Glutathione S-Transferases (GSTT1 and GSTM1) Genes Polymorphisms and Response and Prognosis of Chinese Patients with De Novo Acute Myeloid Leukemia.

Abstract The GSTT1 and GSTM1 genes are polymorphic in humans, with the phenotypic absence of enzyme activity caused by a homozygous inherited deletion of the gene. A number of prior studies have reported on GST genotype and outcome of therapy for AML. In this study, we analyzed the prognostic significance of gene polymorphism of GSTT1, GSTM1 in Chinese patients with de novo AML other than M3. A total of 254 cases were entered. There are 157 males and 97 females, ranging in age from 15 to 75 years (median: 32 years). Patients were diagnosed following WHO criteria, 81 were AML with t(8;21) AML1/ETO, 54 were AML with inv(16) or t(16;16) CBF-β/MYH11, 4 were AML with 11q23 abnormalities (MLL), 1 was minimally differentiated, 3 were AML without maturation, 44 were AML with maturation, 17 were acute myelomonocytic leukemia, 42 were acute monocytic leukemia, and 8 were acute erythroid leukemia. All the patients were treated with HAD regimen (Homoharringtonine, HHT, 2.5mg/m2 intravenously on days 1 to7; Ara-c, 150 mg/m2/d continuous infusion on days 1 to 7, and DNR,45 mg/m2 intravenously on days1 to 3.) as induction therapy. Postremission therapy consisted of HA regimen (HHT and Ara-c)(course 1 and 4), DA regimen (DNR and Ara-c)(courses 2 and 5), and MA regimen (MTZ and Ara-c) or HAM (Ara-c 1g/m2,q12h, intravenously on days 1 to 4, combined with MTZ 8mg/m2, intravenously on days 5 to 7(courses 3 and 6). The multiplex PCR method was used to simultaneously amplify and analyze GSTM1,GSTT1, and β-globin from patients. 21 patients died before marrow recovery or adequate assessment of response. 165 (68.5%) achieved a CR after the first course of chemotherapy and 194 (80.5%) achieved a CR after the second course of chemotherapy. Median follow-up was 36 months (11 to 111 months). 104 patients were last known to be alive after entering the study, the other 138 patients are now decease. Twelve patients lost to follow-up are censored at the date they were last known to be alive. Median OS and median RFS was 22 months and 19 months, respectively. OS rates at 3 years and 5 years were 38.9%±3.5% and 25.2%±6.5%, respectively. RFS rates at 3 years and 5 years were 32.8%±3.9% and 22.4%±5.2%, respectively. The rate of early death after the initiation of chemotherapy was similar between the GSTT1+/ GSTM1+ group and GSTT1− / GSTM1- group. The CR rates was higher in GSTM1+ group(71.9%) than GSTM1− group(60.8%) (OR=1.882; P =0.034) after the initiation of chemotherapy, and The CR rates was higher in GSTT1+ group(82.6%) than GSTT1− group (70.75)(OR=2.204; P =0.024) after the second course of chemotherapy. Overall survival and disease-free survival of patients who achieved complete remission (CR) in GSTT1 and GSTM1 double present group(50.1%±9.6% and 43.1%±9.6% at 5 years, respectively) was better than GSTT1- and/or GSTM1- group(27.2%±4.6% and 15.7%±6.3% at 5 years, respectively) (p=0.03 and p=0.022, respectively). For patients with AML with inv(16)(p13q22) or t(16;16)(p13;q22)(CBFβ/MYH11), Overall survival was better in GSTT1+ group than GSTT1− group(69.7%±10.5% v 27.5%±13.0% at 5 years)(p=0.013). Our data showed AML patients with deletions of GSTM1 or GSTT1 or both had a lower probability to achieve CR on induction therapy as compared to patients with intact GST genes and a shorter survival.

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ASXL1 Mutations in AML: Molecular Biomarker for Secondary AML?

Blood ◽

10.1182/blood.v124.21.2343.2343 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2343-2343

Author(s):

Jingmei Hsu ◽

Anita J. Kumar ◽

Martin P. Carroll ◽

Noelle V. Frey ◽

Nirav N. Shah ◽

...

Keyword(s):

