A clinical perspective on cell markers in acute lymphocytic leukemia.

Two hundred consecutive new patients, with acute lymphocytic leukemia (ALL) have been studied with a battery of five cell marker assays to determine if a classification system with prognostic significance can be developed; 182 have been classified among four groups as follows: 33 T-cell, 3 B-cell, 126 common, and 20 undifferentiated ALLs. Patients with T-cell disease are likely to have unfavorable clinical prognostic features and a poor response to therapy. Rare patients with B-cell disease are closely related clinically to non-Hodgkin's lymphoma. Those with common ALL infrequently have unfavorable clinical features and have a superior outcome to that of T-cell patients. Children with undifferentiated markers seem to respond less well to treatment than do those with common ALL, yet may not be identifiable as poor risk by clinical features. What remains to be resolved with further observation is whether these marker patterns are more reliable indicators of prognosis than the usual clinical determinants predisposing to treatment failure (high white blood cell count, mediastinal mass, and central nervous system disease). At the present time, it appears that in the absence of poor-risk clinical prognostic features, patients with common ALL are more likely to have lasting remissions than those with erythrocyte-rosette-positive T-cell disease or those with ALL that is undifferentiated by markers.

Failure of late intensification therapy to improve a poor result in childhood lymphoblastic leukemia.

This clinical study, begun in 1975, tested the efficacy of early and delayed intensification treatments in children with acute lymphoblastic leukemia. Regardless of presenting features, all patients received 4 weeks of conventional induction therapy with daily prednisone and weekly vincristine and daunorubicin. One-third were randomized to receive, in addition, two doses of asparaginase during induction therapy, while another one-third received four doses of both asparaginase and cytarabine after remission induction. Preventive central nervous system therapy uniformly included 2400 rads cranial irradiation and five doses of intrathecal methotrexate. Remissions were maintained with daily p.o. mercaptopurine and weekly i.v. methotrexate. Of the 277 assessable patients, 254 (92%) entered complete remission, and 102 (37%) remain clinically free of leukemia for 4.6 to 8.0 years (median, 6.3 years). The three treatment groups showed no significant differences in either remission induction rate or outcome, even when the analysis was based on risk assignment. A "late intensification" phase of therapy, added to the maintenance protocol for 65 patients who had been in continuous complete remission for 14 to 30 months, failed to extend remission durations, as judged from statistical comparison with matched controls (p = 0.84). When tested as a time-dependent covariate in the Cox proportional-hazards model, delayed intensification again showed no important effect on duration of complete remission. We conclude that limited early or aggressive late intensification of therapy, as described here, does not improve outcome in childhood acute lymphoblastic leukemia.

Isolated testicular relapse in acute lymphocytic leukemia of childhood: categories and influence on survival.

Isolated testicular relapse complicating first hematologic remission was identified in 31 of 521 boys with acute lymphocytic leukemia (ALL). Three categories of involvement were apparent and could be related to presenting clinical features, duration of initial complete remission, and length of hematologic remission. Among 12 patients with early testicular relapse, most had unfavorable prognostic features when ALL was first diagnosed. All but two of these children experienced marrow recurrence within seven months of testicular relapse. In contrast, the 12 patients who developed testicular disease late in their clinical course have responded much better to further therapy; ten remain in bone-marrow remission for a median of four years beyond testicular relapse. Similarly, five of the seven patients with subclinical testicular leukemia, found at elective biopsy, continue in marrow remission for prolonged periods. Early testicular recurrence is a sign of drug-resistant disease; late recurrence after elective cessation of therapy may represent residual, incompletely treated but still responsive leukemia.

Central nervous system morbidity following an initial isolated central nervous system relapse and its subsequent therapy in childhood acute lymphoblastic leukemia.

The frequency and types of major CNS toxicity and morbidity were analyzed in 107 children with acute lymphoblastic leukemia (ALL) following an isolated primary CNS relapse. Seventy-nine (73%) have had multiple subsequent marrow or CNS relapses requiring intensive and prolonged therapy to the CNS. Median survival time is two years. Of these 79 patients, two thirds have had one or more types of major CNS toxicity, including epileptiform seizures (35), moderate to severe structural abnormalities (24 of 27 evaluated), major motor disabilities (9), blindness (2), CNS infection (6), cranial nerve palsies (2), and intracranial lymphoma (2). The remaining 28 patients (26%) have had no or one additional CNS relapse and have received therapy for a median of eight years. One half of this surviving group of patients have had major CNS toxicity, including seizures (9), major motor disability (2), and intracranial calcifications (12/19). When neuropsychologic evaluations were compared between the 28 survivors and 50 of their contemporaries who had been in initial continuous complete remission, the CNS survivors had significantly lower Full Scale IQ scores (83 +/- 16 v 99 +/- 14, P = less than .001) with similarly lower measures of academic performance. The relative contributions of meningeal leukemia itself and intrathecal or radiation therapy to these effects cannot be determined. Since major CNS sequelae occurred in the majority of patients who had a primary isolated CNS relapse, and the frequency of CNS relapse is dependent on the efficacy of the method of CNS prophylaxis, the best method of avoiding major CNS sequelae is the most effective form of CNS prophylaxis.

