Characteristics of children with acute nonlymphocytic leukemia in long-term continuous remission: A report for childrens cancer study group

Children and young adults less than 18 years of age with acute nonlymphocytic leukemia who remained in long term bone marrow and extramedullary remission for two years or longer since starting maintenance were compared to the remaining responders for the following characteristics: cell type, sex, age at diagnosis, race, pretreatment, white blood count, length of time from start of induction therapy to achievement of an M1 marrow, marrow rating at day 56 of therapy, marrow rating at the start of maintenance therapy, and specific study. Forty-eight patients of a group of 333 qualified as having long term remission (14.4%). Multivariant analysis indicated that patients between the ages of 3 and 10 years (p = 0.003) as well as the length of time to achieve an M1 marrow from the start of treatment (p = 0.03) were the only characteristics associated with achievement of a long term remission. Maintenance therapy was discontinued in 15 patients from 2.5 to 4.8 years after start of maintenance and all patients remained in bone marrow remission for periods from 0+ to 3.0+ years after stopping treatment. Of the 33 who have remained on a continuous maintenance therapy 12 have had bone marrow relapses. These data confirm the prognostic value of age and length of time to achieve remission during induction in acute nonlymphocytic leukemia and suggest that there may be no significant benefit from maintenance therapy continued beyond 2 years for patients in their initial remission.     

Acute myeloblastic leukemia following non-hodgkin lymphoma in an adolescent. A report of a case with preleukemic syndrome,and review of the literature

Reports of acute nonlymphoblastic leukemia occurring after successful treatment of Hodgkin and non-Hodgkin lymphoma (NHL) are appearing with increasing frequency. Two years after completion of LSA²-L² therapy for stage III, poorly differentiated lymphocytic lymphoma, a 16-year-old boy developed a preleukemic state characterized by a refractory macrocytic anemia with excess blasts, dyshematopoiesis, abnormal cluster:colony ratio on in vitro bone marrow culture, and acquired deficiencies of erythrocyte pyruvate kinase, triose phosphate isomerase, and adenylate kinase. Four months later acute myeloblastic leukemia was evident. The RNA index determined by flow cytofluorometry was increased. Four marker chromosomes were found and involved complex translocation of chromosomes 11 and 17 (t11;17) in 100% of the cells, and chromosome 4 (t4q;4) in 10% of the cells. A thorough literature search uncovered four other reports of acute nonlymphoblastic leukemia occurring in children treated for NHL and a total of 58 cases in the adult and pediatric age groups. Over 50% of the patients had AML, were men over 50 years of age, and were treated with radiotherapy and chemotherapy. It is anticipated that additional cases of second malignancies will be reported in this population of patients whose outlook for the curability of the primary malignancy is 75%.     

Prolonged second remissions in childhood acute lymphocytic leukemia: A report from the childrens cancer study group

To date, median duration of second and subsequent remissions in childhood acute lymphocytic leukemia (ALL) has been short, with most studies reporting median remission duration less than 6 months. In May 1979, the Childrens Cancer Study Group (CCSG) undertook a pilot study to assess the efficacy of a vincristine, methotrexate, and L-asparaginase regimen (modified Capizzi) for maintenance in children with ALL in second or subsequent remission. Thirty patients were treated with this maintenance regimen. By life table analysis, predicted median duration of hematologic remission was 57 weeks. Ten patients (33%) were in continuous hematologic remission at 1 year and three (10%) continue in remission > 2 years from maintenance onset. Major toxicity included leukoencephalopathy in four patients, three of whom had experienced at least one central nervous system relapse prior to study entry. Allergic reactions to Escherichia coli L-asparaginase were common. Nine of 30 patients experienced at least one CNS relapse during therapy. We conclude that a modified Capizzi regimen is the most effective regimen reported to date for maintaining second and subsequent remission in childhood ALL. CCSG is currently utilizing this regimen in an ongoing open study.     

