scholarly journals Cytogenetic Abnormalities May Predict Transformation to Acute Myeloid Leukemia in Polycythemia Vera Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4258-4258 ◽  
Author(s):  
Juliana E Hidalgo López ◽  
Adrián A Carballo-Zarate ◽  
L. Jeffrey Medeiros ◽  
Carlos E Bueso-Ramos ◽  
Guilin Tang
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Complex Karyotype ◽  
Abnormal Karyotype ◽  
Cytogenetic Abnormalities ◽  
Group A ◽  
Group B

Abstract Introduction: Cytogenetic abnormalities can be detected in about 20% of patients with polycythemia vera (PV) at initial diagnosis. The accumulated risk for acute myeloid leukemia (AML) transformation from PV has been estimated to be 2.3-14.4% at 10 years. Risk factors for AML transformation suggested in other studies include older age, abnormal karyotype and high leukocyte count. The purpose of this study is to evaluate the association of cytogenetic abnormalities with AML transformation in PV. Methods: We searched the database at our institution for patients with a diagnosis of PV during Jan. 1994 to Apr. 2015. Demographic data, clinical presentations and follow-up, and laboratory data including karyotype before and after AML transformation were collected. Bone marrow morphology, especially evidence of myelodysplasia, myelofibrosis and blast percentage were evaluated. Results: A total of 317 patients with a diagnosis of PV were identified. 36 (11%) patients progressed to AML (Group A), including 15 who presented in chronic phase and 21 in blast phase. The median interval from the diagnosis of PV to AML transformation was 97 months (range, 11 - 331 months). For comparison, 50 patients with similar demographic features during the same time interval but no evidence of AML transformation were also included in the study (Group B). The age of patients in both groups was comparable (median age: 57 vs. 54 years, p=0.2791). All patients were positive for JAK2 V617F mutation. The main therapies for patients with chronic phase PV included phlebotomy, hydrea, and tyrosine kinase inhibitors in a small subset of patients. There was no significant difference of treatments among the patients in groups A and B. Karyotype at chronic phase of PV was available in 15 patients in Group A and all 50 patients in Group B. Eleven (73%) patients in Group A showed an abnormal karyotype in chronic phase. The most common chromosomal abnormalities were trisomy 1q (n=6, 40%), including 4 (27%) patients with [+1, der(1;7)(q10;p10)] resulting in trisomy 1q and del(7q); and complex karyotype (n=3, 20%). Del(20q) and +8 was uncommon, only detected in 1 patient each. In Group B, 11 (22%) patients had an abnormal karyotype, which was much less frequent compared with Group A. No patients in Group B showed a complex karyotype or trisomy 1q; instead, del(20q) (n=6, 55%), +9 and/or +8 (n=5, 45%) were the most common chromosomes abnormalities detected. The median follow-up was 10 years in Group A and 14.5 years in Group B. At the time of AML transformation, 35 (97%) patients in Group A showed an abnormal karyotype, including 21 (58%) patients with a complex karyotype, 22 patients with -5/del(5q) and/or -7/del(7q) and 10 (28%) with trisomy 1q [8 with +1, der(1;7)]. Among the 15 patients who had karyotypic information during the chronic phase, 4 (27%) patients showed clonal evolution and 7 (47%) acquired new unrelated abnormal clones when AML transformation occurred. Morphologically, 15 patients in Group A had sequential bone marrow evaluation from chronic phase to blast phase, 14 (93%) patients developed myelofibrosis and 7 (47%) patients showed multilineage dysplasia during the chronic phase. At the time of AML transformation, 35 (97%) patients showed myelodysplasia. In Group B, 5 (10%) patients developed myelodysplasia and 31(62%) developed myelofibrosis in follow-up bone marrow samples. Conclusion: Cytogenetic abnormalities are associated with AML transformation in PV patients. Patients with an abnormal karyotype, especially with abnormalities of trisomy 1q [+1,der(1;7)(q10;p10)] or a complex karyotype, are at highest risk to develop clonal evolution or acquire new myelodysplasia-related clones [like -5/del(5q) and/or -7/del(7q)] or develop myelodysplasia and transform into AML. On the other hand, cytogenetic abnormalities, such as del(20q), +8 and/or +9, although commonly detected in PV, are associated with a low risk for myelodysplasia and AML transformation. Surveillance for cytogenetic abnormalities is helpful in the risk assessment of AML transformation in PV patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals BCOR Mutations in Acute Myeloid Leukemia: Clonal Evolution and Prognosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-4
Author(s):  
Ashley Zhang ◽  
Yuntao Liu ◽  
Shuning Wei ◽  
Benfa Gong ◽  
Chunlin Zhou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Statistical Difference ◽  
Tp53 Mutation ◽  
Clonal Evolution ◽  
Normal Karyotype ◽  
Abnormal Karyotype ◽  
Acute Myeloid

