Bone marrow chromosomes in acute lymphoblastic leukaemia: a long-term study.

The bone marrow chromosomes of 25 children with acute lymphoblastic leukaemia (ALL) were examined at diagnosis before treatment, during remission, and in 12 cases, also during relapse. Follow-up was for at least six years. At diagnosis, 17 patients had a major population of chromosomally abnormal cells and of these 11 had identifiable clones. The commonest abnormality was hyperdiploidy. Eight patients had predominantly normal cells, but four of these had a minor abnormal clone. In remission, some samples were completely normal but, when pooled, remission samples had a minor population of chromosomally aberrant cells which were rarely clonal. The incidence of structural abnormalities was the same in patients who ultimately relapsed and those who remained in first remission at the end of the study, but the presence of hyperdiploid cells and/or clones in remission was more frequently associated with subsequent relapse. Relapse patterns were of two kinds: in three patients there was a return of the chromosomal abnormalities seen at diagnosis; in six others, chromosomal features in relapse were distinct from those at diagnosis. It is suggested that relapse associated with distinct chromosomal features may represent malignant transformation of a previously unaffected cell line. While chromosomal abnormalities seen prior to treatment can be related to the leukaemic event alone, abnormalities seen in remission and in relapse may result partly from drug and X-ray treatment. The relative importance of treatment and other factors to chromosomal change in ALL is discussed.     

Cytogenetic studies in acute lymphocytic leukemia: special emphasis in long-term survival.

Cytogenetic studies were performed in 331 patients with ALL diagnosed at the National Institutes of Health between January 1961 and January 1976. Four patients had constitutionally abnormal genotypes, three had Down's syndrome, and one had a D/G translocation. Aneuploidy was observed in the pretreatment bone marrow in 49/115 (42.6%) of this series exhibited several general characteristics: aneuploid cells usually coexist with normal stem cells, hyperdiploidy is predominant and wide ranging aneuploidy clusters around a major cell line. The most common chromosomal group involved in aneuploidy is the G group (p=0.001) and the next most common is the B group (p=0.01). Aneuploidy disappeared after successful achievement of remission, and new clones developed in 12 patients during relapse. Two of the four patients originally thought to have a Ph1 chromosome, on trypsin Giemsa handing were proved to have a 21q- chromosome. A higher incidence of aneuploidy was noted in patients under one year or more than 20 years of age and was also higher in patients with low or elevated WBCs at diagnosis. The appearance of aneuploid cells in the bone marrow at the onset or later in the disease is of no prognostic significance but persistence of these lines and the development of total aneuploidy signals a poor prognosis. Eradication of aneuploid cells is therefore essential for the achievement of a long remission and progress to a permanent cure.     

Frequency And Importance Of Change In Blast Cell Karyotype In Relapsing Childhood Lymphoblastic Leukemia

Blast cell chromosome abnormalities at presentation in childhood acute lymphoblastic leukemia (ALL) are common, and dijferent patterns are known to be related to outcome. In contrast, the frequency and importance of further changes at the time of relapse remain unclear. Blast cell karyotype evolution was therefore studied in a group of children with recurrent disease. Of 134 consecutive children diagnosed between 1982 and 1992, 31 had a marrow relapse, and 24 had complete cytogenetic studies at both diagnosis and the time of recurrence. Fourteen (58%) of the 24 showed additional chromosomal abnormalities at relapse, 5 (21%) retained abnormalities identical to those seen at diagnosis, and 5 (21 %) remained cytogenetically normal. The 14 with additional changes had shorter first remissions and showed shorter survival after relapse compared with the others. These findings indicate that emergence of cytogenetically recognizable subclones during the progression of childhood ALL could be a marker of more resistant disease.     

