Second Primary Malignancies In Adult Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3871-3871
Author(s):  
Binay K. Shah ◽  
Krishna B Ghimire
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
General Population ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
P Value ◽  
Second Primary ◽  
Adult Age ◽  
Absolute Excess Risk ◽  
Second Primary Malignancies

Abstract Background Pediatric acute lymphoblastic leukemia (ALL) patients have higher rates of second primary malignancies. There is limited data on second primary malignancies (SPM) among adult patients with ALL. This study was conducted to evaluate SPM in adult ALL patients using US Surveillance, Epidemiology and End Results (SEER) cancer registry database. Methods We analyzed the SEER 13 Registries using multiple primary standardized incidence ratio (MP-SIR) session. We analyzed secondary cancer rates among adult ALL patients during the period 1992 - 2010. We used SEER*Stat software provided by national cancer institute for statistical analysis. Results There were 3,259 adult (age ≥20 years) ALL patients reported in SEER database during 1992-2010. Among them, 65 ALL patients developed 75 second primary malignancies. Fifty-nine ALL patients developed 1 SPM each, 3 ALL patients developed 2 SPM each, 2 ALL patients developed 3 SPM each and 1 ALL patient developed 4 SPM. All site cancers were significantly higher among adult ALL patients compared to general population with observed/expected ratio (O/E): 1.47, p value< 0.05, an absolute excess risk of 24.43 per 10,000 populations. Similarly, oral cavity cancer, respiratory system cancer and hematological SPM were significantly higher in ALL patients than expected in general population. (Table) Conclusions Adult patients with ALL have higher rates of second primary malignancies compared to general population. Disclosures: No relevant conflicts of interest to declare.

Second Primary Malignancies in Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4247-4247
Author(s):  
Binay K. Shah ◽  
Krishna B Ghimire
Keyword(s):  
General Population ◽  
Conflicts Of Interest ◽  
Cancer Registries ◽  
P Value ◽  
Second Primary ◽  
Secondary Cancer ◽  
Scientific Software ◽  
Second Primary Cancers ◽  
Second Primary Malignancies ◽  
End Results

Abstract Abstract 4247 Background: Development of second primary cancers among CML patients is not well studied. With improvement in CML survival, long term risks of CML, including second cancers need to be evaluated. This study was conducted to evaluate second primary malignancies in CML patients using data from the US Surveillance, Epidemiology and End Results (SEER) cancer registries. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER*Stat) database: Incidence - SEER 13 Regs Research Data, Nov 2011 Sub, Vintage 2009 Pops (1992–2009) using MP-SIR Session. We compared secondary cancer rate among adult CML patients (older than 20 years of age) during the period 1992 – 2009. We also evaluated the risk of secondary malignancies in pre- (1992–2000) to post- imatinib (2001–2009) eras. We used SEER MP-SIR session and Graph pad scientific software to calculate p value. Results: The total number of CML patients older than 20 years of age, reported during 1992–2009 period was 8,511. There were 4286 and 4225 CML patients in the pre- (1992–2000) and post- (2001–2009) Imatinib era respectively. All site secondary cancer (n=475) incidence was significantly higher among CML patients compared to general population with observed/expected ratio (O/E):1.28, p=< 0.05, an absolute excess risk of 31.39 per 10,000. Similarly, all sites secondary cancer in post-(2001–2009) Imatinib era was significantly higher compared to pre- imatinib era with O/E ratio of 1.50 vs 1.13, p=0.03. Conclusions: This study showed that overall risk of second malignancies among CML patients is higher compared to general population. The risk of second primary malignancies is higher in post- imatinib era. Disclosures: No relevant conflicts of interest to declare.

Statistically Significant Differences In Toxicities Between L- and PEG Asparaginase In Adult Patients with Acute Lymphoblastic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2121-2121 ◽  
Author(s):  
Gustavo A. Rivero ◽  
Kayleen Bailey ◽  
Amanda Blackford ◽  
Amy Seung ◽  
Steven D. Gore ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Liver Function ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Liver Function Tests ◽  
Adult Patients ◽  
Treatment Regimens ◽  
Glucose Levels ◽  
Post Induction ◽  
And Gender