Background BCOR gene is a transcription repressor that may influence normal hematopoiesis and is associated with poor prognosis in acute myeloid leukemia (AML) with normal karyotype. However, due to the rare mutation frequency in AML (3.8%-5%), clinical characteristics and prognosis of AML patients with BCOR mutation including abnormal karyotype are still unknown. In addition, the clonal evolution of AML patients with BCOR mutation has not been fully investigated. Methods By means of next generation of sequencing, we performed sequencing of 114 genes related to hematological diseases including BCOR on 509 newly diagnosed AML patients (except for acute promyelocytic leukemia) from March 2017 to April 2019. The 2017 European Leukemia Net (ELN) genetic risk stratification was used to evaluate prognosis. Overall survival (OS) was defined as the time from diagnosis to death or last follow-up. Relapse-free survival (RFS) was measured from remission to relapse or death. Clonal evolution was investigated through analyzing bone marrow samples at diagnosis, complete remission (CR) and relapse from the same patient. Result Among 509 AML patients, we found BCOR mutations in 23 patients (4.5%). BCOR mutations were enriched in patients with mutations of RUNX1 (p = 0.008) and BCORL1 (p = 0.0003). Patients with BCOR mutation were more at adverse ELN risk category compared to patients without BCOR mutation (p = 0.007). Besides, there was a larger proportion of patients with normal karyotype in BCOR mutation group but it had not reached statistical difference (62.5% vs 45.5%, p = 0.064). The abnormal karyotype in patients with BCOR mutations included trisomy 8, t(9;11), inv(3), -7 and complex karyotype.There were no significant differences in age, sex, white blood cell count, hemoglobin or platelet count between the two groups. More patients died during induction (13.0% vs 3.5%, p = 0.56) and fewer patients achieved CR after 2 cycles of chemotherapy when patients had BCOR mutations (69.6% vs 82.5%, p = 0.115) but the difference had not reached statistical difference . Patients with BCOR mutations had inferior 2-year OS (52.1% vs 70.7%, p = 0.0094) and 2-year RFS (29.8% vs 61.1%, p = 0.0090). After adjustment for ELN risk stratification, BCOR mutation was still remain a poor prognostic factor. However, the adverse prognostic impact of BCOR mutation is overcome by hematopoietic stem cell transplantation (HSCT), in which there was no difference between BCOR mutation group and wild type group (p = 0.474) (Figure 1). Through analysis of paired bone marrow sample at diagnosis, remission and relapse, we revealed the clonal evolution that BCOR mutation was only detected at diagnosis sample as a subclone and diminished at CR and relapse while TP53 mutation was only detected at relapse with a variant allele frequency (VAF) of 25.5%. We also found BCOR mutation at another patient's diagnosis and relapse sample while TP53 mutation was detected at relapse with VAF of 11.8%. Conclusion BCOR is associated with RUNX1 mutation and higher ELN risk. AML patients with BCOR mutation including normal and abnormal karyotype conferred a worse impact on OS that can be overcome by HSCT. BCOR mutation is a subclone at diagnosis or relapse in some patients, in which TP53 mutation clone occurred at relapse. Disclosures No relevant conflicts of interest to declare.

Cytogenetic Clonal Evolution in Chronic Myeloid Leukemia during Imatinib Mesylate Treatment.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4844-4844
Author(s):  
Hana Klamova ◽  
Jana Brezinova ◽  
Kyra Michalova ◽  
Zuzana Zemanova ◽  
Marek Trneny
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Imatinib Treatment ◽  
Cytogenetic Abnormalities ◽  
Ph Chromosome ◽  
Cytogenetic Evolution

