A Multicenter, Real World Analysis of Primary Central Nervous System Lymphoma in Those with and without Human Immunodeficiency Virus

Abstract Introduction: Representing 4% of central nervous system (CNS) tumors, primary CNS lymphoma (PCNSL) is a rare type of extranodal non-Hodgkin lymphoma (NHL) that involves the brain, leptomeninges, eyes, spinal cord or cerebrospinal fluid without evidence of systemic disease. High-dose methotrexate (HD-MTX)-based regimens that incorporate consolidation with reduced dose whole brain radiation therapy (WBRT) or autologous stem cell transplant have shown 2-year overall survival (OS) rates ranging from 69% to 81% (Morris, JCO, 2013; Omuro, Blood, 2015). Although these data are encouraging, patients whose CNS deficits are too severe to receive treatment will die within the first months of diagnosis. HIV PCNSL has been associated with a poorer performance status and worse OS compared to non-HIV PCNSL. With the advent of combination antiretroviral therapy (ART), HIV PCNSL has become less common and by incorporating HD-MTX into HIV PCNSL treatment, outcomes have improved (Gupta, Neuro Oncol, 2017). In this study, we report the real world survival of PCNSL at 3 large academic centers, including those who received HD-MTX versus those who did not. We also compare survival of HIV PCNSL relative to non-HIV PCNSL. Methods: Adult patients (>18 years of age) with PCNSL at 3 medical centers (UNC Chapel Hill, Vanderbilt Medical Center, Emory University) were included in this analysis. Patients were diagnosed between January 2004 and July 2020. Only the diffuse large B-cell lymphoma (DLBCL) histology was included. Cases were excluded if there was any disease outside of the CNS or if they previously had systemic DLBCL. Demographic information was collected from the medical record, as well as disease-related information, HIV status, HD-MTX treatment (defined as >3g/m2) with or without other chemotherapeutic agents, imaging to determine progression, and survival data. Data were analyzed for the entire cohort as well as compared between HIV and non-HIV subjects. Demographic variables were summarized using appropriate statistics (frequencies, mean and standard deviation) and compared between HIV and non-HIV patients using Fisher's exact tests or Wilcoxon rank sum tests. Progression free survival (PFS) and OS were also compared between HIV and non-HIV patients using log-rank tests. Results: We identified 158 cases of PCNSL. The median PFS for the entire cohort was 1.17y and the median OS was 3.24y. Patients who received HD-MTX had an improved PFS (1.69y vs 0.25y; p=0.0016) and an improved OS (4.01y vs 1.05y; p=0.00075) over those who did not receive HD-MTX. Twenty-six of the 158 cases were HIV positive. Table 1 reports clinical features in HIV versus non-HIV PCNSL patients. Patients with HIV PCNSL were significantly younger than those with non-HIV PCNSL (44y vs 75y), and had a worse performance status (PS>2: 57.7% vs 26.8%). Notably, patients with HIV were less likely to receive HD-MTX compared to patients without HIV (53.8% vs 83.3%). Receiving frontline WBRT trended towards significance in favor of the HIV PCNSL group. Other factors such as gender, deep structure involvement, elevated cerebrospinal fluid protein, and elevated lactose dehydrogenase (LDH) were not significantly different between groups. When comparing HIV to non-HIV PCNSL, there was not a statistically significant difference in PFS (0.30y vs 1.34y; p=0.34), but there was a statistically significant difference in OS (0.30y vs 3.65y; p=0.0023) (Figure 1). When comparing those who received HD-MTX in the HIV group vs non-HIV group, there was not a statistically significant difference in PFS (3.39y vs 1.66y; p=0.45) or OS (3.6y vs 4.0y; p=0.43) (Figure 2). Conclusions: Our analysis shows that real-world survival for PCNSL is modest compared to reported outcomes from clinical trials. Patients who are able to receive treatment with HD-MTX had a significantly improved outcome. HIV PCNSL has worse OS than non-HIV PCNSL, and the median PFS and OS were both several months in the HIV PCNSL group, suggesting an unmet need for both frontline and salvage therapies. The survival difference between HIV PCNSL and non-HIV PCNSL decreased when evaluating only those patients who received HD-MTX. Importantly, fewer patients received HD-MTX in the HIV PCNSL group; and these patients had worse PS. These real-world data may serve as the benchmark for survival outcomes in PCNSL and provide valuable information for designing future trials in patients with PCNSL. Figure 1 Figure 1. Disclosures Dittus: Genentech: Research Funding; AstraZeneca: Research Funding; Seattle Genetics: Research Funding; BeiGene: Other: Advisory Board. Grover: Kite: Other: Advisory Board; ADC: Other: Advisory Board; Novartis: Consultancy; Tessa: Consultancy; Genentech: Research Funding. Cohen: Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy; Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding. Park: G1 Therapeutics: Consultancy; Takeda: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Seattle Genetics: Research Funding, Speakers Bureau; Gilead: Speakers Bureau.

Download Full-text

Maintenance and Consolidation Regimens after a Second Autologous Transplant for Multiple Myeloma: A Decade of Experiences

Blood ◽

10.1182/blood-2019-130619 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5700-5700

Author(s):

Ghulam Rehman Mohyuddin ◽

Maire Okoniewski ◽

Osama Diab ◽

Siddhartha Ganguly ◽

Al-Ola Abdallah ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Standard Of Care ◽

