Distribution of Cytogenetic Abnormalities in African American Multiple Myeloma Patients May be Unique for Different Geographic Regions

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5337-5337
Author(s):  
Manisha Bhutani ◽  
Preeya Patel ◽  
Myra M Robinson ◽  
Rupali Bose ◽  
Kyle Madden ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
African American ◽  
Racial Differences ◽  
Lower Incidence ◽  
Research Funding ◽  
Cook County ◽  
Cook County Hospital ◽  
Cytogenetic Abnormalities ◽  
Significant Difference ◽  
Similar Incidence

Abstract BACKGROUND: Multiple myeloma (MM) is the most common hematologic malignancy in the African American population, with an incidence more than 2 times higher than Caucasian population [Landgren O et al Blood 2006]. Historically, the African American MM patients have had better outcomes compared with other races [Ailawadhi S et al Br J Haematol 2012], but no biologic explanations exist for this observation. Greenberg et al [Blood Cancer J 2015] have recently reported on differences in commonly observed baseline cytogenetic abnormalities (CA) between African American and Caucasian MM patients seen at Mayo Clinic (Rochester, MN), Cook County Hospital (Chicago, IL) and University of Maryland (Baltimore, MD). We examined the MM cohort at our referral center to validate these observations. PATIENTS & METHODS: The Levine Cancer Institute MM database was interrogated for all patients presenting with MM between January 2012 and April 2015. Baseline clinical and pathology variables were compared between the African American and Caucasian cohorts. Continuous variables were compared using nonparametric rank tests, while incidences and proportions (e.g. CAs including t(11;14), t(4;14), monosomy13/del13q and del17p) were compared using Fisher's exact tests. RESULTS: A total of 662 patients were identified; excluding those with MGUS classification, 368 patients were included in the analysis (African Americans n = 130, Caucasian n = 238). The median age of African American MM patients was significantly younger than Caucasian MM patients (median age 60 years vs. 65 years, p=0.010), with similar gender distribution. There was a numerically larger proportion of African American patients with anemia (40.8% vs 30.8%, p =0.166), however, there was no significant difference in degree of BM plasmacytosis amongst the two groups. The overall distribution of MM patients by IMWG risk stratification (Chng et al, Leukemia 2013) was also similar between the two groups. The African American MM patients had a numerically higher incidence of a metaphase abnormality on conventional cytogenetics (21.7% vs. 13.9%, p =0.154). They had a significantly lower incidence of t(11;14) [7.7% vs. 16%, p=0.024], a numerically higher incidence of t(4;14) [6.2% vs. 3.8%, p=0.309], and similar incidence of deletion 13/del13q [22.3% vs. 18.9%, p=NS ] and del17p [7.7% vs. 7.6%, p=NS ]. CONCLUSIONS: The present dataset is the largest single institution report on CA racial differences in MM patients. We found that unlike previous reports of lower incidence of t(4;14) or del17 p in African American MM patients by Greenberg et al, we have observed a higher incidence of t(4;14) and similar incidence of del17p in our experience compared to Caucasian MM patients. The different pattern of CA distribution compared to published literature may represent geographic heterogeneity and potentially influence survival outcomes. Disclosures Cogdill: Celgene: Speakers Bureau; Onyx: Speakers Bureau; Millennium: Speakers Bureau; Novartis: Speakers Bureau. Usmani:Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau; Janssen Oncology: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Pharmacyclics: Research Funding; Millennium: Honoraria, Speakers Bureau; Array BioPharma: Honoraria, Research Funding.

Fluorescence in Situ Hybridization (FISH) abnormalities and Baseline Clinical Features at Diagnosis in African American Multiple Myeloma Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2351-2351
Author(s):  
Megan H Jagosky ◽  
Kyle L Madden ◽  
Blake B Goodbar ◽  
Virginia Thurston ◽  
Manisha Bhutani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
African American ◽  
Board Of Directors ◽  
Clinical Features ◽  
Research Funding ◽  
Advisory Committees ◽  
Significant Difference ◽  
Caucasian Patients ◽  
Caucasian Cohort