Abstract Cytogenetic clonal evolution (CE) - the presence of cytogenetic abnormalities in addition to the Ph chromosome in chronic myeloid leukemia (Ph+ CML) is a known poor prognostic factor associated with disease progression. Occurence of additional cytogenetic abnormalities in both Ph positive and Ph negative mitoses was also described in imatinib treated CML patients and was associated with occuring therapy resistance. The long - term significance is so far poorly understood. Objective. To monitor cytogenetic abnormalities in chronic phase CML patients on imatinib treatment, following long-term interferon alfa (IFN) or hydroxyurea treatment. To compare the haematological disease progression in patients with or without cytogenetic evolution Patients and methods: Cytogenetic evolution was analyzed in 57 patients (median age 56, range 18–73) treated with imatinib in chronic phase, following interferon resistance or intolerance. The duration of IFN application was 22 months (range 3 – 46 months), duration of imatinib treatment was 16 months (range 6 – 55 months). Cytogenetic abnormalities were detected by conventional cytogenetics - caryotype analysis and fluorescence in situ hybridisation (FISH). Results: Complete cytogenetic remission was accomplished in 55 of 57 pts (96%) on imatinib, significant or complete cytogenetic response was observed in 36 of 57 patients (66%). Cytogenetic evolution was observed in 11 patients (19%) treated with imatinib: in the Ph+ clone (9 cases) and in the Ph− clone (2 cases). Median duration of imatinib treatment before the CE identification was 16 months (range 7–36 months). The most common additional abnormality was trisomy 8 (8 pts), second Ph chromosome (4 pts), and del (17) (4 pts). In 5 cases we observed the simultaneous occurence of two different cytogenetic abnormalities. Haematological progression was observed in 7 of 11 patients (63%) following 2 – 22 months imatinib treatment (median 9 months). 5 pts (46%) exited. Six patients live 8–22 months from the detection of cytogenetic evolution. Secondary malignancy was diagnosed in 1 patient. In the group of patients without cytogenetic evolution haematological progression was observed only in 9 of 46 (19.5%) cases, 4 patients died (14.3%). Conclusion: The role of IM concerning the cytogenetic evolution occurence in CML patients is not so far clear, the suppression of the Ph+ clone could enhance the proliferation of resistant ones. In our group of patients CE was documented in 11 patients (19%), in both Ph+ and Ph− cells. Significantly higher was the risk of haematological progression. CML patients treated with imatinib should be regularly monitored with conventional cytogenetic techniques, not only to follow the decrease in the proportion of Ph-positive cells, but also to look for new especially Ph-negative clonal chromosomal abnormalities. A longer follow-up time and systematic monitoring of cytogenetics is needed to establish the prognostic impact of clonal evolution in CML patients treated with imatinib.

Bacterial, Viral and Fungal Infections in Patients after Allogeneic Stem Cell or Bone Marrow Transplantation - A Comparison between Patients with Related and Patients with HLA-Matched Non-Related Stem Cell Donors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4978-4978
Author(s):  
Christina T. Rieger ◽  
Johanna Tischer ◽  
Helmut Ostermann
Keyword(s):  
Bone Marrow ◽  
Candida Albicans ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Fungal Infections ◽  
Stem Cell Source ◽  
Cell Source ◽  
Group A ◽  
Group B

Abstract Bacterial, viral and fungal pathogens frequently cause severe, life-threatening infections in immunocompromised patients after allogeneic stem cell transplantation (SCT). We investigated whether patients with related stem cell donors (group A) developed infections less frequently than patients with HLA-matched, non-related donors (group B). Fifty-nine consecutive patients treated at our transplantation unit between April 2004 and January 2005 were included into the analysis. We documented demographic and clinical characteristics at baseline, treatment, clinical course, microbiological examinations, clinical and radiological signs of infection and mortality. Of the total 59 patients analyzed, 22 received stem cells from related and 37 from HLA-matched non-related donors. Both groups were well balanced regarding age and weight. 50% of the patients in group A and 60% in group B were male. Most frequent diagnoses were acute myeloid leukemia (30 of 59 patients [50.8%]; group A: 68.2%; group B: 40.5%), multiple myeloma (15.2%), acute lymphoblastic leukemia (11.9%) and chronic myeloid leukemia (10.2%). Bone marrow was more often the stem cell source in group A (45.5%/ 10 patients) than in group B (10.8%/ 4 patients), peripheral stem cell transplantation respectively was predominant in the unrelated group (86.5%/ 32 patients) versus the family donor group (54.5%/ 12 patients), cord blood was used as unrelated stem cell source in1 patient (2.7%). Clinically documented infections occurred in 6% in group A and in 14% in group B. Pulmonary infiltrates were observed more frequently in group A (11 patients/ 50%) than in group B (16 patients/ 43.2%). The predominant findings were atypical infiltrates (total 16 patients), followed by signs of fungal (total 7 patients) and bacterial pulmonary infiltration (total 4 patients). Microbiologically documented infections were detected in all patients. The average number of pathogens was equal in both groups. Detected pathogens were HHV-6 (48 patients), coagulase-negative Staphylocci (17 patients), EBV (14 patients) and CMV (11 patients). Three fungal infections were detected by microbiological approaches in group A (2 × Candida albicans, 1 × Pitysporum ovale) compared to nine fungal infections in group B (5 × Candida albicans, 1 × Candida glabrata, 1 × Candida parapsilosis, 2 × Geotrichum capitatum). Two years after transplantation, 55.9% of patients were alive (group A: 68.2%; group B: 48.6%). Patients with AML had a two-year survival of 50% (group A: 53.3%; group B: 46.7%). In our study, we observed no clear relation between frequency of infection and donor type, yet there was a trend towards more invasive fungal infections in the unrelated group (13% group A vs. 24% group B).

