Second Malignancies Among Elderly Multiple Myeloma Patients Exposed to Bortezomib and Other Treatments: An Analysis of the US SEER-Medicare Linked Database,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3972-3972
Author(s):  
Dina Gifkins ◽  
Megan McAuliffe ◽  
Amy Matcho ◽  
Jane Porter ◽  
Scott Chavers ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Hodgkin Lymphoma ◽  
Solid Tumors ◽  
Myeloid Leukemia ◽  
Lymphocytic Leukemia ◽  
Second Malignancy ◽  
Second Malignancies ◽  
Non Hodgkin Lymphoma ◽  
Equity Ownership ◽  
Medicare Database

Abstract Abstract 3972 Second hematologic malignancies have been found to occur at a higher rate among multiple myeloma patients compared to the general population. Although alkylating therapy has been suggested to play a role, the underlying causes remain largely unclear. Increased survival benefit has been documented with the introduction of novel agents over the past decade, and, as noted in other cancers, there may also be a higher occurrence of second malignancies in the era of novel therapies. Recently, data from Phase III studies suggest that patients treated with lenalidomide with prior exposure to melphalan may have an increased risk compared to placebo. However, the contribution of other specific agents has not been well characterized. Evaluation of second malignancies in clinical trial and product safety data for bortezomib has not revealed an increased incidence in bortezomib-treated patients. Additionally, our follow-up study of the VISTA clinical trial participants after 5 years showed no elevation in risk (San Miguel, et al. ASH 2011). To expand our current knowledge, we are conducting a population-based study using the NCI SEER-Medicare database (NCI SEER cancer registry linked with diagnostic and treatment claims data of Medicare beneficiaries) to evaluate bortezomib and other standard treatment exposures in relation to second malignancies subsequent to multiple myeloma. Using the NCI SEER-Medicare database, we identified all multiple myeloma patients with their first diagnosis between 1 Jan 2000 and 31 Dec 2007 aged 66 years or older. Exposure to chemotherapy was identified via Medicare claims, and second malignancies, defined as invasive cancers whose onset was after bortezomib-based therapy and occurring at least 2 months after the initial multiple myeloma diagnosis, were identified from the SEER registries. We identified the number of second malignancies among elderly patients with multiple myeloma and following bortezomib exposure; expanded multivariate analyses, adjusted for exposures, will be presented at the meeting. A total of 9,377 multiple myeloma patients were identified (median age 76 years; 50% males). During the study period, 2,285 (21%) patients had any documented exposure to bortezomib (with or without other treatments). Patients with bortezomib exposure had a median age of 73 years, and 55% were male. Among these 2,285 patients with bortezomib exposure, 33 patients (1.4%) developed a second malignancy (4 [0.2%] hematologic and 29 [1.3%] solid tumors) during the study period after their first documented bortezomib exposure. Hematologic tumors were non-Hodgkin lymphoma (n=3) and acute myeloid leukemia (n=1). Solid tumors were prostate (n=4), bladder (n=4), lung and bronchus (n=3), colon (excluding rectum) (n=3), breast (n=3), and other (n=12). Among the 7,092 multiple myeloma patients with no documented exposure to bortezomib, 320 (4.5%) developed a second malignancy (55 [0.8%] hematologic and 265 [3.7%] solid tumors) during the study period. Hematologic tumors were non-Hodgkin lymphoma (n=16), acute myeloid leukemia (n=7), chronic lymphocytic leukemia (n=2), acute lymphocytic leukemia (n=1), chronic myeloid leukemia (n=1), Hodgkin lymphoma (n=1), and other (n=27). Solid tumors were lung and bronchus (n=46), prostate (n=38), colon (excluding rectum) (n=33), melanoma (n=23), bladder (n=21), breast (n=17), and other (n=87). Based on more than 9,000 elderly multiple myeloma patients, we found a lower prevalence of second malignancies among persons exposed to bortezomib compared to those with no documented bortezomib exposure in our unadjusted analysis. To account for survival and adjust for other exposures, expanded analyses will be presented at the meeting, including standardized incidence ratios and calculations of absolute excess risk among patients exposed to bortezomib and other standard treatments compared to the general SEER population, cumulative incidence of second malignancy for each treatment group adjusting for death as a competing risk, and multivariate analyses to assess risk while adjusting for prior and concomitant treatments and other risk factors. Disclosures: Gifkins: Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. McAuliffe:Millennium Pharmaceuticals, Inc.: Employment. Matcho:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Porter:Millennium Pharmaceuticals, Inc.: Employment. Chavers:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Ponsillo:Millennium Pharmaceuticals, Inc.: Employment. King:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Desai:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Cakana:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Esseltine:Millennium Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership.

