotherapy and followed them for 1.4 to 5 years. Forty-six patients with an HLA-matched donor received allogeneic marrow, and 45 patients without a matched donor received their own marrow taken during remission and purged of leukemic cells with use of monoclonal antibodies. Bone marrow engraftment occurred earlier in patients who received autologous marrow. Recipients of autologous marrow had shorter hospital courses, with significantly fewer peritransplantation deaths than recipients of allogeneic marrow. Post-transplantation relapse of leukemia was the most frequent cause of treatment failure; relapses occurred in an estimated 37 percent of patients with allogeneic grafts in whom graft-versus-host disease developed, 75 percent of patients with allogeneic grafts in whom graft-versus-host disease did not develop, and 79 percent of patients who received autologous grafts. The interval before relapse was significantly shorter in the autologous-marrow group than in the allogeneic-marrow group. Recipients of autologous and allogeneic marrow whose first pretransplantation remissions were short (less than 18 months) had eventual outcomes similar to those whose first remissions were longer than 18 months. Patients with a first remission lasting less than 18 months had an outcome better than that expected with chemotherapy alone. The fractions of "cured" patients were estimated to be 20 percent in the autologous-marrow group and 27 percent in the allogeneic-marrow group--not a significant difference, but because of the limited statistical power of the study, the question of long-term disease-free survival must still be considered open.

The progress of 24 children with acute lymphoblastic leukemia treated with cyclophosphamide, total-body irradiation, and marrow transplantation during a second or subsequent remission was compared with that of 21 children treated with conventional chemotherapy after they had entered a second remission. Eleven of the transplantation group are alive, including nine in continuing complete remission for 17 to 55 months; only two of the chemotherapy group are alive, one in complete remission after 20 months. Relapse was the major cause of failure in both groups. Acute and chronic graft-versus-host disease in the transplantation group and leukoencephalopathy in both groups were the other major causes of morbidity and mortality. This study demonstrates that marrow transplantation currently offers the best chance of long-term remission and potential cure after a child with acute lymphoblastic leukemia has had a relapse in the marrow.

To determine the clinical importance of immunophenotypes in adult acute lymphoblastic leukemia (ALL), we prospectively studied 76 patients with this condition. Before treatment, lymphoblasts were tested for reactivity with monoclonal antibodies to B-cell, T-cell, and myeloid (My) antigens. Unexpectedly, myeloid antigens (MCS-2 or MY9) were identified in 25 patients (33 percent), usually in conjunction with B-cell or T-cell antigens. Among My+ patients, 15 (60 percent) expressed B-cell antigens (B+T-My+); all 6 tested had rearranged immunoglobulin genes. Five patients (20 percent) expressed T-cell antigens (B-T+My+), and one My+ patient expressed both B-cell and T-cell antigens. Only myeloid antigens (B-T-My+) were expressed in four patients (16 percent); three who were tested had germ-line immunoglobulin and T-cell-receptor gene configurations. Although no significant differences in presenting clinical features were found, My+ patients had fewer complete remissions than My- patients (35 vs. 76 percent, P less than 0.01). No differences in response or survival were observed between My+ and My- patients expressing T-cell antigens. However, among those expressing B-cell antigens, My+ patients had fewer complete remissions (29 vs. 71 percent, P = 0.02) and shorter survival (P = 0.03; median, 8.1 vs. greater than 26 months). These findings indicate that expression of myeloid antigen identifies a high-risk group of patients with adult ALL for whom alternative forms of treatment should be investigated.

Chronic lymphocytic leukemia is recognized as having a variable prognosis, but its staging has depended exclusively on anatomical sites of involvement and the presence or absence of anemia and thrombocytopenia. The recent availability of techniques permitting cytogenetic analysis of malignant B lymphocytes led us to examine the karyotypic abnormalities in chronic lymphocytic leukemia and to correlate them with clinical stage, progression of disease, and survival. Of 53 patients with metaphases adequate for study who were followed for a minimum of one year, 21 (40 per cent) had abnormal karyotypes, of which trisomy 12 was the most frequent (25 per cent). Abnormal karyotypes were found to be significant correlates of advanced clinical stage (P less than 0.005) and of shortened survival (P less than 0.05). We conclude that cytogenetic analysis provides useful clinical and prognostic information in patients with chronic lymphocytic leukemia.

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.

We prospectively assigned 289 consecutive children with acute lymphoblastic leukemia to receive one of two treatment programs on the basis of the presence or absence of certain risk factors at the time of diagnosis. Patients at high risk (62 percent of the total) had one or more of the following risk factors: age below two or above nine years, a white-cell count of 20,000 per cubic millimeter or more, the presence of T-cell immunologic markers, radiologic evidence of a mediastinal mass, and involvement of the central nervous system. Patients in both the standard-risk and high-risk groups were treated for two years, receiving intensive remission-induction therapy, central nervous system prophylaxis, weekly administration of high-dose asparaginase, and multiple-drug continuation therapy (which in the high-risk group included doxorubicin and a larger dose of prednisone). At a median follow-up of 35 months, the mean (+/- SE) event-free survival rates at four years among the patients in the standard-risk and high-risk groups were 86 +/- 4 percent and 71 +/- 4 percent, respectively (P = 0.003), for a total event-free survival of 77 +/- 3 percent. Within the high-risk group, the white-cell count at diagnosis and the sex of the patient were not significant prognostic indicators, but age below 12 months at diagnosis was associated with a very poor outcome. As compared with previous methods, this treatment program using four-drug induction and intensive asparaginase therapy has resulted in improved event-free survival in children with acute lymphoblastic leukemia.