Preliminary results of intensive therapy of children and adolescents with acute nonlymphocytic leukemia--a Childrens Cancer Study Group report.
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Adolescent↗
Biomedical subjects
B C Lampkin
Publications and source records attributed to B C Lampkin.
Acute monoblastic leukemia: a unique subtype--a review from the Childrens Cancer Study Group.
The acute non-lymphocytic leukemias (ANLL) are generally treated as a homogeneous group. However, the literature is replete with articles alluding to distinctive features of acute monoblastic leukemia (AMoL). This review addresses the unique clinical, laboratory, epidemiological, and therapeutic features of AMoL. Leukemic monoblasts are distinguished from other cells in the myelocytic series by physical properties such as greater adhesiveness, deformability, and motility. Patients with AMoL often exhibit hyperleukocytosis, disseminated intravascular coagulation, and extramedullary involvement, particularly in the skin, gingiva, and central nervous system (CNS). AMoL occurs predominantly in adults over 40 and children under 10, fifty percent of whom are under 2 years of age at diagnosis. Its relatively common occurrence in infants parallels the high rate of proliferation of monocytes in that age group. Additionally, its occurrence in young children appears to be associated with in utero exposure to marijuana and parental exposure to pesticides and solvents. Therapeutic results are generally poor due to high rates of fatal complications during induction, induction failures, and frequent extramedullary and medullary relapses. This poor outcome is particularly noted in infants. Higher remission induction rates attained with epipodophyllotoxins and incorporation of bone marrow transplantation have not yet resulted in substantial improvement of long-term outcome. Recurrence of disease in the CNS is minimized by the use of intensive CNS presymptomatic treatment, usually incorporating irradiation. Our review suggests that unique and innovative treatment strategies are needed to improve outcome for patients with AMoL.
Adult↗
Improvement in outcome for children with acute nonlymphocytic leukemia. A report from the Childrens Cancer Study Group.
The Childrens Cancer Study Group conducted four therapeutic studies on a total of 1006 children with acute nonlymphocytic leukemia from 1972 to 1983. This report describes the therapeutic strategies of these studies and examines trends in induction rates and long-term outcome over this period. The remission induction rate has changed from 58% in 1972 to 1975 to 80% for the period 1980 to 1983, and the induction mortality dropped from 20% to 6%. Four-year survival probabilities from time of diagnosis have almost doubled from 19% to 36%. Few deaths occurred more than 5 years after diagnosis: children surviving in first remission beyond 5 years had a 92% survival rate and an 86% relapse-free survival rate over the next 5 years. In contrast, median survival after a marrow relapse was less than 6 months and the 6-year survival probability was 4%. The leukocyte count was a significant prognostic factor, and although the mortality for infants was high initially, long-term survival was not decreased.
Antineoplastic Combined Chemotherapy Protocols↗
Remission induction in children with acute non-lymphocytic leukemia using cytosine arabinoside and doxorubicin or daunorubicin: a report from the Childrens Cancer Study Group.
Four hundred ninety evaluable patients were treated on an induction regimen consisting of two to four courses of cytosine arabinoside plus an anthracycline. Overall, 78% of patients went into remission, 10% died during induction, and 12% were induction failures. For the first 152 patients, courses consisted of 7 days continuous infusion with cytosine arabinoside (Ara-C, 100 mg/m2) and 3 days of doxorubicin (30 mg/m2). Because of unacceptable toxicity, particularly for children less than 3 years of age, the anthracycline was changed to daunorubicin, and the doses of both induction drugs for children under 3 was reduced. For children aged 3 years and older the change in anthracycline was associated with a significant increase in induction failures (7% to 16%, P = .04) and a decrease in deaths (15% to 8%, P = .09). For younger children, for whom doses were also changed, the effect was greater; Mortality decreased from 29% to 1% (P less than .0001), and the remission induction rate increased from 66% to 88% (P = .005). The therapy modifications also influenced survival following remission induction: Daunorubicin-treated patients, aged 3 years and over, did significantly better than those given doxorubicin (P = .03), but the opposite was seen in younger children (P = .06). Gastrointestinal and skin toxicities and septicemia were significantly more common when doxorubicin was being used, but the extent of myelosuppression was similar for the two anthracyclines.