Concentration-QTc (C-QTc) Analysis of the MDM2 Inhibitor KRT-232 (formerly AMG 232) in Subjects with Advanced Solid Tumors, Multiple Myeloma, or Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5768-5768
Author(s):  
Adekemi Taylor ◽  
Martine Allard ◽  
Cecile Kresja ◽  
Dana Lee ◽  
Greg Slatter
Keyword(s):  
Multiple Myeloma ◽  
Steady State ◽  
Solid Tumors ◽  
Upper Bound ◽  
Myeloid Leukemia ◽  
Employment Equity ◽  
Equity Ownership ◽  
The Mean ◽  
The Relationship ◽  
Mdm2 Inhibitor

Introduction: KRT-232 is a potent and selective, targeted small molecule inhibitor of human mouse double minute 2 (MDM2) homolog interactions with tumor protein 53 (p53). MDM2 prevents p53 activation and reduces p53-mediated transcription and cell cycle control. KRT-232 is under development by Kartos Therapeutics for treatment of myelofibrosis, polycythemia vera, acute myeloid leukemia (AML) and Merkel cell carcinoma (see NCT03662126, NCT03669965, NCT03787602). The KRT-232 no effect-level for in vitro inhibition of hERG function (10 μM) was approximately 147- and 73-fold greater than KRT-232 unbound Cmax concentrations for steady state doses of 240 mg and 480 mg, respectively, based on population pharmacokinetic (PK)-derived parameters for subjects with AML (Ma et al. submitted, ASH 2019). The primary objective of this analysis was to evaluate the relationship between KRT-232 plasma concentration and changes in heart rate-corrected QT interval duration (QTc) in oncology patients treated in Amgen studies 20120106 (Gluck et al. Invest New Drugs; in press, NCT01723020) and 20120234 (Erba et al. Blood Adv 2019; NCT02016729). Methods Study 20120106 was a 2-part Phase 1 dose-exploration and dose-expansion monotherapy study in advanced solid tumors or multiple myeloma. KRT-232 doses of 15 mg (n=3), 30 mg (n=3), 60 mg (n=4), 120 mg (n=7), 240 mg (n=76), 300 mg (n=4), 360 mg (n=4) and 480 mg (n=6) were administered daily (QD) for 7 days in 21-day cycles. Subjects received up to 31 cycles of treatment. Study 20120234 was a Phase 1b study evaluating KRT-232 alone and in combination with trametinib in relapsed/refractory AML. Subjects received the following KRT-232 doses: 60 mg (n=14; n=10 co-administered with 2 mg trametinib daily [excluded from C-QTc analysis]); n=4 as single agent), 90 mg (n=4), 180 mg (n=5), 240 mg (n=3), and 360 mg (n=10). Doses were administered QD for 7 days in 14-day cycles. Subjects received up to 46 cycles of treatment. In both studies, time-matched PK and ECG measurements were collected intensively during Cycle 1 