Management of acute lymphoblastic leukemia in older patients

Although the median age for adults with acute lymphoblastic leukemia (ALL) is older than 60 years, relatively few of these patients have been enrolled on prospective clinical trials. The presence of coexisting medical disorders and unfavorable cytogenetic and biologic disease characteristics within this population presents considerable challenges for successful treatment using conventional chemotherapy programs. Selected patients have achieved remission and long-term survival following intensive chemotherapy. Philadelphia (Ph) chromosome (BCR/ABL)-positive ALL is particularly common among older patients. The availability of specific tyrosine kinase inhibitors is changing the prognosis for this challenging subset.     

In vitro cellular drug resistance in children with relapsed/refractory acute lymphoblastic leukemia

Cellular drug resistance is thought to be an important cause of the poor prognosis for children with relapsed or refractory acute lymphoblastic leukemia (ALL), but it is unknown when, to which drugs, and to what extent resistance is present. We determined in vitro resistance to 13 drugs with the MTT assay. Compared with 141 children with initial ALL, cells from 137 children with relapsed ALL were significantly more resistant to glucocorticoids, L-asparaginase, anthracyclines, and thiopurines, but not to vinca-alkaloids, cytarabine, ifosfamide, and epipodophyllotoxins. Relapsed ALL cells expressed the highest level of resistance to glucocorticoids, with a median level 357- and >24-fold more resistant to prednisolone and dexamethasone, respectively, than initial ALL cells, whereas the resistance ratios for the other drugs differed from 0.8- to 1.9-fold, intraindividual comparisons between initial and relapsed samples from 16 children with ALL showed that both de novo and acquired drug resistance were involved. Specific in vitro drug-resistance profiles were associated with high-risk relapsed ALL groups. In vitro drug resistance was also related to the clinical response to chemotherapy in relapsed/refractory childhood ALL. We conclude that drug resistance may explain the poor prognosis for children with relapsed/refractory ALL. These day may be helpful to design alternative treatment regimens for relapsed childhood ALL.     

Chemotherapy of acute lymphoblastic leukemia in children.

Between 1969-1973, 75 consecutive children under the age of 15 years with acute lymphoblastic leukemia were treated with a multiple-drug regimen (L-2). Prophylaxis for meningeal leukemia was limited to the repeated intrathecal injections of methotrexate. Seventy-four patients achieved remission; the duration of remissions could be evaluated only for 70. Relapse terminated complete remission within 1-54 months in 21 children. Four of these relapses were confined to the central nervous system. Forty-nine patients continue in complete remission from 23 to 63 months. Chemotherapy has been discontinued in 29 children, and 25 of these remain without evidence of recurrence for 2-27 months posttreatment.     

Transplantation for children with acute lymphoblastic leukemia

EFS for children with ALL continues to increase and is predicted to reach 90% with current therapy. Better understanding of leukemia cell biology and pharmacogenetics has led to the design of more effective treatment and also refined the prognostic features associated with a poor outcome. ALL characterized by the translocation t(9;22) or t(4;11), or by a hypodiploid karyotype or by an incomplete response to induction therapy is likely to relapse. SCT for ALL is largely used to treat patients failing primary chemotherapy but is selectively included as part of initial therapy for children at high risk for relapse. If SCT is going to become the primary therapy for children with ALL in first remission, the regimen-related mortality must approach 0%, and the risk for severe acute and chronic GVHD should be less than 5%. Salvage therapy after ALL relapse remains the major indication for SCT. The time required to find a suitable match has led to the use of cord blood and haploidentical related donors as stem cell sources. For children who relapse, SCT is likely to remain the principal option to promote survival. Efforts to reduce both the risk of relapse and the transplant regimen toxicity, both immediate and delayed, must continue.     