Overall Survival ◽

De Novo ◽

Conflicts Of Interest ◽

Prognostic Significance ◽

Myeloproliferative Neoplasm ◽

Molecular Characteristics ◽

Intermediate Risk ◽

Kaplan Meier ◽

The Impact

Abstract Background: Additional sex combs like transcription factor 1 (ASXL1) is a member of the polycomb group protein. ASXL1 mutation has been implicated in myeloid malignancy transformation. It is hypothesized that mutated ASXL1 leads to the loss of polycomb repressive complex 2 (PRC2) mediated gene repression and subsequent transforming events. Recent studies identify ASXL1 mutation as a poor prognostic marker in patients (pts) with de novo acute myeloid leukemia (AML) who present with intermediate–risk cytogenetic lesions (Patel, NEJM 2012; Schnittger, Leukemia2013). To study the impact of ASXL1 mutations in an unselected AML population, we analyzed clinical and molecular characteristics of patients with untreated AML who express ASXL1 mutation at presentation. Methods: Using next generation sequencing, 254 adult patients with AML seen at the Hospital of the University of Pennsylvania were analyzed for mutations, including ASXL1, using a 33-gene hematologic malignancy panel. Clinical characteristics were obtained from retrospective chart review. Kaplan-Meier estimates were used to calculate overall survival (OS) from time of diagnosis. Living patients were censored at date last seen. Results: ASXL1 mutations were detected in 36/254 (14%) AML pts. There were 29 known pathologic mutations, 1 benign, 1 probable pathologic, and 9 variants of unknown clinical significance (VUS). In 6/36 (16.7%) pts, ASXL1 was the sole mutation identified. Of the 30 pts with additional mutations (Figure 1), 6/30 (20%) pts harbored 2 independent ASXL1 mutations. When the 27 patients with pathologic ASCL mutations were analyzed for co-mutations, TET2 (13/27, 48%) was the most frequent ASXL1 co-mutation. FLT3 (0/27, 0%) and NPM1 (1/27, 3.7%) were notable for their absence. Median age of pts at diagnosis was 69 years (range 23-80). Prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) was noted in 9/36 (25%) and 11/36 (30.6%) pts, respectively. Four pts (11.1%) had received chemotherapy and/or radiation therapy for a prior non-myeloid neoplasm. Karyotype was normal in 18/36 (50%) pts, and 7 additional pts had intermediate cytogenetic lesions. There were 7 pts (19.4%) with unfavorable cytogenetics (complex karyotype (3 pts), 7q- (3 pts), and 5q- (1 pt)). Four pts (11.1%) had a favorable karyotype, with t(8;21) in 3 pts and t(15;17) in 1 pt. At presentation, median white blood cell count (WBC) was 6.4x103/uL (1.0 x -103). In pts whose AML transformed from prior MPN, median WBC was 50 X103/uL (3.3-140). Standard induction chemotherapy with an anthracycline and cytarabine was given to 17/36 (47%) pts. An additional 3/36 (8.3%) pts underwent induction therapy with clofarabine. Complete remission (CR) was documented in 14/20 (70%) evaluable pts. Of the remaining pts, 11 received a hypomethylating agent, and 5 received other therapies. Thirty-day treatment mortality for all 36 pts and for 27 pts with known ASXL1 pathologic mutation was 13.4% and 18.5% respectively. Kaplan-Meier estimate showed a median overall survival of 349 days (median follow up of 107 days (range 15-1570)). For the 27 pts with a pathologic ASXL1 mutation, the OS was 276 days (Figure 2, median follow up of 145 days (range 18-1570)). Conclusion: ASXL1 mutations in de novo AML with intermediate-risk cytogenetics is associated with poor clinical outcome in cooperative group trials. Strikingly we demonstrate in a single institution, retrospective analysis that 66.7% of pts who present with ASXL1 mutations in the setting of previously untreated AML had documented MDS, MPN and/or prior chemotherapy/radiation. Further studies are necessary to evaluate if ASXL1 mutation has independent prognostic significance in AML or if it is primarily a marker for secondary leukemia. Figure 1: ASXL1 and co-mutations Figure 1:. ASXL1 and co-mutations Figure 2: Overall survival for AML patients with ASXL1 pathologic mutation Figure 2:. Overall survival for AML patients with ASXL1 pathologic mutation Disclosures No relevant conflicts of interest to declare.

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Induction Therapy with Dasatinib and Prednisone for Patients with Philadelphia Positive ALL

Blood ◽

10.1182/blood.v126.23.4907.4907 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4907-4907

Author(s):

Abhishek Chilkulwar ◽

Salman Fazal ◽

Jocelyn T. De Yao ◽

Parik Padhi ◽

Cyrus Khan ◽

...

Keyword(s):

