Kaminski, Mark

Novel targeted therapies (small molecule inhibitors, antibody–drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton’s tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.

Abstract Although TP53 is commonly mutated in transformed follicular lymphoma, mutations are reported in <5% of pretreatment follicular lymphoma (FL) specimens. We assayed archival follicular B-cell non-Hodgkin lymphoma specimens from a completed clinical trial, Southwest Oncology Group S0016, a phase 3 randomized intergroup trial of CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone) chemotherapy plus R-CHOP (rituximab-CHOP) compared with CHOP chemotherapy plus 131-iodine tositumomab (radioimmunotherapy [RIT]-CHOP). Subclonal TP53 mutations (median allele frequency 0.02) were found in 25% of diagnostic FL specimens and in 27% of a separate validation cohort. In the R-CHOP arm, pathogenic TP53 mutations were not associated with progression-free survival (PFS) (10-year PFS 43% vs 44%). In contrast, among patients with no detectable pathogenic TP53 mutation, RIT-CHOP was associated with a longer PFS than with R-CHOP (10-year PFS 67% vs 44%; hazard ratio = 0.49; P = .008). No relationship was detected between PFS and the extent of activation-induced cytidine deaminase (AICDA)–mediated heterogeneity. In summary, subclonal TP53 mutations are common in FL and are a distinct phenomenon from AICDA-mediated genetic heterogeneity. The absence of a detectable subclonal mutation in TP53 defined a population that particularly benefited from RIT.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte–predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody–drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1–mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.

Abstract Background: Southwest Oncology Group (SWOG) S0016 was a phase III randomized study that compared safety and efficacy of cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (CHOP-R) with CHOP followed by consolidation with (131) iodine-tositumomab radioimmunotherapy (CHOP-RIT) for previously untreated follicular lymphoma (FL) patients. As reported previously, the study demonstrated excellent outcomes in both arms with 2-year progression-free survival (PFS) of 76% and 80% and 2-year overall-survival (OS) of 97% and 93% in the CHOP-R and CHOP-RIT arms, respectively. (Press. et al. JCO, 2012) We now report the long term outcome of patients who were treated on the S0016 study. Methods: Between 2001 and 2008, 531 previously untreated advanced follicular lymphoma patients were randomized to receive either 6 cycles of CHOP every 3 weeks with 6 doses of rituximab (CHOP-R) or 6 cycles of CHOP every 3 weeks followed by RIT. Patients with advanced-stage disease (bulky stage II, III or IV) with any pathologic grade (1, 2 or 3) were eligible. Results: Patients on CHOP-R (n=264) and CHOP-RIT (n=267) arms had balanced baseline characteristics including age (median 54.5 vs. 53.4 years), presence of B symptoms (29% vs. 26%), pathologic grade 3 (8% vs. 9%), "high" FLIPI risk group (22% vs. 26%), stage IV disease (59% vs. 63%), elevated β2M (53% vs. 55%), bone marrow involvement (56% vs. 55%) and bulky disease (24% vs. 26%). Objective remissions were documented in 226 of 267 eligible patients treated with CHOP-R (85%) and in 226 of 264 patients with CHOP-RIT (86%). Complete remission (CR) rate was 40% in the CHOP-R and 45% in the CHOP-RIT arm. Neutropenia was the most common adverse event (AE) in both arms (48% vs. 51%). Rate of grade 3-5 AEs were not different except for thrombocytopenia which was more common in the CHOP-RIT group (18% vs. 2%). After a median follow-up of 9.6 years (range 0.1 - 14.4 years), the estimated 10-year PFS was 42% (95% CI: 35.6%, 48.5%) in the CHOP-R arm and 57% (95% CI: 50.5%, 63.2%) in the CHOP-RIT arm (p-value = 0.01). 