Abstract Abstract 2121 Background: The use of asparaginase (ASP) in treatment regimens for adult acute lymphoblastic leukemia (ALL) patients (pts) is a challenge due to its toxicity profile. Adverse events associated with ASP use include hypersensitivity reactions, coagulation disorders, hepatotoxicity, pancreatitis and hyperglycemia. Life-threatening complications compromise completion of treatment, and even pt suitability for bone marrow transplantation if required. We report our single institution experience with ASP acute toxicities in adult pts diagnosed with ALL. Methods: From 1993–2007, 135 pts (median age 38 years; range 18–76) were treated with ASP as part of their ALL directed regimen, of which 84 (62%) and 51 (38%) received L and Peg-ASP, respectively. Approximately 794 and 51 doses of L- and Peg-ASP were given, respectively. Acute toxicities were graded according to CTCAE version 3.0 at pre, peak (7d) and post (14d) ASP treatment. Grade 1 (G1) through grade 4 (G4) toxicities were evaluated during both induction and intensification. For each patient, the number and proportion of all toxicities (G1-G4) were calculated. Results: There was a higher frequency of toxicities with L- compared to Peg-ASP after controlling for age and gender. The average proportion of G2-G4 toxicities was 25% for L-ASP pts compared to 13% for Peg-ASP (p < 0.001). G3 toxicities were seen in 78% (65/82) of pts receiving L-ASP and 50% (26/52) with Peg-ASP (p=0.02), and G4 toxicities were seen in 23% (19/83) and 8% (4/52) of L-ASP and Peg-ASP pts, respectively (p=0.07). Additionally, a greater proportion of L-ASP vs Peg-ASP pts (42% v 3%) had elevation of liver function test (ALT) at the post-induction time point (p < 0.001). Similar results were seen for AST, Alk phos and glucose levels (all p values < 0.05). Decreased fibrinogen levels were also seen more frequently in patients receiving L-ASP (57%) vs Peg-ASP (30%) patients (NS). The proportion of laboratory measurements that were G2 toxicity or higher increased with age for L-ASP (0.2% per year, p=0.05) but not Peg-ASP pts (0.06% per year, p=0.55). However, when adjusting for dose agent, the proportion of G2-G4 toxicities was 0.14% higher with each increasing year of age (p=0.05). Furthermore, males also had a greater proportion of G2-G4 toxicities since there was a 4.4% lower rate of toxicities reported for females as compared to males (p=0.05). Notably, higher grade toxicities were seen in pts with increasing age with either L- or Peg-ASP. The median ages for L-ASP pts with a G2, G3 and G4 were 40.5, 41 and 55 years. The median age for those pts who received L-ASP and experienced a G4 toxicity vs those pts who received L and had no G4 toxicities was 55 years old vs 39 (p=0.018). The median ages for Peg-ASP pts with G2, G3, and G4 toxicities were 32, 34 and 57 years respectively. With both L- and Peg-ASP groups combined, the median age for those pts having a G3 toxicity vs those pts without any G3 toxicities was 40 vs 32 years (p=0.012) and for G4 toxicity was 55 vs 36 years (p=0.001). Conclusions: In adult ALL pts who receive ASP, therapy with L-ASP was associated with (1) increased liver function tests including ALT, AST and alk phos as well as a trend for lower fibrinogen levels post induction therapy and (2) a higher likelihood of G4 toxicities as compared to therapy with Peg-ASP. Regardless of the dosing agent, higher grade toxicities were seen in pts with increasing age, although this was most notable in patients who received L-ASP. Male pts receiving ASP were also more likely to suffer from G2 or higher toxicities as compared to female pts. The use of either L- or Peg ASP should be closely monitored in adult patients with ALL and if toxicities arise, it is likely that the older patients will suffer from higher grade toxicities. Disclosures: No relevant conflicts of interest to declare.