Immunophenotypic and age patterns of childhood acute lymphoblastic leukemia in Saudi Arabia.

Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood in the West, characteristically showing a peak incidence in children aged between two and five years, and being predominantly of the common ALL (cALL) phenotype. In this article, we examine the hypotheses that ALL is relatively less common among childhood malignancies in Saudi Arabia; that the cALL phenotype is uncommon; that T cell ALL (TALL) is relatively more common. We report that of 163 children with ALL seen at the King Faisal Specialist Hospital and Research Centre, we find that their median age was 5.0 years with a modal value of 3 years, with a range of 4 months to 14 years; that there were 93 cALL patients who were predominantly young (median age 5.0 years). There were 20 (12.3%) patients with TALL, whose median age was 8.5 years, 35 (21.5%) patients who were null cell ALL and whose median age was 6.0 years, 14 (8.6%) patients with B cell ALL whose median age was 9.0 years, and 3 (1.8%) patients with mixed phenotype ALL. We also identify a group of 6 (3.7%) patients whose blasts were CD10 negative and showed B cell differentiation without surface membrane immunoglobulin. We conclude that age and phenotypic characteristics of ALL patients are mainly similar to ALL in the West but that L3 was much more common. A small group of six patients showed unusual B cell phenotype and require further evaluation and analysis.

Fine-needle aspiration biopsy (FNAB) diagnosis of testicular involvement in acute lymphoblastic leukemia in children.

A series of 106 fine-needle aspiration biopsy specimens obtained from the testes of children with acute lymphoblastic leukemia was reviewed retrospectively. Involvement by leukemia was seen in 34, there was no evidence of disease in 52, and the cellular sample was inadequate in 20. All aspiration smears, except those with leukemic involvement, showed a variable number of Sertoli cells. Testicular leukemia was diagnosed by the presence of numerous leukemic cells and rare or no Sertoli cells. Fine-needle aspiration biopsy is a simple but effective technique for diagnosing leukemic involvement of the testis in children with acute lymphoblastic leukemia.

[Leopard spot chorioretinopathy. Initial manifestation of recurrent acute lymphocytic leukemia]. / Leopardenfleck-Chorioretinopathie. Erstes Anzeichen eines Rezidivs einer akuten lymphozytischen Leukämie.

An 11-year-old girl with a history of acute lymphocytic leukemia of the central nervous system had attained complete remission for almost 3 1/2 years after combination chemotherapy and radiotherapy when she developed iritis and chorioretinopathy of the right eye. Neither an anterior chamber tap nor a diagnostic vitrectomy revealed leukemic cells. Both nonspecific anti-inflammatory therapy and antiviral treatment were unsuccessful. Finally, lymphoblasts were detected in the cerebrospinal fluid and in the bone marrow after repeated lumbar puncture and bone marrow aspiration. Combination chemotherapy alone was resumed, resulting in the resolution of all acute ocular symptoms and bone marrow involvement. Only the leopard-spot-like pigmentary fundus changes persisted. The child has now remained in continuous complete remission for 1 1/2 years.

Childhood acute lymphocytic leukemia.

Childhood ALL is a potentially curable disease. All children suffering from this ailment should be given an opportunity to live by receiving therapy aimed at permanent cure. The disease requires extensive, complex, and costly diagnostic study and treatment. Specialized care is more efficiently given in centers dedicated to treating patients with malignant diseases. The referring physicians are an essential part of the working team delivering care to the children with acute leukemia. Despite improved results, a significant number of patients fail to develop permanent remission. The risk of relapse after cessation of therapy is greatest in the first year and in patients given no specific CNS therapy. However, modern therapy produces a substantial number of long-term leukemia-free survivals in children with ALL, a majority of which persist after cessation of therapy. After cessation of therapy the quality of survival of the vast majority of patients is excellent.

Cyclophosphamide-induced hemorrhagic cystitis in children with leukemia.

The records of 314 children with acute lymphocytic leukemia (ALL) were reviewed to determine the frequency, clinical and laboratory features; contributing factors; and prognosis of cyclophosphamide-induced hemorrhagic cystitis. Twenty-five well-documented cases of hemorrhagic cystitis were identified. While most of the affected children suffered a mild transient illness, 1 patient died as a result of bladder hemorrhage. The doses of cyclophosphamide received by these children ranged widely and did not correlate with the severity of the cystitis. The frequency of this complication did not differ significantly with sex, age or route of administration. However, cystitis was over twice as frequent in black children as in white. Nineteen of 25 cases occurred in the spring and summer months. The group of affected children did not differ significantly from a matched control group in terms of total drug dosage received, incidence of systemic toxicity, mean urine specific gravity, or overall survival.

Non-Hodgkin's lymphoma in children.