Treatment of advanced stage diffuse,small non-cleaved cell lymphoma in childhood: Further experience with total therapy B

Prior to the development of intensive treatments for patients with advanced stage B-cell non-Hodgkin's lymphoma (B-NHL), the prognosis for such patients was dismal. A minority of patients attained long-term, disease-free survival. Since 1981, we have treated 28 children with advanced stage B-NHL with an intensive chemotherapeutic protocol, Total Therapy B. This regimen employs cycles of fractionated high-dose cyclophosphamide, doxorubicin, and vincristine alternating with sequential infusions of high-dose methotrexate and escalating doses of cytarabine, in addition to intensive intrathecal therapy. The planned duration of therapy is approximately 6 months. Two patients had B-cell acute lymphoblastic leukemia and 26 had stage III B-NHL; none had CNS involvement. The median age was 7 years. All 28 patients achieved complete remission (CR). Both patients with B-ALL and 21 of 26 with stage III B-NHL remain in CR, with a median follow-up of 51 months. Treatment failures included 3 patients with recurrent or progressive disease, 1 toxic death in CR, and 1 patient who developed a secondary mediastinal T-cell lymphoblastic lymphoma 4 1/2 years after the diagnosis of B-NHL. The 2- and 5-year event-free survival rates were 85.7 ± 6.6% (SE) and 79.6 ± 8.5%, respectively. Total Therapy B is a highly effective therapy for children with advanced stage B-NHL without CNS involvement. © 1994 Wiley-Liss, Inc.     

Vindesine: A phase II study in childhood malignancies-A report for cancer and leukemia group B

Vindesine, a semisynthetic derivative of vinblastine sulfate, was tested for anti-tumor activity and clinical toxicity in 36 children. The drug was administered to the initial 13 patients entered into the study a 2 mg/m²/day for five days by IV bolus. Because of severe neurotoxicity and life-threatening gastrointestinal toxicity, the regimen in 23 patients was modified to 4 mg/m² IV infusion over four hours, weekly. This latter regimen was well tolerated, with acceptable gastrointestinal, hematological, and neurotoxicity. One child with acute lymphocytic leukemia resistant to vincristine had a transient Ml remission bone marrow. Improvement or stable disease was noted in one patient each with Ewing's sarcoma, neuroblastoma, and Hodgkin's disease.     

Multiagent chemotherapy for children with metastatic neuroblastoma: A report from childrens cancer study group

During the past 10-15 years there has not been a significant improvement in the overall survival of children with metastatic neuroblastoma. From 1971 through 1975, 104 eligible patients were entered on two clinical studies for newly diagnosed cases of stage IV neuroblastoma by the Childrens Cancer Study Group (CCSG). Patient data from both studies were evaluated for activity of cyclophosphamide, imidazole carboxamide, and vincristine and of these same agents plus adriamycin. Response was evaluated by serial measurements of tumor size. Eighty-four patients experienced a complete or partial response. The life-table estimate of median survival on both studies was 11–12 months for all patients and 13-18 months for responders, unchanged from the results of previous CCSG studies. Long-term survival, however, for patients on these studies demonstrates a significant increase compared with results reported from the three previous CCSG studies. Children less than 1 year or greater than 6 years of age at diagnosis showed a significantly improved survival pattern over the intermediate age group. It is suggested that there is a need to consider the induction response pattern and age at diagnosis when planning a maintenance program so that nonresponders can be identified early and considered for treatment with new agents or aggressive multimodal therapy.     

Intellectual function in long-term survivors of childhood acute lymphoblastic leukemia: Protective effect of pre-irradiation methotrexate a childrens cancer study group study

Having demonstrated in a laboratory model that the neurotoxicity of CNS irradiation can be ameliorated with pre-irradiation methotrexate, we retrospectively compared two methods of CNS prophylaxis in childhood acute lymphoblastic leukemia which differed only in the timing of intrathecal methotrexate and radiotherapy. The results of standard IQ tests conducted 2–11 years after 24 Gy of cranial radiotherapy were obtained in 72 patients, of whom 27 had pre-irradiation methotrexate and 45 did not (control group). The two groups were otherwise comparable. In girls, the full-, performance-, and verbal-scale IQ scores were consistently higher in the pre-irradiation methotrexate group than in the corresponding control group (P<0.025). Among girls <5 years of age when irradiated, the mean IQ scores were 25–29 points higher after pre-irradiation methotrexate than after the control treatment (P<0.0007). These results suggest that pre-irradiation methotrexate may help prevent CNS radiotoxicity in children, and that the benefit is dependent on patient age and gender.     

