Introduction
In their lifetime, patients with follicular lymphoma frequently require multiple treatments, which have improved their survival over the past few decades. The expected treatment outcome ...based on lines of treatment in the post-Rituximab era is currently unknown. We analyzed the progression free survival and event free survival by line of treatment to aid estimating clinical endpoints when designing future clinical trials for multiply relapsed patients.
Patients and Methods
Adults (≥18 years) with de novo follicular lymphoma (FL) treated at our center between 1998 and 2007 were eligible (N=1134). 236 patients with ≤2 visits, mixed histology at initial diagnosis, and active concurrent malignancy were excluded. Of the remaining 898 patients, 105 were observed and did not require treatment during the timeframe of this dataset, and 2 had incomplete data, therefore 791 patients were eligible for response, progression and event free survival (PFS and EFS) analysis (Figure 1). Response was documented by investigators based on clinical or radiographic assessment. Complete response was based on radiographic assessment. PFS was defined as start of treatment to progression of disease or death. Patients with inadequate response to treatment, change of treatment, or stable disease without subsequent documented relapse were censored in the PFS analysis. Events for EFS were defined as progression, change of treatment, and death. PFS and EFS of sequential lines of treatment were evaluated by Kaplan-Meier method and compared across lines using log-rank test with adjustment for within-patient correlation. PFS and EFS were compared by other clinical variables using regular log-rank tests.
Results
Median age of diagnosis was 57.3 years with 1:1 male to female ratio. Median overall survival was not reached with median follow up of 9 years (N=898, range 0.2 - 16.8 years, Figure 1A). Median time to first treatment for the entire group was 2.3 months (range 0 - 13.3 years). In first line treatment of the 791 patients, 51% (N=406) received Rituximab with chemotherapy (R-Chemo), 13% (N=101) received chemotherapy only (Chemo), 19% (N=150) received Rituximab monotherapy (R-Mono), and 17% (N=129) received other treatments including radiation and surgery. For second line treatment, 405 patients were treated with about 37% receiving R-Chemo and 34% receiving R-Mono. As line of treatment increased, the percentage of patients with radiographically assessed complete response diminished from 71% at first line treatment to 25% by fifth line treatment (Figure 1B). Median PFS for first, second and third line treatment are 4.8, 1.6, and 1 year, respectively (Figure 2A). Median EFS for first, second and third line treatment are 3.8, 1.1, 0.8 year, respectively (Figure 2B). For subsequent lines of treatment, both median PFS and EFS were <1 year.
Conclusion
Follicular lymphoma is an indolent disease often requiring multiple lines of treatment. However, PFS and EFS for multiple lines of treatment in FL has not been described in the post-Rituximab era. The work has benchmarked the median response by line of treatment. After third line treatment, the PFS was ≤1 year. This analysis serves to aide comparison of different therapies for future drug approval in relapsed FL.
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Hamlin:Xencor: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Horwitz:Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Huya: Consultancy; Infinity: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy; ADCT Therapeutics: Research Funding. Kumar:Celgene: Honoraria, Other: Scientific Advisory Board; Celgene: Research Funding; Adaptive Biotechnologies: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding. Moskowitz:Merck: Honoraria; Seattle Genetics: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria. Moskowitz:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Palomba:Pharmacyclics: Consultancy. Zelenetz:Gilead Sciences: Research Funding.
Summary
Twice‐weekly bortezomib has proven activity in mantle cell (MCL) and indolent lymphomas. This study explored a weekly schedule of bortezomib in follicular lymphoma (FL) and MCL. Although ...weekly bortezomib was better tolerated, the overall response rate (ORR) was inferior (18% vs. 50%, P = 0·02) with no complete remissions (CR) (compared with 18% CR for the twice‐weekly schedule). Progression‐free survival (PFS) was not different. The weekly schedule of bortezomib was less toxic, but yielded fewer and lower quality responses than twice‐weekly bortezomib. Given the similar PFS, the weekly schedule may still be appropriate for some patients.