Allogeneic Transplanst for ACUTE Myeloid Leukemia: Cut Off Levels of WT1 Expression in 207 Patients and Pre-Emptive Therapy of Relapse

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1866-1866
Author(s):  
Carmen Di Grazia ◽  
Simona Geroldi ◽  
Raffaella Grasso ◽  
Maurizio Miglino ◽  
Nicoletta Colombo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cell Transplant ◽  
Allogeneic Hsct ◽  
Group A ◽  
Leukemia Relapse ◽  
Group B ◽  
Acute Myeloid ◽  
Marrow Cells

Abstract Leukemia relapse remains a significant problem in patients with AML undergoing an allogeneic stem cell transplant(HSCT). Wilms Tumour 1 (WT1) expression has been shown to be a sensitive marker of minimal residual disease (MRD), both in patients after induction chemotherapy, as well as in patients undergoing an allogeneic HSCT. Hypotheses. The present study had 2 hypotheses: (1) WT1 expression in marrow cells of AML patients post-HSCT, will predict leukemia relapse and (2) WT1 based pre-emptive immunotherapy (IT) such as abrupt cyclosporin discontinuation and/or donor lymphocyte infusion (DLI), will prevent leukemia relapse. Patients. Bone marrow WT1 expression, was monitored in 207 patients with acute myeloid leukemia (AML) before and monthly after an allogeneic HSCT, until day +150, and then at every other outpatient access. Eligible for IT were patients without acute or chronic GvHD, with increased WT1 expression and a a marrow in hematologic remission. The trigger for IT was 180 WT1 copies in a first group of 122 patients (group A): this was based on the fact that WT1 expression in normal bone marrow is up to 180 copies . In a subsequent group of 85 patients (group B) the cut off for IT, was 100 copies, due to the fact that a first analysis of group A had shown 100 copies to be an earlier predictor of relapse (BJH 2013; 160: 503). DLI were given in escalating doses, starting at 1x105 CD3+ cells/kg in alternative donor grafts and at 1x106/kg in HLA identical grafts. DLI were escalated ½ log every month, in the absence of GvHD, to a maximum dose of 1x107/kg. Sixtyfour patients were eligible for IT, but only 35 received IT: reasons for non intervention were ongoing GHD, unavailable donor and delay in WT1 results. Results-Hypothesis N.1. Following transplantation, WT1 expression, was highly predictive of leukemia relapse: 12 relapses in 99 patients with WT1 < 100 copies /104 abl (12%); 19 relapses in 55 patients with WT1 between 101 and 180 copies (35%) and 37 relapses in 53 patients with WT1 >180 copies (70%) (p<0.0001). The median interval between WT1 positivity and relapse was 75 days in group A and 60 days in group B. Results-Hypothesis N.2. 35 patients received pre-emptive immune intervention, 17 in group A and 18 in group B. The latter had more patients beyond first remission at transplant (56% vs 23%) , more myeloablative regimens (100% vs 65%) and more family haploidentical donors (72% vs 6%); age was comparable. The risk of relapse was 13/17 (76%) for group A and 3/18 (17%) for group B (p<0.001), despite the larger proportion of patients beyond CR1 at transplant. GvHD following DLI occurred in 15% of patients. DLI-related mortality was 0%. The overall 3 year survival for patients in group A and B was 69% vs 47% (p=0.3). The relapse risk in patients of group A eligible but not receiving IT (n=21) was 74%; in group B (n=8) it was 50%. In conclusion, WT1 expression post-transplant is a strong predictor of leukemia relapse in patients with AML, and can be used to trigger pre-emptive immunotherapy, in approximately 50% of eligible patients. IT triggered at a WT1 cut-off level of 100 copies in bone marrow cells, is more effective, as compared to180 copies, in preventing leukemia relapse. Disclosures No relevant conflicts of interest to declare.

scholarly journals Real-Life Data and a Single Center Experience on the Efficacy and Toxicity Profile of Imatinib in the Treatment of Elderly Patients with Chronic Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1905-1905
Author(s):  
Ahmet Emre Eskazan ◽  
Mert Oztas ◽  
Fatih Bektas ◽  
Sevil Sadri ◽  
Dilek Keskin ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Disease Risk ◽  
Disease Stage ◽  
Risk Scores ◽  
Study Patient ◽  
Molecular Responses ◽  
Group A ◽  
Group B

