Prognostic factors in adult acute lymphoblastic leukemia

The prognosis of patients with acute lymphoblastic leukemia (ALL), treated with modern chemotherapeutic regimens, is dependent on a number of variables. The major prognostic factors for survival in adult ALL are age, cytogenetic abnormalities, immunologic subtype, white blood cell (WBC) count, and time to achieve complete remission (CR). Determination of these factors is crucial for adapting post remission therapy in adult ALL. Indeed, risk-adapted strategies based on those biologic and clinical features are currently being applied to improve survival. In this review, we report the different prognostic factors described in adult ALL and discuss the controversies in current adult ALL management in relation with these different features. The data reported are derived from the medical literature and from the experience of the authors. Prognostic factors appear to be time-dependent. This emphasizes their determination according to the phase of treatment. The use of time-segmented multivariate analysis able to distinguish prognostic factors associated with the induction phase and those associated with the post-induction phase of treatment seems suitable to define accurately prognostic models.     

Prognostic significance of high hyperdiploid and triploid/tetraploid adult acute myeloid leukemia

To ascertain the clinical implications of high hyperdiploid (HH; 49–65 chromosomes) and triploid/tetraploid (TT; >65 chromosomes) adult acute myeloid leukemia (AML), all such cases were retrieved from the Swedish AML Registry. Of the 3,654 cytogenetically informative cases diagnosed between January 1997 and May 2014, 68 (1.9%) were HH (n = 50)/TT (n = 18). Patients with HH/TT were older than those with intermediate risk (IR) AML (median 71 years vs. 67 years; P = 0.042) and less often had de novo AML (63% vs. 79%; P = 0.004); no such differences were observed between HH/TT and complex karyotype (CK) AML. The overall survival (OS) was similar between patients with HH/TT and CK AML (median 0.9 years vs. 0.6 years; P = 0.082), whereas OS was significantly longer (median 1.6 years; P = 0.028) for IR AML. The OS was shorter for cases with HH than with TT (median 0.6 years vs. 1.4 years; P = 0.032) and for HH/TT AMLs with adverse abnormalities (median 0.8 years vs. 1.1 years; P = 0.044). In conclusion, HH/TT AML is associated with a poor outcome, but chromosome numbers >65 and absence of adverse aberrations seem to translate into a more favorable prognosis. Thus, HH/TT AMLs are clinically heterogeneous and should not automatically be grouped as high risk.Am. J. Hematol. 90:800–805, 2015. © 2015 Wiley Periodicals, Inc.     

急性白血病止凝血异常的预后意义

目的：探讨急性白血病（AL）患者的止凝血异常及其与预后的关系。方法：运用ELISA或发色底物法对56例AL患者血浆一系列止凝血指标进行了检测。结果：治疗前血浆血栓调节蛋白（TM）、P－选择素、可溶性纤维蛋白单体复合物（SFMC）、组织纤溶酶原激活性（t－PA）、D－二聚体水平显著升高,蛋白C抗原（PC：Ag）、纤溶酶原激活抑制物（PAI）水平低于正常,纤维蛋白原（Fg)、蛋白C活性（PC：A）、蛋白S水平（PS）与正常对照组差异无显著性意义,治疗后除蛋白C活性外均恢复至正常范围内;治疗前后TM升高、治疗前PS降低及PAI升高者预后较差,其中治疗后TM和治疗前PAI是决定患者无复归生存时间的预后因素,治疗后TM、治疗前PS和PAI水平是决定患者总生存时间的预后因素。结论：AL发病过程中存在血管内皮细胞损伤、血小板活化以及凝血、抗凝、纤溶系统的激活,并随病情的好转而逐渐改善;血管内皮损伤、PS消耗及纤溶抑制活性增强与患者的预后密切相关。     

Marrow culture studies in adult acute leukemia at presentation and during remission.