Overall Survival ◽

Induction Therapy ◽

Disease Free Survival ◽

Hematopoietic Stem ◽

Free Survival ◽

Comorbidity Index ◽

High Comorbidity ◽

Disease Free ◽

Matched Donor

Abstract Background: The addition of a Tyrosine Kinase Inhibitor (TKI) to induction chemotherapy has improved the outcome of patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). However, the treatment related mortality and morbidity of intensive treatment increases with age. The use of a TKI alone for induction is less toxic and yields CR rates comparable to combined therapy. Eligibility for post remission hematopoietic stem cell transplantation is less likely to be compromised with TKI induction. We present a retrospective review of patients with Ph+ ALL treated at our institution with dasatinib and prednisone induction who subsequently underwent allogeneic hematopoietic stem cell transplant (allo-HSCT) as post remission therapy. Methods: We retrospectively identified 15 patients with Ph+ ALL treated at our institution between February 2012 and June 2015. Patients received induction therapy with dasatinib at 100 mg or 140mg daily till complete hematological response. Prednisone 60 mg/m2/day (capped at 120 mg daily) was administered until day 24 and then tapered and stopped at day 32. Intrathecal chemotherapy with MTX and Ara-C were administered twice during the induction period. Dasatinib dose reduction/discontinuation was permitted for non-hematological toxicity. Patients who achieved remission proceeded to allo-HSCT if a suitable HLA-matched donor was available. Patients who did not have a suitable HLA matched donor received TKI + POMP maintenance. We calculated CHR, CCyR, disease-free survival (DFS) and overall survival (OS). Results: The median age of patients treated with dasatinib plus prednisone was 62 years (range: 19-73). Baseline patient and disease characteristics are summarized in Table 1. Median WBC count was 22.5 x 109/L. Fourteen of 15 patients treated with dasatinib achieved a CHR (93.3%), 1 patient did not undergo a bone marrow biopsy but had normal blood counts. Median time to CHR was 42 days (range: 22-69). CCYR was obtained in 11 patients (73%) and MMR was achieved in 5 patients (33%). No patient died during induction therapy. The 14 patients who were in CHR after induction, underwent allo-HSCT (n=7), are being evaluated for allo-HSCT (n=3), were unable to undergo allo-HSCT due to a high comorbidity index and/or lack of a suitable donor (n=3) or were lost to follow-up (n=1). Of the 3 patients who were unable to undergo allo-HSCT, 2 patients continue on dasatinib maintenance and 1 patient takes ponatinib. Of 8 patients not yet transplanted 3 relapsed, while only 1 relapse was seen in 7 patients who underwent allo-HSCT. Median DFS was 315 days (range: 57-1061) and median OS was 354 days (range: 107-1082) corresponding Kaplan Meier curves for OS and DFS are shown below. Conclusions: In our adult Ph+ ALL patients induction therapy with dasatinib and prednisone was effective and well tolerated. Patients achieving CHR were able to undergo allo-HSCT with curative intent. This strategy retrospectively appears equal or better than results with induction chemotherapy of conventional variety. Table 1. Patient characteristics Male sex, n (%) 5 (33.3) Age <20, n (%) 1 (6.7) 20-49, n (%) 1 (6.7) ³50, n (%) 13 (86.6) Median (range) 62 (19-73) Median follow-up in months (range) 11.7 (4.1-40) Presenting WBC x 10 9/L < 30, n (%) 8 (53.3) ³ 30, n (%) 7 (46.7) Median (range) 22 (2.8-358.4) Bcr-Abl type p190, n (%) 12 (80) p210, n (%) 2 (13.3) P190 and p210, n (%) 1 (6.7) Bcr-Abl level (1 unknown)* Mean (range) 35.1 (1.8-194.4) Median time to CHR in days (1 unknown), (range) 41.5 (22-69) Induction dose of dasatinib 70mg BID, n (%) 1 (6.7) 100mg daily, n (%) 8 (53.3) 140mg daily, n (%) 6 (40) CCyR after induction achieved, n (%) 11 (73.3) MMR achieved after induction, n (%) 5 (33.3) Dasatinib Dosing after Induction None, n(%) 1 (6.7) 70mg BID, n(%) 1 (6.7) 100mg/day, n(%) 12 (80) 140mg/day, n(%) 1 (6.7) POMP + TKI post induction, n(%) 4 (26.7) Post remission therapy (3 being evaluated for transplant, 1 never achieved CHR, 1 lost to ff-up)+ Transplant, n (%) 7 (46.7) Ponatinib, n (%) 1 (6.7) Dasatinib, n (%) 1 (6.7) HyperCVAD±, n (%) 1 (6.7) TKI maintenance after transplant, n (% of transplanted) 3 (42.9) M351T mutation, n (%) 1 (6.7) F317L mutation, n (%) 1 (6.7) Bcr-Abl detection by PCR with unit in ratio (international scale), +poor performance status or high comorbidity index is the reason for no transplant, ±hyperCVAD initiated but not tolerated. Figure 1. Overall Survival. Figure 1. Overall Survival. Figure 2. Disease Free Survival Figure 2. Disease Free Survival Disclosures Fazal: Novartis: Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Off Label Use: Dasatinib use for newly diagnosed Ph+ ALL.

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An open-labeled, multicentric clinical study of cetuximab combined with intensity-modulated radiotherapy (IMRT) plus concurrent chemotherapy in locoregionally advanced (LA) nasopharyngeal carcinoma (NPC): A 2-year follow-up report.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.5535 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 5535-5535 ◽

Cited By ~ 3

Author(s):

Chun-yan Chen ◽

Chong Zhao ◽

Li Gao ◽

Jin-yi Lang ◽

Jian-ji Pan ◽

...