and less frequently at other visits. Triplicate 12-lead ECG data (N=3) were read by a central laboratory. A linear mixed effects model using R (v 3.5.2) was used to analyze the relationship between KRT-232 plasma concentrations and the QT interval corrected using Fridericia's method (QTcF). Effects of baseline QTcF, study, sex and tumor type on C-QTc were investigated. The upper bound of 2-sided 90% CIs for the mean QTcF change from baseline (ΔQTcF) predicted at Cmax was compared to the 10 ms threshold of regulatory concern (FDA Guidance: E14(R3) 2017; Garnett et al. Pharmacokinet Pharmacodyn 2018). Results ECG and PK data for this analysis were available from 130 subjects. The final model was a linear mixed-effect model with parameters for intercept, KRT-232 concentration-ΔQTcF slope, and baseline QTcF effect on the intercept. Diagnostic plots indicated an adequate model fit. The final C-QTc model was used to predict mean ΔQTcF and associated 2-sided 90% CI mean steady-state KRT-232 Cmax at doses up to the maximum clinical dose of 480 mg QD, in subjects with AML or solid tumors. The mean and upper bound of the 90% CI of ΔQTcF were predicted not to exceed 10 ms at doses of up to 480 mg QD in subjects with AML, multiple myeloma or solid tumors. Mean (90% CI) predicted ΔQTcF values at 480 mg QD were 2.040 (0.486, 3.595) ms for subjects with solid tumors and 4.521 (2.348, 6.693) ms for subjects with AML (Figure A). The KRT-232 concentrations at which the upper bounds of 90% CI of mean ΔQTcF are predicted to reach 10 ms and 20 ms are 4298 ng/mL and 7821 ng/mL, respectively. These concentrations are 2.2- and 4-fold higher, respectively, than the predicted mean steady-state Cmax for 480-mg KRT-232 in subjects with solid tumors, and 1.4- and 2.5-fold higher, respectively, than the corresponding mean steady-state Cmax in subjects with AML. Conclusion Since the mean and upper bound of the 90% CI of mean ΔQTcF were predicted not to exceed 10 ms at KRT-232 doses of up to 480 mg QD in solid tumor or AML patients, KRT-232 should not result in clinically meaningful QT prolongation at the doses currently under investigation in Kartos clinical trials. Disclosures Taylor: Certara Strategic Consulting: Consultancy, Employment. Allard:Certara Strategic Consulting: Consultancy, Employment. Kresja:Kartos Therapeutics: Employment, Equity Ownership. Lee:Kartos Therapeutics: Employment, Equity Ownership. Slatter:Kartos Therapeutics: Employment, Equity Ownership. OffLabel Disclosure: KRT-232 (formerly AMG 232) is a small molecule MDM2 inhibitor