Abstract BACKGROUND: Multiple myeloma (MM) is the most common hematologic malignancy in the African American (AA) population with an incidence more than 2-3 times higher than Caucasians [Landgren O et al Blood 2006]. In the pre-novel therapy era, SEER data [1975-2008] indicated better survival outcomes for AA patients with MM. However, with the recent advent of novel drugs for treatment of MM, the survival gap for Caucasian patients with MM has closed [Ailawadhi S et al Br J Haematol 2012]. A recent pooled analysis of diagnostic cytogenetics in 292 AA MM patients [Greenberg et al Blood Cancer J 2015] reported on differences in commonly observed baseline cytogenetic abnormalities (CA) between AA and Caucasian MM patients. The large and diverse population of patients with MM at our institution prompted us to examine diagnostic cytogenetics in our MM patients along with other clinical features. PATIENTS & METHODS: The MM database was interrogated for all patients presenting with MM between January 2012 and February 2016. Baseline clinical and pathology variables were compared between the AA and Caucasian cohorts. Continuous variables were compared using nonparametric rank tests, while incidences and proportions (e.g. CAs including t(11;14), t(4;14), t(14;16), t(14:20), amplification 1q21, monosomy13/del13q and del17p) were compared using Fisher's exact tests. RESULTS: A total of 398 patients were identified for the analysis (African Americans n = 168, Caucasian n = 230). The median age of AA MM patients was significantly younger than Caucasian MM patients (median age 63 years vs. 68 years, p<0.0001), with a similar sex distribution. There was no significant difference in the degree of anemia, renal insufficiency, serum LDH levels, bone marrow flow cytometry, bone marrow cellularity or plasmacytosis in the two cohorts. Although there was a trend toward more ISS I amongst Caucasian MM patients, there was no statistical difference in ISS stages (p = 0.126) and no significant difference in R-ISS stage between the cohorts (p = 0.361). There was 72.7% agreement between the ISS and R-ISS staging (88 of 121 evaluable subjects had the same stage by ISS and R-ISS staging criteria), while 27.3% of the patients were upstaged from Stage I or II by ISS criteria to Stage III by R-ISS criteria. Of those upstaged, 19 patients were in the Caucasian cohort and 14 were in the AA cohort. The magnitude of this upstaging was significant when evaluated with a Generalized McNemar's test (p < 0.001). Additionally, there was a similar incidence of common FISH abnormalities in the AA cohort compared to the Caucasian cohort [Table 1]. CONCLUSIONS: This is the largest single institution report of FISH data in AA MM patients. Unlike previous reports, we show similar clinical, pathological, and cytogenetic features between AA and Caucasian patients with MM at presentation. It is possible that molecular abnormalities not detectable by FISH in our patient cohort could account for differences in our data and the published literature. Table 1 FISH Abnormalities Table 1. FISH Abnormalities Disclosures Bhutani: Prothena: Research Funding; Takeda Oncology: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Onyx, an Amgen subsidiary: Speakers Bureau. Symanowski:Eli Lilly & Co: Consultancy; Ra Pharma: Consultancy; Caris Life Sciences: Consultancy; Endocyte: Consultancy. Avalos:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Usmani:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Britsol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Array: Research Funding; Pharmacyclics: Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Novartis: Speakers Bureau.

scholarly journals With Equal Access, African Americans with Non-del17p Multiple Myeloma Have Superior Overall Survival, but del17p Still Carries Poor Prognosis across Race: A VA Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4388-4388 ◽  
Author(s):  
Anusha Munjuluri ◽  
Nathanael Fillmore ◽  
Diana Cirstea ◽  
Hassan Yameen ◽  
Sarvari Venkata Yellapragada ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
African Americans ◽  
Racial Differences ◽  
Median Survival ◽  
Lower Incidence ◽  
Research Funding ◽  
Cell Transplant ◽  
Risk Of Death ◽  
Disease Biology ◽  
The Difference