Abstract Background: Although it may vary between different registries, the median age of chronic myeloid leukemia (CML) at diagnosis is between 50-60 years, and approximately 40% of the patients (pts) are diagnosed after age 60 [Hoffmann et al. Leukemia. 2015;29(6):1336-43]. Tyrosinekinase inhibitors (TKIs) have revolutionized the treatment of CML and currently pts with CML may expect to live close to normal lifespan. So the number of elderly CML pts with various potentialcomorbidities started to increase, which then brings out the issues regarding TKI toxicities, medication adherence and responses to TKI treatment. Aim: The aim of this study was to evaluate the efficacy and safety ofimatinib treatment in the elderly population (pts equal to or older than 60 years) with CML and to compare these data with younger pts (pts < 60 years). Patients and Methods: Pts diagnosed and followed in our clinic with CML were enrolled in the study. Patient demographics, dose and duration ofimatinib therapy, disease risk scores, cytogenetic and molecular responses,comorbidities, adverse events (AEs), follow-up durations and outcomes were evaluated from files of the pts, retrospectively. TheCharlsoncomorbidity index (CCI) of each patient was calculated as stated before [Breccia et al.Haematologica. 2011;96(10):1457-61]. Results: The patient cohort was consisted of 158 pts with a median age of 44 years (range, 18 - 83 years). Group A consisted of thirty-three pts who were equal to or older than 60 years (Fig. 1), and there were 125 pts (Group B) who were < 60 years of age (Table 1). The two groups were balanced regarding gender, disease stage, treatments prior to TKI therapy, and the starting dose ofimatinib. There were more pts with intermediate and highSokal risk scores in Group A than that of Group B (p<0.001). Pts in Group A had significantly morecomorbidities (p<0.001) and higher CCI scores (p<0.001) than pts who were < 60 years of age (Table 1). Median time ofimatinib exposure (p=0.001) and follow-up durations (p<0.001) were significantly longer in Group B than those of Group A. There were significantly more hematologicAEs among pts in Group A than pts in Group B (24% vs. 7%, p=0.005). Although not statistically significant, non-hematologicAEs were more common in GroupA (18% vs. 7%, p=0.056), and the rates ofimatinib dose reduction due toAEs were significantly higher in Group A than Group B (33% vs. 9%, p<0.001). Cumulative complete cytogenetic (CCyR) and major molecular (MMR) response rates and the percentage of pts who switched to second-generationTKIs (2GTKIs) were similar in both groups (Table 1). Event-free survival (EFS) rates were comparable (Fig. 2A), however overall survival (OS) rate was significantly higher in Group B (Fig. 2B) (p<0.001). There were 7 pts in both groups who died during the follow-up, but five and 2 pts died due to non-CML related causes in Groups A and B, respectively. OS rates were similar in both groups when non-CML related deaths were excluded (Fig. 2C). Discussion: TKI therapy is relatively safe in elderly pts with CML, and cytogenetic and molecular responses are comparable with that observed in younger pts. In our institute, where pts are followed in a dedicated outpatient CML clinic, cytogenetic and molecular responses were similar in both elderly and younger pts leading to similar percentages of pts who were switched to 2GTKI therapy in both groups. Comorbidities can be problematic in elderly pts in whom CML and TKI relatedAEs are more common. However proper management of theseAEs including careful follow-up and timely TKI dose reductions may lead to successful outcomes. Inferior OS rates were observed in elderly pts with CML, but OS rates were similar in both groups when non-CML related deaths were excluded. Disclosures No relevant conflicts of interest to declare.

scholarly journals Identification of masked polycythemia vera from patients with idiopathic marked thrombocytosis by endogenous erythroid colony assay

Blood ◽  
1994 ◽  
Vol 83 (3) ◽  
pp. 744-748 ◽  
Author(s):  
LY Shih ◽  
CT Lee
Keyword(s):  
Bone Marrow ◽  
Polycythemia Vera ◽  
Subsequent Development ◽  
Culture Technique ◽  
Erythroid Progenitor ◽  
Endogenous Erythropoietin ◽  
Group A ◽  
Group B

We used the methylcellulose-culture technique to determine the utility of the erythroid progenitor growth in vitro from nonadherent T-depleted bone marrow and peripheral blood cells in distinguishing polycythemia vera (PV) from essential thrombocythemia. Thirty patients with PV (group A) and 30 patients who presented with idiopathic marked thrombocytosis with platelet count greater than 1,000 x 10(9)/L and a normal or reduced hemoglobin (Hb) level (group B) were studied at initial presentation. Endogenous (erythropoietin-independent) erythroid colonies (EEC) were found in all patients in group A and 13 in group B. The numbers of EEC were comparable between patients in group A and the 13 patients with EEC in group B, 11 of whom with initial Hb levels ranging between 6.4 g/dL and 12.6 g/dL were found to have PV 2 to 45 months after initial evaluation. The number of EEC did not correlate with the time to the progression of polycythemia, whereas myelosuppression delayed the subsequent development of PV. Of the two patients with EEC in group B who did not develop PV, both received chemotherapy soon after presentation, which might preclude the evidence of polycythemia evolution. None of the other patients in group B who did not form EEC developed PV with a median follow-up of 24 months. This study indicates that the assessment of EEC in bone marrow or blood is helpful in early identification of PV or prediction of polycythemia evolution in patients with marked thrombocytosis in whom polycythemia has been initially masked or anemia is present.

scholarly journals Clinical Significance of Clonal Cytogenetic Heterogeneity (CCH) at Diagnosis in Adult Patients with Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2820-2820
Author(s):  
Hiroaki Shimizu ◽  
Nahoko Hatsumi ◽  
Satoru Takada ◽  
Takuma Ishizaki ◽  
Akihiko Yokohama ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Research Funding ◽  
Clonal Evolution ◽  
Statistical Significance ◽  
Prognostic Impact ◽  
Common Ancestry ◽  
Complex Karyotype ◽  
Abnormal Karyotype ◽  
Cytogenetic Abnormalities