scholarly journals Estimating the Annual Volume of Hematologic Cancer Cases per Hematologist-Oncologist in the United States: Are We Treating Rare Cancers Too Rarely?

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3297-3297
Author(s):  
Aishwarya Ravindran ◽  
Wilson I. Gonsalves ◽  
Shahrukh K. Hashmi ◽  
Prashant Kapoor ◽  
Ariela L. Marshall ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
The United States ◽  
Lymphocytic Leukemia ◽  
Annual Number ◽  
Non Hodgkin Lymphoma ◽  
Hematologic Cancer ◽  
Outcome Relationship ◽  
The Us

Abstract BACKGROUND: While hematologic cancers comprise only 10% of all malignancies, they are divided into >100 distinct World Health Organization subtypes. It is known that higher volume of care is generally associated with better clinical outcomes. However, such a volume-outcome relationship in the medical management of hematologic cancers has not been rigorously explored. The American Society of Clinical Oncology (ASCO) National Census of Oncology Practices shows that the majority of hematologist-oncologists in the United States (US) have a combined hematology-oncology practice (J Oncol Pract 2013). In this study, we estimated the annual number of new and established patients with major hematologic cancers seen on average by a hematologist-oncologist in the US. METHODS: We estimated the number of hematologist-oncologists working in the US using the ASCO workforce information system data from 2011. We utilized statistics from the Surveillance Epidemiology and End Results (SEER) Program to determine the incidence and 37-year limited prevalence of hematologic cancers in 2011. We used 'first malignant tumor per site' statistics as the tumor inclusion method. For potentially curable hematologic cancers (acute lymphocytic leukemia, acute myeloid leukemia, Burkitt lymphoma, diffuse large b-cell lymphoma, Hodgkin lymphoma, and marginal zone lymphoma), we used the estimated 1-5 year survival rates from SEER and excluded patients who survived >5 years, since relapses are rare afterwards. Because prevalence estimates of chronic myelomonocytic leukemia, myelodysplastic syndromes, and certain subtypes of non-Hodgkin lymphoma are unavailable, we were unable to calculate the number of annual established cases. For myeloproliferative neoplasms, we obtained the prevalence estimate from Mehta J, et al (Leuk Lymphoma 2014). We derived the distribution of major non-Hodgkin lymphoma subtypes from the National Cancer Data Base (NCDB) Participant User File. RESULTS: The ASCO workforce information reported a total of 13,084 hematologist-oncologists working in the US in 2011. The Table summarizes the average number of specific hematologic cancer cases seen per hematologist-oncologist in 2011. CONCLUSION: Hematologic cancers are relatively rare but complex. In the US, a hematologist-oncologist on average cares for only 1-2 new patients of any subtype of hematologic cancers annually. The number of established patients is correspondingly low. These numbers are expected to vary by practice setting and disease specialization. As the diagnosis and management of hematologic cancers becomes more sophisticated, future research should explore the potential of a volume to clinical outcome relationship for these providers. Table. Hematologic Cancer Average Annual Number of Cases per Hematologist-Oncologist in the US New Cases Established Cases All Cases Acute lymphocytic leukemia 0.4 1.4 1.8 Acute myeloid leukemia 1 1.5 2.5 Chronic lymphocytic leukemia 1.1 10.7 11.8 Chronic myeloid leukemia 0.4 2.7 3.1 Chronic myelomonocytic leukemia 0.1 - - Hodgkin lymphoma 0.7 2.7 3.4 Multiple myeloma 1.6 6.3 7.9 Myelodysplastic syndromes 1.2 - - Myeloproliferative neoplasms 0.6 22.2 22.8 Non-Hodgkin lymphoma 5.1 - - Anaplastic large cell 0.1 - - Burkitt 0.1 0.3 0.4 Diffuse large B-cell 2 6 8 Follicular 1.1 - - Hairy cell leukemia 0.1 - - Lymphoplasmacytic 0.1 - - Mantle-cell 0.3 - - Marginal zone 0.5 2.1 2.6 Peripheral T-cell, not otherwise specified 0.1 - - Disclosures No relevant conflicts of interest to declare.

Malignant Hematology

2012 ◽  
Author(s):  
David P. Steensma
Keyword(s):  
Hodgkin Lymphoma ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Lymphocytic Leukemia ◽  
Hematologic Neoplasms ◽  
Small Lymphocytic Lymphoma ◽  
Non Hodgkin Lymphoma ◽  
Myeloid Neoplasms ◽  
Plasma Cell Disorders ◽  
Heavy Chain Disease

The hematologic neoplasms include lymphoproliferative disorders (eg, chronic lymphocytic leukemia [CLL]/small lymphocytic lymphoma [SLL], large granular lymphocyte leukemia, hairy cell leukemia [HCL], Hodgkin lymphoma, non-Hodgkin lymphoma), plasma cell disorders (multiple myeloma, light chain amyloidosis, Waldenström macroglobulinemia, POEMS syndrome, heavy chain disease, plasmacytoma), chronic myeloid neoplasms (chronic myeloid leukemia, the BCR/ABL-negative myeloproliferative neoplasms, myelodysplastic syndromes), and acute leukemia (acute myeloid leukemia, acute lymphocytic leukemia). In addition, clonal but not overtly malignant conditions are common in the general population, including monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B lymphocytosis (MBL).

