bluuebunny/crossref_metadata_2025 huggingface dataset:
Discontinuation of tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia in chronic phase (CML-CP) in US clinical practice after guideline updates.
Authors: Atallah Ehab L. , Sadek Islam , Maegawa Rodrigo O. , Cao Xiting , Latremouille-Viau Dominick , Pivneva Irina , Rossi Carmine , Guerin Annie , Kota Vamsi
Published: May 2020

7548

Background: NCCN CML practice guidelines were updated in 11/2016 and in 9/2019 to include considerations for discontinuation of TKI therapy in patients (pts) with CML-CP. This study characterized TKI discontinuation practices in the US after these updates and drew parallels with a similar study conducted prior to these guideline updates (Ritchie et al. Leuk Lymphoma. 2019). Methods: Pt charts of adult CML-CP pts with TKI discontinuation (1/2017-12/2018) outside a clinical trial after achieving an adequate response were abstracted (11/2019-12/2019) via an online case report form by US oncologists/hematologists. Physicians’ assessment of adequate response (TKI duration, molecular response [MR], MR duration) and relapse were described. Results: 61 physicians (academic: 43%; community-based practices: 57%) contributed 153 pt charts. Most physicians were from large practices (57%), had > 10 years (y) experience since completing subspecialty training (59%), and treated a median of 30 CML pts in the last 2y; 56% did not have access to precise molecular response monitoring for BCR-ABL of ≥4.5 log when attempting TKI discontinuation. Pts with TKI discontinuation had mean age 56 years, were mostly male (60%), white (69%), and had TKI discontinued in first-line (96%). Most common reasons for TKI discontinuation were pt request (54%) and adverse events (18%), besides achieving an adequate response. Physicians’ assessment of adequate response for TKI discontinuation are reported in the Table. 21% of pts (academic: 12%; community: 30%) relapsed after TKI discontinuation (treatment-free remission [TFR] failure; 66% relapsed within 1y). Conclusions: Although NCCN CML practice guidelines provide guidance for discontinuation of TKI therapy, there remains heterogeneity in US practice and TKI discontinuation is predominantly attempted in first-line (similar to Ritchie et al. 2019). TKI discontinuation is being practiced without adequate sensitive tools mandated by practice guidelines to monitor response. Broader application of practice guidelines for optimal TKI therapy discontinuation in CML-CP pts is needed, particularly in community-based practices, to improve long-term TFR rates. [Table: see text]
An independent review of arterial occlusive events (AOEs) in the ponatinib (PON) phase II PACE trial (NCT01207440) in patients (pts) with Ph+ leukemia.
Authors: Januzzi James L , Garasic Joseph , Kasner Scott , McDonald Vickie , Petrie Mark C , Seltzer Jonathan , Mauro Michael J. , Croce Kevin , Berman Ellin , Deininger Michael W.N. , Hochhaus Andreas , Pinilla-Ibarz Javier , Nicolini Franck E. , Kim Dong-Wook , DeAngelo Daniel J. , Kantarjian Hagop M. , Xu Jing , Srivastava Shouryadeep , Naranjo Daniel , Cortes Jorge E.
Published: May 2020