Vincristine (NSC-67574), cytosine arabinoside (NSC-63878), 6 thioguanine (NSC-752) and daunorubicin (NSC-82151) (VAT-D): A pilot study of combination chemotherapy for remission induction in acute myeloid leukemia in adults

Fifteen newly diagnosed unselected adult patients with acute nonlymphocytic leukemia were treated in a pilot study of the combination of vincristine, cytosine arabinoside, 6-thioguanine, and daunorubicin (VAT-D) for remission induction therapy. Eleven of fifteen (75%) achieved a remission bone marrow. Median duration of remission was seven months in all responders (11 patients). The 11 patients achieving initial remission reached a median survival of 14 months. Twelve of seventeen attempts at reinduction of remission with VAT-D were successful. The total amount of daunorubicin required for induction was less than that required in the majority of reported acute leukemia treatment regimens utilizing daunorubicin.     

Secondary malignancies in a child with Hodgkin's disease: Peripheral T-cell lymphoma and myelodysplastic syndrome evolving into acute nonlymphoblastic leukaemia

Hodgkin's disease (HD) has been linked to an increased risk of second malignant neoplasms (SMN), especially non-Hodgkin's lymphoma (NHL) and acute nonlymphoblastic leukaemia (ANLL). The mutagenic property of cytotoxic therapy as well as defective immunity have been implicated as playing a major role in the development of SMN in patients previously treated for HD. We report a case of a 14-year-old girl with HD who developed two different second malignancies within a latent period of 28 months following HD diagnosis. The patient presented initially with bilateral cervical and supraclavicular as well as mediastinal and paraaortic lymphadenopathy. She was staged as IIIA, nodular sclerosing type HD, and was given eight alternative cycles of MOPP-ABVD followed by “mantle” field radiotherapy to a total dose of 3.3 Gy plus 0.4 Gy to the upper mediastinum. Within 8 months following the completion of therapy, a period of myelodysplasia and progressive severe immune deficiency, considered as a result of initial treatment, occurred. Eighteen months after HD diagnosis while the patient was continuously neutropenic and heavily immunocompromised, a peripheral T-cell lymphoma of the angiocentric immunoproliferative lesion type (AIL) Grade III, appeared in both lungs within and beyond the radiation field, with no evidence of HD in biopsy specimens. After institution of a new chemotherapy regimen. (L17M), a satisfactory response regarding NHL lesions was noted. However, 10 months later the myelodysplastic syndrome (MDS) accompanied by complex chromosomal abnormalities evoluted to frank ANLL with a rapid fatal course. This case supports the hypothesis that combined modality treatment accompanied by severe immunodeficiency may result in the development of multiple second malignancies even within a very short latent period, especially in a subgroup of HD patients who may be at particularly increased risk for second cancers. © 1996 Wiley-Liss, Inc.     

Desensitization to pegaspargase in children with acute lymphoblastic leukemia and lymphoblastic lymphoma

Hypersensitivity to pegaspargase is associated with inferior survival in pediatric patients with acute lymphoblastic leukemia and lymphoblastic lymphoma. In the past year, drug‐supply shortages have led to the lack of an available alternative to pegaspargase. Rather than omit asparaginase from the treatment of acute lymphoblastic leukemia or lymphoblastic lymphoma patients with hypersensitivity to pegaspargase, we continued pegaspargase treatments for nine pediatric patients, utilizing a rapid desensitization protocol. There were no adverse events related to the pegaspargase during desensitization, and all patients who were checked had asparaginase serum levels above the threshold of 0.1 IU/mL at 7 to 14 days after pegaspargase therapy.     