51% of responders on the CHOP-R arm and 38% of responders on the CHOP-RIT arm have relapsed (p-value= 0.01). The estimated 2-year relapse-free survival was 76% for CHOP-R patients and 81% for CHOP-RIT patients (p-value=0.15). There were 48 deaths in the CHOP+R arm and 59 deaths in the CHOP-RIT arm with an estimated 10-year OS of 82% (95% CI: 76.3%, 86.4%) with CHOP-R and 77% (95% CI: 70.5%, 81.4%) with CHOP-RIT (p-value = 0.18). (Figure-1) During the follow-up, 41 patients (15.4%) in the CHOP-R arm and 37 patients (14%) in the CHOP-RIT arm developed secondary malignancies. MDS/AML were more common in the CHOP-RIT arm (11 patients; 4.2%) compared to CHOP-R arm (5 patients; 1.9%) with a relative risk of 2.2 (95% CI: 0.8-6.3) (P-value 0.12). Conclusion: With almost 10 years of follow-up, patients with FL treated on protocol S0016 show outstanding survival in both CHOP-R and CHOP-RIT arms, and represent the best published long-term outcomes to date in this disease. Indeed, almost half of patients enrolled still remain progression-free, confirming registry experiences. While CHOP-RIT provided significantly longer PFS and lower relapse rate compared to CHOP-R in our study, the OS rate was not different between 2 arms due in part to higher incidence of fatal MDS/AML in the CHOP-RIT group, emphasizing the importance of long-term follow-up, and calling into question the validity of PFS as a surrogate for OS in this setting. Given these outstanding outcomes, we believe chemoimmunotherapy should remain the standard induction approach for patients with high-risk FL until long-term follow-up of alternative approaches demonstrates superiority. Support: NIH/NCI grants CA180888, CA180819, CA180821 and in part by GlaxoSmithKline Disclosures Shadman: Emergent: Research Funding; Acerta: Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding. Rimsza:NCI/NIH: Patents & Royalties: L.M. Rimsza is a co-inventor on a provisional patent, owned by the NCI of the NIH, using Nanostring technology for determining cell of origin in DLBCL.. Gopal:Paid Consultancy- Gilead, Janssen, Seattle Genetics, Spectrum, Research funding- Gilead, Janssen, Pfizer, BMS, Merck, Teva, Takeda, Spectrum, Seattle Genetics: Consultancy, Honoraria, Research Funding. Maloney:Juno Therapeutics: Research Funding; Genentech/Roche: Honoraria. Cheson:Gilead: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. Smith:Amgen: Other: Educational lecture to sales force; TGTX: Consultancy; Celgene: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; Portola: Consultancy; Juno: Consultancy; Gilead: Consultancy; AbbVie: Consultancy. Fisher:Seattle Genetics: Consultancy; Gilead: Consultancy; Johnson and Johnson: Consultancy. Friedberg:Bayer: Other: Data Safety Monitoring Committee. Press:Roche / Genentech: Consultancy, Research Funding.

Background: Activation induced cytidine deaminase (AICDA or AID) causes somatic hypermutation (SHM) of the immunoglobulin heavy chain variable genes (IGHV). It has been widely hypothesized that aberrant targeting of AICDA creates additional driver mutations and intra-clonal heterogeneity which enables clonal evolution and thus disease progression. This hypothesis predicts that greater AICDA-mediated intraclonal heterogeneity will be associated with shortened progression free survival (PFS). To definitively test this hypothesis that AICDA-mediated heterogeneity is linked to risk of progression, we evaluated available samples from the largest US-based phase 3 trial of untreated follicular lymphoma patients treated with CHOP-based therapies, SWOG trial S0016. Methods: We have previously shown that ultradeep sequencing of two genes, the expressed IGHV and the 5' UTR of the translocated BCL2 allele, provide unrelated measures of AICDA-mediated genetic heterogeneity (Spence, J Immunol. 