Pharmacogenetics of outcome in children with acute lymphoblastic leukemia

Acquired genetic characteristics of acute lymphoblastic leukemia (ALL) cells are used to individualize therapy, whereas germ line genetic characteristics generally are not. We determined whether ALL outcome was related to 16 genetic polymorphisms affecting the pharmacodynamics of antileukemic agents. Of 246 children, 116 were treated on the lower-risk (LR) and 130 on the higher-risk (HR) arms of a St Jude protocol. Patients in the HR group with the glutathione S-transferase (GSTM1) non-null genotype had greater risk of hematologic relapse (P = .03), which was further increased by the thymidylate synthetase (TYMS) 3/3 genotype (P = .03). These genotypes remained predictive in multivariate analyses (P < .001 and .003, respectively). No genotypes were predictive in the LR arm. Expression of these 2 genes in ALL blasts was lower in those with low-activity genotypes. For central nervous system relapse, among the HR group, the vitamin D receptor start site (P = .02) and intron 8 genotypes (P = .04) predisposed, whereas for LR patients the TYMS 3/3 genotype predisposed (P = .04). The GSTM1 non-null and TYMS 3/3 genotypes are plausibly linked to drug resistance. Polymorphisms interact to influence antileukemic outcome and represent determinants of response that can be used to optimize therapy.     

Assessment of megakaryopoiesis in children with acute lymphoblastic leukemia

The effect of the underlying disease and chemotherapy on megakaryopoiesis has not been extensively studied in children with acute lymphoblastic leukemia (ALL) during and at the end of therapy. Using a serum-free assay, we assessed the megakaryocyte (Mk) colony formation in vitro from bone marrow mononuclear cells of 25 children with ALL during chemotherapy and shortly after the cessation of it. Twelve children with solid tumors without bone marrow involvement and cord blood from 10 full-term normal vaginal deliveries were used as controls. A significant reduction in the number of Mk colonies was observed at diagnosis of ALL, and Mk colony formation remained lower than controls throughout the different phases of leukemia treatment. Our study suggests that defects in megakaryopoiesis of children with ALL in long-term remission may persist during chemotherapy and at least shortly after the end of it.     

Current approach to relapsed acute lymphoblastic leukemia in children

Recurrent acute lymphoblastic leukaemia(ALL) is a common disease for pediatric oncologists and accounts for more deaths from cancer in children than any other malignancy. Although most patients achieve a second remission, about 50% of relapsed ALL patients do not respond to salvage therapy or suffer a second relapse and most children with relapse die. Treatment must be tailored after relapse of ALL, since outcome will be influenced by well-established prognostic features, including the timing and site of disease recurrence, the disease immunophenotype, and early response to retrieval therapy in terms of minimal residual disease(MRD). After reinduction chemotherapy, high risk(HR) patients are clear candidates for allogeneic stem cell transplantation(SCT) while standard risk patients do better with conventional chemotherapy and local therapy. Early MRD response assessment is currently applied to identify those patients within the more heterogeneous intermediate risk group who should undergo SCT as consolidation therapy. Recent evidence suggests distinct biological mechanisms for early vs late relapse and the recognition of the involvement of certain treatment resistance related genes as well cell cycle regulation and B-cell development genes at relapse, all providing the opportunity to search for novel target therapies.     

Oral health status in children with acute lymphoblastic leukemia

Leukemia is a malignancy of the bone marrow. Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and accounts for nearly 75% of all newly diagnosed leukemias and 25% of all malignancies in childhood. The aim of the present study was to review the oral health status in children with ALL. Databases were explored using various combinations of the following keywords: "acute lymphoblastic leukemia", "children", "inflammation", "pediatric", "periodontal disease" and "periodontitis". Oral inflammatory conditions including chelitis, gingivitis, herpetic gingivostomatitis, mucositis, oral candidiasis, periodontitis and ulcerations are common manifestations in children with ALL. RESULTS: Periodontal inflammatory conditions and oral mucositis were reported to be significantly higher in children with ALL as compared to healthy controls. Tooth morphological disorders including agenesis, microdontia, short roots and developmental defects in the enamel and dentin were more often observed in children with ALL as compared to healthy controls. Children with ALL have a reduced salivary flow rate, which makes them more susceptible to dental caries as compared to healthy children. Malocclusion due to microdontia may also trigger temporomandibular joint disorders in children with ALL; however, this relationship needs further investigations. CONCLUSION: Oral inflammatory conditions including mucositis and gingivitis are common in children with ALL as compared to healthy children. Tooth morphological disorders including microdontia and enamel and dentin are common manifestations in children with ALL.     