Keyword(s):

Overall Survival ◽

Disease Free Survival ◽

Concurrent Chemotherapy ◽

Stage Iii ◽

Chinese Patients ◽

Recurrence Free Survival ◽

Spontaneous Bleeding ◽

Cervical Lymph Nodes ◽

Free Survival

5535 Background: To evaluate the safety and efficacy outcomes of concurrent cetuximab plus IMRT and cisplatin in Chinese patients with LA NPC. Methods: Patients with primary stage III-IVb (UICC/AJCC 2002 staging system) and non-keratinizing NPC were enrolled in this prospective, multicentric, phase II study. Cisplatin (80mg/m2,q3week) and cetuximab (400mg/m2 one w before radiation, and then 250mg/m2/w) were given concurrently. The prescription dose of IMRT to GTVnx (primary tumor in nasopharynx) was 66 Gy - 75.9 Gy, GTVnd (positive cervical lymph nodes) was 60 Gy - 70Gy, The response rate was evaluated according to RECIST 1.0 criteria, and adverse events (AEs) were graded according to NCI CTCAE V3.0 criteria. Results: From July 2008 to April 2009, 100 patients were enrolled (74 male), with median age of 43 years. The proportion of stage III, IVa and IVb patients were 71%, 22% and 7% respectively. 99% of enrolled patients completed the planned treatment. AEs were within the expected range and manageable. No toxic death occurred during the treatment. Acneiform skin eruptions, mucositis, in-field dermatitis, xerostomia and neucopenia were the most common seen AEs, with 64% grade 2/3 acneiform eruptions, 26% grade 2/3 in-field dermatitis, 90% ≥ grade 2 mucositis (2 cases of grade 4 mucositis with spontaneous bleeding), 40% ≥ grade 2 xerostomia and 8% grade 2/3 neucopenia. With a median follow-up time of 23.5 months, the 2 year overall survival (OS), disease-free survival (DFS), local recurrence-free survival, regional (cervical lymph node) recurrence free survival and distant metastasis-free survival rates for the ITT population were 91%, 89%, 90%, 90% and 89%, respectively Multivariate analysis showed that N stage was the only prognostic factor for OS (p=0.0392, HR=2.946) and DFS (p=0.0062, HR=4.246) in these patients. Conclusions: Cetuximab combined with IMRT plus concurrent cisplatin in patients with LA NPC shows satisfactory 2-year locoregional control rate and 2-year overall survival. The combination seems to be well tolerated with a manageable side-effect profile.

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Prognostic Significance of Karyotype in Octogenarian Patients (Pts) with Acute Myeloid Leukemia (AML)–An International Study

Blood ◽

10.1182/blood.v118.21.2521.2521 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2521-2521

Author(s):

Meir Wetzler ◽

Jessica Kohlschmidt ◽

Krzysztof Mrózek ◽

Herve Dombret ◽

Hartmut Döhner ◽

...

Keyword(s):