Age Factors↗
Familial Wiedemann-Beckwith syndrome and a second Wilms tumor locus both map to 11p15.5.
Wilms tumor of the kidney occurs with increased frequency in association with two clinically and cytogenetically distinct congenital syndromes, the Wiedemann-Beckwith syndrome (WBS) and the triad of aniridia, genitourinary anomalies, and mental retardation (WAGR). Constitutional deletions in the latter situation and similar alterations in sporadic Wilms tumors have implicated the chromosomal 11p13 region in neoplastic development. In contrast, some sporadic cases of WBS have been reported to have a constitutional duplication of chromosome 11p15. In order to resolve this seeming paradox, we have analyzed a family segregating WBS for linkage to DNA markers mapped to chromosome 11p. Consonant with the cytogenetic alterations in sporadic WBS cases, we obtained evidence for tight linkage of the mutation causing the syndrome to markers located at 11p15.5. Also consistent with this localization, we identified a subset of Wilms tumors, not associated with WBS, which have attained somatic homozygosity through mitotic recombination, with the smallest shared region of overlap being distal to the beta-globin complex at 11p15.5. These data provide evidence that familial WBS likely results from a defect at the same genetic locus as does its sporadic counterpart. Further, the data suggest there is another locus, distinct from that involved in the WAGR syndrome, which plays a role in the association of Wilms tumor with WBS.
Beckwith-Wiedemann Syndrome↗
Biologic characteristics and treatment of acute nonlymphocytic leukemia in children. Report of the ANLL Strategy Group of the Childrens Cancer Study Group.
Today approximately 75 per cent of children with ANLL can be induced into a complete remission and approximately 40 per cent will have an event-free survival for more than 3 years, irrespective of whether they received a bone marrow transplantation or chemotherapy after induction. In order to achieve these results very intensive therapy is required. The morbidity and mortality of treatment are high. The length of therapy needed after induction of remission is not known. Whether or not maintenance therapy is required is perhaps related most directly to the intensity of the therapy employed. Similarly, the role of bone marrow transplantation in patients in first remission, treatment of CNS leukemia, and treatment of chloromas are controversial. There is general agreement that WBCs over 100,000, acute monoblastic leukemia in infants less than 2 years of age, and certain chromosomal abnormalities are associated with a poor prognosis. Although there has been a dramatic improvement in the treatment of ANLL over the past 15 years, stratification of therapy based on biologic parameters, and alteration of treatment based on the early responses to treatment may be required before further advances will be made.
Acute Disease↗
Current chemotherapeutic treatment strategies in childhood acute nonlymphocytic leukemia.
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Acute Disease↗
Indications for and benefits of intensive therapies in treatment of childhood cancers.
There has been a striking improvement in the overall numbers of children and adolescents who become disease-free and remain disease-free as a result of intensive therapy as defined today, for the following cancers: acute nonlymphocytic leukemia (ANLL), non-Hodgkin's lymphoma (NHL), poor risk acute lymphocytic leukemia (ALL), osteosarcoma, and Ewing's sarcoma. The therapy for each of these tumors, with the exception of osteosarcoma, consisted of combination chemotherapy with or without radiotherapy and was started as soon after diagnosis as possible. Aggressive therapy of osteosarcoma has consisted of surgical removal of lung metastases and chemotherapy. Intensive chemotherapy recently has included the use of high doses of certain drugs such as cytosine arabinoside (Ara-C), methotrexate, VP-16-213 and melphalan in the treatment of patients with tumors that are currently difficult to treat.
Acute Disease↗
Megakaryoblastic leukemia in an infant. Establishment of a megakaryocytic tumor cell line in athymic nude mice.