The clinical and pathological features of 64 children with non-Hodgkin's malignant lymphoma seen between April 1962 and June 1973 are described. Forty-one children had diffuse, undifferentiated, non-Burkitt lymphoma (lymphoblastic lymphoma). They tended to be boys under 10 years of age and their median survival was 1 year. Almost one-third are surviving for 1-11 years, most in initial complete remission. Nineteen children had diffuse, poorly differentiated, histiocytic lymphoma. They tended to be boys more than 10 years of age, their median survival was only 6 months, and only the 3 patients with Stage I peripheral node tumour survived. Two children had nodular, lymphocytic, poorly differentiated lymphoma and 2 had lymphoma resembling the Burkitt type. From our clinical and pathological observations, we conclude that non-Hodgkin's malignant lymphomata in children cannot be separated from the acute lymphocytic, histiocytic and unclassified leukaemias by cytological or histological methods. What is called diffuse, undifferentiated, non-Burkitt type, or lymphoblastic lymphoma is actually acute lymphocytic leukaemia without apparent invasion of marrow and peripheral blood by neoplastic lymphocytes at time of diagnosis. What is termed diffuse, histiocytic lymphoma is acute histiocytic leukaemia without apparent infiltration of marrow and peripheral blood at initial presentation. One could say just as well that acute lymphocytic leukaemia is Stage IV lymphoblastic lymphoma and that acute histiocytic leukaemia is Stage IV histiocytic lymphoma. Further classification of lymphocytic and histiocytic cancers by newer functional, chemical and morphological methods should include both what is called lymphocytic or histiocytic leukaemia and what is called non-Hodgkin's lymphoma as one group of diseases, susceptible to subclassification by the new methods. We recommend that Stage I lymphocytic and histiocytic cancers be treated with local irradiation. Patients with Stages II-IV tumours should receive anti-leukaemic forms of therapy including prolonged multiple agent chemotherapy and preventive central nervous system irradiation. Staging laparotomy should be considered in patients with Stage I tumour in low cervical, axillary and inguinal nodes.

Multiple dysmorphic features and pancytopenia: a new syndrome?

Various degrees of bone marrow aplasia have been described in association with distinctive congenital anomalies such as the Fanconi Pancytopenia Syndrome (F.P.S.), Thrombocytopenia Absent Radii Syndrome (T.A.R. Syndrome) the Aase Syndrome and Diamond-Blackfan Anemia. This case report describes a child with pancytopenia and several dysmorphic features which have never collectively been described in any of the bone marrow aplasia syndromes listed above. In this paper, we report a constellation of dysmorphic features and pancytopenia which may constitute a new syndrome.

Risk factors for hyperglycemia in children with leukemia receiving L-asparaginase and prednisone.

We determined retrospectively the frequency and risk of hyperglycemia in 421 children with leukemia who had received L-asparaginase and prednisone as part of their remission induction therapy. Forty-one patients (9.7%) developed this complication, 39 within one week after the first dose of L-asparaginase. Hyperglycemia resolved in all patients and in 32 before the end of the four-week induction period. Age, obesity, and Down syndrome each had a significant bearing on the frequency of hyperglycemia. Children 10 years of age or older were more likely to develop the complication than were younger children. When more than one factor was present in a child, the risk of hyperglycemia increased significantly. A family history of diabetes mellitus also appeared related to an increased risk of hyperglycemia. Childhood leukemia patients with any of the risk factors identified here should be closely monitored for glucosuria while receiving prednisone and L-asparaginase for remission induction.

Phase I study of neocarzinostatin in children with cancer.

Twenty-three children with advanced cancer refractory to conventional therapy received weekly iv doses of neocarzinostatin for 5 weeks. Doses were escalated from 500 to 6750 units/m2/week. Four types of toxic manifestations occurred: acute reactions consisting of shaking chills with or without fever and cyanosis (rigor), hypersensitivity, vomiting, and marrow depression. Evidence of oncolytic activity was limited to patients with acute leukemia in whom phase II trials at doses between 3000 and 4500 units/m2 appear warranted.

A reappraisal of the results of stopping therapy in childhood leukemia.

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.

Endodermal sinus (yolk sac) tumor in infants and children. A clinical and pathologic study: an 11 year review.

We reviewed the clinical features, treatment, and results of children with gonadal and extragonadal yolk sac (endodermal sinus) tumors seen in the King Faisal Specialist Hospital and Research Centre between 1976 and 1987. There were nine children (seven girls and two boys) with ages ranging from 7 months to 12 years (median of 3.5 years). Sites of origin included the vagina (two cases), face (two cases), sacrum (two cases), mediastinum (one case), ovary (one case), and testicle (1 case). All children had elevated alpha-fetoprotein (AFP) at diagnosis. One girl had complete surgical excision of an ovarian tumor at the time of diagnosis, and one boy had surgical excision of the testis. In the remaining seven children, the tumor was unresectable. Surgery was limited to a biopsy in six children. All patients received different combinations of chemotherapy, including vincristine (VCR), actinomycin D (Act-D), cyclophosphamide (Cyclo), adriamycin (Adria), bleomycin (Bleo), cis-platinum (CDDP), vinblastine (VBL), and VP-16. Of the nine patients, one was lost to follow-up while in remission, five died, one was lost to follow-up, and three are alive and disease-free at 15, 55, and 67 months from diagnosis. This review demonstrates an unusual preponderance of the extragonadal form of endodermal sinus tumor among our patients.