2014). Furthermore, the number of AICDA-mediated mutations in the 5' UTR of BCL2, but not in IGHV, correlates with the number of AICDA-mediated mutations at other known AICDA sites throughout the genome (such as PIM1, BCL6, RHOA, etc). Genomic DNA was prepared from all available paraffin-embedded specimens. Ultra-deep, amplicon-based sequencing (~10,000x) with internal controls to establish specimen-specific signal-to-noise parameters allowed sensitive and specific detection of sequence variants at 0.2% (FDR 1%). Results: For subjects with (152) and without (419) available specimens, the median duration of follow-up (11.3 years), the number of patients who progressed (60%), and other patient characteristics (demographics, histology, stage, FLIPI) were indistinguishable. Sequencing data that fulfilled strict quality metrics for low frequency variants were obtained for >75% of the specimens (114 for BCL2; 120 for IGHV); further analysis was restricted to these subjects. The extent of intraclonal variation within both the IGHV and the 5' UTR of BCL2 was highly variable. For BCL2, a median of 7 mutations/case were detected (range 0-61); the mutations were highly skewed to the RCYW motif (p<0.001), the preferred target of AICDA. These mutations defined a median of 5 subclones/case (range 1-22). The clonal IGHV was somatically mutated (<0.98 germline identity) in 94% of samples (median 0.89). For IGHV, a median of 113 subclones/case were detected (range 0-1531). Consistent with our prior study, no correlation was seen between the number of mutations detected in the IGHV and BCL2 or the number of subclones defined by IGHV and BCL2. Neither the number of mutations in nor the number of subclones defined by BCL2 or IGHV were prognostic. Cox regression showed no relationship between PFS and mutation number or subclone count based on either IGHV or BCL2 (hazard ratios are indistinguishable from 1; parameters were treated both as a continuous variables and dichotomized as quartiles). Furthermore, receiver operator curves did not suggest a cut point for any of these measures that would predict disease progression at any time (areas under the curve are indistinguishable from 0.5). Conclusions: Several measures of AICDA-mediated mutation and resulting subclonal heterogeneity were not found to be prognostic in previously untreated, advanced stage FL treated with CHOP-based regimens. In contrast, AICDA-mediated mutations have been reported to accrue during transformation from low grade FL to large cell lymphoma. This paradox calls for a more refined model to explain the role of AICDA in the progression of FL. Support: NIH/NCI grants U10CA180888, U10CA180819, U10CA180821, R21CA198072(WRB); and in part by GlaxoSmithKline. Disclosures Rimsza: NanoSting: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution]. Leonard:Bayer Corporation: Consultancy; AstraZeneca: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Sandoz: Consultancy; ADC Therapeutics: Consultancy; Miltenyi: Consultancy; BeiGene: Consultancy; Sutro Biopharma: Consultancy; Celgene: Consultancy; Nordic Nanovector: Consultancy; Gilead: Consultancy; Karyopharm Therapeutics: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Bayer Corporation: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Merck: Consultancy; MorphoSys: Consultancy; AstraZeneca: Consultancy; Epizyme, Inc: Consultancy; Akcea Therapeutics: Consultancy; Miltenyi: Consultancy; ADC Therapeutics: Consultancy; BeiGene: Consultancy; Karyopharm Therapeutics: Consultancy; Merck: Consultancy; Sandoz: Consultancy; Gilead: Consultancy; Akcea Therapeutics: Consultancy; MorphoSys: Consultancy; Nordic Nanovector: Consultancy; Sutro Biopharma: Consultancy. Fisher:Celgene: Consultancy; Barclays: Honoraria; AstraZeneca: Consultancy; prIME: Honoraria. Smith:Portola Pharmaceuticals: Research Funding. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee.

Abstract Background: TP53 is reported to be mutated in about 20% of transformed and/or relapsed follicular lymphoma (FL) specimens but in fewer than 5% of pre-treatment FL specimens. The disparity in the reported prevalence of TP53 mutations at diagnosis versus transformation/relapse suggests that TP53-mutated subpopulations, which are too small for detection, might be present at the time of diagnosis in tumors destined to relapse. To test this hypothesis, we developed a more sensitive assay for TP53 mutations and applied the assay to SWOG S0016, a phase III randomized intergroup trial of CHOP chemotherapy plus rituximab (R-CHOP) compared with CHOP chemotherapy plus 131-iodine tositumomab (radio-immunotherapy (RIT)-CHOP) for previously untreated follicular non-Hodgkin lymphoma. Methods: Formalin Fixed Paraffin Embedded (FFPE) biopsies were available for 213/571 enrollees. 