A 17-month-old infant with clinical and pathologic features of acute megakaryoblastic leukemia and myelofibrosis developed soft tissue metastases. Tissue from an orbital metastasis was biopsied and transplanted into a nude mouse. Histologically the tumor was composed of pleomorphic cells with single convoluted nuclei or multilobed nuclei and prominent granular cytoplasm and had an alveolar histologic pattern in some areas. The ultrastructural features of the tumor cells include multilobed nuclei with prominent nucleoli and cytoplasmic granules with the characteristics of alpha-granules. The tumor has been successfully passaged over a 1-year interval and appears to be a stable megakaryoblastic tumor cell line (CHRF-288). Cells from the tumor line are reactive for factor VIII related antigen and also have GpIIb IIIa complex antigen on the plasma membrane surface. This tumor line may be a useful system for investigation of megakaryocytic functions including the production and regulation of the various factors they produce.
Animals↗
The use of urethane sponge matrix to assess in vivo recovery of murine cellular immunity following syngeneic bone marrow transplantation.
A unique method for assessing the in vivo recovery of cellular immunity following sublethal irradiation and syngeneic bone marrow transplantation of CBA/J mice is described. This method employs the serial surgical implantation of a urethane sponge matrix followed by impregnation of the sponge matrix with alloantigen. Sponge matrices were harvested from each mouse subject at 2 weeks, 4 weeks, and 8 weeks post transplant with and without treatment with interleukin-2. Recovery of cellular immunity was assessed as a function of cytotoxic T lymphocyte activity via cell-mediated lympholysis using chromium labeled targets. Repetitive procedures of implantation and removal of the matrices from the same animal were surgically feasible and were exceptionally well tolerated by the animals with insignificant morbidity thereby permitting continuous monitoring of immunologic recovery. Although the results of treatment with interleukin-2 were inconclusive, this method provides a sensitive, technically manageable means by which to assess an antigenic response in vivo at predetermined time intervals utilizing the same mouse subject. The method additionally affords the potential of being applicable to the in vivo assessment and manipulation of other aspects of the immune response.
Animals↗
Effects of dimaprit on growth and differentiation of human promyelocytic cell line, HL-60.
The human promyelocytic cell line HL-60, differentiates in response to a variety of agents including dibutyryl cAMP and agents which increase intracellular cAMP concentrations (phosphodiesterase inhibitors, PGE2, and cholera toxin). HL-60 is also known to be rich in H2 -histamine sensitive adenylate cyclase activity. The present study was therefore designed to test the effects of H2-stimulation on growth and differentiation of HL-60 using the potent H2 agonist dimaprit. Dimaprit markedly increased cAMP production in a dose-dependent manner reaching maximal levels after 30-60 minutes. Intracellular cAMP levels decreased thereafter and by 24 hours were approximately 2-3 fold increased above control. Intracellular cAMP levels were not altered by dimaprit (10(-7)M to 10(-4)M) at 4 days in culture compared to either untreated HL-60 cells or dimethylsulfoxide (DMSO) (1.3%) treated cells. While exponential growth was unaltered by dimaprit (10(-7)M to 10(-4)M) as compared to control, dimaprit induced i) morphologic maturation to the myelocyte and metamyelocyte form with no differentiation seen beyond the metamyelocyte even after 6 days in culture, ii) increased NBT reductase activity and iii) dose-dependent increase in lysozyme activity which could be completely blocked by cimetidine, a specific H2 antagonist. Dimaprit-induced differentiation of HL-60 cells was associated with an initial but transient increase in intracellular cAMP production. Maturation beyond the metamyelocyte stage was not observed. Acquisition of NBT reductase and lysozyme activity correlated with morphologic maturation.
Bone Marrow↗
Immunologic, morphologic and chromosomal characterization of a cell line (TC78) established from a child with acute lymphoblastic leukemia.