Cytogenetic studies in acute lymphocytic leukemia: Special emphasis in long-term survival

Cytogenetic studies were performed in 331 patients with ALL diagnosed at the National Institutes of Health between January 1961 and January 1976. Four patients had constitutionally abnormal genotypes, three had Down's syndrome, and one had a D/G translocation. Aneuploidy was observed in the pretreatment bone marrow in 49/115 (42.6%) of the patients and at some stage of disease in 54.1% of the patients. Aneuploidy in this series exhibited several general characteristics: aneuploid cells usually coexist with normal stem cells, hyperdiploidy is predominant, and wide ranging aneuploidy clusters around a major cell line. The most common chromosomal group involved in aneuploidy is the G group (p = 0.001) and the next most common is the B group (p = 0.01). Aneuploidy disappeared after successful achievement of remission, and new clones developed in 12 patients during relapse. Two of the four patients originally thought to have a Ph¹ chromosome, on trypsin Giemsa banding were proved to have a 21q- chromosome. A higher incidence of aneuploidy was noted in patients under one year or more than 20 years of age and was also higher in patients with low or elevated WBCs at diagnosis. The appearance of aneuploid cells in the bone marrow at the onset or later in the disease is of no prognostic significance but persistence of these lines and the development of total aneuploidy signals a poor prognosis. Eradication of aneuploid cells is therefore essential for the achievement of a long remission and progress to a permanent cure.     

Single-Voided Urinary Dopamine and Neuroblastoma

Blast cell chromosome abnormalities at presentation in childhood acute lymphoblastic leukemia (ALL) are common, and dijferent patterns are known to be related to outcome. In contrast, the frequency and importance of further changes at the time of relapse remain unclear. Blast cell karyotype evolution was therefore studied in a group of children with recurrent disease. Of 134 consecutive children diagnosed between 1982 and 1992, 31 had a marrow relapse, and 24 had complete cytogenetic studies at both diagnosis and the time of recurrence. Fourteen (58%) of the 24 showed additional chromosomal abnormalities at relapse, 5 (21%) retained abnormalities identical to those seen at diagnosis, and 5 (21 %) remained cytogenetically normal. The 14 with additional changes had shorter first remissions and showed shorter survival after relapse compared with the others. These findings indicate that emergence of cytogenetically recognizable subclones during the progression of childhood ALL could be a marker of more resistant disease.     

Preponderant mitotic activity of nonleukemic cells plays an important role in failures to detect abnormal clone in childhood acute lymphoblastic leukemia

At diagnosis, clonal chromosomal abnormalities are found in the bone marrow blasts in more than two thirds of children with acute lymphoblastic leukemia (ALL). Practically, however, failure to detect these abnormalities is frequent and usually attributed to poor marrow sampling, inadequate metaphases, and/or a preponderant mitotic activity among nonleukemic cells. The authors applied fluorescence in situ hybridization (FISH) techniques to re-examine 30 cases of karyotypically "normal" childhood ALL to explore the role of preponderant mitotic activities of nonleukemic cells in failures to detect clonal abnormalities. The FISH test were performed using TEL/AML1 fusion gene probe and the centromere probes for chromosome 8 and 10 to detect the t(12;21) translocation and/or hyperdiploidy. Half of the karyotypically "normal" ALL cases examined have been found to have abnormal clones with t(12;21) rearrangement and/or hyperdiploidy by this specially designed FISH assay. Contrary to expectation, the authors found a higher incidence (52%) of clonal abnormalities in cases where over 20 metaphases had been examined than in cases (44%) where fewer than 20 metaphases had been analyzed. These findings suggest that a preponderant mitotic activity of nonleukemic cells plays an important role in failures to detect an abnormal clone by conventional cytogenetic studies. Therefore, karyotypically "normal" childhood ALL patients should undergo FISH studies to rule out the presence of t(12;21) and/or hyperdiploid clone.     

Lack of prognostic value of T-, B- and null-lymphocytes in adult acute leukemia

The distribution of T-, B- and null-lymphocytes was studied in the peripheral blood of 38 adult patients with acute nonlymphocytic leukemia (ANLL) and 15 with acute lymphocytic leukemia (ALL) at first diagnosis, during induction treatment, and in remission. Thirteen ANLL and 9 ALL patients were followed until relapse and during reinduction therapy. T- and B-cells were detected by specific membrane marker. The pre- and posttreatment pattern of lymphocyte subpopulations was analyzed to determine their prognostic significance for remission incidence, remission duration, and survival. It was observed that in both types of leukemia, T-cells are more affected by the leukemic process and cytostatic drugs than B-cells. Nonresponding patients possibly have a reduced potential for recruiting precursor T- and B-cells. At first diagnosis, no significant correlation was found between pre- or posttreatment variables and prognosis. At relapse, ANLL patients had a longer second remission when a high proportion of B-cells was found; ALL patients with a high lymphocyte count before and after treatment, experienced longer survival.     