Abstract Background:Although cytogenetic abnormalities at diagnosis are recognized as one of the most potent prognostic factors in acute leukemia patients, CCH acquisition at diagnosis, which are considered as a result of clonal evolution of leukemia cells, is not taken into account in prognostic classifications. Recent studies reported that CCH acquisition was observed in 24 - 32% of adult AML patients with abnormal karyotype, was more likely to occur in patients with older age and complex karyotype, and showed adverse prognostic impact. However, the clinical significance of CCH acquisition has not been investigated in adult ALL patients to date. Patients and methods: Of the 238 adult ALL patients diagnosed between 1990 and 2016, 120 patients with abnormal karyotype at diagnosis, who underwent intensive chemotherapy, were included in this study. CCH was defined as presence of two or more cytogenetically abnormal clones. A defined ancestral clonal evolution included either mother-daughter and/or branched patterns. In the mother-daughter pattern, a daughter clone showed all cytogenetic abnormalities of a mother clone plus additional abnormality(s), which define a distinct subclone. In a branch pattern, all subclones possessed common cytogenetic abnormalities suggesting presence of a common ancestry, but each subclone acquires unique additional abnormality(s), which define them as distinctive subclones. Both patterns of cytogenetic clonal evolution were sometimes seen in a patient. Composite karyotypes were applied to patients where a common ancestry could not be clearly determined because of too complicated cytogenetic findings. Fisher's exact test was used to compare binary variables. The logistic regression model was used for multivariate analysis of predisposing factors. Overall survival (OS) was estimated with the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazard model was used for multivariate analysis of prognostic factors. Values of p < 0.05 were considered to indicate statistical significance. Results:Of the 120 patients included in this study, 64 patients were male, and 56 were female. The median age was 50 years (range, 16-79 years). Karyotypes at diagnosis were Philadelphia chromosome (Ph) in 56 patients, complex in 15, and t(8;14) in seven. According to the definition described above, 47 patients (39%) showed CCH at diagnosis, and two (4%) among them were categorized as composite karyotype. Of the 45 patients harboring a defined ancestral clonal evolution, numbers of subclones were two, three, and four in 32 patients (68%), 11 (24%), and 2 (4%), respectively. Mother-daughter pattern, branched pattern, and both were seen in 34 patients (76%), 5 (11%), and 6 (13%). In univariate analysis for predisposing factors of CCH acquisition, only younger age was significantly associated with CCH acquisition (48% in age <= 50 vs. 29% in age > 50; p = 0.04), but not karyotype. This statistical significance was confirmed with multivariate analysis (odds ratio = 0.44; p = 0.03). When investigating the prognostic impact of CCH acquisition, patients were divided into Ph-negative or Ph-positive ALL groups. In the 64 Ph-negative ALL patients, the CR rates were not significantly different between patients with or without CCH (78% vs. 78%, respectively; p = 1.00). The OS rates were similar between two groups (26% vs. 39% at five years, respectively; p = 0.56). Multivariate analysis for OS revealed that complex karyotype and t(8;14) were independent prognostic factors, but not CCH acquisition. Likewise, in the 56 Ph-positive ALL patients, CCH acquisition was not significantly associated with the CR rates (92% vs. 78%, respectively; p = 0.27), and the OS rates did not significantly differ between the two groups (34% vs. 40% at five years, respectively; p = 0.90). In multivariate analysis for OS, no independent prognostic factor was identified. Conclusion: Adult ALL patients with abnormal karyotype acquired CCH at diagnosis with a frequency comparable to that of AML patients. However, unlike AML patients, CCH acquisition was more frequently observed in younger population and did not show any prognostic impact in ALL patients. These findings suggested that biological backgrounds of CCH acquisition at diagnosis were possibly different between in patients with ALL and AML. So, to confirm these important findings, clinical studies with larger study subjects are warranted. Disclosures Handa: Celgene: Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Impact of Proteomic Profile of Peripheral Blood and Bone Marrow Sera on Molecular Response in Patients with Chronic Myeloid Leukemia: Preliminary Data

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5515-5515
Author(s):  
Nicola Sgherza ◽  
Vito Garrisi ◽  
Giacoma De Tullio ◽  
Simona Serratì ◽  
Angela Iacobazzi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Preliminary Data ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Differentially Expressed ◽  
Molecular Response ◽  
Proteomic Profile ◽  
Group A ◽  
Group B