Outcome After First Relapse In Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3084-3084
Author(s):  
Shinichi Kako ◽  
Heiwa Kanamori ◽  
Naoki Kobayashi ◽  
Akio Shigematsu ◽  
Yasuhito Nannya ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Median Duration ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Salvage Chemotherapy ◽  
Adult Patients ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
First Relapse

Abstract Abstract 3084 With modern intensive chemotherapy, 78% to 93% of adult patients with acute lymphoblastic leukemia (ALL) achieve complete remission (CR). However, the disease-free survival rate is only 30% to 40% due to the high rate of relapse. A part of relapsed patients can achieve second remission (CR2) with salvage therapy, and allogeneic hematopoietic stem cell transplantation (HSCT) in CR2 will be the only curative strategy. Prognosis after relapse in adult patients with ALL is considered to be extremely poor, but reports as to the outcome after relapse have been limited. To elucidate the outcome of relapsed patients and prognostic factors after relapse, we retrospectively collected and analyzed clinical data from 69 institutions in Japan on patients with Philadelphia-chromosome (Ph) negative ALL, aged 16–65 years, who relapsed after first CR (CR1) between 1998 and 2008. A total of 332 patients were included in this study. The median age of them was 35 years, and 165 patients were male. Median duration of CR1 was 290 days (range 15–7162 days), and median follow-up time after relapse was 319 days (range 3–3689 days). Fifty-eight and 4 of them relapsed after allogeneic and autologous HSCT in CR1, respectively. The overall survival (OS) rate was not significantly different between patients who relapsed after allogeneic HSCT in CR1 and those who relapsed after chemotherapy only (50.0% vs. 43.4% at 1 year and 10.6% vs. 16.3% at 5 year, respectively). Among 270 patients who relapsed after chemotherapy only, 234 patients received salvage chemotherapy after relapse, and 123 patients achieved CR2 (52.5%). Sixty-two patients out of those 123 patients underwent allogeneic HSCT in CR2. Median duration between the achievement of CR2 with salvage chemotherapy and allogeneic HSCT in CR2 was 76 days. OS rate was significantly better in patients who underwent allogeneic HSCT in CR2 following salvage chemotherapy than those who did not (74.1% vs. 55.1% at 1 year and 44.7% vs. 11.6% at 5 year, respectively) by a landmark analysis limiting patients who were surviving without disease at 76 days after the achievement of CR2. In multivariate analysis of factors that included allogeneic HSCT in CR2 following salvage chemotherapy as a time-dependent covariate, lower white blood cell count at relapse (less than 10000/μl) and allogeneic HSCT in CR2 were associated with better OS rate among patients who achieved CR2 following salvage chemotherapy. Forty-six patients underwent allogeneic HSCT in non-CR after receiving salvage chemotherapy. A part of them survived long, and 5 year OS rate was 20.9%. In conclusion, the prognosis of adult patients with relapsed Ph-negative ALL is poor. Allogeneic HSCT after first relapse could improve the prognosis. Disclosures: No relevant conflicts of interest to declare.

Accumulation Of Gene Alterations Of TP53, Crebbp and IKZF1 Is a Prognostic Factor In Adult Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1386-1386
Author(s):  
Kenji Tokunaga ◽  
Shunichro Yamaguchi ◽  
Taizo Shimomura ◽  
Hitoshi Suzushima ◽  
Yutaka Okuno ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Genomic Dna ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Statistical Significance ◽  
Philadelphia Chromosome ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Adult Patients ◽  
Genomic Deletions