Culture of bone marrow and/or blood cells in a semisolid agar system from 43 adults with acute nonlymphoblastic leukemia at first presentation showed two distinct growth patterns at 14 days. In 53% of patients cells failed to grow (type O), while in the remainder an abnormal growth pattern (type B) with small numbers of diffuse colonies and excessive numbers of cell clusters was seen. The response following chemotherapy was significantly better in the patients whose cells failed to grow. Serial culture studies, performed in 9 patients throughout remissions of 100-1112 days, which had been maintained by intermittent chemotherapy, showed wide fluctuations in proliferative activity. These ranged from no growth to marked proliferation with predominance of clusters and small numbers of diffuse colonies, indistinguishable from the type B pattern seen in 47% of patients at first presentation. The possibility is discussed that the periods of failure to grow, and/or those in which a type B pattern emerged, represented sporadic reactivation of leukemic cells.     

Prognostic significance of elevated serum beta 2-microglobulin levels in adult acute lymphocytic leukemia.

PURPOSE: Elevated serum beta-2 microglobulin (beta 2M) levels are associated with poor prognosis in several lymphoproliferative disorders including multiple myeloma and lymphoma. Their prognostic relevance in acute lymphocytic leukemia (ALL) is unknown. We analyzed the associations of serum beta 2M levels at diagnosis with pretreatment characteristics and with prognosis in adult ALL. PATIENTS AND METHODS: One hundred fifty-nine adults with newly diagnosed ALL were investigated. Serum beta 2M levels were determined at diagnosis, on fresh peripheral blood samples, using a radioimmunoassay, the Pharmacia beta 2 Micro RIA (Pharmacia Diagnostics, Uppsala, Sweden). Statistical correlations were assessed by standard methods, and further independent prognostic value of serum beta 2M was determined by multivariate analysis. RESULTS: Patients with beta 2M levels of 4.0 mg/L or above had a lower complete response rate (61% versus 80%; p = 0.02), a significantly worse survival (p < 0.01), and a significantly higher association with development of central nervous system (CNS) leukemia (p < 0.01). High beta 2M levels were more common among patients with older age, with elevated creatinine, bilirubin, and alkaline phosphatase levels, with low albumin levels, and with B-cell disease. Multivariate analysis for survival indicated the beta 2M level to be an independent prognostic variable (after adjusting for pretreatment creatinine level and age). The evaluation of beta 2M levels within low- and high-risk groups for CNS disease suggested an association of elevated beta 2M levels with a worse incidence of CNS disease in the high-risk patients. CONCLUSION: Monitoring serum beta 2M levels may provide significant prognostic information in adults with ALL and should be included in their pretreatment evaluation. Its importance in childhood ALL requires investigation.     

Prognostic significance of IKZF1 deletion in adult B cell acute lymphoblastic leukemia: a meta-analysis

The IKAROS family zinc finger 1 (IKZF1) gene is frequently altered in adults with B cell acute lymphoblastic leukemia (ALL). Although many studies have indicated that IKZF1 alterations might be associated with poor outcomes in adults with ALL, the results remain controversial. A previous meta-analysis demonstrated the negative prognostic significance of IKZF1 deletion in ALL. However, most of the included studies (14 out of 15) were conducted in pediatric patients with ALL, and age was identified as a significant source of heterogeneity. Thus, performing the present meta-analysis provides valuable information to further elucidate the prognostic value of IKZF1 deletion in adults with ALL. Eight studies were identified that had been published prior to August 1, 2016. The studies included a total of 1008 patients. Hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival (OS) and disease-free survival (DFS)/relapse-free survival (RFS)/progression-free survival (PFS)/event-free survival (EFS) were pooled to estimate the prognostic power of IKZF1 deletion. Pooled HRs suggested that IKZF1 deletion had a negative impact on both OS (HR?=?1.40, 95% CI 1.13–1.73) and DFS/RFS/PFS/EFS (HR?=?1.67, 95% CI 1.28–2.17) in the overall population. Subgroup analyses indicated that IKZF1 deletion could independently predict unfavorable OS (HR?=?1.60, 95% CI 1.25–2.06) and DFS/RFS/PFS/EFS (HR?=?1.67, 95% CI 1.28–2.17) in BCR-ABL1-negative but not in BCR-ABL1-positive B cell ALL patients. Our meta-analysis suggests that IKZF1 deletion is a poor prognostic factor for adults with B cell ALL and may be more valuable in BCR-ABL1-negative B cell ALL patients.     