Prognosis in acute lymphoblastic leukemia of childhood as determined by cytogenetic studies at diagnosis

Fifty-one children with acute lymphoblastic leukemia on a common protocol of treatment were classified according to presence or absence of chromosomal abnormalities found at the time of diagnosis in bone marrow and/or blood. Twenty-two or 43% had normal karyotypes while 29 (57%) had clonal abnormalities using the Giemsa-trypsin banding technique. Thirteen of the 29 (45%) chromosomally abnormal patients relapsed while only three of 21 (14%) with normal karyotypes have relapsed with a median follow-up of 49.5 months (42-76 months). (One child with a normal karyotype did not respond to therapy.) Several hypotheses have been offered to attempt to explain the significantly better prognosis of patients with no observable initial chromosomal aberrations.     

Chromosomal Analysis of Childhood Acute Lymphoblastic Leukemia: As a Routine Examination for Diagnosis and Prognosis

Chromosomal analysis was performed as a routine examination for diagnostic and prognostic evaluation of children with acute lymphoblastic leukemia (ALL) in six cases encountered during a one-year period. The results obtained are as follows. 1. Chromosomal abnormality of leukemic cells was observed in five out of six cases (approximately 80%). 2. Translocation 4; 11 or 14q+, which are known as a risk factor of ALL, were observed in three patients. Two of three patients died within six months of the onset of disease. One case was diagnosed as congenital leukemia with remarkable leukocytosis, and the other case was accompanied by hypereosinophilic syndrome. The remaining one patient, who is now in complete remission, is 13 years old, which is within the period of risk ages exceeding 10 years of age. 3. The case with 1q+ had no risk factor; however, he had a relapse 19 months after the diagnosis. Thus this particular chromosomal rearrangement appeared to be one of the risk factors. 4. The case with 6q-, which has been reported to have a good prognosis in some cases of ALL, has no risk factor, and has been in complete remission. These results seem to confirm the usefulness of chromosomal analysis for the evaluation of the clinical course of ALL.     

Survival and endocrine outome after testicular relapse in acute lymphoblastic leukaemia

Accepted 4 November 1996
Survival and endocrine status in a cohort of boys with acute lymphoblastic leukaemia (ALL) who started treatment between 1972and 1987 and subsequently developed a testicular relapse were analysed. During this period there was a significant improvement in the overall event free survival for boys, but no significant decrease in the testicular relapse rate. Thirty three boys had an apparently isolated testicular relapse, whereas 21 boys had a combined relapse. The event free survival for boys with an isolated testicular relapse was 59% at six years (95% confidence interval (CI) 42 to 74%). The event free survival for the 16 patients with a combined relapse who received a second course of treatment was 32% (95% CI 17 to 60%). Those patients receiving adequate second line treatment for an isolated testicular relapse whose first remission was longer than or equal to two years had an event free survival of 82% (95% CI 63 to 93%) at six years. No boy relapsing within two years from diagnosis has survived. Endocrine late effects are significant, with 82% of the boys requiring hormonal treatment at some stage for induction of puberty or continuing pubertal maturation, or both. It is concluded that, despite the increasing intensity of initial treatment for ALL, isolated testicular relapse is treatable by conventional means in most patients. Careful endocrine follow up of these patients is essential as most will require hormone replacement treatment.