7550

Background: The final 5-year analysis of the PACE trial, which evaluated use of PON in pts with refractory chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia, identified a 25% incidence of AOEs (Cortes, Blood 2018) from a search utilizing > 400 preferred terms (PTs) defined by MedDRA and related to vascular ischemia or thrombosis. We performed a retrospective review using an independent Endpoint Adjudication Committee (EAC) to better understand clinically relevant AOE rates in PACE. Methods: The EAC consisted of 3 cardiologists, 1 hematologist, and 1 neurologist to review AOEs (identified using > 500 terms) in PACE using American College of Cardiology/American Heart Association (ACC/AHA) definitions for major adverse cardiovascular events (MACE), and to review pt profiles including event, severity, concomitant medication, and hospitalization data. These results were compared with MedDRA PT search results. The EAC was blind to dose, dose modification, and investigator causality opinion. Results: The PACE review included 449 heavily pretreated pts with Ph+ leukemia (median age, 59 y; 47% female; 93% ≥2 tyrosine kinase inhibitors). With median follow-up 37.3 mo in all pts, AOEs were identified by MedDRA PT search in 25% of pts and EAC-verified in 17% (Table). In each category listed in the table, the EAC verification identified fewer AOEs and serious AOEs. Serious AOEs were identified by MedDRA PT search in 20% of pts and EAC-verified in 16%. Events that were not associated with a cardiovascular etiology or failed to meet the MACE definition set forth by the ACC/AHA were determined by the EAC not to be an AOE. Conclusions: The independent EAC review showed a lower rate of clinically relevant AOEs than was reported in PACE, suggesting an earlier possible overestimation that may not accurately reflect the risk of AOEs with PON. The ongoing PON dose-ranging OPTIC study will further evaluate the PON risk:benefit profile. Clinical trial information: NCT01207440 . [Table: see text]
Molecular diagnostic testing patterns in patients (pts) with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) in the Connect MDS/AML Registry.
Authors: George Tracy , Patel Jay L. , Abedi Mehrdad , Cogle Christopher R. , Erba Harry Paul , Garcia-Manero Guillermo , Grinblatt David L. , Kiselev Pavel , Komrokji Rami S. , Louis Chrystal Ursula , Maciejewski Jaroslaw P. , Nifenecker Melissa , Pollyea Daniel Aaron , Roboz Gail J. , Savona Michael R. , Scott Bart L. , Sekeres Mikkael A. , Steensma David P. , Thompson Michael A. , Foucar Kathryn
Published: May 2020

7553

Background: MDS and AML diagnosis requires an integrated approach including morphologic, cytogenetic and molecular testing. The WHO classification criteria for MDS and AML diagnosis were updated in 2016; however, the impact on clinical practice is unclear. We investigated molecular testing patterns for pts with MDS or AML treated in academic (AC) or community/government (CO/GOV)-based centers in the Connect MDS/AML Registry. Methods: The Connect MDS/AML Disease Registry (NCT01688011) is a large ongoing, US, multicenter, prospective observational cohort study of pts with MDS (aged ≥ 18 yrs) or AML (aged ≥ 55 yrs). Patient data were collected for this analysis upon enrollment from 12 Dec 2013 to 13 Dec 2019, the analysis cut-off. Differences in molecular testing between MDS and AML pts were evaluated and logistic regression used to assess factors associated with increased molecular testing. Results: As of 13 Dec 2019, 800 MDS pts and 626 AML pts were enrolled; median age was 74 vs 71 yrs, 66.3% vs 61.5% were male, and 73.5% vs 60.2% were insured by Medicare/Medicaid. A greater proportion of AML pts (77.5%) had molecular testing vs MDS pts (29.1%). Of 380 MDS pts enrolled before 2017 (< 2017), 16.8% had molecular testing, increasing to 40.2% in 420 MDS pts enrolled from 2017 onward (≥ 2017). Of 289 AML pts enrolled < 2017, 68.9% had molecular testing, increasing to 84.9% in 337 AML pts enrolled ≥ 2017. Mean number of mutations tested increased between < 2017 and ≥ 2017 from 6.9 to 12.7 in MDS pts and from 6.1 to 10.4 in AML pts. Of the 11 mutations most frequently tested ≥ 2017 in MDS and AML pts, 0% and 36%, respectively, have FDA-approved targeted therapies. Gene mutations tested differed between MDS and AML pts; ASXL1 was most frequently tested in MDS pts (68.2%) and FLT3-ITD in AML pts (89.7%). Testing rates increased between < 2017 and ≥ 2017 for ASXL1 from 48.4% to 75.7% in MDS pts and for FLT3-ITD from 84.4% to 93.4% in AML pts. Factors associated with increased testing were age < 75 (vs ≥ 75) yrs, ELN score ≥ 2 (vs 1) and enrollment at AC site (vs CO/GOV) (all P < 0.01) in AML pts and age < 80 (vs ≥ 80 yrs; P < 0.01), AC site (vs CO/GOV; P < 0.01), and geographic region outside the Midwest ( P = 0.015) in MDS pts. Conclusions: While molecular testing rates have increased since the publication of the WHO 2016 criteria, molecular testing rates for MDS pts remain lower than those for AML pts in real-world clinical practice. Elderly pts and pts enrolled in CO/GOV sites were found to have lower rates of molecular testing in both MDS and AML patient cohorts.
Phase II study of lower-dose pracinostat plus azacitidine safety and efficacy in patients with high/very high-risk myelodysplastic syndromes.
Authors: Atallah Ehab L. , Khaled Samer K. , Cooper Brenda W. , Warlick Erica D. , Ramies David A. , Li Joanne , Spezia Riccardo , Mappa Silvia , Keng Michael Kenneth
Published: May 2020