Prognostic significance of CD56 antigen expression in acute myeloid leukemia

BACKGROUND AND OBJECTIVES. CD56 antigen expression has been reported in several hematologic malignancies. In acute myeloid leukemia (AML)M2 with t(8;21) and acute promyelocytic leukemia (APL) it has been found to be consistently associated with an unfavorable prognosis, whereas in other AML subtypes its role remains uncertain. We investigated CD56 expression in a cohort of AML patients in order to assess its frequency and prognostic relevance. DESIGN AND METHODS. Immunophenotypic analysis including that of CD56 antigen was available for 171 consecutive AML patients (139 with AML and 32 with APL), enrolled between December 1995 and December 1999 at a single institution. A sample of fresh bone marrow cells taken at diagnosis was recorded as positive when at least 20% of the cells double-stained with specific monoclonal antibodies against CD56 and CD33 antigens. RESULTS. CD56 positivity was demonstrated in 37 cases (21.6%). Its frequency was lower in M4 (6%) and higher in M5 (37%). The median percentage for CD56+ blasts was 56% (range 21-99%). CD56 positivity did not correlate with age, sex, blast count, favorable or unfavorable cytogenetics at diagnosis, nor did it influence the outcome in terms of complete remission (CR) duration (606 vs. 417 days, p=n.s.) or overall survival (OS) (210 vs. 277 days, p= n.s.). In the APL subgroup a significant difference in relapse rate was found at 3 years (71.4% in the CD56 positive group vs. 12% in the CD56 negative group, p=0.005). INTERPRETATION AND CONCLUSIONS. Our data confirm that CD56 positivity in APL patients at diagnosis is associated with a worse prognosis, suggesting that close molecular monitoring is necessary in CD56 positive APL patients. In contrast, the prognostic role of CD56 remains uncertain in the other AML subtypes.     

Prognostic significance of HOXB4 in de novo acute myeloid leukemia

As research into hematopoiesis advances, new factors associated with hematopoietic stem cell (HSC) activity have been discovered, and the contribution of HSC factors to hematopoiesis is now actively being investigated. Since the involvement of stem cells is considered to be important in hematological malignancies as well as normal hematopoiesis, we examined the expression of newly defined HSC factors including HOXB4, TCFEC, HMGB-1, FOS, and SPI-1 in the bone marrow (BM) from de novo acute myeloid leukemia (AML) patients. Expression levels of mRNA extracted from frozen specimens of AML patients and normal controls were measured by real-time polymerase chain reaction (PCR). Among the HSC factors, HOXB4 exhibited significantly higher expression in the BM of AML as compared with normal controls. Immunostaining for HOXB4 revealed that the HOXB4-positive cell ratios correlated well with the expression levels of mRNA for HOXB4 in AML BM. Based on the HOXB4-positive cell ratio, AML patients were divided into two groups (cases with higher ratios and lower ratios). The group with higher HOXB4-positive cell ratios had better prognoses as compared with the group with lower ratios. Multivariate analysis confirmed the HOXB4-positivity as an independent predictor of overall survival of AML patients. Lastly, mRNA expression levels for HOXB4 were inversely correlated with the expression levels of at least two genes, including ABCB1, which is known to be a multidrug-resistance gene. Our study distinguishes a subgroup of AML with higher HOXB4 expression and better prognosis, and this might be reflected by relative drug sensitivity in leukemic cells.     