Abstract BACKGROUND. Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by an aberrant protein (BCR–ABL) which is a constitutively active tyrosine kinase. According to the latest ELN recommendations for the management of CML, molecular response (MR) is best assessed according to the International Scale (IS) as the ratio of BCR-ABL1 transcripts to ABL1 transcripts, or other internationally recognized control transcripts. It is expressed and reported as BCR-ABL1% on a log scale where 10%, 1%, 0.1%, 0.01%, 0.0032%, and 0.001% correspond to a decrease of respectively 1 (MR1), 2 (MR2), 3 (MR3), 4 (MR4), 4.5 (MR4.5) logs below the standard baseline that was used in the IRIS study. Recent advances in the proteomic field have allowed us to better understand the biology of several cancer types and/or discover new candidate biomarkers, but very few data are available in CML. AIMS. The purpose of this study was to evaluate a possible correlation between depth of MR and proteomic profile in sera samples obtained from the peripheral blood and bone marrow of CML patients. PATIENTS AND METHODS Samples were consecutively and prospectively obtained from 20 CML patients observed between January and June 2014 at the Hematology Unit of the National Cancer Research Centre “Istituto Tumori Giovanni Paolo II” in Bari, Italy. Each individual involved in the study signed an informed consent form authorizing the Institute to utilize their biological tissues for research purposes. All patients at diagnosis displayed the classic t(9;22) Ph chromosome according to standard cytogenetics. The BCR/ABL transcript at RT-PCR was b3a2 in 13 patients and b2a2 in 7 patients. Peripheral blood and bone marrow samples were centrifuged within 30 minutes of sample taking. Serum specimens were immediately collected and frozen at −80°C. Twenty sera from peripheral blood were sampled from 5 patients in MR1 response, four in MR2, eight in MR3, two in MR4 and 1 patient at diagnosis; for eleven patients serum from bone marrow was also available; in particular 2 were sampled from patients in MR1, 3 in MR2, 4 in MR3, 1 in MR4 and 1 at diagnosis. Patients were grouped in two cohorts: the first comprised those with lower molecular response to MR3 (group A: 10 patients) and the second greater than or equal to MR3 (group B: 10 patients). The association of proteomic profile with molecular response was performed using the SELDI ToF Mass Spectrometry platform. Each specimen was spotted on an IMAC30 metal affinity protein-chip, prepared according to the manufacturer's instructions, and analyzed in duplicate. RESULTS Fourteen differentially expressed peaks were highlighted when comparing peripheral sera from group A and group B, but none was statistically significant. When comparing 11 available serum samples from the bone marrow of groups A (6) and B (5), four peaks (m/z 10629, m/z 3889, m/z 7772, m/z 7987) were reported as differentially expressed in a statistically significant way (p<0.05). Focusing the differential expression analysis in peripheral sera only on MR1 patients (including one patient at diagnosis) versus MR4 patients, one peak at m/z 11092 was identified as significantly and differentially expressed (p < 0.05) (Figure 1). Similarly, comparing bone marrow sera only from MR1 and MR4 patients respectively, 32 peaks were differentially expressed. Once again the peak at m/z 11092 resulted under expressed in MR1 patients, and interestingly the single patient at diagnosis had the lowest value. No statistical differences were evidenced when comparing peripheral blood and bone marrow sera obtained from b3a2 and b2a2 patients. CONCLUSIONS These preliminary data suggest that an over-expression of m/z 11092 in serum obtained from peripheral blood and bone marrow could be associated with a deeper molecular response; further investigations are needed on a larger number of patients in order to confirm or refute our results and, to definitively characterize the peak at m/z 11092. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Ph-Abnormal Clones Emerged during Imatinib Therapy: Clinical Report and Clonal Analyses on 23 Patients from GIMEMA Working Party (GWP) in CML Registry.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2936-2936
Author(s):  
Elisabetta Abruzzese ◽  
Alessandro Gozzetti ◽  
Alfonso Zaccaria ◽  
Nicoletta Testoni ◽  
Sara Galimberti ◽  
...  
Keyword(s):  
Cell Culture ◽  
Bone Marrow ◽  
Biological Significance ◽  
Specific Inhibitor ◽  
Chronic Phase ◽  
Working Party ◽  
Clinical Report ◽  
Bone Marrow Biopsies ◽  
Cytogenetic Abnormalities