Introduction: BCL-2 is an anti-apoptotic protein that is commonly overexpressed in hematologic malignancies, including Non-Hodgkin Lymphoma (NHL). Venetoclax is a selective, potent, orally ...bioavailable BCL-2 inhibitor. Patients (pts) with relapsed/refractory (R/R) NHL were enrolled in a phase 1, open-label, dose-escalation, multicenter study to determine the safety, pharmacokinetics, and efficacy of venetoclax monotherapy. We present updated data on the safety profile and efficacy as of June 10, 2015.
Methods: Venetoclax was administered once-daily until progressive disease or unacceptable toxicity. To mitigate the risk of tumor lysis syndrome (TLS), a 3-week period with a stepwise, intrapatient dose ramp-up was used, starting at 200 mg and reaching a maximum dose level of 1,200 mg in the dose escalation cohorts. In a safety expansion cohort, stepwise escalation from 400 mg to 800 mg to 1200 mg was evaluated. Adverse events (AEs) were graded according to NCI-CTCAE version 4.0. Responses were assessed using 2007 Cheson IWG response criteria including CT scans beginning at week 6.
Results: Accrual is complete with 106 pts enrolled. NHL subtypes included in the dose escalation cohorts (200-1200 mg/day) were diffuse large B-cell lymphoma (DLBCL, n=20), follicular lymphoma (FL, n=14), mantle cell lymphoma (n=28), Waldenström macroglobulinemia (n=4), marginal zone lymphoma (n=3), and multiple myeloma (n=1). NHL subtypes enrolled in the safety expansion cohort (1200 mg/day) were DLBCL (n=21) and FL (n=15).
The current analysis focuses on pts with DLBCL and FL from the dose escalation and safety expansion cohorts. Data on other subtypes will be presented at the meeting. In total, 57/70 pts with DLBCL and FL have discontinued (n=49 due to PD, n=3 due to AE, n=2 withdrew consent, n=2 proceeded to transplant and n=1 due to non-compliance). Treatment emergent-AEs of any grade in ≥20% of the 70 pts with DLBCL or FL were diarrhea and fatigue (each 44%), nausea (33%) and vomiting (23%). Treatment-emergent grade 3/4 AEs in ≥5 pts, were anemia (14%), fatigue (9%) and thrombocytopenia (7%). Serious adverse events in ≥2 pts were hyponatremia (4%), and dehydration, diarrhea, and febrile neutropenia (each 3%). Two events of laboratory TLS were previously reported. There were no new events of laboratory TLS and no pts had clinical TLS.
Among 41 pts with DLBCL, 7 were DLBCL-Richter's transformation (RT) and 2 had primary mediastinal large B-cell lymphoma (PMBCL). The median age was 68 (range: 25-86). The median number of prior therapies was 3 (range: 1-8). Five (12%) had rituximab-refractory disease. The median time on venetoclax for pts with DLBCL was 5 months (range: 0.4-9). The overall response rate (ORR) was 15% 3 (9%) CR and 2 (6%) PR for pts with DLBCL (n=34). The median duration of response for DLBCL was 3.3 months (range: 2-4) with no responses ongoing and the median duration of SD was 2.3 months (range: 1-15). One pt with SD remains on study at 9 months of venetoclax. Two responders (1 with DLBCL who achieved CR and 1 with PMBCL who achieved PR) proceeded to allogeneic hematopoietic stem cell transplant. The ORR was 43% (3 PR) for pts with DLBCL-RT (n=7). One pt with PR remains on study at 18 months of venetoclax.
Among 29 pts with FL, the median age was 64 (range: 46-75). The median number of prior therapies was 3 (range: 1-10). Eight (28%) had rituximab-refractory disease. The median time on venetoclax was 7 months (range: 1-19). The ORR was 34% 3 (10%) CR and 7 (24%) PR for pts with FL (n=29). All 3 patients with CR were enrolled in the dose escalation cohorts. The median duration of response was 10 months (range: 1-30) and the median duration of SD was 4.2 months (range: 2-18). Eleven patients remain on study. Response rates are summarized in the table.
