Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy

Cytogenetic clonal evolution (CE) is a known poor prognostic factor in Philadelphia chromosome-positive chronic myelogenous leukemia (Ph-positive CML). However, its prognostic relevance in the era of imatinib therapy is unknown. We investigated the independent prognostic relevance of CE in 498 patients with Ph-positive CML treated with imatinib for chronic or accelerated phases. One hundred twenty-one patients had CE alone (n = 70) or with other accelerated phase criteria (n = 51). Patients were compared in 4 categories: chronic phase (n = 295), CE only (n = 70), accelerated phase without CE (n = 82), and accelerated phase with CE (n = 51). Statistical methods used established methodologies for univariate and multivariate analyses. In chronic and accelerated phases of CML, CE was not associated with significant differences in major or complete cytogenetic response rates, but it was an independent poor prognostic factor for survival by multivariate analyses in both chronic (P =.005) and accelerated phase (P =.03). Multivariate analyses conducted at the 3-month landmark (including the 3-month cytogenetic response) identified the lack of cytogenetic response at 3 months to be a stronger independent poor prognostic factor for survival than CE for both chronic (major cytogenetic response versus other) and accelerated phase (any cytogenetic response versus other). We conclude that cytogenetic CE is not an important factor for achieving major or complete cytogenetic response with imatinib mesylate therapy, but it is an independent poor prognostic factor for survival in both chronic and accelerated phases of CML. The 3-month cytogenetic response to imatinib mesylate refined the prognostic relevance of such studies in patients on imatinib mesylate therapy.     

Prognostic significance of additional cytogenetic abnormalities at diagnosis of Philadelphia chromosome-positive chronic granulocytic leukemia

Of 661 patients with Philadelphia chromosome (Ph)-positive, nonblastic chronic granulocytic leukemia, 58 had cytogenetic abnormalities in addition to the Ph at the time of diagnosis. Twenty patients had reduplication of the Ph in one or more metaphases. Twenty-one patients with a single Ph exhibited hyperdiploidy in one or more metaphases. Eleven patients had two or more hypodiploid metaphases as their only numerical abnormality. The remaining six patients had a variety of abnormalities. Many patients had more than one type of abnormality. Survival of patients in the different subgroups was similar, but these 58 patients had a shorter course than the 603 patients without additional cytogenetic abnormalities (P less than .02). Survival curves for the two populations did not diverge until the 2-year point, after which the annual death rate among patients with additional cytogenetic abnormalities was approximately 40% higher than that of patients without such abnormalities. The two populations had similar relative risk values according to a hazard ratio formula previously described by the International CGL Prognosis Study Group. Thus, they would have been expected to have essentially identical survival curves. We conclude that the presence of additional cytogenetic abnormalities at the time of diagnosis constitutes an independently significant prognostic feature with an unusually delayed influence on survival.     

Prognostic significance of cytogenetic abnormalities in T‐cell prolymphocytic leukemia

T‐cell prolymphocytic leukemia (T‐PLL) is an aggressive mature T‐cell neoplasm. The most common cytogenetic abnormality associated with T‐PLL is inv(14)(q11.2q32) involving TCL1, but other abnormalities also have been reported. In this study, we correlated cytogenetic abnormalities with clinical outcome in 97 T‐PLL patients, including 66 men and 31 women with a median age of 63 years (range, 34‐81). Twenty‐seven patients had a normal karyotype (NK), one had two chromosomal aberrations, and 69 had a complex karyotype (CK). Patients with a CK had poorer overall survival (OS) than patients with a NK (P = .0016). In the CK group, the most common aberrations involved 14q (n = 45) and 8q (n = 38). Additional deletions of chromosomes 17p, 11q, 6q, 12p, 13q were observed frequently. No individual cytogenetic abnormality impacted OS. Patients with ≥5 aberrations had an OS of 11 months versus 22 months in patients with <5 aberrations (P = 0.0132). Fluorescence in situ hybridization for TCL1 successfully performed in 27 cases showed rearrangement in 8/10 (80%) NK versus 16/17 (94%) CK cases. OS of patients with TCL1 rearrangement and/or 14q aberrations was not significantly different from patients without TCL1 rearrangement and 14q aberrations (P = .3467). Patients with refractory disease showed worse OS in both the NK and CK groups (P = .0014 and P < .0001, respectively), compared with patients who achieved remission but then relapsed. Stem cell transplantation did not appear to improve OS regardless of karyotype complexity. In conclusion, patients with T‐PLL often have a CK which is a poor prognostic factor, particularly in patients with ≥5 cytogenetic aberrations.     