Prognostic impact of persistent cytogenetic abnormalities at complete remission in adult patients with acute lymphoblastic leukemia

In acute myelogenous leukemia, the persistent detection of abnormal cytogenetics at complete remission (ACCR) is associated with inferior outcomes. However, the prognostic significance of ACCR in adult patients with acute lymphoblastic leukemia (ALL) is unknown. We evaluated 272 adult patients with ALL and abnormal cytogenetics at baseline who were treated with frontline induction chemotherapy, achieved complete remission (CR) and had cytogenetic analysis performed at the time of CR. ACCR was observed in 26 patients (9.6%). Median relapse‐free survival was 22 months (95% CI, 12 months to not reached) for patients with ACCR vs. 48 months (range, 30–125 months) in patients with normal cytogenetics at CR (NCCR; P = 0.31). Median overall survival also did not differ significantly between the ACCR (99 months [range, 17 months to not reached]) and NCCR groups (67 months [range, 47 months to not reached], P = 0.86). The specificity of ACCR for minimal residual disease (MRD) positivity by multi‐parameter flow cytometry (MFC) was 43%, and there was overall poor correlation between these two methods for the detection of residual disease. When patients were stratified by MRD status, the presence or absence of persistent cytogenetic abnormalities at CR did not add additional prognostic information. This study suggests that there is poor association between MRD assessment by MFC and the presence or absence of cytogenetic abnormalities at CR in adult patients with ALL. ACCR was not associated with adverse outcomes in ALL and did not add additional prognostic information when MRD status by MFC was known. Am. J. Hematol. 91:385–389, 2016. © 2016 Wiley Periodicals, Inc.     

Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China

The 2-hydroxyglutarate (2-HG) has been reported to result from mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes and to function as an “oncometabolite.” To evaluate the clinical significance of serum 2-HG levels in hematologic malignancies, acute myeloid leukemia (AML) in particular, we analyzed this metabolite in distinct types of human leukemia and lymphoma and established the range of serum 2-HG in appropriate normal control individuals by using gas chromatograph–time-of-flight mass spectrometry. Aberrant serum 2-HG pattern was detected in the multicenter group of AML, with 62 of 367 (17%) patients having 2-HG levels above the cutoff value (2.01, log₂-transformed from 4.03 μg/mL). IDH1/2 mutations occurred in 27 of 31 (87%) AML cases with very high 2-HG, but were observed only in 9 of 31 (29%) patients with moderately high 2-HG, suggesting other genetic or biochemical events may exist in causing 2-HG elevation. Indeed, glutamine-related metabolites exhibited a pattern in favor of 2-HG synthesis in the high 2-HG group. In AML patients with cytogenetically normal AML (n = 234), high 2-HG represented a negative prognostic factor in both overall survival and event-free survival. Univariate and multivariate analyses confirmed high serum 2-HG as a strong prognostic predictor independent of other clinical and molecular features. We also demonstrated distinct gene-expression/DNA methylation profiles in AML blasts with high 2-HG compared with those with normal ones, supporting a role that 2-HG plays in leukemogenesis.Acute myeloid leukemia (AML) represents a group of clonal hematopoietic progenitor malignancies with considerable diversities in clinical and biological features (1). In addition to clinical parameter, such as age and white blood cell counts (WBC), a variety of biomarkers have been shown to be predictive of outcome in AML patients, including cytogenetic characteristics and patterns of recurrent gene mutations in the blasts, as exemplified by nucleophosmin (NPM1), fms-related tyrosine kinase 3 (FLT3), and CCAAT/enhancer binding protein-alpha (CEBPA) (1). Even with the remarkable progress of genomic studies on AML (2, 3), clinically useful biomarkers with prognostic values are still needed in a part of cases for better clinical management, particularly in cytogenetically normal AML (CN-AML) patients. Of note, gene mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) were reported recently not only in gliomas but also in AML (4, 5). The prognostic significance of these mutations appears controversial in AML (6–10), although a metaanalysis suggests a poor outcome in cases with IDH1 mutations (11).IDHs are key enzymes that participate in the tricarboxylic acid metabolic cycle. Three members (IDH1, IDH2, and IDH3) are encoded by the IDH gene family and their activities are NADP(+)/NAD(+)-dependent. IDH1 and IDH2 catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Mutant enzymes form a heterodimer, which display reduced catalytic activity to produce α-KG but a newly acquired activity to convert α-KG to 2-hydroxyglutarate (2-HG) (12). Recent studies have suggested that 2-HG may be an “oncometabolite” and play a role in driving malignant phenotype (13–15). Interestingly, 2-HG has been shown to competitively inhibit α-KG–dependent dioxygenases, such as the ten-eleven-translocation 2 (TET2) enzyme, and disturb the epigenetic regulatory network, leading to genome-wide histone and DNA damages with hypermethylation (12–14). Notably, in patients with d-2-hydroxyglutaric aciduria, there is an elevated risk of brain tumors (15). 2-HG can be metabolized by the enzyme 2-HG dehydrogenase (D2HGDH), but until now the possible contribution of genetic variants of this enzyme to the turnover of 2-HG has not yet been addressed.Although IDH1/2 mutations are biomarkers in gliomas, the serum levels of 2-HG in these mutations are usually normal (16). In AML harboring IDH1/2 mutations, serum 2-HG concentrations were elevated in some cases (17–21). Very recent reports suggested that high 2-HG could predict IDH1/2 mutations in AML and be used as a marker for minimal residual disease during clinical remission (21, 22). However, the significance of serum 2-HG levels in prognosis remains obscure. In this work, we examined the levels of 2-HG as a part of the metabolomic study in a large series of AML cases, as well as other hematologic malignancies and healthy controls, and characterized their relevant clinical and molecular features. In particular, we attempted to address the potential prognostic value of 2-HG in AML.     