Conclusions: Venetoclax monotherapy demonstrated a tolerable safety profile in pts with R/R NHL. Several pts with DLBCL had an initial response to venetoclax, but this response was not sustained. In FL, venetoclax monotherapy achieved an ORR of 34% indicating clinical benefit, as evidenced by long durations on therapy. These results suggest that the optimal role of venetoclax for treatment of DLBCL and FL will be in combination therapies. Venetoclax is currently being evaluated in combination with bendamustine and rituximab and in combination with R or obinutuzumab plus CHOP in phase 2 studies of pts with FL.
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Gerecitano:Genentech: Consultancy, Other: Advisory Board; AbbVie: Consultancy, Other: Advisory Board. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Roberts:Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax: Employment; AbbVie and Genentech: Research Funding. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Consultant and speaker bureau for Genentech: Consultancy; AbbVie and Genentech: Research Funding. Kahl:Genentech: Consultancy; AbbVie: Research Funding; Teva: Consultancy. Pagel:Actinium Pharmacetuicals, Inc.: Equity Ownership. Puvvada:AbbVie and Genentech: Research Funding. Kipps:AbbVie: Consultancy, Research Funding. Anderson:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Dunbar:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Gressick:AbbVie: Employment, Equity Ownership. Wagner:AbbVie: Employment, Equity Ownership. Kim:AbbVie: Employment, Equity Ownership. Heitner Enschende:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy.
The molecular analysis of established cancer cell lines has been the mainstay of cancer research for the past several decades. Cell culture provides both direct and rapid analysis of therapeutic ...sensitivity and resistance. However, recent evidence suggests that therapeutic response is not exclusive to the inherent molecular composition of cancer cells but rather is greatly influenced by the tumor cell microenvironment, a feature that cannot be recapitulated by traditional culturing methods. Even implementation of tumor xenografts, though providing a wealth of information on drug delivery/efficacy, cannot capture the tumor cell/microenvironment crosstalk (i.e., soluble factors) that occurs within human tumors and greatly impacts tumor response. To this extent, we have developed an ex vivo (fresh tissue sectioning) technique which allows for the direct assessment of treatment response for preclinical and clinical therapeutics development. This technique maintains tissue integrity and cellular architecture within the tumor cell/microenvironment context throughout treatment response providing a more precise means to assess drug efficacy.
To determine the safety and efficacy of substituting weekly or twice-weekly bortezomib for vincristine in the R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen in patients with ...relapsed/refractory indolent and mantle cell lymphoma (MCL).
Of the 57 patients in this phase I trial, 55 participated in 1 of 2 dosing schedules that included rituximab (375 mg/m(2)) and cyclophosphamide (750 or 1,000 mg/m(2)) administered on day 1 of each 21-day cycle and prednisone (100 mg orally) days 2 to 6. In the once-weekly schedule, bortezomib was administered on days 2 and 8; on the twice-weekly schedule, bortezomib was given on days 2, 5, 9, and 12. Bortezomib and cyclophosphamide were alternately escalated. A separate cohort of 10 patients in the twice-weekly schedule received concurrent pegfilgrastim (PegG) on day 2.
Both schedules of R-CBorP (rituximab, cyclophosphamide, bortezomib, and prednisone) were well tolerated. Most toxicities across all dose levels and cycles were grade 1 or 2. The overall response rates for patients on the weekly (n = 13) and twice-weekly (n = 33) schedules were 46% 23% complete response/complete response unconfirmed (CR/CRu) and 64% (36% CR/CRu), respectively. Concurrent PegG did not increase hematologic toxicities in this regimen. A randomized phase II study is under way to further compare toxicity and efficacy of the 2 dosing schedules.
R-CBorP is a safe and effective regimen in patients with relapsed/refractory indolent and MCLs. Most toxicities were grade 1 or 2, and a promising response rate was seen in this phase I study.
Background:
Lymphoma is a clinically and molecularly heterogenous disease. Next generation sequencing of primary lymphoma samples has identified common recurring genomic alterations (GAs). The ...distribution and frequency of recurring GAs across lymphoma subtypes remains unknown because prior studies vary in sequencing methods, depth of coverage, and specimen source. In this study, we benchmark the distribution of GAs across different lymphoma subtypes by prospectively analyzing lymphoma cases and performing comprehensive DNA/RNA targeted sequencing of genes commonly found in hematologic malignancies using the Foundation One Heme (F1H) clinical assay.
