Outcome following late marrow relapse in childhood acute lymphoblastic leukemia

Thirty-four children with acute lymphoblastic leukemia, who developed bone marrow relapse after treatment was electively stopped, received reinduction, consolidation, continuing therapy, and intrathecal (IT) methotrexate (MTX). Sixteen children who relapsed within six months of stopping treatment had a median second-remission duration of 26 weeks; all next relapses occurred in the bone marrow. In 18 children who relapsed later, the median duration of second remission was in excess of two years, but after a minimum of four years' follow-up, 16 patients have so far relapsed again (six in the CNS). CNS relapse occurred as a next event in four of 17 children who received five IT MTX injections only and in two of 14 children who received additional regular IT MTX. Although children with late marrow relapses may achieve long second remissions, their long-term out-look is poor, and regular IT MTX does not afford adequate CNS prophylaxis. It remains to be seen whether more intensive chemotherapy, including high-dose chemoradiotherapy and bone marrow transplantation, will improve the prognosis in this group of patients.     

Chemotherapy for bone marrow relapse of childhood acute lymphoblastic leukemia

Results of the BMF study group trials ALL-REZ 83 and 85 for relapsed acute lymphoblastic leukemia (ALL) are presented. For children with late marrow relapse, remission rates of about 90% were seen in both studies. In children treated for early marrow relapse, the remission rate in study ALL-REZ 85 was superior (86% vs 62%). The probability of event-free survival for all patients and for those with early marrow relapse was also statistically significant (P<0.05). children=" with=" t-cell=" all=" had=" an=" extremely=" unfavourable=" prognosis=" in=" both=">Supported by the Deutsche Krebshilfe e. V.     

Differences in DNA-fingerprints between remission and relapse in childhood acute lymphoblastic leukemia

DNA "fingerprint" (DNA-F) analysis, based on the polymorphism caused by numeric variations in the tandem repeats of minisatellite areas of the human genome, has a potential capacity to reveal even minor genomic changes. In this study we have applied DNA-F to the detection of residual disease in leukemia. In order to identify normal and leukemic cell populations, we used two molecular probes: Jeffrey's minisatellite probes and M13 wild type phage probe, which detect different sets of polymorphic fragments in the human genome. Comparison of varying minisatellite fragments between remission and relapse was performed by Southern blot hybridization in seven patients with acute lymphoblastic leukemia (ALL). The results suggest that Southern hybridization with DNA "fingerprint" probes can prove to be a sensitive method in the detection of minimal residual disease in ALL.     

Multidrug resistance-associated protein 1 predicts relapse in Iranian childhood acute lymphoblastic leukemia

Multidrug resistance (MDR) is a main cause of failure in the chemotherapeutic treatment of malignant disorders. One of the well-known genes responsible for drug resistance encodes the multidrug resistance- associated protein (MRP1). The association of MRP1 with clinical drug resistance has not systematically been investigated in Iranian pediatric leukemia patients. We therefore applied real-time RT-PCR technology to study the association between the MRP1 gene and MDR phenotype in Iranian pediatric leukemia patients. We found that overexpression of MRP1 occurred in most Iranian pediatric leukemia patients at relapse. However, no relation between MRP1 mRNA levels and other clinical characteristics, including cytogenetic subgroups and FAB subtypes, was found.     

The optic nerve as the site of initial relapse in childhood acute lymphoblastic leukemia

Three children with acute lymphoblastic leukemia (ALL) developed isolated optic nerve relapse as the initial site of disease recurrence. They were part of an early cohort of 39 children with non-B-cell, non-T-cell ALL without central nervous system (CNS) involvement, treated regardless of initial leukocyte count with intrathecal chemotherapy for CNS prophylaxis. Although the optic nerve is a known site of relapse in patients with systemic and meningeal ALL, it has not been reported to occur in otherwise relapse-free patients. Early diagnosis and treatment prevented blindness and allowed for long-term survival (57+, 49+, and 97+ months, respectively) and possibly cure. Since these patients were treated in a new manner and exhibited a new pattern of relapse, their clinical courses were reviewed. Features considered worrisome, but not diagnostic of CNS leukemia may be of greater import when intrathecal medications are utilized as primary CNS prophylaxis. An expanded definition of CNS leukemia may be necessary.     

Testicular relapse in acute childhood leukemia

The successful induction and maintenance of hematologic remission in childhood acute leukemia has led to the recognition of extramedullary leukemia as a major clinical problem [1–6]. The central nervous system is the most common site of extramedullary relapse [1,7–12], A more recently recognized form of extramedullary relapse is the testis [13–22]. This paper will review a series of patients with childhood acute leukemia who suffered testicular relapse. Modes of therapy for testicular relapse and research conducted into the etiology of testicular relapse will be discussed.     