Prognostic value of cytogenetics in adult patients with Philadelphia-negative acute lymphoblastic leukemia

The prognostic value of cytogenetics in adult acute lymphoblastic leukemia (ALL) is not as established as in childhood ALL. We have analyzed the outcome and prognostic value of karyotype in 84 adults diagnosed with Philadelphia-negative ALL from a single institution that received induction chemotherapy and had successful karyotype performed. The most frequent finding was normal karyotype in 35 (42%) cases, followed by aneuploidies in 20 cases (24%) and t(4;11)(q21;q23)/MLL/AF4 in 5 (6%), and the remaining 24(27%) cases carried miscellaneous clonal abnormalities. The group of patients with t(4;11)(q21;q23)/MLL/AF4, hypodiploidy and low hyperdiploidy (less than 50 chromosomes) showed a worse outcome than those with normal karyotype and miscellaneous abnormalities in terms of overall survival (OS) (3 years OS; 47% vs. 13%, p?=?0.014) and relapse-free survival (RFS) (3 years RFS; 44% vs. 27%, p?=?0.005). Other cytogenetic prognostic classifications reported to date were tested in our series, but any was fully reproducible. In conclusion, karyotype is a useful tool for risk assessment in adult ALL. We have confirmed the bad prognosis of t(4;11)(q21;q23)/MLL/AF4 and hypodiploidy. Besides, low hyperdiploidy could also define a high-risk group of patients who might be candidates for more intensive treatment.     

Prognostic significance of testicular relapse in boys with acute lymphoblastic leukemia.