Methods:
After obtaining proper consent, archived specimens from 183 samples formalin fixed paraffin embedded (FFPE) N=141, peripheral blood N=28, BM aspirate N=14 distributed across lymphoma subtypes (including 62 DLBCL, 38 T cell lymphoma, 32 FL, 17 CLL, 13 MCL) were sequenced to high, uniform coverage averaging >600x for DNA, >20 million pairs for RNA. GAs were determined, including base substitutions, small insertions and deletions, rearrangements, and copy number alterations. Significant non-synonymous variants were identified as mutations from the COSMIC database, amplifications of established oncogenes, or homozygous deletions and/or clear loss-of-function mutations of known tumor suppressors. Fisher's exact test with Monte Carlo estimation corrected by false discovery rate was used for associations.
Results:
Samples from prospectively consented patients were banked for a median of 30 days prior to genomic analysis, range 1 day to 6.5 yr. Sequencing data was reported a median of 16 days from sample date receipt. GAs were identified in 95% of samples, with a median of 4 GAs/sample. The most common GAs were TP53 (29%), MLL2 (27%), BCL2 (25%), CDKN2A/B (17%) and CREBBP (14%). Alterations of chromatic modifiers (80%), BCR/NFkB components (51%), and cell cycle pathway (44%) were most common. In our group of unpaired follicular lymphoma samples (N=7 treatment naïve, N=25 treatment exposed), the number of GAs increased with treatment exposure. We found similar gene and biological signatures regardless of prior therapy; however differences emerge in genes of potential clinical relevance. Sequencing profiles augmented or altered the pathologic diagnosis in 11 of 183 (6%) of the cases. Importantly we were able to classify the GAs as actionable, potentially actionable and variants of unclear significance to better define the clinical relevance of targeted genomic sequencing.
Conclusions:
Integration of comprehensive next generation targeted genomic sequencing and clinical analysis in lymphoma provides an opportunity to describe the spectrum and incidence of GAs across different lymphoma subtypes and provide guidance on application of genomic profiling. This work serves to benchmark GAs across all lymphoma subtypes in a clinically relevant population and enables design of basket trials selecting patients based on shared genomic and biologic similarity instead of lymphoma subtype. To our knowledge, this is the largest repository of clinically annotated genomic sequencing in lymphoma.
Table 1Total SpecimensN = 183Median Age at Diagnosis57Range 21 - 84Median Age at Biopsy61Range 21 - 91Sex • Male • Female113 7062% 38%Biospecimen source • Paraffin embedded • Peripheral blood • Marrow aspirate141 28 1477% 15% 8%Patient consent • Prospective consent • Retrospective consent145 3879% 21%Prospectively consented patients (N=145) Median Days to Result Median Age of Sample16 30 days8 - 81 1 day - 6.5 yr
Palomba:Janssen: Consultancy. Gerecitano:Genentech: Consultancy, Other: Advisory Board; AbbVie: Consultancy, Other: Advisory Board. Matasar:Spectrum: Consultancy; Genentech: Consultancy. Straus:Millenium Pharmaceuticals: Research Funding. He:Foundation Medicine, Inc.: Employment, Equity Ownership. Balasubramanian:Foundation Medicine: Employment, Equity Ownership. Stephens:Foundation Medicine, Inc.: Employment, Equity Ownership. Miller:Foundation Medicine: Employment. Levine:Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Consultancy. Younes:Celgene: Honoraria; Johnson and Johnson: Research Funding; Novartis: Research Funding; Bayer: Honoraria; Bristol Meyer Squibb: Honoraria; Sanofi-Aventis: Honoraria; Seattle Genetics: Honoraria, Research Funding; Curis: Research Funding; Janssen: Honoraria; Takeda Millenium: Honoraria; Incyte: Honoraria.