Prognostic significance of genetic markers in chronic myelogenous leukemia patients after bone marrow transplantation

Chronic myelogenous leukemia (CML) is a malignant disease of hematopoietic stem cell with a biphasic or triphasic clinical course and most often, with a fatal outcome. Significant progress in improving outcome for patients with CML has been achieved over past years. This can be attributed to marked improvement in therapeutic protocols and increased use of bone marrow transplantation (BMT) which remains the most effective option for long-term disease control of patient with CML. The residual leukemic activity in patients after BMT remains a central clinical question. To effectively monitor minimal residual disease leukemic activity after BMT, molecular genetic techniques are currently utilized in conjunction with cytogenetic assays. Because the clinical significance of detection minimal residual disease in CML remains to be determined, we performed cytogenetic analysis and PCR amplification technique in 37 Ph+ CML patients. All patients received transplants for CML in Bratislava between years 1992 and 1999. Our results suggest that PCR positivity after transplant is of limited prognostic significance for particular individuals and can be used to identified groups of individuals at elevated risk of relapse.     

Prognostic impact of cytogenetic abnormalities in patients with de novo acute nonlymphocytic leukemia

Detailed cytogenetic analyses were performed on specimens from 198 patients with de novo acute nonlymphocytic leukemia (ANLL), including high-resolution banding studies in 79 patients. One hundred ninety-two patients received induction therapy with daunorubicin and cytosine arabinoside (Ara-C) with an overall complete response rate (CR) of 63%. Responding patients received repetitive cycles of Ara-C-based intensification therapy. Clonal abnormalities were detected in 69% of the patients with specimens adequate for cytogenetic analysis. Certain cytogenetic changes were closely associated with French-American- British (FAB) morphology, age, and outcome: t(8;21) (closely associated with FAB M2), t(15;17) (associated with FAB M3), and abn 16q22 (associated with FAB M4EOS) tended to occur in younger patients and were associated with favorable outcomes in terms of both CR rate and long-term disease-free survival. In contrast, 19% of patients who had - 5/5q- and or -7/7q- and seven patients with trisomy 8 were older, had a poor prognosis, and usually failed to achieve remission (CR) because of chemotherapy-resistant leukemia. The adverse effect on CR rate and duration in this group of patients was independent of age, and there was no association with particular morphologic subtypes. These data suggest that cytogenetic findings should influence future therapeutic choices. In particular, patients with abnormalities associated with poor responses may be considered for investigational approaches and may also provide insights into mechanisms of drug resistance.     

Prognostic factors influencing feasibility of cytogenetic and molecular analysis in leukapheresis products in chronic myelogenous leukemia patients

Conventional cytogenetic (CC) study and molecular analysis were performed in 150 leukapheresis products from 36 patients diagnosed with chronic myelogenous leukemia who were included in an autologous stem cell transplantation program. The aims of the study were to evaluate the effectiveness of these two methods for the detection of residual disease in the harvest and to identify the factors influencing the number of cycling cells present in the apheresis products. Progenitor cell mobilization procedures performed late after diagnosis (>12 months), a short interval between interferon-alpha discontinuation and mobilization (<3.5 months), and an intensive mobilization regimen (idarubicin, cytarabine, and etoposide, ICE protocol) were associated with a low probability of obtaining 25 metaphases, which was achieved in only 41 instances (25% of the samples). In 38 samples, less than ten metaphases were obtained; a peripheral blood leukocyte count <1.0x10(9)/l at mobilization and mononuclear cell counts in the bag <0.5x10(8)/kg significantly increased the probability to obtain less than ten metaphases for CC analysis. Previous interferon-alpha treatment during > or =12 months and low mononuclear cell counts in the bag (<0.5x10(8)/kg) increased the probability of not obtaining mitosis for cytogenetic analysis. Molecular analysis by the polymerase chain reaction (PCR) technique did not give discriminate information in the samples not evaluable by cytogenetics due to the high frequency of PCR-positive results. We conclude that new techniques such as hypermetaphase fluorescence in situ hybridization (FISH), interphase FISH, or quantitative PCR need to be routinely employed in the study of leukapheresis samples of chronic myelogenous leukemia patients for a better assessment of the neoplastic contamination of the infused products.     