Among 107 boys with acute lymphoblastic leukemia who achieved initial complete remission after treatment according to two therapeutic protocols for standard and high risk leukemias, respectively, in 14 (13%) testicular leukemia was observed. Isolated testicular involvement was noted in 4, and combined with medullary relapse in 10 patients. The prognosis was worse in children with high risk leukemias (mainly in those with more than 20 x 10(9)/l white blood cells and/or with less than 50 x 10(9)/l platelets). Prognosis depended also on the type of relapse. It was better in isolated as well as in late testicular relapse. It was worse in combined relapses as well as in early testicular involvement. Bilateral wedge biopsy of the testes was performed in 16 boys at the end of chemotherapy and leukemic infiltration was shown in none of them. Two to 13 months thereafter, in four boys testicular relapse developed, and in 2 boys bone marrow relapse followed 9 and 13 months later. Wedge biopsy of the testes in boys with leukemia does not seem to be of importance neither for diagnosis of testicular relapse nor for improving prognosis.     

Bcl-2蛋白在成人急性白血病表达的临床意义

目的:检测Bcl-2蛋白在不同阶段成人急性白血病的表达分布,分析Bcl-2蛋白表达是否可以作为预测化疗反应的指标。方法:选择成人急性白血病患者骨髓标本72例,分3组:初治组18例,完全缓解(CR)组38例,复发组16例。正常对照组6例。以流式细胞仪和单克隆抗体检测Bcl-2蛋白表达,进行统计学分析。结果:①Bcl-2蛋白在初治组、CR组和复发组表达率分别为11.11%、18.42%、62.50%。复发组表达率显著高于初治组和CR组(均P<0.01),初治组和CR组表达率差异无统计学意义(P>0.05);②Bcl-2在急性髓细胞白血病和急性淋巴细胞白血病表达率分别是24.07%(13/54)和33.33%(6/18);两组差异无统计学意义(P>0.05);③Bcl-2蛋白表达阳性组与阴性组CR率分别是36.84%和77.36%(P<0.01)。结论:Bcl-2蛋白在成人急性白血病复发组高表达并且与CR率低相关。     

Clinical significance of minimal residual disease in adult acute lymphoblastic leukemia

Monitoring minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) is a useful way for assessing treatment response and relapse. We studied the value of MRD and showed a correlation with relapse for 34 adult patients with ALL. MRD was evaluated by real-time quantitative polymerase chain reaction (RQ-PCR) with probes derived from fusion chimeric genes (BCR/ABL) (n = 12) or PCR-based detection of clonal immunoglobulin and T cell receptor gene rearrangements (n = 16), or both (n = 6). We analyzed 27 of the 34 patients who could be examined for MRD on day 100 after induction therapy. The overall survival (OS) rate (45.0%) and relapse-free survival (RFS) rate (40.0%) at 2 years in complete remission (CR) patients with MRD level ≥10^?3 (n = 12) were significantly lower than those in CR patients with MRD level <10^?3 (n = 15) (OS rate 79.0%, RFS rate 79.4%) (log-rank test, P = 0.017 and 0.0007). We also applied multicolor flow cytometry for comparison with MRD results analyzed by PCR methods. The comparison of results obtained in 27 follow-up samples showed consistency in 17 samples (63.0%) (P = 0.057). MRD analysis on day 100 is important for treatment decision in adult ALL.     

Prognostic significance of CD20 expression in childhood B-cell precursor acute lymphoblastic leukemia

CD20 expression is associated with inferior survival in adults with acute lymphoblastic leukemia (ALL). We analyzed the prognostic impact of CD20 expression in 353 children with B-cell precursor ALL treated in 3 consecutive St Jude Total Therapy studies. CD20 expression (> 20%) was found in 169 patients (48%) and was more frequent in patients between 1 and 10 years of age than in those younger than 1 or older than 10 years (P = .001). None of 14 patients with MLL-AF4 expressed CD20. There was no association between CD20 expression and E2A-PBX, TEL-AML1, ploidy, white blood cell count at diagnosis, or sex. In contrast to the experience in adult ALL, our patients with CD20 expression tended to have a better treatment outcome than those without the expression: 5-year event-free survival 84% +/- 2.9% versus 78% +/- 3.1% (P = .08). These data suggest that CD20 expression is not associated with inferior outcome in pediatric patients treated with contemporary regimens.