BACKGROUND: In multiple myeloma (MM), deletion of TP53/17p (del17p), present in around 10% of patients, is associated with shortened survival. Lower incidence of del17p is reported in African Americans (AA) compared to European Americans (EA), alluding to possible contribution of disease biology to racial differences in outcome among AA and EA patients with MM. Our recent report of a significantly superior age-adjusted risk of death in AA compared to EA patients in the younger (<65) Veteran population also suggests that AA may have a genetic predisposition that renders them to have better therapeutic outcome or have more indolent subtypes of MM. Here we investigated the incidence and impact of del17p on outcome in AA and EA patients with MM at the VA. METHODS: We identified 2677 patients with MM from 1999 to 2017 using the VA's nationwide Corporate Data Warehouse for whom information on del17p was available. We extracted data on patients' age, race, ISS stage, therapy at induction and stem-cell transplant (SCT) utilization. Test results for del17p were extracted from lab panel and pathology reports. Our analysis is focused on patients with this data. RESULTS: Of the 2677 MM patients evaluated for del17p by conventional cytogenetics and/or FISH, self-reported race information was available in 2432 patients, among which AA constituted 35.6% (867) and EA 64.4% (1565). AA had a greater proportion of younger (<65) patients compared to EA (49.48% vs 33.87%, p<0.001). Overall, among those tested, del17p was reported in 7.4% of all patients, but the incidence was significantly lower in AA compared to EA (4.73% vs 8.82%, p<0.001), largely due to the difference in incidence of del17p in younger AA vs EA (3.73% vs 8.30%, p = 0.005). The rates of del17p across different ISS stages were not significantly different, nor did ISS stage differ across race. As expected, del17p was associated with shortened survival. In the full cohort, median survival was 2.26 years for patients with del17p and 4.27 years for those without (p<0.001). These differences were also observed within race (1.74 vs 4.95 in AA, p<0.001, 2.34 vs 4.13 in EA, p<0.001) and age groups (2.67 vs 5.49 in younger, p<0.001; 2.12 vs 3.5 in older, p<0.001). We found no significant racial differences in survival between AA and EA patients with del17p deletion (1.74 vs 2.34, p=0.47) regardless of age category. However, importantly we noted a significant racial difference in the median survival between younger AA and EA without del17p (7.75 vs. 4.87 years, p=0.006). In contrast, in older patients without del17p we observed no significant difference in survival across race. To understand the difference in survival between younger AA and EA without del17p, we compared ISS stage, ECOG status, and novel therapy (bortezomib, lenalidomide, and thalidomide) and SCT utilization between these groups. No significant differences were observed apart from a small difference in utilization of bortezomib in AA patients as compared to EA at induction (63.1% vs 58.3%, p = 0.029). To assess whether bortezomib utilization had any impact on survival, we compared survival among younger AA and EA without del17p after stratifying into three treatment regimens: bortezomib/dex (Vd), lenalidomide/dex (Rd), and RVd. We observed superior survival for AA as compared to EA across all three regimens (Vd: 5.82 vs 3.63 years, p=0.022; Rd: 8.15 vs 5.10, p=0.029; RVd: median not reached vs 6.95, p=0.72), suggesting that the difference in bortezomib utilization was not responsible for the observed difference in survival. Interestingly, among 198 patients with del17p for whom the percentage of cells with deletion was reported, we observed that higher (>55%) clonality was associated with lower median survival compared to those with low clonality (5-55%) (0.97 vs 2.42, p=0.049). The difference was even more significant with a threshold of 35% (p=0.015). CONCLUSIONS: Our large study identified significantly lower incidence of del17p in younger AA compared to EA. We found no racial disparity in survival among AA and EA with del17p regardless of age. In contrast, in the absence of del17p, younger AA demonstrated significantly better survival as compared to younger EA and better response to bortezomib- and lenalidomide-based doublet and triplet induction regimens, suggesting possible differences in disease biology other than del17p that may contribute to a more indolent course and increased sensitivity to therapy. Disclosures Yellapragada: Celgene: Research Funding; Novartis: Employment, Other: Spouse Employment ; BMS: Research Funding; Takeda: Research Funding. Munshi:Takeda: Consultancy; Janssen: Consultancy; Oncopep: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; Adaptive: Consultancy; Adaptive: Consultancy.

scholarly journals Analysis of Racial Differences in the Incidence of a Targetable Biomarker, t(11;14), in Patients with Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-2
Author(s):  
Fang Liu ◽  
Jeries Kort ◽  
Shashirekha Shetty ◽  
Ravikumar Kyasaram ◽  
John Shanahan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
African American ◽  
Racial Differences ◽  
Racial Disparity ◽  
Categorical Variables ◽  
Female Ratio ◽  
Cytogenetic Abnormalities ◽  
Blood Cancer ◽  
Chromosome 13 ◽  
Monoclonal Gammopathies