We characterized a cell line established from bone marrow cells from a child with acute lymphoblastic leukemia. This cell line, TC78, had lymphoblastic morphology and was cytoplasmic peroxidase and esterase negative. The cells did not have T- or B-cell properties such as E- or EAC-rosette forming ability, reactivity with monoclonal T-cell or B2 antibodies, or immunoglobulin synthesis. We concluded that TC78 was a pre-pre B-cell line based on the following monoclonal antibody staining pattern: BA-1+, BA-2+, cALLa+, Ia+, 2H7+ and OKB2+. Growth in 'Dickie' culture and reactivity with 1G10 myeloid antibody suggested coexpression of lymphoid and myeloid characteristics. However, 1G10 expression proved dependent on culture conditions, illustrating one caveat in application of monoclonal antibodies in lineage determination.
Antigens, Neoplasm↗
Solid malignancies in children and adolescents.
The cure rate in childhood cancer has improved markedly during the past 20 years. In the 1960s the cure rate was about 20 to 30 per cent, but today more than 50 per cent of children and adolescents with cancer are being cured. This improvement is principally due to multidisciplinary teamwork in diagnosing, staging, and treating children with cancer; newer and more chemotherapeutic agents; and a recognition that combination therapy consisting of surgery, radiotherapy, and chemotherapy is frequently indicated.
Adolescent↗
Correlation of chromosome abnormalities with patient characteristics, histologic subtype, and induction success in children with acute nonlymphocytic leukemia.
Cytogenetic analyses of bone marrow cells were performed in 195 children with acute nonlymphocytic leukemia (ANLL) at diagnosis, as part of Childrens Cancer Study Group Study No. 251. Ninety-six patients (49%) exhibited clonal abnormalities, including trisomy 8 in 18 patients, t(8;21) in 11, t(15;17) in seven, loss of a sex chromosome in seven, monosomy 7 in seven, and the Philadelphia chromosome in four. Clonal abnormalities were found significantly more often in younger patients. Furthermore, recurring cytogenetic abnormalities tended to correlate with specific ages. For example, t(8;21) was associated significantly with children over four years of age, while -7 associated with overall loss of genetic material from the long arm of chromosome 7 (7q) and 11q- were associated significantly with younger children. Recurring chromosome abnormalities also correlated with specific ANLL histologic subtypes, such as t(8;21) with acute myelogenous leukemia and t(15;17) with acute promyelocytic leukemia. Presence or absence of cytogenetic abnormalities was compared with the ability of patients to achieve remission. Individuals exhibiting clonal abnormalities in bone marrow cells had an equally likely chance of achieving remission (74%) as those individuals with normal karyotypes (75%). Nonrandom chromosome abnormalities associated with a high induction success rate included +8 with a 94% induction success rate (P = .13) and t(8;21) with a 91% success rate (P = .46). Patients exhibiting the -7 abnormality associated with overall loss of 7q had a significantly less successful induction outcome, with only 28% achieving remission (P = .02); three of seven patients with t(15;17) died during induction therapy.
Acute Disease↗
Phase II trial of a complex polyriboinosinic-polyribocytidylic acid with poly-L-lysine and carboxymethyl cellulose in the treatment of children with acute leukemia and neuroblastoma: a report from the Children's Cancer Study Group.
Therapeutic efficacy and toxicity were evaluated in 28 children with acute lymphoblastic leukemia, in ten with acute nonlymphoblastic leukemia (ANLL), and in 13 with metastatic neuroblastoma. All were refractory to standard chemotherapeutic agents and 25 were refractory to an investigational drug. The initial dose was 12 mg/m2/day and was based on an established maximal dose tolerated in adults. This dose was found to be intolerable in 5 of 5 children with leukemia. Similarly an initial dose of 9 mg/m2/day was intolerable in 4 of 5 patients with leukemia. The starting dose in the next 28 children with leukemia or neuroblastoma was 3 mg/m2. This drug was gradually increased to the highest tolerated dose by 3-mg/m2 increments. Fifteen children with acute lymphoblastic leukemia, 3 children with ANLL, and 2 children with neuroblastoma received the drug daily. Seven patients with ANLL and 7 patients with neuroblastoma received the drug biweekly. Seventeen patients with acute lymphoblastic leukemia, 6 patients with ANLL, and 5 patients with neuroblastoma had an adequate trial of the drug. An adequate trial was defined as a minimum of 5 weeks of therapy unless progressive disease developed. Side effects of the drug were striking and included fever, hypotension, myalgia, bone pain, arthralgia, arthritis, abdominal pain, liver toxicity, thrombocytopenia, and neurotoxicity. No complete remission occurred although interferon levels above 100 units/ml were induced in nearly 50% of the patients.