Advisory Board ◽

Advisory Committees ◽

Fda Approval ◽

Novel Drugs ◽

Significant Difference

Introduction: Autologous stem cell transplant (ASCT) followed by maintenance is the standard of care for eligible patients with multiple myeloma (MM). For patients that relapse, a second ASCT remains a viable option. However, the maintenance regimen to use for such patients remains an unanswered question, particularly in those with prior lenalidomide exposure. We retrospectively analyzed patients receiving two autologous transplants for a diagnosis of MM at our institution from 2008 to 2018 to determine maintenance strategies and outcomes upon completion of a second transplant. Methods: A total of 189 patients received two or more autologous transplants for MM at our institution from 2008 to 2018. Patients with planned tandem transplants, or those that proceeded directly to another transplant without interval progression were excluded. The remaining 135 patients were analyzed. Results: Patient characteristics are shown in Table 1. After first ASCT, 94 out of 135 patients (69.6 %) started maintenance therapy. The most commonly used maintenance regimen was lenalidomide in 63 patients, followed by bortezomib in 12 patients and thalidomide in 10 patients. Median time to initiation of maintenance from the date of transplant was 3.9 months. Overall median progression free survival (PFS) from transplant was 24.7 months with no significant difference between groups that received lenalidomide (median PFS: 21.2 months) or bortezomib (median PFS: 19.2 months, p:0.12). 10 (15.8%) patients discontinued lenalidomide due to toxicity, and 1 patient (8.3%) discontinued bortezomib due to toxicity. The median time from the onset of disease progression post first ASCT to time of second ASCT was 5.8 months. Strategies used post second ASCT includedconsolidation with triplet regimens followed by de-escalation (n=11) versus monotherapy (n=100). Table 2 highlights differing maintenance regimens used after the second ASCT. Median time from second ASCT to initiation of maintenance was 4.0 months. Median PFS post ASCT was 20.7 months. There was no statistically significant difference in PFS between the different regimens used (p=0.26), although there was a numerically higher discontinuation rate due to toxicity with older agents such as lenalidomide and bortezomib compared with newer agents such as daratumumab and pomalidomide. There was no statistically significant difference in the cytogenetic risk profile (p=0.21) or stage at diagnosis (p=0.36) between the groups that received different types of maintenance agents. However, patients receiving daratumumab as maintenance were more likely to have received more lines of therapy (median 5 for Daratumumab vs 3 for Lenalidomide, p=0.0001), and more likely to have previous exposure to daratumumab prior to second ASCT (92% vs 0% for other agents p=0.0001). Patients receiving daratumumab, carfilzomib or triple therapy were more likely to have been refractory to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) (p=0.0001). Despite stratifying for use of newer novel drugs (FDA approval after 2010- pomalidomide, daratumumab, carfilzomib) vs older novel drugs (FDA approval before 2010- lenalidomide, bortezomib, thalidomide), there was no difference in PFS ( 21.2 months vs 20.4 months, p= 0.92), between these groups when used as part of a maintenance strategy. Conclusions: Our data show a variety of maintenance and consolidation regimens are used for patients with MM after their second ASCT. In this single-center, retrospective analysis, there was no clear superiority of a consolidative strategy using triplet over monotherapy, and no superiority of newer agents compared to older agents. This suggests that toxicity, prior therapies and their tolerance may be the more important patient-related factors for consideration when selecting an agent/agents. Randomized, prospective data will be important to ascertain the standard of care in this situation. Disclosures Ganguly: Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau; Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board. McGuirk:Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation.

Download Full-text

A Randomized Phase 3 Trial Of Melphalan-Lenalidomide-Prednisone (MPR) Or Cyclophosphamide-Prednisone-Lenalidomide (CPR) Vs Lenalidomide Plus Dexamethsone (Rd) In Elderly Newly Diagnosed Multiple Myeloma Patients

Blood ◽

10.1182/blood.v122.21.536.536 ◽

2013 ◽

Vol 122 (21) ◽

pp. 536-536 ◽

Cited By ~ 10

Author(s):

Antonio Palumbo ◽

Valeria Magarotto ◽

Sara Bringhen ◽

Massimo Offidani ◽

Giuseppe Pietrantuono ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Alkylating Agents ◽

Second Primary ◽

Newly Diagnosed ◽

Advisory Committees ◽

Significant Difference ◽

Grade 3 ◽

To Receive

Abstract Background Rd and MPR are effective treatments in newly diagnosed multiple myeloma (NDMM) patients (pts). In this study we compared a non-alkylating containing regimen (Rd) vs alkylating-based regimens (MPR/CPR) in elderly transplant ineligible NDMM pts. Methods Patients were randomized (2:1) to receive nine 28-day cycles of MPR/CPR or Rd. MPR: lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days; CPR: cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day (eod) in >75 years pts; lenalidomide 25 mg/day for 21 days; prednisone 25 mg every other day. Rd: lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years. After induction, patients were randomized to receive maintenance with lenalidomide alone (10 mg/day for 21 days) or with prednisone (25 mg eod on days 1-28), until disease progression. The primary endpoint was progression-free survival (PFS). Results Between October 2009 and October 2012, 659 pts were enrolled ( MPR/CPR:439 and Rd:220), and 641 pts were evaluable (MPR/CPR:430 and Rd:211). Patient characteristics were well balanced in the 2 groups: median age was 73 years in both groups, 38% of pts were older than 75 years, 27% had ISS stage III in both groups, 21% of patients both in the MPR/CPR and in the Rd groups had unfavorable FISH profile [t(4;14) or t (14;16) or del17p]. After induction, the response rates were similar in the 2 groups: at least PR rate was 75% versus 79% (p=0.52) and CR rate was 9% versus 7% (p=0.35), in the MPR/CPR and Rd group, respectively. No significant difference in response rate were reported between two alkylating containing regimens. After a median follow-up of 21 months, the 2-year PFS was 55% in MPR/CPR and 49% in Rd (HR=0.86, 95% CI: 0.66-1.12, p=0.26), and 2-year OS was 84% in MPR/CPR and 80% in Rd (HR= 0.93, 95% CI: 0.60-1.41, p=0.71) At least one grade ≥3 hematological adverse event was reported in 51% with MPR/CPR and 29% with Rd (p<0.001), with a significant difference between the two alkylating agents (67% MPR and 31% CPR, p<0.001). At least one grade ≥3 extra-hematologic toxicities were similar in the two groups (31% with MPR/CPR and 28% with Rd, p=0.77). with no difference between two alkylating agents (31% both in MPR and CPR group). Second primary malignancies (SPM) were reported in 5 MPR patients (1 hematologic and 4 solid) in 1 CPR patient (hematologic) and in 2 Rd patients (both solid). Conclusion In a community-based population, triplet alkylating combinations did not lead to different PFS or OS clinical benefits over doublet therapy. Updated results will be presented at the meeting. Disclosures: Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Bringhen:Celgene: Honoraria. Giuliani:Celgene: Research Funding. Cavallo:Celgene: Honoraria; Celgene: Membership on an entity’s Board of Directors or advisory committees. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Download Full-text

Differences in Presentation and Survival Outcomes for African American Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-119948 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5647-5647 ◽

Cited By ~ 1

Author(s):

Nisha Joseph ◽

Vikas A. Gupta ◽

Craig C Hofmeister ◽

Charise Gleason ◽

Leonard Heffner ◽

...