Abstract Aims Mutations of the genes associating with cell differentiation or proliferation are recognized as factors of tumorigenesis or prognosis in hematological malignancies. In pediatric acute lymphoblastic leukemia (ALL), alterations of IKZF1 (a factor of lymphocyte differentiation), TP53 (a cell cycle regulator) and CREBBP (a histone modifier) are found as possible prognostic markers for stratification of treatments. On the other hand, in adult ALL, clinical significance of such alterations remains to be determined. In the present work, we examined whether the mutations in those genes affected the incidence and prognosis in adult ALL patients. Methods We investigated 87 adult patients with newly diagnosed ALL treated with JALSG protocols between 1986 and 2011. Age ranged from 15 to 86 years, with a median of 51 years. We obtained cDNA and genomic DNA from the peripheral blood or bone marrow mononuclear cells at diagnosis. CREBBP mutations are dominantly identified in the histone acetyltransferase (HAT) domain. HAT domain in the CREBBP gene was amplified by PCR using cDNA and was subjected to direct sequencing. Additionally other histone modifiers, EZH2, EED, and UTX, were sequenced as the same as in CREBBP. TP53 exons 5 – 8 and 10, in which mutations were commonly reported, were sequenced using genomic DNA. We amplified IKZF1 using RT-PCR for detecting aberrant dominant negative isoforms: Ik6 and Ik10. Genomic deletions of IKZF1 were assessed with RQ-PCR or genomic DNA PCR. We compared clinical profiles between patients with and without such gene mutations. The present study was approved by the Institutional Review Boards and informed consent was obtained from each patient according to guidelines based on the revised Declaration of Helsinki. Results In 87 adult patients with ALL, alterations of CREBBP, EED, TP53 and IKZF1 were detected in 7 (9.5%), 3 (4.8%), 6 (6.9%) and 42 (50%), respectively. None of EZH2 and UTX mutation was found. The alterations of CREBBP and IKZF1 at diagnosis in adult patients were more frequent than those in pediatric patients ever reported. Some gene mutations were not found frequently. Each gene mutation per se did not significantly affect prognosis. We tried to predict the prognosis by scoring gene mutations and chromosomal abnormalities. Philadelphia chromosome (Ph) has great impact to prognosis of patients with ALL. We scored the number of mutated genes and Ph for each patient. As the score was higher, adult patients with ALL had poorer relapse-free survival (P=0.0439) and OS (P=0.4819), but statistical significance was not detected in this small cohort. Conclusions and Discussion Single gene mutations, such as IKZF1, can predict the prognosis in pediatric ALL. In adult ALL, however, only few gene mutations are reported to be promising prognostic factors which have impacts to treatment outcomes. Scoring system may be a useful method for predicting prognosis and stratifying treatment in adult ALL. Our study implies the possibility that a variety and heterogeneity of genetic alterations in adult ALL are associated with the pathogenesis for treatment resistance and prognostic marker of adult ALL. Disclosures: No relevant conflicts of interest to declare.

Second primary malignancies in anal carcinoma.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 534-534 ◽  
Author(s):  
Binay Kumar Shah ◽  
Nibash Budhathoki
Keyword(s):  
Cancer Patients ◽  
Anal Cancer ◽  
Anal Carcinoma ◽  
Kaposi Sarcoma ◽  
Hematologic Malignancies ◽  
Adult Patients ◽  
Second Primary ◽  
Need To Evaluate ◽  
Absolute Excess Risk ◽  
Second Primary Malignancies

534 Background: Survival of cancer patients is increasing. Therefore, there is a need to evaluate long term complications in cancer survivors. There is no data on second primary malignancies in anal cancer. This study was conducted to evaluate second primary malignancies in patients with anal carcinoma. Methods: We selected adult patients diagnosed with anal cancer from National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) 13 database We calculated the risk of second primary malignancies in the anal cancer patients using multiple primary standardized incidence ratio (MP-SIR) session of SEER*stat software. Results: Among 7,661 patients with anal carcinoma, 3,196 were men and 4,465 were women. Median follow up duration was 87 months (range: 7-239 months). Median age at the time of diagnosis of SPM was 69.33 yrs (range: 34-103 yrs). Median latency for SPM was 52 months (range: 6-219 months). A total of 675 patients (9.07%) developed 747 second primary malignancies, with an observed/expected (O/E) ratio of 1.41 (95% confidence interval =1.32-1.52, p<0.001), and an absolute excess risk of 55.36 per 10,000 populations. Significant excess risks were observed for oral cavity and pharyngeal tumor, rectal and anal canal tumor, laryngeal tumor, lung and bronchial cancer, Kaposi sarcoma, hematologic malignancies, ovarian, vaginal, and vulval tumors. Conclusions: The risk of second primary malignancies in adult patients with anal cancer is significantly increased compared to general population.

Analysis of second primary cancers in gastroinstestinal stromal tumor patients using SEER database.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 327-327
Author(s):  
Krishna Bilas Ghimire ◽  
Barsha Nepal ◽  
Binay Kumar Shah
Keyword(s):  
General Population ◽  
Solid Tumors ◽  
Stromal Tumor ◽  
P Value ◽  
Second Primary ◽  
Seer Database ◽  
Second Primary Cancers ◽  
Increased Risk ◽  
Second Primary Malignancies ◽  
End Results