Intermediate dose methotrexate in childhood acute lymphoblastic leukemia resulting in decreased incidence of testicular relapse

Six hundred thirty-four children with acute lymphoblastic leukemia (ALL) were randomized to receive sanctuary therapy consisting of either cranial irradiation (CRT) plus intrathecal (IT) methotrexate (MTX) or three courses of intermediate-dose methotrexate (IDM) plus intrathecal methotrexate. Two hundred sixty-six male patients achieved a complete response and were evaluable for the effects of prophylactic therapy on the duration of remission. There was one isolated testicular relapse (0.8%) in the IDM group compared with 14 (10%) in the CRT group. The incidence of testicular relapse was significantly lower in the patients treated with IDM (P less than 0.001). High plasma levels of MTX achieved during the 24-hour infusions may result in increased penetration of MTX into the interstitium of the testes, thus allowing for the eradication of sequestered leukemic cells and preventing the emergence of drug resistance resulting from exposure to sublethal concentration of MTX.     

Ikaros 与儿童急性淋巴细胞白血病

Ikaros 是造血细胞分化和免疫系统发育的重要调节因子,并且作为肿瘤抑制因子,Ikaros异常会阻滞 T、B 细胞的发育或导致肿瘤形成。在白血病患者中,Ikaros 发生突变导致患者治疗反应下降及长期生存率降低。Ikaros 在白血病发生和预后中的机制研究已成为人们关注的热点。     

Glucocorticoid receptor in childhood acute lymphoblastic leukemia

Glucocorticoid(GC)hasbeenusedinthetreatmentofchildhoodacutelymphoblasticleukenda(ALL)formanyyears.IthasprovedthattheeffectofGCismediatedthroughaglucocortic0idreceptor(GCR)ofthetargetcell.[1]Therefore,manyexpertshaveconcentratdtheirattentiononGCR,butthereisnoreportonthestudyofGCRinchildho0dALLinChina.InununologicalclassificationofALLmaydifferentiatethecelloriginandclustersofdifferentiation(CD)inleukendacell.Itisoneoftheimportantindicatorstoguidecombinationchemotherapyandt0makeapr0gnos…     

Immunologic markers in childhood acute lymphoblastic leukemia

This article details the immunologic diversity of acute lymphoblastic leukemia in children. A historical review of developments in immunophenotyping is followed by a discussion of how major subgroups of leukemia are best defined today. The relationship of immunologic subtypes to stages of normal lymphoid development is explored, and the clinical impact of immunophenotyping is discussed.     

Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse.

Using flow cytometric techniques capable of detecting 0.01% leukemic cells, we prospectively studied minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) after first relapse. At the end of remission reinduction, 41 patients had a bone marrow sample adequate for MRD studies; 35 of these were in morphologic remission. Of the 35 patients, 19 (54%) had MRD >/=0.01%, a finding that was associated with subsequent leukemia relapse. The 2-year cumulative incidence of second leukemia relapse was 70.2+/-12.3% for the 19 MRD-positive patients and 27.9+/-12.4% for the 16 MRD-negative patients (P=0.008). Among patients with a first relapse off therapy, 2-year second relapse rates were 49.1+/-17.8% in the 12 MRD-positive and 0% in the 11 MRD-negative patients (P=0.014); among those who received only chemotherapy after first relapse, the 2-year second relapse rates were 81.5+/-14.4% (n=12) and 25.0+/-13.1% (n=13), respectively (P=0.004). Time of first relapse and MRD were the only two significant predictors of outcome in a multivariate analysis. We conclude that MRD assays should be used to guide the selection of postremission therapy in patients with ALL in first relapse.     

Genetic susceptibility in childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and a leading cause of death due to disease in children. The genetic basis of ALL susceptibility has been supported by its association with certain congenital disorders and, more recently, by several genome-wide association studies (GWAS). These GWAS identified common variants in ARID5B, IKZF1, CEBPE, CDKN2A, PIP4K2A, LHPP and ELK3 influencing ALL risk. However, the risk variants of these SNPs were not validated in all populations, suggesting that some of the loci could be population specific. On the other hand, the currently identified risk SNPs in these genes only account for 19% of the additive heritable risk. This estimation indicates that additional susceptibility variants could be discovered. In this review, we will provide an overview of the most important findings carried out in genetic susceptibility of childhood ALL in all GWAS and subsequent studies and we will also point to future directions that could be explored in the near future.     