儿童非霍奇金淋巴瘤195例临床病理分析

目的探讨儿童非霍奇金淋巴瘤(NHL)的临床病理特点。方法收集1982年1月—2010年1月诊断的非霍奇金淋巴瘤病例195例,进行临床和病理分析。结果儿童NHL发病年龄高峰在6～8岁,男女之比为2.3∶1,Ⅲ期和Ⅳ期占49.2%。病理组织类型主要有淋巴母细胞性淋巴瘤(LBL)、Burkitt淋巴瘤(BL)、间变性大细胞性淋巴瘤(ALCL);88.8%LBL为T细胞性淋巴瘤,BL皆为B细胞性淋巴瘤,ALCL皆为T细胞性淋巴瘤。37.9%病例首发于淋巴结外组织,56.1%LBL患儿确诊时已累及1个以上部位。结论儿童NHL的临床及病理表现与成人NHL存在很大差异。免疫组化等技术对NHL的病理诊断有重要作用。     

High-dose chemotherapy and blood stem cell autografts for children with first relapsed acute lymphoblastic leukemia: A pilot study of the children's cancer and leukemia study group of Japan (CCLSG)

This study was performed to determine the value of high-dose chemotherapy and peripheral blood stem cell autografts (PBSCT) in the treatment of children with first relapsed acute lymphoblastic leukemia (ALL). Eighteen children underwent PBSCT during the second complete remission (CR) and had a minimum 10 month follow-up. The median age of the patients was 11 yr (range, 2–17 yr). Fifteen patients received the “MCVAC” regimen, one received high-dose MCNU + busulfan therapy, one received high-dose melphalan + VP-16, and one received melphalan + carboplatin + cytosine arabinoside + MCNU. None of these regimens included total body irradiation. Eight patients developed recurrence of the disease at 1 to 19 mo (median, 3 mo) after PBSCT. Patients in whom the first relapse occurred sooner, that is, within 16 mo of initial therapy, tended to have a better survival rate than those who developed relapse after 30 mo (six of seven survived versus four of 11; not significant). Although the preliminary data provided little conclusive information, it did suggest that incorporation of PBSCT in the salvage protocol of relapsed childhood ALL can be justified. © 1994 Wiley-Liss, Inc.     

Epidemiology of childhood acute myeloid leukemia

Although leukemia is the most common childhood cancer diagnosis, the subtype, acute myeloid leukemia (AML), is less common and fewer etiologic studies exist. This review summarizes the major risk factors for AML. We searched the literature using PubMed for articles on childhood AML and reviewed 180 articles. While few risk factors are definitive, we identified several with consistent evidence of a possible effect. Thorough analysis of genetic and epigenetic factors is missing from this literature and methodological issues are unresolved. Future studies should more closely examine causal mechanisms, improve exposure measurement, and include analysis using genetic and epigenetic factors. Pediatr Blood Cancer 2013; 60: 728–733. © 2013 Wiley Periodicals, Inc.     

Disseminated intravascular coagulation in children with cancer: A systematic review

Abstract

Disseminated intravascular coagulation (DIC) may complicate malignant disease. Numerous studies have investigated this association in adults, however only sparse knowledge exists on DIC in pediatric cancer patients. The objective of this article was to systematically review the literature regarding DIC in pediatric malignancies. PubMed and Embase were searched for relevant articles on January 31, 2020. In total, 6,070 articles were identified out of which 24 articles met inclusion and exclusion criteria. These were included in the qualitative synthesis. The National Institutes of Health’s Quality Assessment Tools was used to assess bias in the included articles. The studies were of only moderate quality mainly based on medical charts and demonstrated high heterogeneity, especially as regards to diagnostic criteria. DIC was reported most frequently in patients with acute leukemia, particularly the subtype acute promyelocytic leukemia (APL). Standard coagulation parameters were used as diagnostic laboratory tests supporting the diagnosis of DIC. Hemorrhage was the predominant clinical manifestation, whereas thromboembolic events and organ failure were reported less frequently. Unfractionated heparin, platelet concentrate and fresh frozen plasma were the most frequently used supportive treatment agents. Hemorrhage accounted for the majority of deaths in children with acute leukemia and solid tumors. In conclusion, only a limited number of studies, being heterogenous and of moderate quality, have investigated DIC in pediatric malignancy. Notably, this entity seems to be complicated mainly by hemorrhage. High quality studies are needed to evaluate diagnosis, clinical manifestations and optimal treatment of DIC in childhood cancers.     