7556

Background: Hypomethylating agents (HMA), such as azacitidine (AZA), are the standard of care for patients (pts) with higher-risk myelodysplastic syndromes (MDS). However, overall response rate (ORR=CR+PR) with HMA alone is approximately 30%, with a 2-year overall survival (OS) rate of 50.8%. Preclinical studies show that pracinostat (PRAN), an oral histone deacetylase inhibitor, synergizes with HMA. A study in pts with untreated IPSS intermediate-2/high-risk MDS receiving 60 mg PRAN plus AZA resulted in early discontinuations, mainly due to adverse events (AE), potentially leading to diminished clinical benefit. This follow-up phase II study evaluates a lower dose of PRAN (25% reduction) in combination with AZA in order to reduce toxicity, decrease early discontinuations, and improve outcomes. An interim analysis showed low discontinuation rate and promising efficacy, allowing trial expansion. Herein, we report preliminary safety and efficacy in the overall population. Methods: Open-label, II-stage, phase II trial (NCT03151304) in pts (≥18 years) naive to HMA therapy and with IPSS-R of high/very high-risk MDS. Planned enrollment was 60 pts. Pts received 45 mg PRAN 3 days/week for 3 consecutive weeks plus standard AZA dose for 7 days of each 28-day cycle. Primary objectives were to define the safety/tolerability of the combination and to assess the ORR (CR+PR). OS was a secondary endpoint. Results: Sixty-four pts were enrolled and received ≥1 dose of treatment. Most pts were male (67%), median age was 68 years (range 47–89), and the proportion of pts with high/very high-risk MDS was similar. After 17.6 months’ median follow-up, 31% of pts remain on treatment; 69% of pts discontinued treatment due to stem cell transplant (25%), disease progression (17%), AEs (11%), consent withdrawal (3%), pt noncompliance (3%), death (3%), lost to follow-up (2%), and other (5%). Most common nonhematologic AEs were constipation (55%), nausea (52%), fatigue (45%), decreased appetite (39%), peripheral edema (36%), diarrhea, and dyspnea (31% each). Frequent hematologic AEs were decreased neutrophil count (50%), anemia (39%), decreased platelet count (38%), febrile neutropenia (36%), and thrombocytopenia (30%). ORR was 33% (95% CI 22-46), with 33% achieving CR; 34% of pts had marrow CR. Median OS was 23.5 months (95% CI 16.4-nc), with an estimated 1-year OS of 77%. Conclusions: In pts with high/very high-risk MDS, a lower dose of pracinostat in combination with AZA demonstrated a tolerable safety profile and promising efficacy. Clinical trial information: NCT03151304 .
Expression of CD47 and CALR in myeloproliferative neoplasms and myelodysplastic syndrome: Potential new therapeutical targets.
Authors: Rinaldi Ciro Roberto , Boasman Kristian , Simmonds Matthew
Published: May 2020