Pre-transplant FDG-PET (PET) normalization is the strongest predictor of outcome following autologous stem cell transplant (ASCT) for patients with relapsed or refractory (rel/ref) Hodgkin lymphoma ...(HL) (Moskowitz, AJ. Blood. 2010 Dec 2;116(23):4934-7). Due to its high efficacy in ASCT failures, we aimed to determine whether brentuximab vedotin (BV) can replace ICE (ifosfamide, carboplatin, etoposide) salvage therapy, increase rate of PET normalization, and enhance referral to ASCT for patients (pts) who fail front-line HL therapy. Here we present our phase II study evaluating a novel salvage strategy for rel/ref HL, an intent-to-treat study of PET-adapted sequential therapy with BV and augmented ICE (augICE) prior to ASCT.
Patients with rel/ref HL who have failed 1 prior regimen are enrolling on this phase II clinical trial. Patients receive weekly brentuximab vedotin (BV) administered at 1.2mg/Kg IV weekly for 3 weeks on and 1 week off for 2 cycles, followed by PET. Patients who achieve normalization of PET (Deauville 2 or less) proceed to ASCT. Patients with PET scores of Deauville 3 or higher receive 2 cycles of augICE prior to consideration for ASCT.
41 of planned 46 patients have enrolled; 34 pts completed salvage therapy, of whom 33 proceeded to ASCT. 28 pts are at least 90 days post-ASCT and represent the focus of this report. These 28 pts include 20 (71%) males, 21 (75%) pts with primary refractory or relapse within 1 year of initial treatment, 11 (39%) with B symptoms at enrollment and 11 (39%) with extranodal disease. Median number CD34+ cells/kg collected were 7.44x 10^6 (2.96 - 31.43x10^6). Disease status prior to ASCT was CR (Deauville 2) for 27 pts and PR (Deauville 3) for 1 pt. Salvage therapy for pts in CR prior to ASCT include BV alone (9), BV followed by augICE (16), and BV followed by augICE (with Deauville 4 response) followed by involved field radiation to achieve CR (2). The 1 patient in PR prior to ASCT received BV followed by augICE. Conditioning regimens included BEAM (9), CBV( 9), and high dose chemoradiotherapy (10). Early (within 90 days) transplant-related toxicities include grade 2 pneumonitis (3pts) and grade 3 acute kidney injury (1pt); late toxicities include grade 3 esophageal stenosis (1pt), grade 3 acute kidney injury (1pt), and 1 death (7 months post ASCT) due to progressive multifocal leukoencephalopathy. After a median follow-up of 9.5 months post-ASCT (range 3.3-15.6 months), 2 of 28 pts have progressed (at 2.7 and 4.3 months post ASCT respectively). One achieved a second CR with BV and proceeded to allogeneic stem cell transplant (alloSCT); the second achieved near CR following GND (gemcitabine, vinorelbine, Doxil) and proceeded to alloSCT.
PET-adapted sequential salvage therapy with BV followed by augICE produces high CR rates, adequate stem cell collection, and facilitates referral to ASCT for virtually all pts. Updated results will be presented at the meeting.
Moskowitz:Seattle Genetics: Research Funding. Off Label Use: Brentuximab vedotin is approved for treatment of Hodgkin lymphoma following failure of 2 multi-agent regimens or autologous stem cell transplant. This study is evaluating the use of brentuximab vedotin in the pre-transplant setting for Hodgkin lymphoma. Schoder:Seattle Genetics: Research Funding. Hamlin:Seattle Genetics : Consultancy, Honoraria. Horwitz:Millennium: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Moskowitz:Seattle Genetics: Research Funding.
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Background: Use of the proteasome inhibitor bortezomib has been anecdotally noted to be associated with a number of ocular side effects, including chalazion, vascular events and conjunctivitis. ...This type of adverse event has not been characterized in the literature on bortezomib to date. In this retrospective study, we report the incidence of bortezomib-associated eye disease among patients treated at Memorial Sloan Kettering Cancer Center, and identify risk factors for development of ocular side effects.
Methods: A retrospective review was conducted to identify all patients treated with bortezomib at Memorial Sloan Kettering Cancer Center between February 1999 and August 2013. Patients with bortezomib-associated eye disease were identified using ICD-9 diagnosis codes as shown in table 1. Patients were included if eye disease occurred after the first date of bortezomib administration and until one week after the last date of administration. Other data collected included dates, total dose and route of bortezomib administration. To identify statistically significant correlations between disease incidence and other variables, FisherÕs exact test was applied to discrete variables, and Wilcoxon rank sum test was applied to continuous variables.