Acute Disease↗
Phase II trial of poly(I,C)-LC, an interferon inducer, in the treatment of children with acute leukemia and neuroblastoma: a report from the Children's Cancer Study Group.
A Phase II study of poly(I,C)-LC was performed in 28 children and adolescents with acute lymphoblastic leukemia (ALL), 10 with acute nonlymphoblastic leukemia (ANLL), and 13 with metastatic neuroblastoma. All were refractory to standard chemotherapeutic agents and 25 to an investigational drug. Initial doses of 12 mg/m2 and 9 mg/m2 were intolerable. However, 9 mg/m2 was tolerable in the majority of patients when the drug was started at 3 mg/m2 and increased by 3 mg/m2 increments. Fifteen children with ALL, three with ANLL, and two with neuroblastoma received the drug daily. Seven patients with ANLL and seven children with neuroblastoma received the drug biweekly. Twenty-eight patients received an adequate trial, which was defined as a minimum of 5 weeks at the maximal tolerated dose, unless there was progressive disease at the maximal tolerated dose. Side effects of the drug were striking, and included fever, hypotension, myalgia, bone pain, arthralgia, arthritis, abdominal pain, liver toxicity, thrombocytopenia, and neurotoxicity. No complete remissions occurred in spite of interferon levels above 100 U in nearly 50% of patients.
Acute Disease↗
Cell kinetics as related to treatment of patients with acute nonlymphoid leukemia.
Much has been learned about normal and leukemic cell kinetics and the effect of drugs on the cell cycle by using classical kinetic techniques in patients with acute nonlymphoid leukemia (ANLL). It was found that in most cases leukemic cells proliferate slower than normal cells. Immature cells after division either died, entered into a resting state, or re-entered the cell cycle. However, classical kinetic features were inconclusive when used as predictors of prognosis. Most drug studies were done by measuring the percent of cells in various phases of the cell cycle from samples of bone marrow obtained before and after giving a drug or drug combination. All drugs used commonly in the treatment of ANLL, except 6-thioguanine, were evaluated singly and some in combination. Some phase of the cell cycle was affected by all of the drugs in most patients. The percent of cells arrested and the time of greatest response varied with the dose. When the kinetic studies were done after giving drugs sequentially, the location of effect and the length of the effect were the same as that seen when the drugs were given singly. More studies are needed using known principles of cell kinetics and bone marrow culture technology. More information about leukemic stem cells can be learned, subsets of patients with ANLL may be more clearly defined, and new treatment protocols may be designed.
Adult↗
Spontaneous remission of presumed congenital acute nonlymphoblastic leukemia (ANLL) in a karyotypically normal neonate.
A 3-hour-old phenotypically normal girl was transferred to Children's Hospital Medical Center because of skin nodules, hepatosplenomegaly, and marked leukocytosis. The predominant cells in the blood, bone marrow, and dermis were monoblasts consistent with congenital leukemia. Known causes of leukemoid reactions were excluded. The infant received two double-volume exchange transfusions but no chemotherapy. As the white blood cell counts decreased, the monocytic cells became more mature, suggesting that the monoblasts had the ability to differentiate. The proliferative capacity of the marrow appeared to be normal as determined by the ability of marrow cells to form colonies in soft agar. Chromosomal analysis of bone marrow blasts including trypsin--Giemsa banding was normal. Three weeks after birth the patient's CBC and physical examination were normal, and the bone marrow was normal by 4 months of age. The patient has remained in remission for over 3 years.
Age Factors↗