327 Background: Development of second primary cancers among gastrointestinal stromal tumor (GIST) patients is not very well studied. This study was conducted to evaluate second primary malignancies in GIST patients using U.S. Surveillance, Epidemiology, and End Results (SEER) cancer registry database. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER Stat) database: Incidence - SEER 13 Regs Research Data, Nov 2011 Sub, Vintage 2009 Pops (1992-2009) using MP-SIR session. We analysed secondary cancer rate among adult GIST patients during the period 1992-2009. We also compared the risk of secondary malignancies in pre- (1992-2001) to post-imatinib (2002-2009) eras. We used SEER MP-SIR session and Graph pad scientific software to calculate p value. Results: There were 2,436 (693 in pre-imatinib era and 1,743 in post-imatinib era) GIST patients reported during 1992-2009 period in SEER database. Among them, 163 GIST patients developed second primary malignancy, which is significantly higher than expected in general population, with observed/expected (O/E) ratio: 1.31, p value = <0.05, (95% CI: 1.11-1.52) and excess risk of 39.76 per 10,000 population. The total number of second primary cancers in GIST in pre- and post-imatinib eras were 69 and 94, p value = <0.0001 with observed/expected (O/E) ratio of 29.18 and 48.22 respectively. The total number of second primary solid tumors in pre- and post-imatinib era was: 59 and 84, p value=0.0008 and O/E ratio: 20.18 vs 43.32 respectively. Conclusions: This study showed overall increased risk of second primary malignancies among GIST patients as compared to general population. There was significantly increased risk of second primary malignancies, especially solid tumors in post-imatinib era. [Table: see text]

scholarly journals The Role of Genetic Polymorphisms ofTPMTandNUDT15Genes in Adult Patients with Ph-Negative Acute Lymphoblastic Leukemia in Russia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 21-22
Author(s):  
Ekaterina S. Kotova ◽  
Olga A. Gavrilina ◽  
Igor A Yakutik ◽  
Andrey B. Sudarikov ◽  
Elena N. Parovichnikova ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Genetic Polymorphisms ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Rt Pcr ◽  
Significant Toxicity ◽  
Allele Specific ◽  
Better Than

Context: TPMTandNUDT15polymorphisms are involved in the toxicity and therapeutic efficacy of thiopurine drugs (6-mercaptopurine (6-MP)). The frequencies of polymorphisms of these genes are different across diverse populations. The role ofTPMTandNUDT15genes in adult patients (pts) with Ph-negative acute lymphoblastic leukemia (ALL) in Russia is still unclear. Objective:Evaluation of frequency and significance ofTPMTandNUDT15polymorphisms in the cohort of adult Ph-negative ALL pts treated by the RALL-2016 protocol. Design and Patients:Since April 2017 till July 2020 56 adult Ph-negative ALL patients treated by RALL-2016 protocol were included in the research ofTPMTandNUDT15polymorphisms. Median age was 32 у (range, 18-54), m/f: 39 (70%) / 17 (30%). B-ALL/LBL were diagnosed in 26 (46,4%) pts, T-ALL- in 26 (46,4%) and MPAL- in 4 (7,2%). Genomic DNA was extracted from peripheral blood samples of given pts. Genetic polymorphisms inNUDT15(*2, *3)and TPMT(*2, *3A, *3B, *3C)genes were detected using the allele-specific RT-PCR. The dose of 6-MP was calculated only for 54 pts from 56 (one of these pts stopped the therapy and another received the 1 st phase of induction by RALL-2016 without 6-MP). According to the RALL-2016 protocol 6-MP dose correction imply: if the level leukocytes&lt;2,0*109/l, thrombocytes &lt;100*109/l pts got 50% from the required dose. The therapy of 6-MP was stopped, if the level leukocytes &lt;1,0*109/l, thrombocytes &lt;50*109/l. On the 2 induction therapy by the protocol, the doses of 6-MP were calculated only for 47 pts with CR. The group of pts who didn't have remission on the 36 day by the protocol took the drug without corrections. Results:From 54 pts CR rate was 87 % (n=47) and resistance - 13% (n=7). One patient died in CR. The frequency ofTPMTandNUDT15polymorphisms in study group was 17,8 % (n=10): 6 (23%) of 26 pts with B-ALL, 3 (11,5 %) of 26 pts -T-ALL and 1 (25%) of 4 pts - MPAL. In our cohort these polymorphisms were found significantly more frequently in pts with B-ALL (p&lt;0.001). These polymorphisms were detected in 8 (80%) men and 2 (20%) women (p=0.432). All detected polymorphisms were presented as heterozygous variants:NUDT15*3was in 2 (20%) pts,TPMT*2-1(10%),TPMT*3A-6 (60%),TPMT*3C-1 (10%). The doses of 6-MP in 5 pts withTPMTandNUDT15and 42 pts withWTwere 54% (27-89%) vs 71% (25-100%), respectively. Statistics analysis didn't show correlation between the 6-MP toxicity (difference of the fact dose of 6-MP therapy) and the polymorphisms in our cohort (fig.1). The frequency of resistance cases didn't different in cohort with/withoutTPMTandNUDT15polymorphisms in 3 (37, 5%) from 8 pts and 4 (10, 5%) from 42 pts, respectively. Only 1 patient with heterozygousTPMT*2died in CR due to toxicity and infection. Two-years overall survival (OS) in pts with the genetic polymorphisms was worse 75 % than in pts without them - 83,6% (p=0,67) (fig.2). Conclusions:In our study the frequency ofTPMTandNUDT15polymorphisms in adult pts with Ph-negative ALL was 17,8%. The statistical analysis showed that polymorphisms of these genes were detected more frequently in pts with В-ALL. Only one patient withTPMT*2had significant toxicity on the therapy of 6-MP and died in CR. However, we don't know whether this is due to deficient 6-MP metabolism. We didn't find a correlation between the 6-MP toxicity and the polymorphisms in our pts. There is a tendency that OS within 2-years in pts withoutTPMTandNUDT15polymorphisms is better than in the group of pts with them. But our cohorts are small and require further study. Keywords:acute lymphoblastic leukemia, toxicity, 6-mercaptopurine,TPMT,NUDT15 Disclosures No relevant conflicts of interest to declare.