     

Comparative genomic hybridization in pediatric acute lymphoblastic leukemia

Comparative genomic hybridization (CGH) was used to clarify the chromosomal status of 15 patients diagnosed with childhood acute lymphoblastic leukemia (ALL). Bone marrow samples from 10 of the 15 patients were selected because no metaphases were obtained for cytogenetic analysis. Three patients with normal trypsin and giemsa banding (GTG) karyotypes were also studied by CGH to determine whether significant abnormalities might have been missed by banding analysis, and samples from an additional 2 patients with hyperdiploidy were also included. Seven of the 10 patients with failed GTG banding analysis were found to be chromosomally abnormal by CGH; 2 out of 3 patients with normal GTG band karyotypes were abnormal, indicating that the metaphases available for karyotyping were not malignant cells, and that CGH analysis of hyperdiploid samples provided more accurate resolution than karyotyping alone. The prognostic value of chromosomal aberrations detected by CGH and the efficiency of the technique suggest a central role for CGH in routine clinical cytogenetics.     

Bone marrow karyotypes of children with nonlymphocytic leukemia.

Bone marrow (BM) karyotypes from 16 consecutive children presenting with nonlymphocytic leukemia were established with the use of banding techniques, before therapy. The two patients with chronic myeloid leukemia (CML) showed the Philadelphia (Ph1) translocation (9q+;22q-). Five of the 14 patients with an acute nonlymphocytic leukemia (ANLL) presented no acquired cytogenetic abnormalities, but one of these five showed a high level of hypodiploidy. One patient with AML evidenced a variant of the Ph1 chromosome originated as a translocation (12p+;22q-). Nonrandom abnormalities (-7; 7q-; +8; t(8;21); -21) were found in six patients, isolated or in association with otheraberrations. Among the random abnormalities, apparently balanced translocations and chromosomal deletions were observed. In ANLL, no correlation could be found between morphologic diagnosis and cytogenetic findings. On the other hand, the presence of BM cells with a normal karyotype at diagnosis was associated with an improved remission rate and survival time. Followup studies were performed in four ANLL patients with an abnormal cell clone at diagnosis. Three of them achieved hematologic remission; their BM karyotype was found to be normal at that stage. In the 4th patient, generalization of the abnormal karyotype in BM cells was seen in the terminal phase of the disease.     

Long-term survivors of acute lymphoblastic leukemia — risk of relapse after cessation of therapy

The results of cessation of therapy (COT) in 64 long-term survivors (disease-free survival of five years or more) of acute lymphoblastic leukemia (ALL) were analyzed to determine the incidence of relapse off therapy. Thirty-seven of the patients had intermittent central nervous system (CNS) prophylaxis. Total follow-up from diagnosis varied from 5.75 to 27.75 years. The median time off therapy was three years (range, 8 months to 26 years). Eighty-six percent (55/64) of the patients continue in their initial remission. Eight patients had relapse, and one patient had a morphologically different leukemia at recurrence. All the relapses occurred between five to eight years from diagnosis and the cumulative rate of relapse for this period was 0.14. There was no significant difference in the rate of relapse for those receiving CNS prophylaxis (0.08) versus those not receiving CNS prophylaxis (0.19). The difference in the relapse rates for boys (0.24) versus girls (0.04) was statistically significant (P=0.04). Isolated testicular relapse (ITR) was not seen in any of the 34 boys. The present study confirms the earlier observations by others that relapse is uncommon in ALL patients remaining in remission longer than seven to eight years. ALL patients treated with intermittent CNS prophylaxis administered throughout the period of maintenance chemotherapy appear to be at no greater risk for relapse off therapy than those treated with high-dose initial cranial irradiation and intrathecal methotrexate. The longer duration of therapy and the use of a repetitive reinduction regimen for maintainance seem to be associated with a decreased risk of ITR after discontinuation of therapy for boys and men. There appears to be a small but definite risk of “second” leukemia in the long-term survivors of leukemia.     