Progress in the treatment of childhood acute leukemia: A review

The dramatic improvements in the survival experience for children diagnosed with acute leukemia are analyzed using data collected through hospitals participating in the National Cancer Institute's End Results Group Program between 1950 and 1973. Children under 15 years of age who were diagnosed with both acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL) showed moderate improvements in the 1950s, but beginning in the 1960s those with ALL did far better. Statistically significant differences at the 0.05 level were noted between their three-year survival rates for all cohorts analyzed between 1960 and 1973. For the 1970-1973 cohort, three-year survival rates were 49% and 20% for ALL and ANLL, respectively, and five-year survival rates were 34% and 12%. Between 1950 and 1976 the age-adjusted incidence rate for all childhood leukemias remained relatively stable in a sample of five geographic areas, changing from 4.6 per 100,000 children under 15 years of age to 4.3 per 100,000. In contrast, the corresponding age-adjusted mortality rate fell approximately 45% over the same period, from 4.4 per 100,000 to 2.4 per 100,000.     

Histiocytosis X: Clinical trial of chlorambucil: A report from childrens cancer study group

A prospective study for histiocytosis X was designed to determine whether “good risk” patients, ie, those without evidence of dysfunction of liver, lung, or hemopoietic system, would respond to single agent therapy; in this case chlorambucil (CMB) used in a dose of 5 mgm/m² /day. If there was no response after an adequate trial period, treatment was initiated with four drugs using a combination of prednisone, vinblastine, cyclophosphamide and methotrexate. There were 26 evaluable patients, 57% of whom were less than two years of age at onset of therapy. There were three complete and four partial responses to CMB for a response rate of 26.9%. Sixteen patients received an adequate trial of four-drug therapy with three complete and two partial responses for a response rate of 33%. These responses were inferior to those previously reported for either single agents or combined therapy in histiocytosis X.     

Expression of myeloid differentiation antigens in acute nonlymphocytic leukemia: Increased concentration of CD33 antigen predicts poor outcome—A report from the childrens cancer study group

Ninety-eight cryopreserved specimens of acute nonlymphocytic leukemia (ANLL) cells obtained at initial diagnosis of children enrolled on the Childrens Cancer Study Group 251 protocol (CCG 251) were examined by indirect immunofluorescence using four monoclonal antibodies to myeloid differentiation antigens. The relationship between the level of differentiation of ANLL cells as determined by their antigen phenotype and the clinical outcome of treatment, including complete remission (CR) rate, survival, and event-free survival, was evaluated. Most leukemic specimens were determined to express the CD33 antigen (L4F3), a 67-kD protein. Because the level of differentiation of normal myeloid cells is reflected by the concentration of the CD33 antigen expressed, samples were categorized as CD33-bright (immature) versus CD33-dull (mature). Patients with CD33-bright leukemic blasts had a marginally inferior CR rate to those with CD33-dull blasts (P = 0.08). With respect to survival and event-free survival, there was a significantly inferior outcome in the CD33-bright patients (P = 0.04 and P = 0.06, respectively). Reactions of ANLL with anti-CD15 antibody (1G10), anti-CD36 antibody (5F1), or anti-CD17 antibody (T5A7) did not predict clinical outcome. This study indicates that patients whose ANLL blasts displayed the CD33 antigen in an amount associated with immature myeloid cells experienced a worse outcome than patients with ANLL blasts that expressed a phenotype associated with more mature cells. © 1992 Wiley-Liss, Inc.