147 samples fulfilled inclusion criteria: 1) sufficient DNA for 3 PCR-reactions each at 250 ng gDNA (~40,000 diploid equivalents; 5'UTR and all exons of TP53 were amplified in 3 multiplexed reactions to obtain consistently sized amplicons); 2) appropriate size distribution of DNA products after library preparation (~300 bp). To maintain specificity with high read-coverage, each PCR included an amplicon of eUCR41 (eukaryotic ultra-conserved region) to provide specimen-specific metrics of DNA-damage and sequencing noise. Sequence reads (Ilumina 300 nt paired end) were merged, mapped to reference (>10,000x coverage), and single nucleotide variants (SNV) were called using LoFreq based on case and base-change error thresholds (from the eUCR41 data). Pathogenicity of each TP53 sequence variant was based on a consensus of the Seshat and IARC databases. Variant Allele Frequencies (VAF) of passenger SNVs (5'UTR of BCl2) allowed normalization to the minimum tumor fraction. Results: A total of 73 SNVs within TP53 were detected in 147 FFPE specimens (80 RIT-CHOP; 67 R-CHOP); the SNVs in 34 patients (23%; 17-30% 95% CI) created missense or nonsense mutations which met criteria for pathogenicity. The VAF for these SNVs ranged from 0.008 to 0.7 (median 0.02) and 82% had a VAF of less than 0.1. Among the 34 patients with a pathogenic TP53 mutation, no relationship was observed between the VAF and time to progression. The group of 34 patients with a pathogenic TP53 mutation had a shortened Progression Free Survival (PFS) (HR=1.68; p=0.035) and Overall Survival (OS) (HR=2.02; p=0.045). However, the relationship between TP53 mutations and PFS depended on treatment: for the R-CHOP arm, the pathogenic TP53 mutations were not associated with PFS (10-year PFS 44% vs 42%); in contrast, for the RIT-CHOP arm, pathogenic TP53 mutations were associated with a shortened PFS (10 year PFS 27% vs 65%; HR=3.2; p=0.001) (see figure). Furthermore, among patients with no detectable pathogenic TP53 mutation, RIT-CHOP was associated with a longer PFS than R-CHOP (10 year PFS 65% vs 44%; HR=0.58; p=0.046). Conclusions: Using specimens from SWOG S0016, we find that pathogenic TP53 mutations are present in 23% of untreated, advanced stage FL specimens, a considerably higher fraction than reports based on less sensitive methods. Long term follow-up of S0016 has shown that the RIT-CHOP arm had a small but statistically significant improvement in the 10-year PFS compared to R-CHOP (Shadman 2018). We now show that the interaction of RIT and TP53-status substantially affects PFS. First, in the cohort without a detectable TP53 mutation, a longer PFS was observed with RIT-CHOP than R-CHOP. Second, in the cohort with a detectable TP53 mutation, a shorter PFS was observed with RIT-CHOP than R-CHOP. This observation is consistent with the well-defined role of TP53 as the mediator of the apoptotic response to ionizing radiation. Therefore, an assay which detects subclonal populations with TP53 mutations defines two cohorts for which the inclusion of radio-immunotherapy had substantial and opposite effects on the risk of progression. Finally, this identification of subclonal TP53 mutations as a predictive biomarker highlights that preserving specimens from clinical trials to mine with new technologies can be key to the advancement of precision medicine. We wish to recognize the late Dr. Oliver Press for his central role in S0016 and his many contributions to SWOG. Support: NIH/NCI grants U10CA180888, U10CA180819, U10CA180821, R21CA198072 (RB); and in part by GlaxoSmithKline. Figure. Figure. Disclosures Rimsza: NanoString: Other: Inventor on the patent for the Lymph2Cx assay. Leonard:Juno: Consultancy; ADC Therapeutics: Consultancy; Pfizer: Consultancy; Gilead: Consultancy; Sutro: Consultancy; Biotest: Consultancy; United Therapeutics: Consultancy; BMS: Consultancy; Bayer: Consultancy; Genentech/Roche: Consultancy; Celgene: Consultancy; MEI Pharma: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Friedberg:Bayer: Honoraria.