Suppressed neutrophil function in children with acute lymphoblastic leukemia

Infection is a major obstacle in cancer chemotherapy. Neutropenia has been considered to be the most important risk factor for severe infection; however, other factors, such as impaired neutrophil function, may be involved in susceptibility to infection in patients undergoing chemotherapy. In this study, we analyzed neutrophil function in children with acute lymphoblastic leukemia (ALL). Whole blood samples were obtained from 16 children with ALL at diagnosis, after induction chemotherapy, and after consolidation chemotherapy. Oxidative burst and phagocytic activity of neutrophils were analyzed by flow cytometry. Oxidative burst of neutrophils was impaired in ALL patients. The percentage of neutrophils with normal oxidative burst after PMA stimulation was 59.0 ± 13.2 or 70.0 ± 21.0% at diagnosis or after induction chemotherapy, respectively, which was significantly lower compared with 93.8 ± 6.1% in healthy control subjects (P = 0.00004, or 0.002, respectively); however, this value was normal after consolidation chemotherapy. No significant differences were noted in phagocytic activity in children with ALL compared with healthy control subjects. Impaired oxidative burst of neutrophils may be one risk factor for infections in children with ALL, especially in the initial periods of treatment.     

Allogeneic hematopoietic cell transplantation for infants with acute lymphoblastic leukemia

The role of transplantation in infants with acute lymphoblastic leukemia (ALL) is not defined. We analyzed results of 40 infants diagnosed before age 12 months who received a hematopoietic cell transplant (HCT) between July 1982 and February 2003 in first complete remission (CR1; n = 17), CR2/3 (n = 7), or relapse (n = 16). Patients were conditioned with cyclophosphamide with total body irradiation (n = 39) or busulfan (n = 1). Donors were matched related (n = 8), mismatched related (n = 16), or unrelated (n = 16). Graft-versus-host disease (GVHD) prophylaxis was methotrexate or cyclosporine (n = 7) or methotrexate plus cyclosporine (n = 33). Thirty-nine patients engrafted, 20 developed acute GVHD, and 7 developed chronic GVHD. Sixteen patients relapsed and 7 died of other causes. Patients in CR1 had disease-free survival (DFS) of 76% compared with 45% for CR2/CR3 and 8% for relapse (P < .001). Of 33 patients with cytogenetic data, 26 (79%) had MLL gene rearrangement. Fourteen of these 26 were in CR1 and 11 survive in remission. Outcome was associated with phase of disease, but having the MLL gene was not a factor predictive of outcome. Late effects included growth and other hormone deficiencies. These data demonstrate that infants with ALL and MLL gene have excellent DFS when they received transplants in CR1, and consideration for transplantation in CR1 is warranted.     

Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia

One-hundred thirty-nine patients with acute lymphoblastic leukemia (ALL) and hypodiploidy (fewer than 45 chromosomes) were collected from 10 different national ALL study groups and single institutions. Patients were stratified by modal chromosome number into 4 groups: 24 to 29 (N = 46); 33 to 39 (N = 26); 40 to 43 (N = 13); and 44 (N = 54) chromosomes. Nine patients were Philadelphia chromosome (Ph) positive (4 cases: 44 chromosomes; 5 cases: 40-43 chromosomes) and were not considered further. Event-free survival (EFS) and overall survival (OS) of the remaining 130 patients were 38.5% ± 4.4% and 49.8% ± 4.2% at 8 years, respectively. There were no significant differences in outcome between patients with 24 to 29, 33 to 39, or 40 to 43 chromosomes. Compared with patients with fewer than 44 chromosomes, patients with 44 chromosomes had a significantly better EFS (P = .01; 8-year estimate, 52.2% vs 30.1%) and OS (P = .017; 69% vs 37.5%). For patients with 44 chromosomes, monosomy 7, the presence of a dicentric chromosome, or both predicted a worse EFS but similar OS. Doubling of the hypodiploid clone occurred in 32 patients (24-29 chromosomes [n = 25] and 33-39 chromosomes [n = 7]) and had no prognostic implication. Children and adolescents with ALL and hypodiploidy with fewer than 44 chromosomes have a poor outcome despite contemporary therapy.      

Lineage-related polypeptide markers in acute lymphoblastic leukemia detected by two-dimensional gel electrophoresis.