Keyword(s):

African American ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Newly Diagnosed ◽

Long Term Outcomes ◽

Advisory Committees ◽

Entire Cohort ◽

Significant Difference

Abstract Background : Though the incidence of MM is two- to threefold higher in the African American (AA) population compared to Caucasians, reported long term outcomes are less favorable presumably due to inequities in access to healthcare. Little is known about the biology or disease presentation among AAs. We have conducted a retrospective analysis of our institutional data of 1000 patients treated with RVD induction therapy, specifically assessing differences in presentation, disease biology, and outcomes in AA patients. Methods: A total of 1000 newly diagnosed MM patients were treated with RVD induction therapy [R - 25 mg/day (days 1-14), V - 1.3 mg/m2 (days 1, 4 8, 11) and D - 40 mg once/twice weekly as tolerated every 21 days] from January 1st 2005 until August 31st 2016. Dose-adjustments were made based on the treating physician's discretion and patient tolerability. Demographic and outcomes data for the patients were obtained from our IRB approved myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: Of the 1000 patients included in the analysis, 564 (56.4%) of patients were white (W), and 339 (33.9%) were AA, consistent with the demographic representation of the state of GA and our institutional referral population. Median age of this cohort was 61 years (range 16-83), 57 for AA patients (range, 24-83) compared to 62 (range, 16-81) in white patients, suggesting the onset is earlier among AA which has been previously reported in population based studies. Other notable characteristics include: 42.5%M/57.5% F for AA cohort and 61.7%M/38.3%F for white cohort. In regard to stage, AA: 73.9% stage I/II, 26.1% stage III; W: 77.1% stage I/II, 22.9% stage III, showing no difference in prognostic staging at presentation. There was no statistically significant difference in the presenting labs between AA and whites except for hemoglobin, with more AA patients presenting with Hgb≤9.9 g/dL (45.7% AA vs 32.5% W, p <.0001). In terms of prevalence of high-risk cytogenetics, there was no significant difference between the two cohorts in: complex karyotype 16% white/14.4% AA; t(14;16) 2.4% W/2.8% AA; t(4;14) 4.7% W/5.0% AA; t(11;14) 11.7% W/15.9% AA; or del1p 6.5%W/7.8%AA. However, there were significant differences found in the rates of: amp 1q 19.2% W/10.6% AA, (p<.0001), del13 28.3% W/19.6% AA (p=.003), and del17p 11.7% W/7.2% AA (p=.019), all three significantly less frequent in AAs. Median time to transplant for the entire cohort was 5 months (range, 1-124), and median time to best response was 3 months (range, 0-39). There was no significant difference in the number of patients who underwent ASCT (84% W vs 82% AA, p=.241), nor in ≥VGPR rates post-induction and 100 days post-ASCT: 69.9% W vs 64.5% AA (p=.056) and 88.1% W vs 86.7% in AA patients (p=.317), respectively. Median PFS for the entire cohort was 63 months, 62 months (54-69.9) for white patients versus 65 months (53-76.9) for AA patients (p=0.403). At a median follow up of 38 months, median OS has not yet been reached. Conclusions: This is the largest reported cohort of myeloma patients treated with RVD induction, with one-third of the patients representing the AA population. In our dataset, AAs are diagnosed 5 years younger, with lower hemoglobin at presentation and lower rates of amp1q, del13 and del17p when compared to whites. When offered the same induction regimen and opportunity for ASCT, AAs tend to experience the same survival benefits as their white counterparts. The lack of significant difference in PFS or OS suggests standardization and improved access to care could lead to better long-term outcomes in the AA population. Disclosures Hofmeister: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Heffner:Genentech: Research Funding; Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Kite Pharma: Research Funding. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Kaufman:BMS: Consultancy; Janssen: Consultancy; Karyopharm: Other: data monitoring committee; Abbvie: Consultancy; Roche: Consultancy. Lonial:Amgen: Research Funding. Nooka:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Follicular Lymphoma Grade 3A Exhibits Pathological and Cytogenetic Diversity, but Similar Prognosis Compared to FL Grade 1-2: Pooled Analysis of 1757 Follicular Lymphomas from the PRIMA and Relevance Trials

Blood ◽

10.1182/blood-2018-99-115831 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 778-778

Author(s):

Camille Laurent ◽

Danielle Canioni ◽

Bettina Fabiani ◽

Véronique Meignin ◽

Catherine Chassagne-Clément ◽

...

Keyword(s):