TEL deletion analysis supports a novel view of relapse in childhood acute lymphoblastic leukemia.

PURPOSE: TEL (ETV6)-AML1 (RUNX1) chimeric gene fusions are frequent genetic abnormalities in childhood acute lymphoblastic leukemia (ALL). They often arise prenatally as early events or initiating events and are complemented by secondary postnatal genetic events of which deletion of the non-rearranged, second TEL allele is the most common. This consistent sequence of molecular pathogenesis facilitates an analysis of the clonal origins of relapse in this leukemia, which has some unusual clinical features. EXPERIMENTAL DESIGN: We compared the boundaries, by microsatellite mapping, of TEL deletions at relapse versus diagnosis in 15 informative patients. Moreover, we compared the relatedness of diagnostic and relapse clones using immunoglobulin and T-cell receptor genes rearrangements and clonotypic TEL-AML1 genomic fusion. RESULTS: Five patients retained the apparent same size TEL deletion, seven had larger deletions, and three had smaller deletions at relapse. In all of the cases evaluated, the clonal relatedness of diagnostic and relapse cells was confirmed by the retention of clonotypic TEL-AML1 genomic sequence and/or at least one identical immunoreceptor gene rearrangement. CONCLUSIONS: These data provide further evidence that TEL deletions are secondary to TEL-AML1 fusions in ALL. They are compatible with the novel idea that in at least some cases of childhood ALL, remission occurs with persistence of a preleukemic "fetal" clone, and subsequent relapse reflects the emergence of a new subclone from this reservoir after an independent "second hit," i.e., independent TEL deletion. To our knowledge, the study is the most extensive and comprehensive analysis of the relationship between diagnostic and relapse clones in childhood ALL presented thus far.     

Diagnosis and management of relapse in acute lymphoblastic leukemia

Although the results are steadily improving, the treatment of the child with lymphoblastic leukemia in relapse remains unsatisfactory. Owing to the very nature of relapse, it is highly unlikely that future chemotherapy protocols will provide curative treatment for the majority of patients with recurrent disease. Therefore, the greatest possible emphasis must be given to further improvements and refinements in front-line (initial) therapy so as to prevent relapse from ever occurring. Our goal should be to put the relapse leukemia specialist "out of business."     

Clinically isolated mandibular relapse in childhood acute leukemia

With improved methods for preventing extramedullary relapse in the leptomeninges and gonads, the problem of clinically isolated relapse at other sites has become more significant. The authors report here two children with acute leukemia who developed mandibular relapse while in complete hematologic remission. One had been off chemotherapy for acute lymphoid leukemia for 2.5 years. The other child is apparently the first patient with promyeloid morphologic features to experience relapse at this site. Both children are in second complete remission and off treatment after local radiation therapy and second courses of chemotherapy. Review of these two and five previously reported isolated mandibular relapses in childhood leukemia indicate that they are usually delayed until after cessation of therapy. Treatment with radiation and combination chemotherapy can result in long remission and possibly cure.     

Treatment of meningeal relapse in childhood acute lymphoblastic leukemia. I. Results of craniospinal irradiation

Fourteen children were treated for isolated meningeal relapse occurring seven to 44 months (median, 14 months) after prophylactic cranial irradiation (2,400 rad/12 fractions) and intrathecal methotrexate (IT MTX, 12 mg/m2 for four doses during cranial irradiation). Eight had "high-risk" acute lymphocytic leukemia with age less than 2 years, white blood cell counts greater than 20,000, or T cell markers. Treatment for central nervous system leukemia included IT MTX (12 mg/m2 twice weekly until clearance of spinal fluid cytology) followed by craniospinal irradiation (CSI, 3,000 rad/20 fractions to the cranium and 1,800 rad/12 fractions to the spine). No maintenance IT MTX was given. Systemic chemotherapy was continued or reinstituted for a minimum of one year after CSI. No instance of second meningeal relapse has occurred. Five patients remain in secondary complete remission 66+, 54+, 36+, 26+, and 24+ months after meningeal relapse. Disease-free survival was limited by marrow relapse in eight patients (2-20 months after CSI) and testicular relapse in one. No acute toxicities were noted with CSI. Myelosuppression occurred in seven patients. Infections within two months of CSI were noted in five. No neurologic sequelae are apparent. Serial neuropsychometric studies in 10 patients revealed a significant decline in mean values on Global IQ scales. Long-term survival with acceptable toxicity is possible following aggressive, prompt treatment of meningeal relapse occurring after prophylactic cranial irradiation. Hematologic relapse remains the major obstacle to long-term disease-free survival.