Overall Survival ◽

Molecular Markers ◽

De Novo ◽

Prognostic Significance ◽

Disease Free Survival ◽

Molecular Testing ◽

Npm1 Mutation ◽

Significant Difference ◽

The Impact ◽

Disease Free

Abstract Abstract 2521 We asked whether a modified European LeukemiaNet (ELN) karyotype-based classification without molecular markers has prognostic significance in AML pts aged 80 to 89 years (y). We queried the German-Austrian AML Study Group (AMLSG; 7 pts), the Acute Leukemia French Association Group (ALFA; 17 pts), the German AML Cooperative Group (AMLCG; 35 pts) and the Cancer and Leukemia Group B (CALGB; 81 pts) for pts treated with intensive induction (7+3 or similar) on whom conventional karyotype analyses were completed and reviewed centrally. Of the 140 pts, including 82 (59%) men and 58 (41%) women, with a median age of 82 y (range, 80–89), 117 pts had de novo and 23 had secondary or therapy-related AML (s-AML/t-AML). There were 2 pts in the modified Favorable Group [t(8;21) and inv(16)], 67 pts in the modified Intermediate I Group [cytogenetically normal (CN-AML) pts], 44 pts in the ELN Intermediate II Group [t(9;11) and abnormalities (abn) classified as neither favorable nor adverse] and 27 pts in the ELN Adverse Group [inv(3) or t(3;3), t(6;9), t(v;11)(v;q23), -5 or del(5q), -7, abn(17p) and complex karyotype (≥3 abn)]. In order to assess the impact of karyotype on outcome, we eliminated early deaths. The complete remission (CR) rate for all 92 (66%) pts surviving beyond 30 days (d) was 46% and their median disease-free survival (DFS) was 6 months (mo); 35% were disease-free at 1 y and 12% at 3 y. Similarly, the median overall survival (OS) for pts surviving beyond 30 d was 6 mo, with 35% alive at 1 y and 11% at 3 y. There was no difference in DFS or OS based on AML type (de novo v s-AML/t-AML; Table 1). As shown in Table 2, pts in the modified Intermediate I Group had better OS than pts in the Adverse Group (P=0.03). Among CN-AML pts with molecular testing completed, 9/21 (43%) were NPM1-mutated (mut), 8/25 (32%) had FLT3-internal tandem duplication (ITD) and 1/12 (8%) was CEBPA-mut. Interestingly, FLT3-ITD did not have prognostic significance in the CN-AML cohort alive beyond 30 d (data not shown), but NPM1 mutation resulted in trends for higher CR rates (67% v 25%, P=.09) and longer OS (91 v 10 mo, P=0.07) in the CN-AML cohort alive beyond 30 d (Figure). Of note, there was no difference between the 2 larger cohorts (AMLCG and CALGB) in regards to pt characteristics or outcome in de novo pts; there were insufficient numbers of pts with s-AML/t-AML to compare the 2 cohorts. We conclude that there is a difference in accrual to clinical trials of octogenarian AML pts among the different cooperative groups. Further, CN-AML pts had better OS in octogenarian AML, and NPM1 mutation may be of prognostic significance among the CN-AML pts.Table 1:Treatment outcome by disease presentation for 92 pts alive beyond 30 dEnd Pointde novo AML (n = 78)s-AML/t-AML (n = 14)All pts (n = 92)P de novo v s-AML/t-AMLCR, no. (%)35 (45)7 (50)42 (46).78DFS.76 Median, y0.50.60.5.27 % Disease-free at 1 y36 (26–51)29 (4–61)35 (21–49) % Disease-free at 3 y14 (5–29)012 (4–24)OS Median, y0.50.60.5 % Alive at 1 y35 (24–46)36 (13–59)35 (25–45) % Alive at 3 y14 (6–23)011 (5–19)Table 2:Disease outcome by ELN karyotype-based classification without molecular markers for 92 pts alive beyond 30 dEnd PointIntermediate I (n = 43)Intermediate II (n = 29)Adverse (n = 20)PCR, no. (%)23 (53)13 (45)6 (30).23DFS.17* Median, y0.60.40.3 % Disease-free at 1 y36 (17–56)40 (16–63)17 (1–52) % Disease-free at 3 y23 (8–41)00OS.03† Median, y0.90.40.3 % Alive at 1 y43 (28–57)33 (16–50)21 (7–41) % Alive at 3 y17 (8–31)5 (0–20)5 (0–22)*Only Intermediate I compared to Intermediate II (too few pts in the Adverse Group)†This is overall P-value. Adjusted P-values were not significant for the differences between Intermediate-I and Intermediate-II Groups (P=.26) and between Intermediate-II and Adverse Groups (P=.87). There was a statistically significant difference between Intermediate-I and Adverse Groups (P=.03)Figure.Overall survival by NPM1 status in CN-AML ptsFigure. Overall survival by NPM1 status in CN-AML pts Disclosures: Krug: MedA Pharma: Honoraria; Novartis: Honoraria; Alexion: Honoraria; Boehringer Ingelheim: Research Funding; Sunesis: Honoraria.

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Treatment outcome in patients undergoing surgery for carcinoma larynx and hypopharynx: A follow-up study

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.15545 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 15545-15545

Author(s):

B. T. Varghese ◽

P. Sebastian

Keyword(s):

Quality Of Life ◽

Overall Survival ◽

Prognostic Significance ◽

Disease Free Survival ◽

Surgical Oncology ◽

Voice Rehabilitation ◽

Voice Preservation ◽

Disease Free

15545 Background: In the Regional Cancer Centre (RCC) Trivandrum, India, carcinoma of the larynx account for approximately 5% of all new registries and carcinoma of the hypopharynx for another 3%. It is estimated that the division of surgical oncology RCC has performed about 200 laryngectomies since it’s beginning (1989). Currently i.e. after the year 2000,about 30–40 laryngectomies are estimated to be performed a year thus forming about 3–4% of overall major head and neck surgeries performed which is around 1000 cases per year. 80% of these surgeries are salvage procedures for failed radical radiation/chemoradiation. Aim: (1) To evaluate the role of surgery in disease free and overall survival. (2) To evaluate the prognostic significance of factors that generally affect the surgical outcome in laryngectomies. (3) To evaluate the morbidity associated with salvage surgeries and laryngectomies involving complex reconstructions. (4) To follow up all the patients and evaluate quality of life. (5) To evolve a protocol for selecting cases for primary and salvage laryngectomy. (6) To evolve a protocol for reconstructing the pharynx after laryngectomies. Methods: All patients who have undergone laryngectomy at the Division of Surgical Oncology RCC from June 1995 to Dec 2005 are included in the study which retrospectively records the age and sex distribution initial TNM staging and staging of recurrence/ residual disease at the time of surgical salvage, the indications and types of laryngectomy, and reconstructive options used and analyze the therapeutic outcome, disease free survival (DFS), overall survival (OS), voice preservation, post operative voice rehabilitation and quality of life. Major outcome measures Complications and factors contributing to it, DFS, OS, Voice Preservation, Postoperative rehabilitation and Quality of life. Results and Conclusions: An update of the results as on 31/12/05 the final conclusions and recommendations will be presented.( The study is currently on going with the Institutional Review Board (IRB) and the local Ethical committee (EC) clearance already obtained.and final document is expected to to be prepared by March 2006). No significant financial relationships to disclose.