Introduction Compared with Caucasian Americans (CA), African Americans (AA) have an increased incidence of multiple myeloma (MM), earlier age at diagnosis, and overall better prognosis [1]. The molecular mechanisms underlying such racial disparity are not well understood. Using targeted next generation sequencing assay or traditional fluorescence in situ hybridization (FISH) methods, previous studies reported that t(11;14) is more common in AA compared with CA with MM and monoclonal gammopathies [2,3]. However, the number of AA cases studied were small and conflicting data exists. Clinical trials in relapsed or refractory MM indicate that t(11;14) is a biomarker which may be used to predict response to a therapeutic agent (venetoclax) which targets BCL-2 [4,5]. Identifying racial differences in molecular biomarkers would be helpful in our understanding of the known racial disparities of incidence in MM and in the development of therapeutic trials. Methods 737 patients with newly diagnosed MM or smoldering myeloma (SM) at University Hospitals Seidman Cancer Center between 2009 and 2020 were identified. All had myeloma FISH panel sent at diagnosis, which included trisomy of chromosomes 3, 7, or 11, deletion 13q14.3 or loss of chromosome 13, deletion 17p13.1, 1q21 (CKS1B) amplification, and 14q32.3 rearrangements. IGH/CCND1 [t(11;14)(q13;q32)] dual fusion probe was used prior to 2018. Extra signal would trigger reflex test for IGH/FGFR3 [t(4;14)(p16.3;q32)] and IGH/MAF [t(14;16)(q32;q23)]. IGH break apart probe was used since 2018. IGH rearrangement would trigger reflex testing for translocation partners as listed above. Between-group differences were assessed with T-test for continuous variables, and Chi-square / Fisher's exact test for categorical variables. Results Of the 737 patients (661 MM, 76 SM), 502 (68.1%) were self-reported as CA, 213 (28.9%) were AA, and 22 (3.0%) were of other races or listed as unknown. Median age was 71 among CA and 70 among AA (p=0.67). The male-female ratio was 291/211 (58% male) among CA and 101/112 (47% male) among AA (p=0.0095). Overall t(11;14) was detected in 4.5% of cases, 5.2% CA and 2.8% AA (p=0.165); among 661 MM, t(11;14) was tested positive in 30/656 (4.57%), including 23 (5.1%) CAs, 6 (3.1%) AAs, and 1 others (p= 0.80); among 76 SM, t(11;14) was tested positive in 3/76 (3.95%), all were CAs. The percentages of patients who tested positive for other cytogenetic abnormalities were as follows: trisomy 3,7, or 11 was detected in 35.6% CA and 32.4% AA (p=0.42); 1q21 amplification was detected in 25.5% CA and 23.9% AA (p=0.72); deletion 13q14.3 or loss of chromosome 13 was detected in 16.5% CA and 10.7% AA (p=0.08); deletion 17p13.1 was detected in 6.4% CA and 5.2% AA (p=0.54); t(4;14) was detected in 2.8% CA and 1.4% AA (p=0.27); t(14;16) was detected in 0.4% CA and 0.5% AA (p=0.89) Conclusions This retrospective series of 737 MM and SM patients did not find an increased incidence of the targetable biomarker t(11;14) in AA patients. The overall percentage of t(11;14) cases was lower than expected. The lack of our finding a racial difference differs from some other reports, perhaps due to a fairly enriched AA population. There were also no significant racial differences found in other cytogenetic abnormalities. Further investigation at the molecular level should be performed to elucidate the mechanisms of racial disparity in MM. References [1]. Landgren O, Devesa S, Mink P, et al. African-American multiple myeloma patients have a better survival than Caucasian patients: a population-based study including 28,636 patients. Blood. 2009;114:1832. [2]. Kzandjian D, Hill E, Hultcrantz M, et al. Molecular underpinnings of clinical disparity patterns in African American vs. Caucasian American multiple myeloma patients. Blood Cancer J. 2019;9(2):15. [3]. Baughn LB, Pearce K, Larson D, et al. Differences in genomic abnormalities among African individuals with monoclonal gammopathies using calculated ancestry. Blood Cancer J. 2018;8(10):96. [4]. Kortüm KM, Einsele H. First targeted therapy in multiple myeloma. Blood. 2017;130(22):2359-2360. [5]. Kumar S, Harrison S, Cavo M, et al. A phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. EHA Library. Abstract LB2601. Disclosures No relevant conflicts of interest to declare.

scholarly journals Metaphase Cytogenetics for Risk Stratification in Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4396-4396
Author(s):  
Patrick Mellors ◽  
Moritz Binder ◽  
Rhett P. Ketterling ◽  
Patricia Griepp ◽  
Linda B Baughn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Risk Stratification ◽  
Board Of Directors ◽  
Research Funding ◽  
Multivariable Analysis ◽  
Risk Modeling ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cytogenetic Abnormalities ◽  
Improve Risk Stratification