Table 1Diagnosis codes used for identification of bortezomib-associated ocular disease.Diagnosis codes identified as “chalazion”Diagnosis codes identified as “other eye disease”Hordeolum Externum Blepharitis Chalazion BlepharoconjunctivitisConjunctival Hemorrhage Conjunctivitis Acute Conjunctivitis Optic Neuritis Conjunctiva Vascular Abnormality Retinal Hemorrhage Eye Swelling or Mass Purulent Endophthalmitis Disorders of Eyelid Keratoconjunctivitis Arterial Branch Occlusion Retinal Vasculitis Vitreous Hemorrhage Mucopurulent Conjunctivitis Retinal Vascular Occlusion Conjunctivitis NEC Inflammation Eyelid NOS
Results: 1122 patients were administered bortezomib between February 1999 and August 2013 at Memorial Sloan Kettering Cancer Center. Patients received bortezomib as IV (78.5%) or SC (19.9%) injections (1.6% (18 patients) received both IV and SC injections). Total doses of bortezomib ranged from 5.1mg to 505.2mg (median dose 60.56 mg). 53 patients (4.7%) developed eye disease during the period of bortezomib administration. Of these, 23 (2.0%) developed chalazion, while 30 (2.7%) developed other eye disease. The median dose administered prior to the first episode of eye disease was 34.41mg (range 2.10-147.40mg). The median time from first dose of bortezomib to the first event was 106 days (range 1-2154 days). Incidence of eye disease was positively correlated both with higher cumulative dose of bortezomib (p<0.0001) and with greater total time on bortezomib (p<0.0001). In addition, patients who received bortezomib both intravenously and subcutaneously were statistically more likely to develop eye disease than those who received bortezomib only via one route (p<0.0001). Patients who were documented as having relevant eye disease preceding bortezomib administration were not found to be more likely to develop eye disease during bortezomib therapy than those with no prior history of eye disease. There was also no correlation between the incidence of multiple episodes of eye disease during bortezomib therapy and any of the variables tested.
Conclusions: Bortezomib is an important part of treatment regimens for many patients with multiple myeloma and lymphoma. However, its use is associated with side effects, most notably neuropathy, which sometimes necessitates dose reduction or drug discontinuation. In this study we document the incidence of bortezomib-associated eye disease in the total cohort of patients treated with bortezomib over 14.5 years at a large academic medical center. We find that the development of eye disease is associated with higher total dose and greater duration of bortezomib administration.
Moskowitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Research Funding; Merck: Research Funding. Hamlin:Gilead, Spectrum, Seattle Genetics, Genentech: Consultancy; Spectrum, GSK, Jansen and Jansen/Pharmacyclics, Portola, Seattle Genetics: Research Funding.
Background:
Several retrospective series have characterized the genomic landscape in many lymphoma subtypes. However, as these studies used different sequencing methods, depth of coverage, and ...specimen source, the incidence of alterations in many lymphoma subtypes remain unknown. Even when common genomic alterations were identified within a lymphoma subtype, the incidence and spectrum of the alterations varied. In this study, we prospectively examined the incidence of genomic alterations across different lymphoma subtypes using the Foundation One Heme (FOH) assay.
Methods:
FOH testing was offered to patients in routine clinical practice. Formalin-fixed paraffin-embedded (FFPE) tissue, bone marrow aspirate or peripheral blood were examined using the FOH targeted sequencing assay. Hybridization capture from 405 cancer related genes and 31 genes commonly rearranged in cancer was applied to ≥ 50ng of DNA extracted from 49 tumor specimens and sequenced to high, uniform coverage. Genomic alterations, which include: base substitutions, small insertions and deletions (indels), rearrangements, and copy number alterations, were determined.