We have utilized two-dimensional polyacrylamide gel electrophoresis, coupled with ultrasensitive silver staining, to identify lineage-related polypeptide markers in lymphoblasts from children with acute lymphoblastic leukemia. Twelve polypeptides were detected that could distinguish between the major subgroups of acute lymphoblastic leukemia. These included a new marker for common acute lymphoblastic leukemia and markers for cells of B and T lineages. Analysis of the two-dimensional patterns also allowed the tentative identification of T-cell lineage in two cases with an otherwise undifferentiated non-T-cell non-B-cell phenotype. Two-dimensional electrophoresis thus provides a powerful tool for the delineation of the cell of origin in leukemia.     

Cytogenetic study of 105 children with acute lymphoblastic leukemia

Cytogenetic analysis was performed on 105 children with acute lymphoblastic leukemia (ALL). Adequate mitoses for study were obtained in 79 of the cases (71%). A normal karyotype was found in 18 patients (23%), while clonal chromosomal abnormalities were detected in 61 patients (77%). The karyotypes fell into five categories according to modal number: normal (18 patients), pseudodiploid (27 patients), hypodiploid (3 patients), hyperdiploid with 47-50 chromosomes (11 patients), and hyperdiploid with greater than or equal to 51 chromosomes (20 patients). Structural chromosome changes were found in 50 patients (63%); translocations were encountered in 15 of these patients (19%). The chromosome most often participating in translocations was number 19. Modal number was found to be an independent prognostic factor. Modal numbers 47-50 were associated with the poorest prognosis. The hyperdiploid clone with more than 50 chromosomes and the normal karyotype had the best prognosis.     

No difference in outcome between children and adolescents transplanted for acute lymphoblastic leukemia in second remission

Acute lymphoblastic leukemia (ALL) in second complete remission is one of the most common indications for allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients. We compared the outcome after HCST of adolescents, aged 14 to 18 years, with that of children (ie, patients < 14 years of age). Enrolled in the study were 395 patients given the allograft between January 1990 and December 2007; both children (334) and adolescents (61) were transplanted in the same pediatric institutions. All patients received a myeloablative regimen that included total body irradiation in the majority of them. The donor was an HLA-identical sibling for 199 patients and an unrelated volunteer in the remaining 196 patients. Children and adolescents had a comparable cumulative incidence of transplantation-related mortality, disease recurrence, and of both acute and chronic graft-versus-host disease. The 10-year probability of overall survival and event-free survival for the whole cohort of patients were 57% (95% confidence interval, 52%-62%) and 54% (95% confidence interval, 49%-59%), respectively, with no difference between children and adolescents. This study documents that adolescents with ALL in second complete remission given HSCT in pediatric centers have an outcome that does not differ from that of patients younger than 14 years of age.     

Premature adiposity rebound in children treated for acute lymphoblastic leukemia

The adiposity rebound (AR), when body mass index begins to increase after its nadir in childhood, is a critical period for the regulation of energy balance and adult obesity risk. The aim of the present study was to test whether children treated for acute lymphoblastic leukemia (ALL) experience premature AR. This might, in part, explain their tendency to develop obesity. Timing of AR was assessed by visual inspection of body mass index plots in 68 patients treated for ALL in first remission. This sample comprised all eligible patients treated in Scotland between 1991 and 1998, age 30 months or less at the time of diagnosis. Timing of AR in patients was compared against a cohort of 889 healthy British children studied during the 1990s using the same method. AR occurred significantly earlier in the patients treated for ALL (chi(2) test, P < 0.001). The AR had occurred in 43% (29 of 68) of the patients and 4% (40 of 889) of the comparison group by age 37 months. At 49 months AR had occurred in 81% (55 of 68) of the patients and 21% (190 of 889) of the comparison group. Treatment of ALL is associated with a significantly advanced AR. This might, in part, explain the extremely high prevalence of obesity in long-term survivors. Clinical management should focus on minimizing excess weight gain during therapy to reduce long-term obesity risk.     

Clinical and biological characteristics of adult biphenotypic acute leukemia in comparison with that of acute myeloid leukemia and acute lymphoblastic leukemia: a case series of a Chinese population

Background

Biphenotypic acute leukemia is a rare disorder that is difficult to diagnose. It displays features of both myeloid and lymphoid lineage. There is still a lack of studies in biphenotypic acute leukemia in a Chinese population. We present here a comprehensive investigation of the clinical and biological characteristics, and outcome of biphenotypic acute leukemia in our hospital in over a seven year period.