Introduction: Abnormal metaphase cytogenetics are associated with inferior survival in newly diagnosed multiple myeloma (MM). These abnormalities are only detected in one third of cases due to the low proliferative rate of plasma cells. It is unknown if metaphase cytogenetics improve risk stratification when using contemporary prognostic models such as the revised international staging system (R-ISS), which incorporates interphase fluorescence in situ hybridization (FISH). Aims: The aims of this study were to 1) characterize the association between abnormalities on metaphase cytogenetics and overall survival (OS) in newly diagnosed MM treated with novel agents and 2) evaluate whether the addition of metaphase cytogenetics to R-ISS, age, and plasma cell labeling index (PCLI) improves model discrimination with respect to OS. Methods: We analyzed a retrospective cohort of 483 newly diagnosed MM patients treated with proteasome inhibitors (PI) and/or immunomodulators (IMID) who had metaphase cytogenetics performed prior to initiation of therapy. Abnormal metaphase cytogenetics were defined as MM specific abnormalities, while normal metaphase cytogenetics included constitutional cytogenetic variants, age-related Y chromosome loss, and normal metaphase karyotypes. Multivariable adjusted proportional hazards regression models were fit for the association between known prognostic factors and OS. Covariates associated with inferior OS on multivariable analysis included R-ISS stage, age ≥ 70, PCLI ≥ 2, and abnormal metaphase cytogenetics. We devised a risk scoring system weighted by their respective hazard ratios (R-ISS II +1, R-ISS III + 2, age ≥ 70 +2, PCLI ≥ 2 +1, metaphase cytogenetic abnormalities + 1). Low (LR), intermediate (IR), and high risk (HR) groups were established based on risk scores of 0-1, 2-3, and 4-5 in modeling without metaphase cytogenetics, and scores of 0-1, 2-3, and 4-6 in modeling incorporating metaphase cytogenetics, respectively. Survival estimates were calculated using the Kaplan-Meier method. Survival analysis was stratified by LR, IR, and HR groups in models 1) excluding metaphase cytogenetics 2) including metaphase cytogenetics and 3) including metaphase cytogenetics, with IR stratified by presence and absence of metaphase cytogenetic abnormalities. Survival estimates were compared between groups using the log-rank test. Harrell's C was used to compare the predictive power of risk modeling with and without metaphase cytogenetics. Results: Median age at diagnosis was 66 (31-95), 281 patients (58%) were men, median follow up was 5.5 years (0.04-14.4), and median OS was 6.4 years (95% CI 5.7-6.8). Ninety-seven patients (20%) were R-ISS stage I, 318 (66%) stage II, and 68 (14%) stage III. One-hundred and fourteen patients (24%) had high-risk abnormalities by FISH, and 115 (24%) had abnormal metaphase cytogenetics. Three-hundred and thirteen patients (65%) received an IMID, 119 (25%) a PI, 51 (10%) received IMID and PI, and 137 (28%) underwent upfront autologous hematopoietic stem cell transplantation (ASCT). On multivariable analysis, R-ISS (HR 1.59, 95% CI 1.29-1.97, p < 0.001), age ≥ 70 (HR 2.32, 95% CI 1.83-2.93, p < 0.001), PCLI ≥ 2, (HR 1.52, 95% CI 1.16-2.00, p=0.002) and abnormalities on metaphase cytogenetics (HR 1.35, 95% CI 1.05-1.75, p=0.019) were associated with inferior OS. IR and HR groups experienced significantly worse survival compared to LR groups in models excluding (Figure 1A) and including (Figure 1B) the effect of metaphase cytogenetics (p < 0.001 for all comparisons). However, the inclusion of metaphase cytogenetics did not improve discrimination. Likewise, subgroup analysis of IR patients by the presence or absence of metaphase cytogenetic abnormalities did not improve risk stratification (Figure 1C) (p < 0.001). The addition of metaphase cytogenetics to risk modeling with R-ISS stage, age ≥ 70, and PCLI ≥ 2 did not improve prognostic performance when evaluated by Harrell's C (c=0.636 without cytogenetics, c=0.642 with cytogenetics, absolute difference 0.005, 95% CI 0.002-0.012, p=0.142). Conclusions: Abnormalities on metaphase cytogenetics at diagnosis are associated with inferior OS in MM when accounting for the effects of R-ISS, age, and PCLI. However, the addition of metaphase cytogenetics to prognostic modeling incorporating these covariates did not significantly improve risk stratification. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding. Kapoor:Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Adult Acute Lymphoblastic Leukemia and Cytogenetic Abnormalities in Different Racial and Ethnic Subgroups.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4547-4547
Author(s):  
Deimante Tamkus ◽  
Ahmad Jajeh ◽  
Ebenezer Berko ◽  
David Osafo ◽  
Decebal Griza ◽  
...  
Keyword(s):  
African American ◽  
Acute Lymphoblastic Leukemia ◽  
African Americans ◽  
Lymphoblastic Leukemia ◽  
Normal Karyotype ◽  
Cook County ◽  
Female Ratio ◽  
Cytogenetic Abnormalities ◽  
Hispanic Patients ◽  
Chromosomal Changes

Abstract Inferior survival of African American and Hispanic patients with acute lymphoblastic leukemia (ALL) has been reported. The reason for this is unclear. A retrospective analysis was conducted to see if abnormal cytogenetics account for the differences. We have analyzed cytogenetic studies of 39 adults (16 year and older) with newly diagnosed ALL who were consecutively treated at John Stroger Hospital of Cook County between 1997 and 2005. The study population included 13 (33%) African Americans, 18 (46%) Hispanics, 6 (16%) Caucasians, and 2 (5 %) other ethnic background adults. Male to female ratio was 2:1. Mean age at diagnosis was 26 (range between 16 and 71 years). A clonal cytogenetic abnormality was detected in 27 patients, and 12 patients had normal karyotype. Patients with t (9;22)(q34;q11), BCR-ABL + by FISH, t (4;11)(q21;q23), +8, −7 cytogenetic abnormalities were assigned to an unfavorable cytogenetic group. This group was composed of 14 patients. None of our study patients had favorable cytogenetics: del (12p), t(12p), t(14q11-q23), inv(14)(q11;q32) or t(10;14)(q24;q11). Remaining 25 patients with normal karyotype (n=12) or miscellaneous cytogenetic abnormalities (n=13) were classified as normal risk group. 54 % of African Americans had unfavorable cytogenetics, compared with 33 % Caucasians and 17 % Hispanics. Translocation t (9;22) alone or in association with other cytogenetic abnormalities was most commonly seen. 9 patients had single, and 18 had multiple chromosomal changes. Hispanic group had more complex cytogenetic changes when compared with the African American or Caucasian groups. Unfavorable cytogenetic abnormalities may account for inferior survival in African Americans, but other factors such as compliance or pharmacogenetics should be evaluated, especially in the Hispanic patient population.