Clonal cytogenetic abnormalities in patients with chronic myeloid leukemia in complete cytogenetic response to imatinib mesylate

The emergence of clonal chromosomal abnormalities in Philadelphia-negative cells during treatment with imatinib in patients with Philadelphia-positive chronic myeloid leukemia has been reported. We add information to this issue presenting a series of 29 patients in complete cytogenetic response after imatinib treatment, three of whom developed clonal aberrations.     

Prognostic impact of acquisition of cytogenetic abnormalities during the course of chronic myelomonocytic leukemia

Karyotypic abnormalities are detected in 20–40% of chronic myelomonocytic leukemia (CMML) patients at initial diagnosis and have been shown to correlate with patients' outcome. The significance of acquisition of cytogenetic abnormalities (ACA) during the course of CMML, however, is largely unknown. In a cohort of 314 CMML patients, karyotypic abnormalities were detected in 106 (34%) patients at the time of diagnosis; and ACA were detected in 80 (25%) patients after a median interval of 17 months (range, 2–117 months). The most frequently observed ACA were a complex karyotype, followed by +21, ?7/del(7q), del(20q), i(17q), and ?17/del(17p). ACA appeared to occur more frequently in patients with a normal or lower risk karyotype. Progression to AML was seen in 44 of 80 (55%) patients with ACA versus 67 of 234 (29%) patients without ACA (P < 0.0001). Presence of ACA predicted an inferior leukemia‐free survival (LFS) by univariate (P = 0.0435) and multivariate analysis (HR = 1.892, P = 0.006). While acquisition of a complex karyotype was positively correlated with AML progression (P = 0.0086), del(20q) was associated with a stable disease (P = 0.0198). We conclude that ACA occur in ～20–30% of CMML patients during the course of disease, and are significantly associated with AML progression and a shorter LFS. Karyotypic abnormalities, either present at diagnosis or acquired during the course of disease, have prognostic implication in CMML patients. Am. J. Hematol. 90:882–887, 2015. © 2015 Wiley Periodicals, Inc.     

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.     

Interferon-alpha produces sustained cytogenetic responses in chronic myelogenous leukemia. Philadelphia chromosome-positive patients

OBJECTIVES: To evaluate the frequency and the course of complete cytogenetic responses in interferon-alpha (IFN-alpha)-treated patients with chronic myelogenous leukemia. DESIGN: Two prospective trials in consecutive patients. SETTING: A major tertiary cancer center. PATIENTS: Ninety-six consecutive patients with chronic myelogenous leukemia with disease duration of less than 1 year. INTERVENTION: Patients received partially pure IFN-alpha intramuscularly, from 3 to 9 million U/d (51 patients) or recombinant IFN-alpha 2a (Roferon, Hoffmann-LaRoche, Inc., Nutley, New Jersey), 5 million U/m2 body surface area daily (45 patients). MEASUREMENTS: Hematologic and cytogenetic tests were administered. MAIN RESULTS: Seventy of the patients (73%) achieved hematologic remission (95% CI, 63% to 81%), and 18 (19%) had complete suppression of the Philadelphia chromosome on at least one cytogenetic test. A complete cytogenetic response was induced in 7 of 51 or 14% (CI, 6% to 26%) of the patients treated with the partially pure IFN-alpha and in 11 of 45 or 24% (CI, 13% to 40%) of the patients treated with recombinant IFN-alpha 2a. The difference in complete cytogenetic response between the two groups was 10.7% (CI, - 5% to 26%; P greater than 0.2). Eleven patients had durable, ongoing, complete cytogenetic responses from 6 to more than 45 months (median, more than 30 months). CONCLUSION: This study was the first to show sustained, complete cytogenetic responses in a subset of patients with chronic myelogenous leukemia treated with single-agent therapy. The nature of this remission, that is, whether it depends on continuous therapy, requires further study.     