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TILs Immunophenotype in Breast Cancer Predicts Local Failure and Overall Survival: Analysis in a Large Radiotherapy Trial with Long-Term Follow-Up

Cancers ◽

10.3390/cancers12092365 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2365 ◽

Cited By ~ 1

Author(s):

Ewan Millar ◽

Lois Browne ◽

Iveta Slapetova ◽

Fei Shang ◽

Yuqi Ren ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Prognostic Significance ◽

Disease Free Survival ◽

Automated Image Analysis ◽

Breast Cancer Patients ◽

Long Term Follow Up ◽

Inflammatory Chemokines

Aim: To determine the prognostic significance of the immunophenotype of tumour-infiltrating lymphocytes (TILs) within a cohort of breast cancer patients with long-term follow-up. Methods: Multiplexed immunofluorescence and automated image analysis were used to assess the expression of CD3, CD8, CD20, CD68, Fox P3, PD-1 and PD-L1 in a clinical trial of local excision and radiotherapy randomised to a cavity boost or not (n = 485, median follow-up 16 years). Kaplan–Meier and Cox multivariate analysis (MVA) methodology were used to ascertain relationships with local recurrence (LR), overall survival (OS) and disease-free survival (DFS). NanoString BC360 gene expression panel was applied to a subset of luminal patients to identify pathways associated with LR. Results: LR was predicted by low CD8 in MVA in the whole cohort (HR 2.34, CI 1.4–4.02, p = 0.002) and luminal tumours (HR 2.19, CI 1.23–3.92, p = 0.008) with associations with increased stromal components, decreased Tregs (FoxP3), inflammatory chemokines and SOX2. Poor OS was associated with low CD20 in the whole cohort (HR 1.73, CI 1.2–2.4, p = 0.002) and luminal tumours on MVA and low PD-L1 in triple-negative cancer (HR 3.44, CI 1.5–7, p = 0.003). Conclusions: Immunophenotype adds further prognostic data to help further stratify risk of LR and OS even in TILs low-luminal tumours.

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Acute Monocytic Leukemia (French-American-British classification M5) Does Not Have a Worse Prognosis Than Other Subtypes of Acute Myeloid Leukemia: A Report From the Eastern Cooperative Oncology Group

Journal of Clinical Oncology ◽

10.1200/jco.2004.08.060 ◽

2004 ◽

Vol 22 (7) ◽

pp. 1276-1286 ◽

Cited By ~ 44

Author(s):

Martin S. Tallman ◽

Haesook T. Kim ◽

Elisabeth Paietta ◽

John M. Bennett ◽

Gordon Dewald ◽

...

Keyword(s):

Overall Survival ◽

Myeloid Leukemia ◽

Eastern Cooperative Oncology Group ◽

Disease Free Survival ◽

Acute Monocytic Leukemia ◽

Oncology Group ◽

Monocytic Leukemia ◽

Free Survival ◽

Disease Free ◽

Acute Myeloid

Purpose Acute monocytic leukemia is a distinct subtype of acute myeloid leukemia (AML) with characteristic biologic and clinical features. This study was designed to compare the outcome of patients with M5 to that of other subtypes of AML, and to identify differences in M5a and M5b. Patients and Methods We reviewed all patients with AML M5 entered in three clinical trials for newly diagnosed AML conducted by the Eastern Cooperative Oncology Group between 1989 and 1998. Eighty-one patients, 21 with M5a and 60 with M5b, were identified. Results The complete remission rate was 62% for all patients with M5; 52% for patients with M5a and 65% for patients with M5b (P = .3), and 60% for the 1,122 patients with non-M5 AML entered on the same clinical trials (P = .8 for M5 v non-M5). The 3-year disease-free survival was 26% for all M5 patients; 18% for M5a and 28% for M5b (P = .31), and 33% for non-M5 patients (P = .13 for M5 v non-M5). The 3-year overall survival was 31% for all M5 patients; 33% for M5a and 30% for M5b (P = .65), and 30% for non-M5 (P = .74 for M5 v non-M5). The karyotypes of patients with AML M5 were heterogeneous. CD11b was the only leukemic cell antigen expressed differently in M5a (53%) compared to M5b (77%) to a significant degree (P = .02). Conclusion AML M5 represents an immunologically heterogeneous population similar to non-M5 AML with a prognosis that is not dependent on morphology. The disease-free survival and overall survival of patients with M5a, M5b, and non-M5 appear not to differ with currently available therapy.

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Karyotypic Instability Is Common in t(8;21) AML at Relapse.

Blood ◽

10.1182/blood.v108.11.4452.4452 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4452-4452

Author(s):

Tomoya Maeda ◽

Fumiharu Yagasaki ◽

Daisuke Okamura ◽

Maho Ishikawa ◽

Nobutaka Kawai ◽

...