The Use of Novel Agents In Patients with Multiple Myeloma Initially Treated with Allogeneic Stem Cell Transplantation Results In A Significant Prolongation of Post Relapse Survival.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4580-4580
Author(s):  
Christopher P. Venner ◽  
Heather Sutherland ◽  
John Shepherd ◽  
Yasser Abou Mourad ◽  
Michael J. Barnett ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Research Funding ◽  
Statistical Significance ◽  
Novel Agents ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Significant Prolongation ◽  
Significant Difference ◽  
Relapsed Disease

Abstract Abstract 4580 Background: The use of allogeneic hematopoietic stem cell transplant (alloHSCT) in the treatment of Multiple Myeloma (MM) remains controversial. Although there is hope that alloHSCT may result in a cure, relapse continues to be a significant problem. The morbidity associated with late complications of allogeneic transplantation further compounds the issues faced when addressing relapsed disease. The use of Novel Agents (NA) in this patient population has been poorly characterized. Here we present our experience of NA use in patients initially treated with alloHSCT. Patients: 108 patients underwent an allografting procedure for their MM at our center between 1989 and 2009. 84 received a fully myeloablative procedure (15 received donor lymphocyte infusion). 24 received an autologous HSCT followed by a reduced intensity allogeneic procedure. 56 have relapsed with this population making up our primary cohort for analysis. 22 patients received NAs and very few patients received them prior to transplant (4/108). Endpoints examined were post relapse survival after the initial HSCT procedure (PRS), overall survival from time of initial treatment (OS) and progression free survival (PFS) measured in months (m). Results: Of the entire cohort of 108 patients median OS was 78.6m (95% CI; 24.5–132.6). Median PFS was 23.6m (95% CI; 15.4–31.8). Of the non-relapsed patients (n = 52) the median OS was 125.9m. In this cohort 67% of the deaths occurred within 1.5 years. Of the relapsed patients (n = 56) median PFS was 18.7m (95% CI; 14.6–22.8), median PRS was 31.5m (95% CI; 17.0–46.0), and median OS was 67.0m (95% CI; 31.6–102.5). The effect of NA was examined in the cohort of relapsed patients. No significant difference was noted in PFS between those exposed to NA and those who were not exposed (19.0m (95% CI; 10.1–22.8) vs 13.7m (95% CI; 5.8–21.6); p = 0.27). Exposure to NA showed improvements in PRS (42.3m (95% CI; 7.3–77.2) vs 10.4m (95% CI; 5.2–15.7); p = 0.01, Figure 1). A trend toward superior OS was noted (71.4m (95% CI; 37.9–105.5) vs 24.6m (95% CI; 3.0–46.1); p = 0.11) although this did not reach statistical significance. Conclusion: Ongoing management of relapsed patients with multiple myeloma in the post alloHSCT setting remains a significant challenge. This retrospective study demonstrates that the use of NA is both safe and effective in treating relapsed disease. The predominant impact of these drugs is seen in the relapsed setting. Exposure to NA correlates with a 22m improvement in PRS. A 46m improvement in OS is noted however, likely due to the small cohort, it failed to reach statistical significance. Disclosures: Sutherland: Celgene: Honoraria; Orthobiotech: Honoraria. Shepherd:Celgene: Honoraria; Orthobiotech: Honoraria. Nevill:Celgene: Honoraria. Toze:Hoffman La Roche: Consultancy, Honoraria, Research Funding; Genzyme: Honoraria, Research Funding; Glaxo Smith Kline: Honoraria.

Clinical and Molecular Features Of Young Patients With Myelodisplastic Syndromes (MDS)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1566-1566
Author(s):  
Bilori Bilori ◽  
Hideki Makishima ◽  
Bartlomiej P Przychodzen ◽  
Mohamed Ashkar ◽  
Rohan Garje ◽  
...  
Keyword(s):  
Family History ◽  
Research Funding ◽  
Somatic Mutations ◽  
Myeloproliferative Neoplasm ◽  
Young Patients ◽  
Blood Disorders ◽  
Older Population ◽  
Cytogenetic Abnormalities ◽  
Significant Difference ◽  
History Of