Tumor Marker CA 15-3 in Hematological Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4329-4329
Author(s):  
Zoi Saouli ◽  
Athanasios Papadopoulos ◽  
Georgia Kaiafa ◽  
Fotios Girtovitis ◽  
Georg Charisopoulos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Acute Leukemia ◽  
Healthy Volunteers ◽  
Hodgkin Lymphoma ◽  
Hematological Malignancies ◽  
Myeloproliferative Disorders ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
Non Hodgkin Lymphoma

Abstract Introduction: CA 15-3 is a glycoprotein expressed in several adenocarcinomas, especially of the breast. It is used to detect recurrent or metastatic disease. Elevated levels can also be found in adenocarcinomas of the ovary, lung, pancreas, and colon, and are also related to benign breast or ovarian disease, endometriosis, hepatitis, pregnancy and lactation. To our knowledge with the exception of multiple myeloma, there are no references for the significance of the CA 15-3 in hematological malignancies. Aim of our study was to evaluate the levels of CA 15-3 in patients with various hematological malignancies. Material and Methods: 84 patients with hematological malignancies were tested: MDS 27 pts, non Hodgkin lymphoma 12 pts, Hodgkin’s lymphoma 3 pts, chronic lymphocytic leukemia 13 pts, acute leukemia: 7 pts, multiple myeloma 8 pts, chronic myeloid leukemia 3 pts and other chronic myeloproliferative disorders 11 pts. 55% of the patients were men with average age of 55 (17–87) and 45% were women with average age of 52 (35–64). A group of 45 healthy volunteers’ blood donors was also tested. Immunoradiometric assay (IRMA) has been used to determine the circulating levels of the CA 15-3 marker. Results: None of the healthy volunteers had elevated Ca 15-3 levels. Among the 84 patients, 31 (36,9%) had elevated levels of CA 15-3. In MDS 10/27 pts, in Non Hodgkin Lymphoma 5/12 pts, in Hodgkin Lymphoma 1/3 pts, in Chronic Lymphocytic Leukemia 5/13 pts, in Multiple Myeloma 4/8 pts, in acute leukemia 1/7 pts and in other myeloproliferative disorders 4/11 pts. The CA 15-3 levels in hematological patients were higher than the ones in the healthy group. The difference was statistically significant (p <0.0001), (Table 1). 31 patients who where either untreated or had recurrent disease (subgroup a), had elevated CA 15-3 levels (36,8 ± 8,9 U/ml) while the rest 53 patients who were under therapy or were in remission (subgroup b) had normal levels (14,3 ± 5,2 U/ml). A statistically significant difference between the two subgroups was observed, (p <0.0001), (Table 2). The low risk MDS patients (RA, RARS) had normal level of CA 15-3, while the high risk MDS patients (RAEB, RAEB-t, CMML) had high levels of CA 15-3. Conclusions: CA 15-3 can be an indicative marker of the activity of a hematological malignancy. Also, it might be of value in monitoring hematological diseases and response to therapy. Table 1 Ca 15-3 (U/ml) Patients (total, n=84) 23 ± 12,3 Normal Subjects (n=45) 14,1 ± 4,6 p < 0.0001 Table 2 Ca 15-3 (U/ml) Subgroup a 36,8 ± 8,9 Subgroup b 14,3 ± 5,2 p < 0.0001

Second Malignancy After Treatment for Non-Hodgkin Lymphoma: a Systematic Review and a Meta-Analysis of Population-Based and Cohort Studies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1918-1918
Author(s):  
Stefano Sacchi ◽  
Monica Pirani ◽  
Luigi Marcheselli ◽  
Raffaella Marcheselli ◽  
Alessia Bari ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Myeloid Leukemia ◽  
Observational Studies ◽  
Meta Analysis ◽  
Population Based ◽  
Second Malignancy ◽  
Second Cancer ◽  
Haematological Malignancies ◽  
Non Hodgkin Lymphoma