Abstract Background: The pivotal phase 3 ECHELON-1 study demonstrated superior efficacy of brentuximab vedotin plus doxorubicin, vinblastine and dacarbazine (A+AVD) versus doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in patients with previously untreated advanced stage classical Hodgkin lymphoma (cHL) with a 2-year modified progression-free survival (mPFS) of 82.1% in the A+AVD group versus 77.2% in the ABVD group (Hazard Ratio=0.77; 95% confidence interval [CI] 0.60, 0.98; p=0.04). PN is a known toxicity associated with anti-mitotic agents, including vinblastine and the MMAE component of brentuximab vedotin. In the ECHELON-1 study, the incidence of any-grade PN events was 67% (442 of 662 patients) and 43% (286 of 659 patients) in the A+AVD and ABVD arms, respectively; the incidence of grade ≥3 PN was 11% and 2%, respectively. At the time of the initial analysis, 67% of A+AVD-treated patients had either resolution (43%) or improvement (24%) of PN events. A total of the 92% of ongoing PN events were grade 1 (64%) or grade 2 (29%). Here, we report rates of PN resolution and improvement in patients participating in the ECHELON-1 study after long-term follow-up. Methods: Patients with Stage III or IV cHL were randomized 1:1 to receive up to six cycles of A+AVD (n=664) or ABVD (n=670). Pre-existing PN was an exclusion factor at study entry. Peripheral neuropathy was determined on the basis of a standardized MedDRA query; patients who developed PN were monitored throughout the study and those with ongoing PN at end of treatment were followed for resolution or improvement during the post-treatment follow-up period; follow-up visits were scheduled for every 12 weeks ±1 week until 36 months, then every 6 months until study closure. PN resolution was defined as completely resolved and improvement was defined as improved by ≥1 grade from worst grade as of the latest assessment. Results: At the time of the primary analysis, 51% (226/442) and 61% (174/286) of patients in the A+AVD and ABVD arms, respectively, had resolution or improvement of PN events at EOT. Upon continued follow-up (~10 additional months) for approximately 30 months (range 0-78.5) after end of treatment, 76% (335/442) of patients with PN in the A+AVD arm had either complete resolution (59%, 260/442) or improvement (17%, 75/442) of their PN events compared with 82% (234/286) with either resolution (72%) or improvement (10%) in the ABVD arm. In the A+AVD arm, 90% of ongoing PN cases (n=182) were grade 1/2; grade 1=58% (n=106), grade 2=32% (n=58). Residual grade 3 PN was reported in 9% (n=17) of patients (1 patient with grade 4 PN died before resolution). In the ABVD arm, residual PN (n=81) was grade 1 (65%; n=53), grade 2 (30%; n=24), and grade 3 (5%; n=4). For the subset of patients with PN that had not resolved by end of treatment, the median time to resolution of all PN events from AE start date was 28 weeks for A+AVD and 14 weeks for ABVD, the median time to improvement of PN was 39 weeks for A+AVD and 18.5 weeks for ABVD. Conclusions: After approximately 2.5 years of continued follow-up, PN continues to resolve and improve for patients who were treated with A+AVD or ABVD in the ECHELON-1 study. In both study arms, the majority of ongoing PN cases are grade 1 or grade 2. Further follow-up is ongoing. Disclosures Radford: Celgene: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Speakers Bureau; GlaxoSmithKline: Equity Ownership; Takeda: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; AstraZeneca: Equity Ownership. Connors:Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Roche Canada: Research Funding; Genentech: Research Funding; Cephalon: Research Funding; Bristol Myers-Squibb: Research Funding; Janssen: Research Funding; Bayer Healthcare: Research Funding; NanoString Technologies: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Merck: Research Funding; F Hoffmann-La Roche: Research Funding; Amgen: Research Funding; Lilly: Research Funding. Younes:Astra Zeneca: Research Funding; J&J: Research Funding; Curis: Research Funding; BMS: Honoraria, Research Funding; Bayer: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Merck: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Novartis: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Gallamini:Takeda: Consultancy, Speakers Bureau. Ansell:Affimed: Research Funding; Merck & Co: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding. Gopal:Aptevo: Consultancy; Janssen: Consultancy, Research Funding; Merck: Research Funding; Gilead: Consultancy, Research Funding; Brim: Consultancy; Spectrum: Research Funding; Takeda: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy; Teva: Research Funding; Asana: Consultancy. Flinn:Trillium: Research Funding; Calithera: Research Funding; Forma: Research Funding; Portola: Research Funding; Verastem: Research Funding; Janssen: Research Funding; Infinity: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Constellation: Research Funding; Merck: Research Funding; Curis: Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Incyte: Research Funding; ArQule: Research Funding; Verastem: Consultancy, Research Funding; Celgene: Research Funding; Agios: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Pfizer: Research Funding; TG Therapeutics: Research Funding; Kite: Research Funding; BeiGene: Research Funding. Pettengell:CTI: Honoraria; Pfizer: Honoraria; Roche: Honoraria; Servier: Honoraria; Takeda: Honoraria. Dlugosz-Danecka:Servier: Consultancy; Roche: Consultancy. Engley:Seattle Genetics: Employment. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Liu:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Purevjal:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Miao:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Gautam:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Kuruvilla:Janssen: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Foundation: Research Funding; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Karyopharm: Honoraria; Celgene: Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria; Merck: Consultancy, Honoraria; Amgen: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Leukemia and Lymphoma Society Canada: Research Funding.