Follicular Lymphoma ◽

Board Of Directors ◽

Tumor Cells ◽

Research Funding ◽

Statistical Difference ◽

Prognostic Significance ◽

Advisory Board ◽

Genomic Diversity ◽

Advisory Committees ◽

Significant Difference

Abstract Introduction: Follicular lymphoma (FL) is graded as 1, 2, 3A and 3B based on the number of centroblast cells. Although FL grade 3A is considered as a low-grade lymphoma, its prognostic significance compared to FL grade 1-2 remains controversial, especially for particular morphological variants with large cleaved cells or blastoid features, which are not recognized as a specific entity. Method: In order to clarify these points, FL grade 3 patients (pts) were selected from a large series of 2247 untreated pts enrolled in two LYSA trials: PRIMA (evaluating rituximab (R) maintenance after R-chemotherapy) and RELEVANCE (evaluating lenalidomide plus rituximab (R2) followed by R2 maintenance versus R-chemotherapy). FL3B pts were excluded from both trials. Sufficient material and clinical informations were available for 1757 out of 2247 pts. Among them, 161 pts including 88 of 950 PRIMA pts (9.2%) and 73 of 734 RELEVANCE pts (9.2%) were classified as FL3A. Among these FL3A cases, a panel of 7 expert hematopathologists identified 48 cases (2.7% of 1757 analyzed FL cases) which contained a significant component of large cleaved cells or medium-sized blastoid cells but did not meet grade 3B criteria. These cases were called FL3 "unclassified" (FL3U) as compared to classical FL3A (cFL3A) cases. We then analyzed the correlations between the histologic grade, phenotypic/cytogenetic features and clinical outcome. Results: FL3U were characterized by: i) proliferation of large cleaved tumor cells with moderately coarse to fine chromatin and absent or inconspicuous nucleoli (n=30) or predominance of medium-sized blastoid tumor cells with fine chromatin and small nucleoli (n=18) and ii) expression of CD20 and at least one germinal center marker. Mean of MYC and MUM1 protein expression in FL3U were 18% [from 3 to 25%] and 14.8% [3-35%], respectively, with no significant difference with cFL3A. Ki67 expression was higher in FL3U than in cFL3A (55.6% [20-90%] vs 41.3% [2-85%]) (p=0.008). Expression of p53 protein was slightly higher in FL3U than in cFL3A (37% [10-80%] vs 34.9% [8-90%] (p=0.052). FL3U had a tendency to harbor less frequent BCL2 rearrangements than cFL3A (74% vs 95%) (p=0.0620), whereas BCL6 rearrangements were significantly higher in FL3U than in cFL3A (29% vs 0%) (p=0.0034). The frequency of MYC rearrangements and 1p36 deletions in FL3U (9.6% and 6% of FL3Us, respectively) showed no significant difference with cFL3A. No detectable alteration in IRF4 locus was seen in both FL3U and cFL3A. The median age of FL3U pts was 58 years with 1:1 ratio of males to females and most pts had advanced stage at diagnosis with frequent marrow infiltration and intermediate to high FLIPI score. Outcome of pts with FL3U was not significantly different to that of cFL3A pts in Cox multivariate analyses. After a median follow-up of 117 months for PRIMA and 38 months for RELEVANCE, 89.6% of FL3U and 85.2% of cFL3A were alive with no significant difference between the 2 groups (p=0.4507). There was also no statistical difference in progression free survival (PFS) between the 2 groups (p= 0.1479). Similarly, we did not found any statistical difference in PFS between FL3U and FL1-2 and between FL1-2 and cFL3A (p=0.9210 and p=0.5375, respectively); as well as in overall survival (OS) (p=0.6223 and p=0.0960, respectively). Finally, the outcome of the whole group of FL3A pts including cFL3A and FL3U variants was similar to FL1-2 pts. Conclusion: FL grade 3A exhibits pathological and genomic diversity due to FL3U variants characterized by higher amounts of medium-sized blastoid or large cleaved cells, higher Ki67 proliferative index and p53 expression, together with increased frequency of cytogenetic BCL6 alterations and lower frequency of BCL2 rearrangements. However, in both PRIMA and RELEVANCE trials, FL3U pts showed no significant difference in terms of PFS or OS as compared to both FL1-2 and cFL3A pts. These results indicate that FL3A represents a spectrum of proliferations with variable maturity, proliferative activity and genomic alterations that may be intermediate points of progression toward FL3B/transformation. They suggest that the distinction between cFL3A and FL3U variant, as well as between FL1-2 and FL3A may not have any prognostic significance using modern rituximab- or lenalidomide-based treatments, although this has to be confirmed with different drug combinations. Disclosures Cartron: Gilead Sciences: Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria; Janssen: Honoraria. Morschhauser:Epizyme: Consultancy; Janssen: Other: Scientific Lectures; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Salles:Acerta: Honoraria; Janssen: Honoraria, Other: Advisory Board; Epizyme: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Novartis: Consultancy, Honoraria; Servier: Honoraria, Other: Advisory Board; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Other: Advisory Board; Morphosys: Honoraria; Gilead: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Merck: Honoraria; Takeda: Honoraria; Servier: Honoraria. Xerri:Janssen: Other: Travel.

Download Full-text

Real-World Outcomes with Bortezomib-Containing Regimens and Lenalidomide Plus Dexamethasone for the Treatment of Transplant Ineligible MM Patients: A Multi-Institutional Report from the National Myeloma Canada Research Network (MCRN) Database

Blood ◽

10.1182/blood-2018-99-117363 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2008-2008 ◽

Cited By ~ 1

Author(s):

Victor Jimenez-Zepeda ◽

Donna E Reece ◽

McCurdy R Arleigh ◽

Esther Masih-Khan ◽

Eshetu G Atenafu ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Small Sample ◽

Research Network ◽

National Database ◽

Categorical Variables ◽

Advisory Committees ◽

Entire Cohort

Abstract Introduction: Bortezomib-containing regimens (BCRs) have been the standard frontline approach for the treatment of transplant ineligible multiple myeloma (TIMM) patients in Canada for many years. Based on recent randomized clinical trial results lenalidomide and dexamethasone (Ld) has become another provincially funded option in Canada in the same therapeutic space. We aimed to compare the effect of BCRs and Ld for the treatment of TIMM using the newly-formed Myeloma Canada Research Network Multiple Myeloma Database (MCRN-MM-DB) project. This web-based centralized platform can track and characterize real-world outcomes of patients treated at major Canadian institutions and includes both legacy data dating back to 2007 (from 4 centres) as well as ongoing prospective data collection (from 11 centres) analyzed up to 01/07/18. Patients and Methods: The primary objective was to assess the ORR, PFS and OS for TIMM patients treated with CyBorD/CyBorP, Ld, VMP or VD/VP, each given as reported previously but with dose-adjustments at the discretion of the treating physician to maintain patients on therapy. The two-sided Fisher exact test was used to test for differences between categorical variables. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test; a p value of <0.05 was considered significant. Results: 842 TIMM patients were evaluated. Clinical characteristics are shown in Table 1. Median OS and PFS for the entire cohort were 54.1 and 20.4 months, respectively. ORR and ≥VGPR better rates were 83% and 52% for the entire cohort. A ≥VGPR rate of 53%, 46%, 56% and 51% were observed for patients treated with CyBorD/P, VMP, Ld and VD/VP, respectively (p=0.3). The median PFS was longer for Ld patients (25 months) compared to CyBorD/CyBorP, VMP and Vd/VP (19.3, 20.5 and 13.7 months, respectively), (p=0.03, Fig 1a); there was no significant difference in PFS between the 2 different alkylating-agent containing regimens when combined with bortezomib + steroids (CyBorD/P vs VMP, p =0.9). Median OS was 51, 59.5, 29.4 and 66.5 months for those patients treated with CyBorD/CyBorP, VMP, VD/VP and Ld, respectively (p=0.07, Fig 1b). When the OS and PFS for CyBorD/P (typically given for a fixed duration of 9 cycles) were compared with Ld in a subset analysis, the p-values were 0.08 and 0.008, respectively. Conclusions: 1) OS was not significantly different in patients treated with either a bortezomib-containing triplet that includes an alkylator + steroid or continuous Ld. 2) The BCR triplets and Ld were more efficacious than the bortezomib + steroid doublet (VD/VP) for both OS and PFS although, the small sample size and adverse factors, such as frailty and comorbidities, may have influenced the findings. 3) The results in the real-world setting, i.e., a median PFS in the range of 1.5-2 years and median OS of 4.5-5.5 years, confirm triplet-based BCRs and Ld as current valid standards of care for frontline therapy in TIMM. 5) This study confirms the utility of a large comprehensive national database to benchmark current results for comparison with newer regimens as they are introduced into the Canadian therapeutic landscape. Disclosures Arleigh: Celgene: Honoraria; Janssen: Honoraria. Sebag:Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Leblanc:Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Louzada:Janssen: Honoraria; Celgene: Honoraria; amgen: Honoraria; pfizer: Honoraria. Venner:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria.