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。     

Prognostic significance of dysplastic features of hematopoiesis in patients with de novo acute myelogenous leukemia

 The detection of dysplastic features of hematopoiesis in de novo acute myeloid leukemia (AML) by light microscopy is defined as AML with trilineage myelodysplasia (AML/TLMD). The prognostic relevance of these dysplastic features for patients with de novo AML remains unclear. In order to evaluate the role of dysplasia in de novo AML, bone marrow aspirates from 69 patients were analyzed prospectively and investigated separately for erythropoiesis, granulopoiesis and megakaryopoiesis by three independent investigators. The overall complete remission (CR) rate was 48.8% and partial remission (PR) or nonresponders consituted 52.2% of the patients investigated. The median overall survival time was 5 months with a disease-free interval of 3.5 months for all patients. Dysgranulopoiesis (DysG) was observed in 30.4%, dysmegakaryopoiesis (DysM) in 50.7%, and dyserythropoiesis (DysE) in 43.5%. Of all patients, 26.0% showed trilineage dysplastic features and were thus classified as AML/TLMD. A significantly worse prognosis (Kaplan-Meyer plot, Student's t–test) was calculated for those patients with detection of only DysG (p=0.002), DysM (p=0.02), DysE (p=0.04) as compared with patients without any dysplastic signs. An unfavorable karyotype was correlated with patients showing DysG (P=0.02) and DysM (P=0.04). For these patients with an unfavorable karyotype, the occurrence of any dysplastic features had no additional prognostic impact. Dysplastic features (DysG, DysM, DysE) seem to be an important prognostic factor in de novo AML correlating with short overall survival. DysG and DysM correlated well with the appearance of unfavorable chromosomal abnormalities. It may be reasonable to assume that patients with dysplastic features should be considered for more aggressive treatment schedules at the time of diagnosis. Received: 25 March 1997 / Accepted: 10 July 1997     

Polyclonal hematopoiesis in interferon-induced cytogenetic remissions of chronic myelogenous leukemia.

Interferon (IFN) therapy of early chronic myelogenous leukemia (CML) frequently produces partial or complete cytogenetic remission of the disease. Patients with complete cytogenetic remission often continue on therapy for several years with bone marrow showing only diploid (normal) metaphases. We studied hematopoiesis in five female patients with major cytogenetic remissions from CML during IFN therapy. Clonality analysis using the BstXI PGK gene polymorphism showed that granulocytes were nonclonal in all patients during cytogenetic remission. BCR region studies showed rearrangement only in the one patient whose remission was incomplete at the time of sampling. Granulopoiesis is nonclonal in IFN-induced remissions of CML and may be derived from normal hematopoietic stem cells.     

Prognostic significance of karyotypic abnormalities in B cell chronic lymphocytic leukemia: an update

Cytogenetic analyses by G-banding and/or Q-banding techniques of leukemic B cells were performed in 102 patients with chronic lymphocytic leukemia (CLL), including six with prolymphocytic leukemia (PLL), one with hairy cell leukemia (HCL), and one with Waldenstrom's macroglobulinemia (WM) from 1979 through 1983. Follow-up after cytogenetic study ranged from 24 to 70 months. Seventeen patients had stage 0, 10 had stage I, 31 had stage II, and 44 had stage III or IV. Adequate metaphases were obtained for karyotypic analysis in 86 (84%) of 102 patients. Of these 86 patients with adequate metaphases, 43 had normal karyotypes (50%) and 43 had abnormal karyotypes (50%), of which trisomy 12 was the most frequent. Ten patients had trisomy 12 as the sole abnormality, 14 had trisomy 12 in combination with other abnormalities, and the remaining 19 had other abnormalities without trisomy 12. Abnormal karyotypes were more frequently associated with patients with advanced stages than those with early stages of the disease. Response rate to chemotherapy was significantly higher in patients with normal karyotypes than in those with abnormal karyotypes. Of eight patients who subsequently developed Richter's syndrome, seven initially had complex karyotypic changes with or without trisomy 12. These observations suggest that the chances of development of Richter's syndrome in CLL patients with multiple chromosome changes may be much higher than in those with either simple trisomy 12 or a normal karyotype. Mean frequency of abnormal metaphases was significantly higher in patients with complex trisomy 12 in combination with other changes than in those with trisomy 12 as the sole abnormality.(ABSTRACT TRUNCATED AT 250 WORDS)     

Complete cytogenetic response to interferon-alpha in a patient with chronic myelogenous leukemia undergoing hemodialysis

We describe a complete cytogenetic response to interferon-alpha in a patient with chronic myelogenous leukemia undergoing chronic hemodialysis. Although IFN-alpha therapy has been applied to patients with chronic hepatitis C receiving hemodialysis, the pharmacokinetics of IFN-alpha in patients with poor renal function still remain unclear. In the present patient, the serum IFN-alpha concentration remained high even 48 hours after injection (42.9 IU/ml), and IFN-alpha was almost completely removed by hemodialysis (< 6 UI/ml). The patient was treated with IFN-alpha (3 x 10(6) IU, three times a week), and cytogenetic disappearance (0%) of the Ph-positive clone was confirmed 31 months after the start of therapy. Recombinant human erythropoietin (Epo) was used to treat anemia due to renal failure and IFN-alpha therapy. The anemia was controllable with Epo, and no adverse effect was observed.     