Abstract Abstract 1918 Poster Board I-941 Background: The risk of second malignancy in non-Hodgkin lymphoma (NHL) survivors have been described in several studies, but the available evidence have yielded conflicting results. Thus, we performed a systematic review and a meta-analysis on population-based and cohort studies to provide a quantitative assessment of the available evidence on the risk of secondary occurrence of cancer after treatment for NHL. Primary aims of our research were to evaluate the pooled Relative Risk (RR) of second cancer for overall malignancies and for every cancer. Methods: A Medline search from 1985 to 2008 was conducted for identification of relevant observational studies that provide estimates of RR, as measured by standardized incidence ratios (SIR) that is the observed-expected ratio of second malignancy appearing during follow up of NHL. The reference lists of identified articles were inspected to identify additional papers. Criteria for including studies in the meta-analysis were: a) studies on naïve patients with any stage of NHL, b) studies reporting measure of SIR or data allowing such outcome to be derived and c) English language. The article included, had to have been published in peer-reviewed literature. We did not exclude papers on the base of therapeutic regimens. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed. Pooled RR and 95% confidence interval (CI) were calculated using random effect models. Tests on heterogeneity and sensitivity analysis was conducted. Also, the publication bias was evaluated. Results: Eleven papers meet the inclusion criteria reporting RRs for all malignancies. These studies included 223,593 patients affected by NHL of which 14,952 presented a second cancer. RRs ranged from 0.93-1.90 and the meta-RR for second malignancy was 1.24 (95%CI: 1.11-1.39). The analysis on solid tumours, excluding haematological malignancies, based on seven studies did not show a significantly higher risk for secondary cancer: the meta-RR was 1.06 (95%CI: 0.84-1.34). However, some kind of cancer showed a statistically significant excess of risk, as lung cancer (meta-RR on nine studies: 1.46 95%CI: 1.33-1.59) and bladder cancer (meta-RR on eight studies: 1.42 95%CI: 1.33-1.51). Prostate (meta-RR on ten studies: 1.08 95%CI: 0.93-1.24) and breast cancer (meta-RR on eleven studies: 0.99 95%CI: 0.83-1.19) has demonstrated no evidence of association with NHL therapy. Moreover, we found a higher risk of developing Hodgkin lymphoma and myeloid leukemia (respectively meta-RR on seven studies: 6.44 95%CI: 5.59-11.55 and meta-RR on five studies: 7.81 95%CI: 2.59-24.46). Regarding leukemia, however we have to consider that they include either acute or chronic leukemia and sometime could also include higher risk myelodisplastic syndrome . No evidence of publication bias was observed. Conclusion: Although there exist a number of paper on this topic, until now there are not been attempts to perform a meta-analysis on RR of second malignancies after treatment for NHL. Indeed comparative analysis on the incidence of second cancer presents several issues, including the heterogeneity of NHL, the source of data, the time during which the study was performed, the different schedule of chemotherapy, the dosage of radiotherapy used in the different period of time and the length of follow-up. Although these problems could reduce the accuracy of the meta-analysis, our results indicate that NHL treatment is associated with a significantly higher risk of second malignancy, in particular for some specific cancer like lung and bladder and same haematological malignancies as Hodgkin lymphoma and myeloid leukemia. Finally, we think that it is important to determine by meta-analysis the incidence of each second cancer in survivor of NHL as for some malignancies screening test could be performed and early diagnosis could be made. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Racial and ethnic disparities in hematologic malignancies

Blood ◽  
2017 ◽  
Vol 130 (15) ◽  
pp. 1699-1705 ◽  
Author(s):  
Kedar Kirtane ◽  
Stephanie J. Lee
Keyword(s):  
Hodgkin Lymphoma ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Ethnic Disparities ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Racial And Ethnic Disparities ◽  
Future Directions ◽  
Non Hodgkin Lymphoma ◽  
Solid Malignancies

Abstract Racial and ethnic disparities in patients with solid malignancies have been well documented. Less is known about these disparities in patients with hematologic malignancies. With the advent of novel chemotherapeutics and targeted molecular, cellular, and immunologic therapies, it is important to identify differences in care that may lead to disparate outcomes. This review provides a critical appraisal of the empirical research on racial and ethnic disparities in incidence, survival, and outcomes in patients with hematologic malignancies. The review focuses on patients with acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma, myeloproliferative neoplasms, and myelodysplastic syndrome. The review discusses possible causes of racial and ethnic disparities and also considers future directions for studies to help decrease disparities.