Download Full-text

Front-Line Treatment with Obinutuzumab ± Chlorambucil for Chronic Lymphocytic Leukemia in Real-World Clinical Practice: Results of a Multinational, Multicenter Study By Eric and Icllsg

Blood ◽

10.1182/blood-2019-122309 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1766-1766

Author(s):

Yair Herishanu ◽

Adir Shaulov ◽

Riva Fineman ◽

Sandra Bašić-Kinda ◽

Ariel Aviv ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Entire Cohort ◽

Real World Setting ◽

High Risk Disease ◽

Frontline Treatment

Chronic lymphocytic leukemia (CLL) occurs in older individuals with a median age at diagnosis of 72 years. In recent years, there has been considerable progress in the frontline therapy of elderly/physically unfit patients with CLL. The German CLL11 trial showed that addition of obinutuzumab to chlorambucil (G-Clb) prolongs progression free survival (PFS) and overall survival (OS) compared to chlorambucil alone or in combination with rituximab. More recently, obinutuzumab together with ibrutinib or venetoclax were shown to be superior to G-Clb with regard to PFS, but there was no advantage in terms of OS. In this retrospective, multinational and multicenter co-operative study the European Research Initiative on CLL (ERIC) and the Israeli CLL Study Group (ICLLSG) evaluated the efficacy of frontline treatment with G-Clb in patients with CLL, in a "real-world" setting. Our analysis excluded CLL patients with documented del(17p) or TP53 mutations since they are no longer treated with chemotherapy. Results: A total of 437 treatment-naïve patients with CLL from 51 medical centers located in 13 countries were included. The median age of this patient population was 75.9 years; 59.7% were men, median CIRS total score was 8 and estimated creatinine clearance 61.1 mL/min. Seventy four patients had Binet stage A (17.2%), 167 (38.8%) stage B and 190 (44.1%) stage C. Results of FISH and IGHV mutational status were available for 332 and 115 patients, respectively. High-risk cytogenetics, del(11q) was documented in 18.7% patients and IGHV-unmutated gene in 64.4%. The vast majority of patients were treated with G-Clb (N=408) and the rest with obinutuzumab monotherapy (G-monotherapy, N=29). The clinical overall response was 86.5%, including clinical complete and partial responses in 41.6% and 45.8% of cases, respectively. The median observation time was 14.1 months (m) and the median PFS of the entire cohort was 27.6m (95% CI, 24.2-31.0). The PFS for G-Clb was significantly better than G-monotherapy (P=0.001; HR=0.38, 95% CI: 0.22-0.67), being the 2-year PFS estimates 61.8% and 52.8%, respectively. The median PFS was significantly shorter for patients with del(11q) (19.2m) compared to those with normal FISH (not reached, P<0.001), del(13q) (29.9m, P<0.001) and trisomy12 (not reached, P=0.027). Patients with IGHV-unmutated had a trend for shorter PFS compared to those with IGHV-mutated gene (median PFS 25.3m vs. not reached, respectively. p=0.06). In a multivariate analysis, older age, high risk-disease, lymph nodes >5cm, G-monotherapy, reduced cumulative dose of obinutuzumab and status less than CR, were independently associated with shorter PFS. Seventy patients (16%) received a second-line treatment. The median OS for the entire cohort has not been reached yet and 2-year OS estimate is 88%. In conclusion, in a "real-world" setting, frontline treatment with G-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were observed in patients with high-risk disease [del(11q) and/or IGHV-unmutated] and those treated with G-monotherapy. Thus, even today in the era of novel drugs, G-Clb can be considered a legitimate frontline treatment in unfit CLL patients with low-risk disease [non-del(11q) and IGHV-mutated]. Disclosures Herishanu: Roche: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Simkovic:Roche: Honoraria; University Hospital Hradec Kralove: Employment; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Honoraria. Mauro:Gilead: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Coscia:Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Research Funding. Scarfo:AstraZeneca: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Tedeschi:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; SUNESIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria. Gimeno Vázquez:JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Assouline:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Levato:Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria. Rigolin:Gilead: Speakers Bureau; Gilead: Research Funding; AbbVie: Speakers Bureau. Loscertales:Janssen: Honoraria; Roche: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Gilead: Honoraria. Ghia:Dynamo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno/Celgene: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Gilead: Consultancy, Honoraria, Research Funding.

Download Full-text

P16, c-Myc, SOX11, P53, ki67 and CD71Protein Expression in Aggressive Morphological Variants of Mantle Cell Lymphomas Compared to Classical Morphological Mantle Cell Lymphomas in Multiple Clinical Trials

Blood ◽

10.1182/blood-2019-129790 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2820-2820

Author(s):

Barbara Burroni ◽

Anne Moreau ◽

Mathieu Baldacini ◽

Antoine Martin ◽

Steven Le Gouill ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Who Classification ◽

Progression Free Survival ◽

Advisory Board ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Significant Difference ◽