Abstract MDS typically affects older adults, and hereditary factors have been considered less contributory to disease pathogenesis. Moreover, their impact is obscured by the complexity of the clinical presentation and history. Similarly, familial MDS and pediatric MDS is rare and likely distinct from adult MDS occurring in younger adults. Younger MDS patients (pts), excluding those who present with treatment-related disease, may represent a distinct subtype of MDS characterized by a specific molecular pattern of lesions. We compared two groups of MDS pts focusing on pathological diagnosis at presentation, family history of solid malignancies and blood disorders (Leukemia and MDS) in first and second degree relatives, cytogenetic abnormalities and somatic mutations. Our analysis of 1030 MDS pts included MDS, MDS/myeloproliferative neoplasm (MPN) and secondary acute myeloid leukemia (sAML) pts. Overall the median age at presentation of this population was 71years (range 14-100); we classified the younger subset as those falling into the lower 8thpercentile of age to identify. Accordingly, the younger population was characterized by age less than 50 years (range 14-49; median age 41), and the older population age ≥ 50years (range 50-100; median age 75). Treatment-related MDS was excluded. Younger MDS pts more frequently presented with higher-risk disease compared to the older population (46% vs. 31%; P=.004). There was no significant difference between the two groups with regard to family history of cancers (40 vs. 47%; P=.21) and blood disorders (10 vs. 6%; P= .1). When we compared cytogenetic abnormalities between these patient subsets, there was no difference in detection of rate of abnormal cytogenetics (53% vs. 52%; P=.5) or complex karyotype (23 vs. 25%; P=.86). However, del 20q was more common in the older subset (19 vs. 6%; P=.03). We then investigated somatic mutational patterns using new generation deep sequencing for the 60 most commonly encountered MDS mutations (defined in the 200 MDS exome cohort presented in other abstract from our group). Data were available for 26 younger pts and 179 older pts. By analyzing comprehensive mutational spectrum, the average number of somatic mutational events (mean; 2.4/case) was significantly higher in the older subgroup compared to the younger (1.8/case; P<.001). RUNX1, PHF6, TP53 (12% each) are the most frequently affected genes in MDS associated with the younger population. Interestingly, germline mutations of these 3 genes are all associated with congenital syndromes, which lead to susceptibility for hematological neoplasms. Conversely, somatic mutations of TET2 (24%) and ASXL1 (15%) were most prevalent in the older MDS cohort. Notably, these 2 genes associated with older populations were less prevalent in younger MDS cases (<4%; P=.02 and < 4% P=.11 for TET2 and ASLX1 respectively). In contrast, there was no significant difference between these subgroups (old vs. young MDS) in the frequency of RUNX1 (9 vs. 12%; P=.67), U2AF1 (11 vs. 12%; P=.88), BCOR family (9 vs. 15%; P=.35), PRC2 family (10 vs. 4%; P= .34), RAS family (11 vs. 12%; P=.88), or many other gene mutations. In sum, 8% of MDS pts present at a younger age in our cohort. MDS in younger pts presents with more advanced disease and is less commonly affected by del20q- and TET2 mutations, consistent with less common myeloproliferative features in this population. Disclosures: Makishima: AA & MDS international foundation: Research Funding; Scott Hamilton CARES grant: Research Funding.

Ornithine Decarboxylase: Novel Prognostic Marker and Target for Multiple Myeloma Therapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1824-1824
Author(s):  
Sonali Panchabhai ◽  
Ilana Miriam Schlam ◽  
Sinto Sebastian Chirackal ◽  
Rafael Fonseca
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Prognostic Marker ◽  
Ornithine Decarboxylase ◽  
Therapeutic Target ◽  
Research Funding ◽  
Preclinical Model ◽  
Advisory Committees ◽  
Survival Difference ◽  
Significant Difference

Abstract Multiple myeloma (MM) is an age dependent second most common hematopoietic malignancy which remains incurable despite recent advances in therapies. Monoclonal gammopathy of undetermined significance (MGUS) is a common premalignant condition that precedes MM. Dysregulation and mutations of myriad of molecules is implicated in pathogenesis of MM. Cyclins (CCND) are almost universally dysregulated in MGUS and MM, while c-MYC overexpression and sometimes RAS mutations are associated with MGUS to MM progression. c-MYC, because of its strong association in this malignant transformation and it being a master regulatory factor is a logical therapeutic target. But, a therapeutic approach to target c-MYC has not been successful. So a strategy to target either upstream or downstream molecules in c-MYC pathway is worth considering. Ornithine decarboxylase (ODC) is one such downstream effector of c-MYC which regulates polyamine synthesis and thus regulates cell proliferation. ODC is also downstream of RAS which makes it common to two of the important oncogenes involved in MM. To know whether ODC plays a role in MM pathogenesis, we looked into its gene expression profile in the MM patients. In the Mayo cohort of 100 patients we found significant difference in ODC expression as disease progresses from MGUS to MM. We found significant survival difference in MM patients from this cohort which were divided by ODC expression and this survival difference was more pronounced in non-hyperdiploid group (median survival were for ODC < 1 - 66 mo vs for ODC > 1 - 29.5 mo, Figure 1A) which is a known poor prognostic group. When looked at ODC expression among different TC classes in MMRC dataset, we find ODC expression significantly higher in known high risk and poor prognostic groups 4p16 and MAF than other groups. These findings suggest higher ODC expression associated with poor survival. To further strengthen our observation, we analyzed TT3 group of Arkansas cohort and we observe prolonged event free survival (Figure 1B) and overall survival in patients with low ODC expression as compared to patients with high ODC expression (Figure 1C). After establishing poor prognostic role of ODC, we wanted to test it as a potential therapeutic target. For this purpose, we employed DFMO (Difluromethylornithine) which is the enzymatic irreversible inhibitor of ODC. We tested 15 different MM cell lines for proliferation with DFMO, majority of them respond to DFMO and IC 50 ranged from 28uM to 70 uM. DFMO generally halted cell cylce in G1S and had a cytostatic effect. We further tested efficacy of DFMO in combination with standard anti-myeloma agents lenalidomide, bortezomib, Vorinostat, melphalan and dexamethasone. We found these combinations to be synergistic except with melphalan where the combination was antagonistic. We therefore suggest that DFMO, which has a good toxicity profile can be advantageous in MM patients who are relatively old and many times cannot tolerate extensive chemotherapy for its toxicity. Moreover since it is synergistic in preclinical model with two main anti-myeloma agents lenalidomide and bortezomib, it may well be combined with both to decrease the amount of drug needed and hence toxicity. We think it will be especially beneficial to those patients who have high ODC levels. So we propose ODC to be a prognostic marker and therapeutic target in MM. Disclosures Chirackal: Mayo Clinic: Patents & Royalties: Filed a professional US patent for quantifying cellular anti-oxidative capacity. Fonseca:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Onyx/Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Applied Biosciences: Membership on an entity's Board of Directors or advisory committees.