Keyword(s):

Induction Therapy ◽

De Novo ◽

Prognostic Significance ◽

Disease Free Survival ◽

High Dose ◽

Kit Mutation ◽

Patients Âgés ◽

Karyotypic Instability ◽

First Relapse ◽

Kit D816v

Abstract The t(8;21) is one of the most frequent chromosomal translocation in acute myeloid leukemia (AML). The t(8;21) AML is commonly associated with a favorable prognosis in regard to overall survival (OS) as well as high complete remission (CR) rate. However, approximately 35–45% of patients in first CR will relapse within 5 years. In t(8;21) AML, a worse outcome has been reported in patients with a high presenting white blood cell count, expression of CD56, and activating mutation of c-Kit (D816V). The clinical outcome of t(8;21) AML in first relapse have not been clarified. Further, factors predicting the outcome of patients in first relapse have not been defined. In this study, we evaluated the clinical features, the prognostic significance of c-Kit (D816V) mutation and karyotype instability in 14 relapsed patients among 32 de novo t(8;21) AML patients treated in our institution during the period 1987 to 2006. These 32 patients’ ages ranged from 15 to 73 years (median, 46 years) and they were classified as RAEB-T (n=2), M1 (n=2) and M2 (n=28) according to the FAB classification. Another additional cytogenetic aberrations at diagnosis were loss of Y (n=5), del(9q) (n=3), del(7q) (n=1), and trisomy 4 and 6 (n=1). Of the 32 patients, 14 (44%) were treated with BHAC-DMP (behenoylcytosine arabinoside, daunorubicin, 6-mercaptopurine, and prednisolone) induction therapy and 18 (56%) were treated with induction therapy consisted of an idarubicin or daunorubicin in combination with cytarabine (200mg/m2 for 7 days). For post remission therapy, 26 (82%) were received sequential multiagent chemotherapy and 6 (18%) were received high dose cytarabine alone. All patients achieved first CR (100%), median OS and disease-free survival (DFS) was 5.1 years and 2.4 years, respectively. 14 (44%) had a relapsed and the median duration from initial diagnosis to relapse amounted to 10.5 months (range, 3.8 months to 2.4 years). Among the 14 relapsed patients treated with salvage therapy, 9 (64%) of patients achieved second CR and median OS and DFS after first relapse was 2.0 years and 1.0 year. 4 patients (12%) with c-Kit (D816V) mutation at first diagnosis relapsed within 12 months with the same mutation and died within 2.2 years. Karyotype examination at first relapse were performed in 12 patients and additional karyotypic abnormalities were found in 6 patients. Three or more complex aberrations involving del(5q), del(6q), del(7q) or del(9q) were found in all of 6 patients. Among 6 patients showing karyotypic evolution (KE), 5 achieved second CR and relapsed again shortly. Two patients with KE had c-Kit D816 mutation at diagnosis, however, c-Kit mutations of exon 17 and 8 were not detected in 4 patients with KE at diagnosis and during the course of disease. In conclusion, karyotypic instability is common in t(8;21) AML at relapse and is not associated with c-Kit mutation. Karyotypic instability may contribute to the development of refractoriness of AML to chemotherapy.

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Treatment Experience of Acute Lymphoblastic Leukemia with Hgm/LAL07 Regimen at Hospital General De Mexico

Blood ◽

10.1182/blood.v126.23.4871.4871 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4871-4871

Author(s):

Christian Omar Ramos Peñafiel ◽

Humberto Baldemar Castellanos Sinco ◽

Efreen Montaño Figueroa ◽

María Guadalupe Leon Gonzalez ◽

Etta Rozen Fuller ◽

...

Keyword(s):