Mantle Cell ◽

Scientific Advisory

On behalf of the Lymphoma Study Association (LYSA) Introduction: Aggressive Mantle Cell Lymphoma variant (A-MCL), including blastic and pleomorphic morphological variants, is a rare subtype of MCL whose frequency varies around 10-15% of all newly-diagnosed MCL patients. According to 2017 World Health Organization (WHO) classification, the diagnosis of A-MCL is based on morphology. A high proliferation rate on Ki-67 staining is not sufficient to be classified as a blastoid or pleomorphic subtype. This might induce diagnostic confusion. The aim of the present retrospective study is to investigate whether or not the CD71, c-Myc, SOX11, P53, ki67 and P16 expressions assessed by immunohistochemistry (IHC) can distinguish A-MCL from classical MCL (C-MCL). We also investigate the prognostic value of these markers in A-MCL patients. Methods: We re-investigated all MCL patients presented with A-MCL (n=110) at diagnosis and who have been enrolled in six prospective clinical trials. At time of inclusion, a centralized pathological review was performed to confirm the diagnosis of MCL. Cases were initially classified according to the 2008 WHO classification (LYMA, MCL-SA, MCL-SJ, RIBVD and RIPAD trials) or according to the 2017 WHO classification (MCLR2-ELDERLY trials). For the present study, we performed a supplemental pathology review by a panel of 5 hematopathologists experts from the LYSA group according to 2017 WHO classification. We identified 75 cases (out of 110) of A-MCL (8 blastic and 67 pleomorphic variants) which represent 15% of all MCL enrolled in these six trials. We have compared A-MCL characteristics to C-MCL who had specimens available for TMA (n=412 C-MCL out of 487 patients enrolled). IHC was performed on TMA, using the six selected antibodies and were scored by quantifying the percentage of cells stained on each spot. Patients available for survival analysis (53 A-MCL and 312 C-MCL) were drawn from all studies (except from the MCLR2-Elderly study that is ongoing). Different cut-offs were considered for progression free survival (PFS) and overall survival (OS) for each variable. The proliferation index was evaluated with Ki67 classical determination eyeballing and Ki67 reading by grid counting. Cut-offs for each of these markers were determined using X-tile software, which determines the optimal value for classifying patients into groups based on overall and progression-free survival. Results: At baseline, the aggressive forms were similar to classical forms in terms of demographic characteristics (age at diagnosis, localization and sex). p53 protein expression was significantly higher in A-MCL patients than in C-MCL (p<0.001) like p16 (p=0.002), c-MYC (p<0.001), CD71 (p<0.001) and Ki67 index (both classical and by grid) (p< 0.001). There was no statistically significant difference in SOX11 expression. In univariate analyses, elevated levels of P16 (>10%), c-MYC (>30%) Ki67 (>40%) were associated with poorer OS and PFS in the cohort of A-MCL and C-MCL patients. There was no significant difference in survival both for OS and PFS regarding P53 (>30%). In multivariate analysis stratified by trial, Ki67 by grid>40% (HR=2.303[1.479-3.585] ; p =0.0002) and c-MYC >30% (HR=1.865 [1.060-3.279] p =0.0305) were predictive for OS whereas only Ki67 by grid >40% (HR=2.055 [1.434, 2.944], p<0.0001) was a significant prognostic factor for PFS. Conclusion: CD71, c-Myc, P53 and P16 expression levels assessed by IHC are higher in A-MCL as compared to C-MCL. These markers could therefore be recommended in routine practice to distinguish between A-MCL and C-MCL. We also found that patients with Ki67 count by grid >40% had significantly shorter PFS and OS and patients with high Myc expression >30% had a significantly poorer OS. Thus, MYC expression and Ki67 by IHC is a suitable test for routine diagnostic practice to assess A-MCL prognosis. Disclosures Le Gouill: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Ribrag:argenX: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dreyling:Novartis: Other: scientific advisory board; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Sandoz: Other: scientific advisory board; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau. Hermine:Celgene: Research Funding; Novartis: Research Funding; AB science: Consultancy, Equity Ownership, Honoraria, Research Funding.

Download Full-text

A Randomized Phase II Study of Low-Dose Decitabine Versus Azacitidine in Patients with Low- or Intermediate-1-Risk Myelodysplastic Syndromes: A Report on Behalf of the MDS Clinical Research Consortium

Blood ◽

10.1182/blood.v128.22.226.226 ◽

2016 ◽

Vol 128 (22) ◽

pp. 226-226 ◽

Cited By ~ 2

Author(s):

Elias J. Jabbour ◽

Nicholas J. Short ◽

Xuelin Huang ◽

Abhishek Maiti ◽

Tapan M. Kadia ◽

...

Keyword(s):

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Low Dose ◽

Progressive Disease ◽

Cytogenetic Response ◽

Advisory Board ◽

Advisory Committees ◽

Entire Cohort ◽

Transfusion Independence

Abstract Background: The outcome of patients (pts) with lower-risk myelodysplastic syndrome (MDS) is heterogeneous, with some pts having a particularly poor prognosis. Low doses of hypomethylating agents (HMAs) have been shown to be active in lower-risk MDS. We evaluated the relative safety and efficacy of low-dose decitabine (DAC) and azacitidine (AZA) in pts with lower-risk MDS. Methods: Adult pts with de novo or secondary low- or intermediate-1-risk MDS, CMML or MDS/MPN were eligible for this study. Pts with prior HMA exposure were excluded. Pts were randomized in a Bayesian adaptive design to receive either AZA 75 mg/m2 IV/SC daily or DAC 20 mg/m2 IV daily for 3 consecutive days on a 28-day cycle; pts were more likely to be assigned to the better performing treatment arm. The primary efficacy outcome was the overall improvement rate (OIR) defined as the composite of complete remission (CR), marrow CR, and hematologic improvement. Secondary outcomes included safety profile, cytogenetic response, conversion to transfusion independence, event-free survival (EFS), and overall survival (OS). EFS was defined as the time to HMA failure, progressive disease, transformation to acute myeloid leukemia (AML) or death from any cause. Results: Between 11/2012 and 2/2016, 113 pts with lower-risk MDS have been treated, 40 (39%) with AZA and 73 (71%) with DAC. The median age of the entire cohort was 70 years (range, 44-88 years), and the majority of pts (81%) were intermediate-1-risk by IPSS. Baseline characteristics of the 2 treatment groups were well-balanced and are summarized in Table 1. The median number of cycles received was 9 (range 1-41 cycles). Of the 39 pts in the AZA arm and 70 pts in the DAC arm who have received at least 2 cycles of therapy and were evaluable for response, the OIR was 53% in both groups. The CR rate with AZA and DAC was 38% and 29%, respectively (P=0.29). Among pts with abnormal karyotype at baseline, complete or partial cytogenetic response was observed in 24% of pts in the AZA arm and in 63% of pts in the DAC arm (P=0.01); the rate of complete cytogenetic response was 6% and 26% in the two groups, respectively (P=0.09). Of the 18 pts in the AZA arm and the 38 pts in the DAC arm who were transfusion dependent at baseline and evaluable for response, 17% and 32% achieved transfusion independence, respectively (P=0.24) The median duration of follow-up for the entire cohort was 20 months (range, 2-42 months). Twenty four pts in the AZA arm (60%) and 23 pts in the DAC arm (32%) have come off study due to lack of response or progressive disease. There was a trend toward prolonged EFS with DAC compared to AZA (median EFS: 19.6 months vs. 13.7 months; 1-year EFS rate: 73% vs. 57, respectively; P=0.15; Figure 1A). Twelve pts in the AZA arm (30%) and 17 pts in DAC arm (23%) have died. The median OS was similar between DAC and AZA (median OS not reached for both; 1-year OS rate: 87% vs. 84%, respectively; P=0.80; Figure 1B). Progression to AML occurred in 5 pts (13%) in the AZA arm and 6 pts (8%) in the DAC arm. Both agents were overall well-tolerated. Cycle delays were required in 23% and 37% of pts and dose reductions were required in 5% and 12% of pts treated with AZA and DAC, respectively. Infection or neutropenic fever occurred 2 pts (5%) treated with AZA and in 5 pts treated with DAC (7%). No grade 4 adverse events were observed in either treatment arm. Conclusions: Low-dose AZA and DAC are effective and well-tolerated in pts with lower-risk MDS. Early results suggest that low-dose DAC may result in superior EFS compared to low-dose AZA. A randomized trial comparing low-dose AZA, low-dose DAC, AZA x 5 days, and best supportive care in lower-risk MDS is ongoing. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; BMS: Research Funding; Ariad: Research Funding; Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; Karyopharm: Honoraria, Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Abbvie: Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Roboz:Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding.