An Fc-Engineered Humanized Anti-CD40 Monoclonal Antibody, XmAb5485, Exhibits Potent Activity in Vitro and in Vivo against Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia and Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 881-881 ◽  
Author(s):  
Eugene A. Zhukovsky ◽  
Holly Horton ◽  
Matthias Peipp ◽  
Erik Pong ◽  
Matthew Bernett ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Line ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Lymphocytic Leukemia ◽  
Non Hodgkin Lymphoma

Abstract CD40, a transmembrane glycoprotein belonging to the tumor necrosis factor receptor family, is an attractive target for cancers of lymphoid origin since it is expressed on most mature B-cell malignancies, some early B-cell acute lymphocytic leukemias, and multiple myeloma. Finding efficient therapies for multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and rituximab-refractory Non-Hodgkin Lymphoma (NHL) represents an unmet need. Several anti-CD40 antibodies, both agonistic and antagonistic, have demonstrated objective responses in early clinical NHL trials and thus validated this antigen as a target for lymphoproliferative diseases. Here we present the characterization of a novel Fc-engineered and humanized anti-CD40 antibody, XmAb®5485, that was generated using our XmAb antibody engineering technology. This antibody is highly cytotoxic against lymphoma, leukemia and multiple myeloma cell lines as well as primary cancer cells. XmAb5485 is characterized by: i) increased affinity for Fc gamma receptors (FcgR), ii) improved effector function, and iii) significantly increased antitumor potency. We investigated several direct and indirect (Fc-mediated) mechanisms of antibody-mediated cytotoxicity in vitro. The potency (EC50) of XmAb5485 in antibody-dependent cell-mediated cytotoxicity (ADCC) increased up to 150-fold relative to the native non Fc-engineered version (anti-CD40 IgG1) of the antibody in a screen of Burkitt’s lymphoma [BL], CLL and MM-derived cell lines. In the same cell lines, ADCC potency and maximal efficacy (% lysis) of XmAb5485 were also superior to that of rituximab: 74- and 1.3-fold higher in CLL, 12.5- and 1.4-fold higher in BL, and 190- and 1.9-fold higher in MM. In a MM cell line with low density of CD40 expression (~3500 per cell) XmAb5485 facilitated efficient ADCC whereas anti-CD40 IgG1 was virtually ineffective. Furthermore, using a BL cell line (Ramos) XmAb5485 displayed antibody-dependent cellular phagocytosis (ADCP) with potency and efficacy increased relative to rituximab (15- and 1.6-fold) and anti-CD40 IgG1 (5- and 1.2-fold). XmAb5485 also exhibited anti-proliferative apoptotic activity that was similar to that of rituximab. Ex vivo, XmAb5485 mediated potent ADCC of multiple primary patient-derived CLL, MCL, and plasma cell leukemia (PCL, an aggressive form of MM) cells, with substantially increased potency and efficacy relative to rituximab; in contrast, anti-CD40 IgG1 displayed minimal or no activity in these primary tumor cells. In vivo, in an established large (210–350 mm3) sc Ramos tumor xenograft model, 6 mg/kg XmAb5485 cured 80% of mice of detectable tumors and displayed statistically significant superiority over anti-CD40 IgG1. In contrast, only 7% of animals in the rituximab cohort were cured. In summary, our data suggest that XmAb5485, an anti-CD40 Fc variant antibody engineered for increased effector function, is a promising next-generation immunotherapeutic for leukemias, lymphomas, and multiple myeloma.

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