ACUTE LYMPHOBLASTIC LEUKEMIA In Qatar: Clinico-Pathological PROFILE and OUTCOME

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4233-4233
Author(s):  
Mohamed A. Yassin ◽  
Firyal Ibrahim ◽  
Mina M. Al-Badri ◽  
Hanadi Rafii El-Ayoubi ◽  
Rami T Kamzoul
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Marrow Transplant ◽  
Adult Patients ◽  
Treatment Modalities ◽  
Final Conclusion ◽  
Allogeneic Bone ◽  
Female Ratio

Abstract Abstract 4233 Background: advances in immunophenotyping, cytogenic, and molecular genetics have not only considerably improved our knowledge of the pathophysiology of acute leukemia’s, but have also contributed to a refined classification of acute lymphoblastic leukemia(ALL)subtypes and outcome. With the different treatment modalities complete remission (CR) rates of 80–85%and leukemia –free survival (LFS) rates of 30–40%can be achieved in adult acute lymphoblastic leukemia (ALL). Aim: to study the clinico-pathological features and outcomes of adult patients patients with acute lymphoblastic leukemia in Qatar Patients & METHODS: thirty adult patients (age>14 years) diagnosed as all at AL-AMAL Hospital, the oncology hematology center in Qatar, the periode betweenJan06 and Jan 2011 were Retrospectively studied with respect to their clinical. morphological, immunopathologica features at presentation and their treatment outcomes, diagnosis was based on combined morphologic, immunophenotyping and cytogenetic studies.treatment protocols used were BFM mainly for adolescent patients,GMALL and UKALL 12 for adults. RESULTS: ALL constituting 25% of all acute leukemia cases diagnosed during the period the study. the median age was 28.5 years with a male to female ratio 21.six were Qatari and 24 non-Qatari. the most common presentation was with symptomatic anemia and fever (63.3%).laboratory features at presentation revealed.WBC.>30*109/L in13((43.3%).Immunophenotyping showed that 25(83.3%)were B-ALL, only one case9450was of the matureB-phenotype(Burkitt is),twenty two (80%) were CD10positive (common/pre Bsubtypes),two were CD10 negative PreB.non were subtype as proBALL.diagnosis of T-ALL was established in 5 (16.7%)patients.aberrantexpression was noted in14 cases (46.6%)combined expression of both CD13&CD33 being the most common seen in seven cases (50%).OUT OF THE 22 CASES 954.550.Five(22.7) had t (9.22)and one (4.5%)t (4.11).normal in 10(45.5%).thirteen patient travelled before having treatment. two pretreatment death (septic shock. two elderly patients with co morbidities were considered for palliative treatment.13patients were treated in doha, 11 out of 13 (84%)went into complete remission (CR) and two (16%) underwent successful allogeneic bone marrow transplant abroad. CONCLUSION: Although.the series is small to have a final conclusion, however, this study showed that almost all of our ALL cases are of the favorable immunological subtypes (common/ pre ALL) with high CR rate. Disclosures: No relevant conflicts of interest to declare.