慢性粒细胞白血病患者sorcin基因表达及其临床意义

目的探讨慢性粒细胞白血病患者可溶性耐药相关钙结合蛋白（sorcin）基因表达与临床耐药和疗效的关系。方法应用半定量逆转录聚合酶链反应（RT—PCR）检测31例慢性粒细胞白血病（CML）患者（CML组）和27例健康人（对照组）sorcin基因表达。结果CML组sorcin基因阳性表达率明显高于对照组（P〈0．01）,其急变期患者阳性率高于慢性期和加速期患者（P分别为0．03和0．18）;CML临床耐药者sorcin基因表达显著高于非临床耐药者,疗效显著低于非临床耐药者。结论CML患者sorcin基因呈高表达,与临床耐药和预后密切相关;sorcin表达可作为检测临床耐药和判断CML患者预后的指标之一。     

Prognostic significance of chromosome abnormalities in chronic lymphocytic leukaemia

Lymphocytes from 33 out of 63 patients with B-cell chronic lymphocytic leukaemia (B-CLL) were successfully stimulated for cytogenetic analysis by means of two B-cell mitogens: pokeweed mitogen and lipopolysaccharide-B, used after pretreatment of the cells with neuraminidase and galactose oxidase. All patients had abnormal clones in 30-100% of the cells analysed. Chromosomes more frequently involved were Nos. 1, 3, 6, 11, 12, 13 and 14. The most common abnormality was a marker 14q+ (breakpoint 14q32) seen in 17 cases; trisomy 12 was observed in seven cases. A clinical scoring system was used to investigate the correlation of chromosome abnormalities with prognosis. The group with 14q+ was often associated with features of progressive disease, namely; prolymphocytoid or Richter transformation, refractoriness to therapy, high WBC and advanced staging. A significant difference in survival was observed between patients with 14q+ and the rest: median survival from diagnosis being 45 months and over 64 months, respectively (P less than 0.05); when survival was calculated from the time of chromosome analysis the values were 8 months and more than 41 months, respectively (P less than 0.01). It is suggested that 14q+ is acquired during the evolution of CLL and that this development may be a key event in the clinical progression of B-CLL. Other abnormalities, including trisomy 12, were not found to be associated with a worse prognosis.     

Prognostic significance of additional chromosomal abnormalities at the time of diagnosis in patients with chronic myeloid leukemia treated with frontline tyrosine kinase inhibitors

Additional cytogenetic abnormalities (ACA) are considered a high risk feature in chronic myeloid leukemia (CML). However, its prognostic significance at the time of diagnosis in the setting of new tyrosine kinase inhibitors (TKIs) is less well understood. Patients with CML in CP with or without ACA at diagnosis treated with frontline TKIs in prospective clinical trials were analyzed for outcomes. Among 603 patients treated, 29 (5%) had ACA. Patients with ACA included 2 of 72 (2.8%) treated with imatinib 400 mg, 9 of 207 (4.3%) with imatinib 800 mg, 10 of 148 (6.7%) with dasatinib, 6 of 126 (4.7%) with nilotinib, and 2 of 50 (4%) with ponatinib. There was a significantly higher rate of complete cytogenetic response (CCyR) at 6 months in patients without ACA (P = .02). However cumulative CCyR and major molecular response (MMR) rates were not different. Similarly, MR4.0 and MR4.5 rates were similar for both groups; two CML‐ACA patients maintained MR 4.5 for at least 2 years. At 5 years, ACA at diagnosis did not significantly impact transformation‐free, failure‐free, event‐free, or overall survival expectations. Acknowledging small sample size estimates, response rates and survival outcomes were comparable in CP with ACA irrespective of whether chromosomal abnormalities were “major route” or other. The presence of ACA at diagnosis does not confer worse prognosis for patients with CML treated with TKI. Thus, the presence of ACA at diagnosis should not alter treatment strategies in these patients.