Abstract Imatinib mesylate (Glivec, Novartis) is a tyrosine kinase specific inhibitor that kills BCR-ABL cells in vitro and in vivo. Cytogenetic abnormalities in Ph-negative cells emerging after treatment-induced suppression of the neoplastic clone have been described. A registry through the GWP in CML has been set and data on 23 patients collected. To acquire insights into the origin of the Ph-negative clone as well as the evolution of the coexisting Ph− and Ph+ cell populations, we have analyzed bone marrow cell segregation, cell culture and morphologic features. Patients characteristics and 28 months follow up are presented. The emergence of a cytogenetic abnormal clone in Ph-negative cells was evidenced in 23 patients after a median of 14.5 months after starting Imatinib. Median age was 51 years, median time from diagnosis 36 months. All patients started Imatinib while in chronic phase and none of the patients had ever presented accelerated or blastic phase. Five patients were treated with Imatinb at onset. Cytogenetics at diagnosis was characterized by the presence of Ph chromosome, except for one patient which presented with normal karyotype, but BCR-ABL B3A2 transcript. No additional abnormalities were evidenced except for one patient which presented with the Ph and a dup(1q)(q11q21). All patients achieved a good response to Glivec with 16 complete, 4 major and 3 minor cytogenetic remissions when additional abnormalities were noticed in Ph-negative cells. The clonal cytogenetic abnormalities included +8 in 13 patients, -Y in 2 patients, one −7, del(5q), del(7q), del(13q), t(6;7)(p24;q21), t(2;6)(p25;q23), and one patient presenting with both +8 and +21. The patient with dup(1q) maintained the abnormality while clearing the marrow from Ph positive cells (constitutional karyotype was normal). Retrospective analyses of stored pellet using FISH in patients presenting +8, −7, or −Y, did not evidence abnormalities in previous samples. Patients that lost cytogenetic response showed that the percentage of the Ph+ cells inversely correlated to the abnormal clone. In 5 patients the abnormal clone was not evidenced in subsequent controls, suggesting the possibility that the abnormalities could be temporary. We performed cell culture on a subgroup of patients demonstrating normal growth in four patients and an abnormal growth in one patient with reduced CFU formation affecting BFU-Es, CFU-GM, and colony size microclusters. FISH analyses on separated CD34+ and CD34-negative cells evidenced that the abnormal clone segregated into the CD34+ compartment suggesting the stem cells involvement. FISH on cultured cells did not demonstrate a growth advantage for Ph+ cells or for the new clone. Bone marrow biopsies presented with reduced cellularity, normal differential and mild dysplastic signs as documented in patients responding to Imatinib. No increased angiogenesis was evidenced. While a longer follow up observation and laboratory analyses are required, we remark that after &gt;2 years follow up the Ph-negative abnormal clone did not tend in our patients to evolve in MDS, nor it seems to be associated with CML clonal evolution and disease progression. Hypothesis regarding the biological significance of these abnormalities are formulated.

No Significant Difference in Therapy Results between Acute Myeloid Leukemia Patients with Myeloblastic Bone Marrow Infiltration within the Range of 20–29% and over 29% at Diagnosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4564-4564
Author(s):  
Sebastian Grosicki ◽  
Jerzy Holowiecki ◽  
Slawomira Kyrcz-Krzemien
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Symptoms ◽  
Bone Marrow Infiltration ◽  
Acute Leukemias ◽  
Significant Difference ◽  
Group A ◽  
Group B ◽  
Acute Myeloid

Abstract Definition of acute myeloid leukemia (AML) includes a heterogenous group of disorders differing in cytogenetics, clinical symptoms and prognosis. A common feature is bone marrow infiltration with leukemic clone which is also present in peripheral blood and different organs. Over thirty years ago the FAB (French-American-British) group defined the morpho-cytochemical classification of acute leukemias and proposed ≥30% leukemic blasts in bone marrow for a threshold between muelodysplastic syndromes and acute leukemias. In 2002 the WHO group of experts decided to decrease this border line to 20%. The question concerning differences in results of particular treatment programs for AML patient subgroups with original blastic bone marrow infiltration within the range of 20–29% and ≥30% remains disputable. To address this question we performed an analysis in 405 patients treated according to the PALG (Polish Adult Leukemia Group) protocol DAC and DA. At diagnosis there were 26 patients with myeloblastic bone marrow infiltration ranging 20–29% (group A) and 379 patients with infiltration ≥30% (group B). In 62,5% patients (n=10) of the group A AML was preceding by myelodysplastic syndrome. In the time period 1999–2002 patients under study received as induction DAC-7 regimen: daunorubicin 60 mg/m2/d iv 1–3; cytarabine 200 mg/m2/d ci 1–7; cladribine 5 mg/m2 2h inf. iv d 1–5 or standard DA-7 regimen (the same regimen without cladribine). Patients achieving CR received two courses of subsequent intensive consolidation:HAM (HD AraC, mitoxantrone)HD AraC with or without cladribine in the DAC-7 or DA-7 arm, respectively.In the case of PR after the first induction course the same regimen was repeated. Post-consolidation therapy was in both arms comparable. Complete remission (CR) rate was comparable in both populations and reached 73% in the group A and 70% in group B. There were also no statistical differences between overall survival (OS) and leukemia free survival (LFS) between both groups. OS after 5 years equals 34% in group A and 27% in droup B and LFS 42% and 27%, respectively (p=NS). Our study proves that there are no differences in treatment results between AML patients with original bone marrow infiltration within 20–29% and ≥30% given the same treatment. It confirms that the revised WHO criteria are reasonable.

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