MyPRSR Molecular Subtypes of Multiple Myeloma Represent All High-Risk FISH Translocations Included in the mSMART 2.0 and R-ISS Guidelines

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3264-3264 ◽  
Author(s):  
Ryan K Van Laar ◽  
Ivan Borrelo ◽  
David Jabalayan ◽  
Ruben Niesvizky ◽  
Aga Zielinski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
High Risk ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Research Funding ◽  
Plasma Cells ◽  
Molecular Subtypes ◽  
Risk Status ◽  
Significant Difference

Abstract Background: There is a global consensus that multiple myeloma patients with high-risk disease require additional monitoring and therapy compared to low/standard risk patients in order to maximize their chances of survival. Current diagnostic guidelines recommend FISH-based assessment of chromosomal aberrations to determine risk status (i.e. t(14;20), t(14;16), t(4;14) and/or Del17p), however, studies show FISH for MM may have a 20-30% QNS rate and is up to 15% discordant between laboratories, even when starting from isolated plasma cells. In this study we demonstrate that MyPRS gene expression profiling reproduces the key high risk translocations for MM risk stratification, in addition to having other significant advantages. Methods: Reproducibility studies show that MyPRS results are less than 1% discordant starting from isolated plasma cells and return successful results in up to 95% of cases. 270 MM patients from Johns Hopkins University (MD) and Weill Cornell Medicine (NY) had both FISH and MyPRS gene expression profiling performed between 2012 and 2016 using standard and previously published methodology, respectively. Results: Retrospective review of the matched FISH and MyPRS results showed: 25/28 (89%) patients wish FISH-identified t(4;14) were classified as MMSET (MS) subtype. 10/10 (100%) patients with t(14;16) or t(14;20) were classified as MAF-like (MF) subtype 62/67 (93%) patients with t(11;14) were assigned to the Cyclin D (1 or 2) subtype. Patients with FISH hyperdiploidy status were classified as the Hyperdiploid (HY) subtype or had multiple gains detected by the separate MyPRS Virtual Karyotype (VK) algorithm, included in MyPRS. TP53del was seen in patients with multiple molecular subtypes, predominantly Proliferation (PR) and MMSET (MS). Assessment of TP53 function by gene expression is a more clinically relevant prognostic marker than TP53del, as dysregulation of the tumor suppressor is affected by mutations as well as deletions. Analysis of the TP53 expression in the 39 patients with delTP53 showed a statistically significant difference, compared to patients without this deletion (P<0.0001). Conclusion: Gene expression profiling is a superior and more reliable method for determining an individual patients' prognostic risk status. The molecular subtypes of MM, as reported by Signal Genetics MyPRS assay, are driven by large-scale changes in gene expression caused by or closely associated with chromosomal changes, including translocations. Physicians who are managing myeloma patients and wishing to base their assessment of risk on R-ISS or mSMART Guidelines may obtain the required data points from either FISH or MyPRS, with the latter offering lower QNS rates, higher reproducibility, assessment of a larger number of cells and a substantially lower price point ($5,480 vs. $1,912; 2016 CMS data). A larger cohort study is now underway to further validate these observations. Figure GEP-based TP53 expression in patients with and without Del17p. P<0.0001 Figure. GEP-based TP53 expression in patients with and without Del17p. P<0.0001 Disclosures Van Laar: Signal Genetics, Inc.: Employment. Borrelo:Sidney Kimmel Cancer Institute: Employment. Jabalayan:Weill Cornell Medical Center: Employment. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding, Speakers Bureau. Zielinski:Signal Genetics, Inc.: Employment. Leigh:Signal Genetics, Inc.: Employment. Brown:Signal Genetics, Inc.: Employment. Bender:Signal Genetics, Inc.: Employment.

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