Download Full-text

A Novel Methodology for Building Longitudinal, Patient-Centric Real World Datasets in Hemophilia A

Blood ◽

10.1182/blood-2021-146160 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 594-594

Author(s):

Mark W Skinner ◽

Gillian Hanson ◽

Tao Xu ◽

Richard Ofori-Asenso ◽

Richard H. Ko ◽

...

Keyword(s):

Board Of Directors ◽

Real World ◽

Stock Options ◽

Research Funding ◽

Hemophilia A ◽

Advisory Board ◽

Real World Data ◽

Advisory Committees ◽

Patient Reported ◽

Privately Held

Abstract Background: There are limited real-world data (RWD) available on the unmet needs of people with mild or moderate hemophilia A (PwHA). This population accounts for 40-52% of all PwHA, including nearly all women with hemophilia A (HA), and is under-represented in scientific literature (Michele, et al. Haemophilia 2014; Benson, et al. Blood Transfus 2018; Peyvandi, et al. Haemophilia 2019). Available claims data from payer databases are confined to billing codes, and lack key information on outcomes and disease characterization (e.g. severity, treatment response.) (Tyree, et al. Am J Med Qual 2006). Registry datasets can require resource-intensive data entry and potentially miss key information about care received at outside facilities, at home, or after patients switch providers (Gliklich, et al. Registries for Evaluating Patient Outcomes: A User's Guide. 2014). To address these data gaps, we developed a novel, patient-centered approach to create a longitudinal healthcare database from individuals with mild and moderate HA in the United States. This study assessed the feasibility of this approach, which integrates medical record data collected during routine clinical care along with patient-reported outcomes (PROs) to provide needed insights into this under-represented population. Methods: Recruitment began in June 2020 via a broad strategy of social media outreach, healthcare provider partnerships, and patient advocacy groups. Eligibility was confined to mild or moderate PwHA, confirmed via physician report within provider notes in combination with baseline factor VIII levels (>5-50% mild, 1-5% moderate.) This study received research ethics board approval and abides by the guiding principles of the Declaration of Helsinki. PwHA enrolled via an online record management platform, PicnicHealth. After signing authorization forms for collection of their electronic health records (EHR) and informed consent to share their de-identified data for research, participants were prompted to enter information on their care providers. Records were gathered from all providers, across any facility, retrospectively as records were available. (Figure 1) All records obtained were made available to the participants via a medical timeline. Records were translated to text via optical character recognition with human review. Data elements from structured text as well as disease-specific elements from narrative text were captured using natural language processing and supervised machine learning. All elements, including visit metadata, conditions, measurements, drugs, and procedures were mapped to standardized medical ontologies and reviewed by a team of nurses. (Table 1) Quality control was assessed via inter-abstractor agreement on outputs with physician review. Patient-reported bleed, treatment, and pain data were collected via online questionnaire for a subset of PwHA, with participants prompted to enter data every 2 weeks. Abstracted EHR data was linked to PRO responses in a de-identified dataset. Cohort and abstraction characteristics were summarized descriptively. Results: From June 1, 2020 to June 30, 2021, 104 PwHA met eligibility criteria for enrollment (65 [62.5%] mild; 39 [37.5%] moderate). Participants saw providers across 34 states in the US, 22.1% (23/104) were female, and 20.6% (14/68) of those with known race/ethnicity status were from minority groups. Records were gathered from a median of six care sites and 16 providers per participant. A median of 50 (IQR [21-93]) clinical documents from 11 years were processed for each PwHA. (Table 2) Inter-abstractor agreement to assess abstraction quality averaged 95.9% for condition, 99.5% for drug name, and 95.4% for drug start date. As of June 2021, the average PRO response rate was 90.3% (150/166 of all requests) and continues prospectively. Conclusions: The patient-centric data collection methods implemented in this study provide a novel approach to build longitudinal real-world data sets. Technology-enabled data abstraction showed consistent high quality when processing the heterogeneous clinical records across disparate providers and care sites, and direct engagement with patients complements potential gaps in the clinical record. Additionally, this approach provides needed data on groups under-represented in RWD and traditional PwHA cohorts, including those with mild and moderate disease and women with HA. Figure 1 Figure 1. Disclosures Skinner: ICER: Membership on an entity's Board of Directors or advisory committees; Spark (DMC): Honoraria; Sanofi: Honoraria; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Honoraria; Pfizer (DMC): Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; uniQure: Research Funding; Takeda: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Freeline: Research Funding; BioMarin: Honoraria, Research Funding; IPA Ltd.: Current holder of individual stocks in a privately-held company; National Hemophilia Foundation: Consultancy; Institute for Policy Advancement Ltd: Current Employment; WFH USA: Membership on an entity's Board of Directors or advisory committees; BCBS MAP: Membership on an entity's Board of Directors or advisory committees. Hanson: PicnicHealth: Current Employment, Current holder of stock options in a privately-held company. Xu: F. Hoffmann-La Roche AG: Current Employment. Ofori-Asenso: F. Hoffmann-La Roche Ltd: Current Employment. Ko: Genentech, Inc.: Current Employment; Genentech, Inc.-Roche: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Cibelli: PicnicHealth: Current Employment. Nissen: Novartis: Consultancy; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company. Witkop: Roche Advisory Panel: Consultancy; National Hemophilia Foundation: Current Employment. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Shapiro: Novartis: Research Funding; Novo Nordisk: Other: Advisory board fees, Research Funding, Speakers Bureau; Octapharma: Research Funding; Pfizer: Research Funding; OPKO: Research Funding; Prometric BioTherapeutics: Research Funding; Sangamo: Other: Advisory board fees, Research Funding; Sigilon Therapeutics: Other: Advisory board fees, Research Funding; Takeda: Research Funding; Kedrion Biopharma: Research Funding; Glover Blood Therapeutics: Research Funding; Genentech: Other: Advisory board fees, Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Bioverativ (a Sanofi company): Other: Advisory board fees, Research Funding; BioMarin: Research Funding; Agios: Research Funding.