CRANIAL COMPUTED TOMOGRAPHY DURING TREATMENT OF CHILDHOOD LYMPHOCYTIC LEUKEMIA

ABSTRACT. Twenty-three children with acute lymphocytic leukemia (ALL) were examined by computed tomography (CT) of the head on two occasions more than 11 months apart. The first CT was performed at the time of diagnosis in 11 children, who were re-examined while still in their first complete remission. They had received prophylactic central nervous system (CNS) treatment consisting of intrathecal methotrexate supplemented by irradiation in 7 cases and intermediate dose methotrexate in 4 cases. Twelve children were receiving treatment for CNS relapse. This included therapeutic irradiation and intrathecal methotrexate. Abnormal CT developed in 7 children. Three CT scans demonstrated areas of decreased attenuation coefficient, one with intracerebral calcifications. In 5 patients, dilatation of the ventricles and cortical sulci had developed. AU CT abnormalities occurred in children in remission after CNS relapse. These results indicate that prophylactic treatment including cranial irradiation with 24 Gy and low cumulative doses of methotrexate is a safe procedure. Patients with CNS leukemia are at risk of developing CNS abnormalities, when they receive treatment with cranial irradiation and methotrexate. The risk is not correlated with age or sex of the child, the duration of the disease, the dose of irradiation or the cumulative dose of methotrexate.     

MRI diagnosis of bone marrow relapse in children with ALL

Background Diffuse marrow replacement in acute leukemia is well known, but there are few reports describing the MRI features of pediatric leukemic relapse. Objective Our purpose was to describe the MRI appearance of pediatric leukemic relapse. Materials and methods A total of 53 consecutive children with a history of ALL were referred for musculoskeletal MRI from 1 January 1998 to 28 February 2007 at one center, and from 1 January 2000 to 2 May 2007 at a second center. From this group, 14 children seen at initial diagnosis of leukemia and 2 children who underwent MRI after therapy for relapse were excluded. The remaining 37 children, 8 with relapse and 29 in remission, were studied. Images of patients with relapse and in remission were reviewed for type and configuration of marrow infiltration; coexisting marrow alterations including osteonecrosis or stress reaction were also reviewed. Results All eight children with relapse demonstrated nodular lesions with well-defined margins. Coexisting osteonecrosis was present in three children (38%) and pathologic fracture in one. Among the 29 children in remission, 9 showed stress reaction/fracture, 14 showed osteonecrosis and 9 showed ill-defined nodules, and in 5 the marrow was completely normal. Conclusion Well-defined nodules in all patients with leukemic relapse suggest that this appearance is characteristic and distinct from the published findings of diffuse marrow replacement in acute leukemia.     

Acute myelogenous leukemia in children: a preliminary report of combination chemotherapy.

Twenty-four children (2 to 21 years) diagnosed as having AML from 1969 to 1972 were randomized to receive either a single combination (COMP or PRAVD) or sequential combination chemotherapy (alternating POMP and PRAVD). Seventeen achieved complete remission. Patients who received POMP alone had the longest median duration of remission (1,400 days) compared to PRAVD (395 days) or POMP-PRAVD (270 days); interpretation of this difference is uncertain, since the numbers in each group are small. Fifteen patients have relapsed, four initially with CNS involvement. Successful reinduction was achieved almost exclusively for patients who had initially received POMP. Survival after first relapse was short. Patients less than 16 years had a median survival of 632 days, compared to 285 days for patiens greater than 16 (p less than 0.05). The high initial induction rate in these patients is encouraging, but the duration remission is inferior to that seen in childhood ALL. Moreover, the slope of the relapse curve is continuous over a five-year period with no definite plateau where it might appear that patients are no longer at risk of relapse. Improved methods for the treatment of childhood ALL and adult AML suggest possible new approaches to AML in children, with prophylactic treatment of central nervous system, late intensification, and immunotherapy.     

Childhood relapsed acute lymphoblastic leukemia: Biology and recent treatment progress