Results:
Specimens from 48 non-consecutive patients with lymphoma (5 new diagnoses, 42 relapsed) were prospectively examined. Represented subtypes include DLBCL (44%), FL (17%), CLL (10%), MCL (10%), MZL (8%), T cell lymphoma (4%), and Hodgkin lymphoma (2%). Median age of diagnosis was 48.1 years (range 29.5-80.6) with a male predominance (69%). The majority (75%) had advanced stage disease at diagnosis, with a median of 3 lines of therapy (range 1-12, n=44). Forty-nine specimens, (1 patient with 2 specimens) were collected from FFPE (70%), peripheral blood (22%) or bone marrow aspirate (8%). Reports resulted after a median 28 days (range 10-48 days) from the time specimens were shipped to Foundation Medicine.
Across 48 patients, 90 distinct alterations were detected with a median of 5 alterations/patient (range 0-11). Genomic alterations were more commonly observed in relapsed aggressive lymphoma compared to relapsed indolent lymphoma (median 6.4 vs 4 alterations/patient, p<0.05) or in newly diagnosed patients. The most common alteration was various IgH translocations (46%) and alterations in cyclin dependent kinases (CDK) genes (CDKN2A, CDKN2B and CDKN2C) (31%). Alterations of p53 (23%) and MLL2 (21%) were also frequently observed. Several rare alterations not previously described in primary lymphomas were identified, including alterations in ATRX, CDH1, MSH6, pyruvate carboxylase, and thrombospondin receptor (CD36). Alterations associated with approved agents or clinical trials were found in 89% of patients and were more frequent in relapsed aggressive B-cell NHL (median 2/patient) versus relapsed indolent B-cell NHL (median 1/patient, p<0.02). Commonly identified actionable alterations included CDK alterations in DLBCL, MCL and CLL, and alterations in the PI3K oncogenic pathway in DLBCL, FL and MZL.
Conclusion:
Application of a comprehensive next generation genomic sequencing assay provides an opportunity to both describe the spectrum and compare the incidence of genetic alterations across different lymphoma subtypes. Preliminary data suggest the vast majority of patients have one or more genomic alterations linked to approved agents or clinical trials. Data collection is ongoing. While the true incidence of each genomic alteration is not defined, the dataset provides the frequency of genomic alterations in a clinically relevant population. Moreover, these data will facilitate design of clinical trials by providing the opportunity to select patients based on shared genomic alterations rather than lymphoma subtype. Table 1Clinical characteristics, N=48Age at diagnosis57.1 (29.5-80.6)N (% of patients)Sex Male Female33 (68.7%)16 (33.3%)Subtype DLBCL21 (43.8%)FL8 (16.7%)CLL5 (10.4%)MCL5 (10.4%)MZL4 (8.3%)T cell lymphoma2 (4.2%)Hodgkin lymphoma1 (2.1%)Other3 (6.3%)Stage at Diagnosis I/II III/IV Not recorded10 (20.8%)36 (75.0%)2 (4.2%)Biopsy sent At diagnosis At relapse6 (12.5%)42 (87.5%)Response to First line Therapy Near CR or CR PR SD PD Unknown22 (45.8%)9 (18.8%)5 (10.4%)3 (8.3%)8 (16.7%)Genomic Alterations with clinical value Potentially Prognostic Potentially Actionable Alterations previously not well described37 (77.0%)43 (89.6%)7 (14.6%)
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Moskowitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Research Funding; Merck: Research Funding. Horwitz:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Infinity: Research Funding; KiowaKirin: Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Research Funding; Amgen: Consultancy; BristolMyers Squibb,: Consultancy; Jannsen: Consultancy. Hamlin:Gilead, Spectrum, Seattle Genetics, Genentech: Consultancy; Spectrum, GSK, Jansen and Jansen/Pharmacyclics, Portola, Seattle Genetics: Research Funding. Matasar:Genentech: Consultancy; Spectrum: Consultancy. Miller:Foundation Medicine: Employment. Stephens:Foundation Medicine: Employment, Equity Ownership. He:Foundation Medicine: Employment. Younes:Novartis: Research Funding; J & J: Research Funding; Curis: Research Funding; Bayer; Bristol Meyer Squibb; Celgene; Incyte; Janssen R & D; Sanofi; Seattle Genetics; Takeda Millenium: Honoraria.
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