Design and Methods

We retrospectively analyzed 452 adult acute leukemia patients diagnosed according to French-American-British (FAB) classification and biphenotypic acute leukemia diagnosed according to European Group for the Immunological Characterization of Leukemias (EGIL) classification, respectively. Biological characteristics, response to treatment, and outcome were examined in biphenotypic acute leukemia patients and compared with that in acute myeloid leukemia and acute lymphoblastic leukemia patients with complete follow-up profiles diagnosed in the same period.

Results

Of 452 acute leukemia patients, 21 cases (4.6%) were diagnosed as biphenotypic acute leukemia. Among them, 14 (66.7%) were B lymphoid and myeloid, 5 (23.8%) were T lymphoid and myeloid, one (4.8%) was T/B lymphoid and one (4.8%) was trilineage differentiation. When compared with acute myeloid leukemia and acute lymphoblastic leukemia, patients with biphenotypic acute leukemia showed significantly higher incidence of CD34 antigen expression, unfavorable karyotypes, and extramedullary infiltration (p<0.05). In this cohort of patients with biphenotypic acute leukemia, t(9;22) was the most common abnormality in chromosome structure. The median disease-free survival and overall survival in biphenotypic acute leukemia patients was five months and ten months, respectively, significantly shorter than those in acute myeloid leukemia and acute lymphoblastic leukemia patients (p<0.05).

Conclusions

The prognosis of biphenotypic acute leukemia patients is poor when compared with de novo acute myeloid leukemia or acute lymphoblastic leukemia. Biphenotypic acute leukemia patients showed a much higher incidence of CD34 antigen expression, complex abnormal karyotype, extramedullary infiltration, relapse, and resistance to therapy after relapse.     

Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants

Acute lymphoblastic leukemia in infants represents an aggressive malignancy associated with a high incidence (approx. 80%) of translocations involving the Mixed Lineage Leukemia (MLL) gene. Attempts to mimic Mixed Lineage Leukemia fusion driven leukemogenesis in mice raised the question whether these fusion proteins require secondary hits. RAS mutations are suggested as candidates. Earlier results on the incidence of RAS mutations in Mixed Lineage Leukemia-rearranged acute lymphoblastic leukemia are inconclusive. Therefore, we studied frequencies and relation with clinical parameters of RAS mutations in a large cohort of infant acute lymphoblastic leukemia patients. Using conventional sequencing analysis, we screened neuroblastoma RAS viral (v-ras) oncogene homolog gene (NRAS), v-Ki-ras Kirsten rat sarcoma viral oncogene homolog gene (KRAS), and v-raf murine sarcoma viral oncogene homolog B1 gene (BRAF) for mutations in a large cohort (n=109) of infant acute lymphoblastic leukemia patients and studied the mutations in relation to several clinical parameters, and in relation to Homeobox gene A9 expression and the presence of ALL1 fused gene 4-Mixed Lineage Leukemia (AF4-MLL). Mutations were detected in approximately 14% of all cases, with a higher frequency of approximately 24% in t(4;11)-positive patients (P=0.04). Furthermore, we identified RAS mutations as an independent predictor (P=0.019) for poor outcome in Mixed Lineage Leukemia-rearranged infant acute lymphoblastic leukemia, with a hazard ratio of 3.194 (95% confidence interval (CI):1.211–8.429). Also, RAS-mutated infants have higher white blood cell counts at diagnosis (P=0.013), and are more resistant to glucocorticoids in vitro (P<0.05). Finally, we demonstrate that RAS mutations, and not the lack of Homeobox gene A9 expression nor the expression of AF4-MLL are associated with poor outcome in t(4;11)-rearranged infants. We conclude that the presence of RAS mutations in Mixed Lineage Leukemia-rearranged infant acute lymphoblastic leukemia is an independent predictor for a poor outcome. Therefore, future risk-stratification based on abnormal RAS-pathway activation and RAS-pathway inhibition could be beneficial in RAS-mutated infant acute lymphoblastic leukemia patients.