Central Nervous System ◽

Bone Marrow ◽

Overall Survival ◽

Nervous System ◽

Acute Lymphoblastic Leukemia ◽

De Novo ◽

Lymphoblastic Leukemia ◽

Disease Free Survival ◽

The Impact

Abstract Introduction Acute lymphoblastic leukemia is a lymphoproliferative malignancy characterized by an uncontrolled growth of lymphoid progenitors of B or T lineage, who evade apoptosis and displace normal hematopoiesis. Based on the pediatric pre-induction steroid, the protocol assessed the impact ALL0288 GIMEMA 7 days pre-induction with steroids, complete remissions (CR). Similar to this study, our institutional protocol also considers the pre-induction with steroids, but unlike the Italian protocol fewer cases steroid responders and a lower rate of complete remissions were recorded. A 36 month follow-up overall survival was 32% The main objective of this study was to evaluate the results at 5 years of follow institutional protocol based on a pre-treatment with steroids HGMLAL07. Patients. We included patients diagnosed with acute lymphoblastic leukemia under morphological criteria French-American-British (FAB) and corroborated by flow cytometry. The criteria for complete remission was seen at 4 weeks of treatment (<5% blasts in bone marrow with normal number of leukocytes and platelets). Prophylaxis central nervous system was carried out by weekly and then monthly lumbar punctures to the maintenance stage. If express the BCR-ABL oncogene was added to treatment Imatinib 400mg PO every 24 hours you first 14 days of each cycle. Materials and methods. Study design. Retrospective cohort study of adult patients treated with institutional protocol HGMLAL07 carriers de novo acute lymphoid leukemia in the period from 2007 to 2015 in the Department of Hematology, General Hospital of Mexico. We excluded patients treated with another induction therapy and those of mixed lineage leukemia. General treatment. It was considered relapse if they had at any time monitoring the presence of more than 10% blasts in bone marrow or isolation in the cerebrospinal fluid. If u have HLA-matched donor, he referred to the area of stem cell transplantation. Statistic analysis. SPSS statistical software version 20.0 was used. Chi-Square test considered significant at p <0.05 (95% CI) was used to test hypothesis testing. Survival analysis was performed using the Kaplan-Meyer test for comparing groups for overall survival and disease-free survival test was used log-rank2. The COX regression model was used for the risk function between different risk variables Results. Of the 262 patients with LLA de novo, 255 patients met the inclusion criteria and were treated with institutional protocol HGMLAL07, 52.9% were male gender (n = 135) and 47.1% (n = 120) Gender female. The mean age was 31 years (range 16- 80 years), the average for older female compared with male (34 versus 29years, p = 0.001, 95% CI). The average of leukocytes at diagnosis was 56.1 x 10 (9) / L. Phenotypically, most were classified leukemia B-cell (95.3%, n = 243) and the remaining T lineage (4.7%, n = 12). Only 3.1% of cases expressed the oncogene BCRABL1 (n = 8). Finally concluding that 62.7% of cases were classified as high risk (n = 160) and 37.3% (n = 95) and normal risk. Response to induction therapy. Of the 255 patients who started the protocol remission induction in 1.6% of confirmed with CNS infiltration diagnosis (n = 4). The complete remission rate was around 82.7% (n = 211), registering an induction mortality 3.9% (n = 10). A total of 34 patients were considered refractory leukemia (n = 34), requiring a second line treatment. Among the variables that showed the impact of the failure to initial treatment (refractory or death) were the type of risk at diagnosis (p = 0.020) and white blood cell count> 30 x 10 (9) / L (p = 0.001). Mean neutrophil recovery was 28 days and the platelet recovery was at 32 days. The main cause of death was infectious processes, followed by central nervous system bleeding. Postremisión treatment and outcome Of the total patients, 51% (n = 130) presented relapse, the main site bone marrow, followed by infiltration of the central nervous system Prognostic factors that impacted on survival The median overall survival (OS) was 1053 days, with survival at 5 years of follow-up of 29%, overall survival at 5 years was influenced by the type of risk (p = 0.020, 95% CI). None of the risk factors impact on survival at one year. The disease-free survival was 11% at 5 years of follow-up, within the variables that impacted on the SLE, a leukocyte count> 30 (9) / L and age> 35 years directly impacted prognosis (p = 0.006 and p = 0.030, 95% CI respectively). Disclosures No relevant conflicts of interest to declare.

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Stromal Cell-Derived Factor 1α (SDF-1α) in Invasive Breast Cancer: Associations with Vasculo-Angiogenic Factors and Prognostic Significance

Cancers ◽

10.3390/cancers13081952 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1952

Author(s):

Elżbieta Zarychta ◽

Barbara Ruszkowska-Ciastek ◽

Kornel Bielawski ◽

Piotr Rhone

Keyword(s):

Breast Cancer ◽

Invasive Breast Cancer ◽

Stromal Cell ◽

Prognostic Significance ◽

Disease Free Survival ◽

Breast Cancer Patients ◽

Roc Curve Analysis ◽

Stromal Cell Derived Factor ◽

A Prospective Study

(1) Background: Tumour angiogenesis is critical for the progression of neoplasms. A prospective study was designed to examine the utility of stromal cell-derived factor 1α (SDF-1α) and selected vasculo-angiogenic parameters for estimating the probability of disease relapse in 84 primary, operable invasive breast cancer (IBrC) patients (40 (48%) with stage IA and 44 (52%) with stage IIA and IIB). (2) Methods: We explored the prognostic value of the plasma levels of SDF-1α, vascular endothelial growth factor A (VEGF-A), the soluble forms of VEGF receptors type 1 and 2, and the number of circulating endothelial progenitor cells (circulating EPCs) in breast cancer patients. The median follow-up duration was 58 months, with complete follow-up for the first event. (3) Results: According to ROC curve analysis, the optimal cut-off point for SDF-1α (for discriminating between patients at high and low risk of relapse) was 42 pg/mL, providing 57% sensitivity and 75% specificity. Kaplan–Meier curves for disease-free survival (DFS) showed that concentrations of SDF-1α lower than 42 pg/dL together with a VEGFR1 lower than 29.86 pg/mL were significantly associated with shorter DFS in IBrC patients (p = 0.0381). Patients with both SDF-1α lower than 42 pg/dL and a number of circulating EPCs lower than 9.68 cells/µL had significantly shorter DFS (p = 0.0138). (4) Conclusions: Our results imply the clinical usefulness of SDF-1α, sVEGFR1 and the number of circulating EPCs as prognostic markers for breast cancer in clinical settings.

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