Download Full-text

Polatuzumab Vedotin Use before Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Aggressive Lymphoma: A US Single Center Experience

Blood ◽

10.1182/blood-2021-152313 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3842-3842

Author(s):

Arushi Khurana ◽

Radhika Bansal ◽

Matthew Hathcock ◽

Adrienne Nedved ◽

Yucai Wang ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Single Center ◽

Infection Rates ◽

Bridging Therapy ◽

Advisory Committees ◽

Single Center Experience ◽

Significant Difference ◽

Car T

Abstract Background: Polatuzumab vedotin (Pola), an antibody drug conjugate targeting CD79b received FDA approval in combination with bendamustine and rituximab (Pola-BR) in June 2019. With CAR-T as destination therapy, the option of Pola-BR appears appealing with its superior efficacy and lack of potential interference with CAR-T due to different target antigens. However, clinical concerns remain regarding prolonged lymphopenia associated with benda and CAR-T manufacturing if used before apheresis. We reviewed the single center experience of all patients with exposure to polatuzumab around CAR-T for R/R aggressive NHL treated at Mayo Clinic Rochester. Methods: A review of patients that received at least one dose of Pola with the intent to proceed to CAR-T between July 1, 2019 and March 31st, 2021 at Mayo Clinic, Rochester were included. Response to therapy was based on 2014 Lugano criteria. Overall survival (OS) was defined as the time from CAR-T infusion to death, and event-free survival (EFS) as the time from CAR-T infusion to disease progression, next treatment, or death. Survival curves were calculated using Kaplan-Meier estimates, and were compared between subgroups using the log-rank test. Cox regression was used for multivariate analysis (MVA). Results: A total of 22 patients were identified during the study period. Of these 18 (82%), made it to CAR-T infusion (17 axi-cel, and 1 -tisa cel). 3 patients died due to progressive disease (PD) before CAR-T and one achieved complete remission (CR). In the pre-CAR-T Pola cohort (n = 22), the median age was 65.5 years (39-73), 50% were males, 96% had advanced stage and IPI ≥ 3. Median prior lines of treatment were 4.5 (2-6), 73% had primary refractory disease and 50% had myc rearrangement. 19 (86%) patients received Pola as bridging therapy and 8 were exposed to Pola before T-cell apheresis. Bendamustine was included in the treatment for 79% (15/19) for bridging therapy and 63% (5/8) with exposure pre-apheresis. For those in the bridging group, the overall response rate (ORR) was 26% (5/19), with one patient achieving CR with Pola-BR. Disease control (defined as those in a partial response [PR] or stable disease [SD]) was seen in 47% (9/19) patients. One of the 8 patients with pre-apheresis exposure to Pola, required an additional attempt at CAR-T manufacturing after the initial failure. At a median follow up of 48 weeks, the EFS and OS in 18 patient cohort with pre-CAR-T Pola exposure were 6.7 weeks (95% CI, 4.3-not reached [NR]) and 15 weeks (95% CI, 9.7-NR), respectively. At the data cut off (7/25/2021), 78% patients had died. As traditional chemo for bridging is a particularly poor prognostic group, we compared Pola-BR bridging group (n = 15), to other traditional chemo bridge group (n = 16) in our CAR-T database. Both groups had comparable baseline characteristics as shown in Table 1 except for higher proportion of patients with B-symptoms in the Pola-BR group at time of CAR-T. There was also no difference in the inflammatory markers (CRP and ferritin) at LD or peak level after CAR-T. Table 2 shows outcomes between the 2 groups with comparable any grade CRS, neurotoxicity, pre and post CAR-T infection rates. Best response ORR to CAR-T was higher in the other chemo group vs. Pola BR (81.2% vs. 33%, p = 0.027). There was a significant difference in the 6-month OS rate (other 81.3% [95%CI, 54.5-96] vs. pola 33.3% [95%CI, 11.8- 61.6], p = 0.007) but no significant difference in the 6-month EFS rate (other 37.5% [95%CI, 15.2-64.6%] vs. pola 13.3% [95%CI, 1.7-40.5%] p = 0.12) between the 2 groups (figure 1). On univariate analysis within the chemo type bridging cohort (Pola-BR + other traditional chemo, n = 31), presence of B-symptoms (HR 4.72, p = 0.002), ECOG PS > 2 at CAR-T (HR 6.75, p = 0.0008), and type of bridge therapy (pola HR 6.57, p = 0.009) were associated with worse OS whereas a response to bridge (PR+SD, HR 0.39, 0.031) was favorable. On MVA, association was maintained for bridge type (pola, p <0.001) and response to bridge (p <0.001). Discussion: Pola based bridge was feasible in this US based cohort without significant issues with CAR-T manufacturing or increased infection rates. However, in this retrospective analysis, use of Pola-BR was associated with inferior outcomes compared to other traditional chemotherapy options. Future studies are required to elucidate whether these difference in outcomes stem from a biological basis versus bias in patient selection. Figure 1 Figure 1. Disclosures Wang: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genentech: Research Funding; InnoCare: Research Funding. Paludo: Karyopharm: Research Funding. Bennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Merck: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Juno: Consultancy; Vineti: Consultancy; Takeda: Research Funding; Gamida Cell: Consultancy; Legend: Consultancy; Sorrento: Consultancy.

Download Full-text