Acute lymphoblastic leukemia (ALL) is the most frequent cancer in children. Despite remarkable improvement in the prognosis of childhood ALL over the past few decades, the treatment of relapsed ALL is still challenging. The prognosis of first ALL relapse is associated with time of relapse after initial therapy, sites of relapse, and immunophenotype. More recently, response to treatment, which is evaluated by assessment of minimal residual disease (MRD), has been found to be clinically significant in relapsed ALL as well as in the initially diagnosed disease. Utilizing these factors, risk‐oriented treatment stratification for first ALL relapse has been established. In the standard‐risk group for first ALL relapse, intensification of conventional ALL‐type therapy can provide a cure in approximately 70% of patients. It is important to assess MRD after reinduction therapy to determine the indications for stem cell transplantation in the standard‐risk group. In contrast, no standardized therapy has been established for the high‐risk group, which accounts for more than half of relapsed ALL patients. Recent studies have shed light on the clonal origin of relapsed ALL, which usually exists as a minor subclone at the time of initial diagnosis. Clonal selection and evolution take place during chemotherapy, resulting in distinct genetic and epigenetic characteristics of relapsed ALL, some of which are linked to drug resistance, a common and problematic feature of ALL after relapse. To overcome resistance to standard ALL‐type therapy, and considering the heterogeneous biological background of high‐risk relapsed ALL, innovative therapies using new agents are necessary.     

Serum lysozyme activity in children with acute leukemia

Serum lysozyme activity was measured in samples from children with acute leukemia, malignant tumours, and in normal children. All children with acute lymphatic leukemia (ALL) had significantly reduced levels of lysozyme at diagnosis, and none of the children fell within the normal range. Children with ALL in complete remission had lysozyme levels comparable to normal children, while children with ALL in relapse also had pathological low levels. Children with ALL in remission and off therapy also had normal levels of lysozyme. Children with acute myelogenous leukemia had normal lysozyme levels, while children with monomyelocytic leukemia had substantially elevated lysozyme levels before treatment. Determination of serum lysozyme activity in children with acute leukemia is of value both for diagnosis and for evaluating the effect of therapy.     

以肥胖为首发症状的复发性中枢神经系统白血病

目的分析罕见的以肥胖为首发症状的中枢神经系统白血病(CNSL)的诊断。方法 1例6岁4个月男孩,近3个月来进行性肥胖伴性格改变,以往患急性淋巴细胞白血病(ALL,普通B细胞,BCR-ABL阴性,中危),经化疗后持续缓解超过2年。根据临床表现做一系列的实验室和影像学检查进行诊断和鉴别诊断,并进行相关中英文文献复习。结果脑脊液(CSF)白细胞中度升高,以单个核细胞为主,伴少量可疑的幼稚淋巴细胞,葡萄糖和氯化物低,蛋白稍高,MRI示脑膜、大脑皮质、下丘脑和垂体柄以及桥脑等中线结构、颅神经根等信号异常。临床检查分析排除单纯肥胖、Cushing综合征等继发性肥胖和结核性脑膜炎;CSF流式细胞术检查发现65%的有核细胞符合ALL细胞的特征而诊断为CNSL复发,经化疗和头颅放疗后缓解。目前中、英文文献只检索到3篇相似病例的个案报道。结论肥胖和性格改变可以是CNSL的首发症状,但由于罕见,需注意与其他疾病鉴别,传统的CSF细胞形态学结合流式细胞术检查将提高CNSL诊断的可靠性。     

Allogeneic bone marrow transplantation in acute lymphoblastic leukemia of children. Analysis of prognostic factors. GEGMO (Bone Marrow Study Group) study

Sixty-five children with acute lymphoblastic leukemia (ALL) underwent allogenic bone marrow transplantation (BMT) from an HLA identical donor, following cytoreduction with cyclophosphamide and total body irradiation (TBI): 15 were transplanted in 1st remission, 43 in 2nd and 7 in 3rd or in 4th. The Kaplan Meier estimate of surviving disease free at 4 years post BMT was 49.9% and the probability of continued remission at 4 years was 63.3%. Fourteen patients relapsed between 90 and 690 days (mean: 240 +/- 88) post BMT. The other causes of BMP failure included: graft versus host disease, veno-occlusive disease and sepsis. No interstitial pneumonitis has been reported. Patients who had a relapse while on chemotherapy had a higher probability of relapse than those who had a relapse while off therapy (p less than 0.01). We conclude that allogeneic BMT is the treatment of choice for children with ALL in second hematologic remission, the interval between diagnosis and first relapse being the most significant prognostic factor. Patients with poor prognosis might benefit from a more intensive chemotherapy/total body irradiation schedule or a BMT earlier in the course of their disease.