Genome-Wide shRNA Screen Implicates Mitogen Activated Protein Kinase (MAPK) Pathway In Glucocorticoid Resistance In Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1296-1296
Author(s):  
Jones L. Courtney ◽  
Christy M. Gearheart ◽  
Fosmire Susan ◽  
Wang Jinhua ◽  
Danielle S. Bitterman ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Mapk Pathway ◽  
Lymphoblastic Leukemia ◽  
Mitogen Activated Protein Kinase ◽  
Leukemic Cells ◽  
P Value ◽  
Sequencing Analysis ◽  
Increased Sensitivity

Abstract Resistance to glucocorticoids (GC) is a hallmark of relapsed acute lymphoblastic leukemia (ALL) and is a predictor of outcome at diagnosis. In spite of the importance of GC in the treatment of ALL and other hematological malignancies the molecular mechanisms that lead to effective eradication of leukemic cells is incompletely understood. To address this problem we have performed a functional screen for genes involved in prednisolone resistance in ALL cell line (Reh) and correlated these results with our previously published results using an integrated genomic analysis to discover genes (pathways) altered at relapse (Hogan et al 2011). Cells were infected with a pooled whole genome shRNA library that contained approximately 80,000 shRNAs targeting 18,000 genes. Deep sequencing was used to identify shRNAs enriched or depleted upon treatment with prednisolone. Three computational methods including; bioinformatics for next generation sequencing analysis (BiNGS), redundancy & fold change analysis (RFC) and strict standardized mean difference (SSMD) were applied to the sequencing data in efforts to obtain the most robust set of candidate genes for validation (Porter et. al, Leukemia 2012, Zhang XD, J Biomol Screen, 2007). Through our primary screen a total of 263 genes were identified to modulate prednisolone sensitivity in ALL. Upon knockdown, 142 genes increased the sensitivity of the cells to prednisolone and 121 genes increased resistance to prednisolone. Five genes overlapped with genes previously identified to be altered at relapse compared to matched diagnosis samples including SLC6A18, AARSD1, MIER3, CDC42BPB, and YAP1. We hypothesize that genes that are altered at relapse in ALL and identified through functional genomics screening to modulate chemosensitivity in vitro, are likely drivers of chemoresistance and eventual relapse. We also performed gene ontology (GO) analysis using DAVID Bioinformatics to identify pathways that may be responsible for altered resistance to prednisolone. This analysis strongly implicated the mitogen-activated kinase (MAPK) pathway. The MAPK was also identified as a pathway with increased activity at relapse through our integrative genomics analysis(Hogan et al 2011). One gene of particular interest was MAP2K4 which encodes for MEK4, an upstream kinase involved in JNK phosphorylation and c-Jun activation. Knockdown of MAP2K4 by shRNA in B-precursor ALL cell lines (Reh and RS4;11) results in statistically significant (p-value < 0.5) increased sensitivity to prednisolone induced apoptosis at a range of prednisolone concentrations but not to other chemotherapy tested (etoposide, doxorubicin, and 6-thioguanine).604. Molecular Pharmacology, Drug Resistance: Poster I Upon treatment with prednisolone MAP2K4 knockdown cells have increased levels of prednisolone responsive genes GILZ (1.4-2.4 fold in Reh, 2.1-3.8 fold in RS4;11) and TXNIP (1.8-5.7 fold in Reh, 2.5-2.6 in RS4;11). Increased sensitivity to prednisolone and increased levels of prednisolone responsive genes was associated with decreased levels of p-JNK that has been previously implicated in regulating glucocorticoid signaling through phosphorylation of the glucocorticoid receptor (GR) at S226 (Roatsky et. al, PNAS 1998, Itoh et. al, Mol. Endo. 2002).s Overall this data suggests that decreased levels of MAP2K4 results in increased sensitivity to GC by increasing GC signaling and implicates MEK4 as novel drug target in ALL. Disclosures: No relevant conflicts of interest to declare.

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