Prognosis and Treatment After Relapse of Acute Lymphoblastic Leukemia and Non-Hodgkin ’s Lymphoma: I985 A Report From the Childrens Cancer Study Group W. ARCHIE BLEYER, MD,**t HARLAND SATHER, PHD,* AND G. DENMAN HAMMOND, MD*

Acute lymphoblastic leukemia and non-Hodgkin’s lymphoma constitute 42% to 45% of the cancers in infants, children, and adolescents: In 1985, an estimated 2025 children were newly diagnosed with these two cancers and 900 (43%)of the pediatric cancer deaths in the United States have been projected to be due to these diseases. The single most important obstacle to preventing these deaths is relapse, and prevention of relapse or salvage of the patient who has had a relapse continues to be a major therapeutic challenge. The most important initial step in the treatment of the child whose disease has relapsed is to determine, to the extent possible, the prognosis. In a child with non-Hodgkin’s lymphoma, a relapse confers an extremely poor prognosis, regardless of site of relapse, tumor histology, or other original prognostic factors, prior therapy, or time to relapse. In the child with acute lymphoblastic leukemia in relapse, the prognosis depends on multiple factors. The primary therapy is chemotherapy or chemoradiotherapy with marrow grafting. Other options exist, including no therapy, or investigational therapy. The therapy selected should be predicated on the prognosis. In the child with an isolated central nervous system (CNS) relapse off therapy, minimum therapy should be administered, particularly if the relapse occurred without prior cranial irradiation. In the child whose relapse is more than 6 months off therapy, conventional therapy should be considered. Also, a patient with an isolated C N S relapse on therapy after prior cranial irradiation should be given moderate therapy. Bone marrow transplantation or high-dose chemoradiotherapy with autologous marrow rescue should be reserved in children with a second or subsequent extramedullary relapse, and possibly for those with a first isolated overt testicular relapse on therapy. Cancer 58590-594, 1986.

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(ALL) and nonHodgkin’s lymphoma (NHL) represent a major portion of childhood cancers. Together they account for 42% to 45% of the cancers in infants, children, and adolescents.’ In 1985, an estimate of 2025 children in the United States were newly diagnosed to have these two malignancies, and they were projected to account for 900 (43%) of the cancer deaths in the United States among patients under 2 1 years of age.’ Thus these acute lymphoid malignancies constitute a major challenge of pediatric oncology. CUTE LYMPHOBLASTIC LEUKEMIA

From the *Departments of Pediatrics, Medicine, and Radiation Oncology, University of Washington, and the Children’s Orthopedic Hospital and Medical Center, Seattle, Washington, and $ Department of Pediatrics, University of Southern California, Los Angeles, California, and the Childrens Cancer Study Group, Pasadena, California. t American Cancer Society Professor of Clinical Oncology, University of Washington School of Medicine, Seattle, Washington. Address for reprints: Childrens Cancer Study Group, 199 N. Lake Avenue, Pasadena, CA 91 101. Accepted for publication February 24, 1986.

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The single most important determinant in preventing further deaths from these diseases is their relapse. If survival is to improve, then either relapse must be obviated or patients who sustain relapse must be salvaged. This report reviews the current status of first relapse in children with ALL or NHL, and suggests, where possible, strategies for salvage of patients in their first relapse. Materials and Methods The database for this study were patients treated by members of the Childrens Cancer Study Group (CCSG) on studies that accrued patients between 1972 and 1983. In ALL, the studies were CCG- I0 1, CCG- 143, CCG- 14 1, CCG- 141A, and the CCG- 160 series. In NHL, the patients on CCG-55 1 were evaluated. The overall treatment and study designs have been previously p ~ b l i s h e d . ~ - ~ Event-free survival is defined as any adverse event after study entry, including remission induction failure, relapse, or death in remission. Disease-free survival refers to any adverse event after successful achievement of remission,

RELAPSED ACUTELYMPHOID MALIGNANCIES Bleyer et al.

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therapy, the site or sites of relapse, the time to relapse from original diagnosis, or, in the patient who has had a relapse off treatment, the time from therapy discontinuation, the therapy before relapse, and, in some instances, the prognostic factors at original diagnosk6 Of these factors, the first one to consider is whether the child has acute lymphoblastic leukemia or non-Hodgkin’s lymphoma.

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Lymphoblostic lN=50/

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Non-Hodgkins Lymphoma If the child has NHL, the data from CCG-55 1 indicates that relapse has a very poor prognosis. CCG-55 1 was the largest study ever conducted in children with NHL, and of 234 children entered into the study, 132 had relapses, and only 10%of these have survived (Fig. 1). This low survival appears to be independent of the type of NHL (lymphoblastic or nonlymphoblastic), the site of relapse (nodal, marrow, CNS, etc.) or the type of treatment. Moreover, there is no known method to identify at the time of relapse which child in every ten will survive. Appropriate therapeutic strategies for this group includes aggressive andfor innovative therapy, or no specific anticancer therapy. If the child has nonlymphoblastic NHL, the therapy must be delivered as rapidly as possible because the rates of tumor cell proliferation and initial mortality appear to be higher in relapsed nonlymphoblastic lymphoma than they are in relapsed lymphoblastic lymphoma. In the CCG-55 1 study the difference in mortality rate was statistically significant (P < 0.001) (Fig. 1).

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Years after Recurrence FIG.I . Survivalafter recurrence of non-Hodglun’s lymphoma on CCG55 I according to histopathologic classification.

including relapse at any site and death during remission. Isolated central nervous system (CNS) relapse means that evidence for relapse is confined to the CNS. Occult testicular relapse refers to the findings on elective routine testicular biopsy of testicular leukemia. Overt testicular relapse indicates testicular leukemia with clinical symptoms or signs, usually testiculomegaly.

Results and Discussion The most important initial step in the individual child who has experienced a relapse is to determine, to the extent possible, the prognosis. The prognosis at relapse depends on a number of factors: original diagnosis (whether the child has leukemia or lymphoma), whether relapse has occurred before, whether relapse has occurred on or off

Off Therapy l N = 8 0 /

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f-00 Theropy lN=23I/ p