7557

Background: Myelodysplastic neoplasms (MPN) and myelodysplastic syndrome (MDS) are myeloid malignancies tendency to evolve into acute myeloid leukaemia. We investigate the expression and cellular localisation of pro-phagocytic CALR and anti-phagocytic CD47 in untreated and treated patients with essential thrombocythemia (ET), polycythemia vera (PV) myelofibrosis (MF), and in MDS patients in comparison with healthy controls. Methods: Mononuclear cells were collected by Ficoll separation, from peripheral blood of 27 MPN (8 PV, 16 ET, 3 MF); 14 MPN patients received cyto-reductive therapies (Hydroxyurea, Anagrelide or Ruxolitinib); 10 MDS patients and 4 controls. Cells were fractionised into 4 compartments: membrane, cytoplasm, cytosol and nucleus. Proteins were extracted using TRIzol, with CALR and CD47 protein expression analysed by western blotting. Results: CD47 showed higher expression of its overall protein on MPN cell membranes when compared with CALR (22% vs 13.9%). We observed a significant reduction of CALR expression in all MPN subtypes when patients were treated with cyto-reductive agents (ET- untreated 43.3% vs treated 2%, PV- 3.6% vs 2.2%, ET- 21% vs 11%). Interestingly we have observed a significant increase in CD47 cell membrane expression after treatment in MF and PV (CD47 in MF- untreated 11.8% vs treated 34.3%, PV-11.4% vs 35.9%). In MDS cells CD47 is overexpressed compared with controls (CD47- 11.31 vs 2.2 fold, respectively) and it mainly located to the membrane. Interestingly the degree of CD47 expression correlated to patients IPSS-R, increasing from low risk to high risk (low – 15.7%, intermediate 1 – 41.3%, intermediate 2 – 53.9% and high – 67.6%). CALR expression is also reduced in MDS cells comparing with controls when split by IPSS-R risk score (low – 9%, intermediate 1 – 11.9%, intermediate 2 – 17%, high – 17.9% Vs control - 29.1%). Conclusions: CD47, but not CALR, is overexpressed on the membrane of patients with MPN and MDS. In MDS, we observed a progressive increase in CD47 expression as the MDS evolve in accordance to the IPSS-R risk score. In MPN patients we observed a significant difference in CD47 expression across different MPN subtypes. The use of anti-CD47 antibodies could represent a new strategy to enhance the pro-phagocytic signal via increasing the CALR expression, and in combination with standard cyto-reduction therapy, might represent a new therapeutical strategy in both MPN and MDS.
First-in-human data of ALLO-501 and ALLO-647 in relapsed/refractory large B-cell or follicular lymphoma (R/R LBCL/FL): ALPHA study.
Authors: Neelapu Sattva Swarup , Munoz Javier , Locke Frederick Lundry , Miklos David Bernard , Brown Robert , McDevitt Jennifer T. , Mardiros Armen , Demirhan Eren , Konto Cyril , Tees Michael Timothy
Published: May 2020

8002

Background: Allogeneic (off the shelf) chimeric antigen receptor (CAR) T cell therapy addresses the logistical challenges and variable product quality of autologous CAR T therapy. ALLO-501 is a genetically modified anti-CD19 CAR T cell product in which the TCR alpha constant gene is disrupted to reduce the risk of graft-versus-host disease (GvHD) and the CD52 gene is disrupted to permit the use of ALLO-647, an anti-CD52 mAb, for selective and prolonged host lymphodepletion. Methods: This is an open-label, Phase 1 trial (NCT03939026) in adults with R/R LBCL/FL who have received ≥ 2 prior lines of therapy; prior anti-CD19 cell therapy is allowed. Patients (pts) receive fludarabine (flu) 90 mg/m2, cyclophosphamide (cy) 900 mg/m2, and ALLO-647 39 or 90 mg followed by ALLO-501 at 1 of 3 dose levels (DL) in a 3+3 design: 40, 120, and 360 × 106 CAR+ T cells. Results: As of 20 January 2020, 12 pts were enrolled: 9 received ALLO-501 at 3 DLs (4, 4 & 1 pts in DL1, DL2 and DL3 respectively), 1 pt discontinued due to kidney injury prior to lymphodepletion and 2 are starting treatment. Of the 9 treated pts aged 42 to 70 years: 5 had LBCL, 2 were female, 3 had primary refractory disease, and 3 had prior autologous stem cell transplants. The median number of prior lines of therapies was 3 (range 2 to 4). All treated pts received 39 mg of ALLO-647. No DLTs or GvHD have been observed to date. Most common Grade (Gr) ≥ 3 adverse events were neutropenia (55.6%), leukopenia (33.3%) and anemia (22.2%). Two pts (22.2%) developed cytokine release syndrome (1 Gr1 and 1 Gr2) that resolved within 72 hrs without steroids or tocilizumab. One pt developed Gr1 neurotoxicity that resolved without treatment. Infections included upper respiratory tract infection (Gr2), CMV (Gr3) and EBV viremia (Gr1), all reported in a single pt and resolved. One pt had a Gr2 infusion reaction to ALLO-647 which resolved with antihistamines. The overall response rate is 78% (95% exact CI: 40%, 97%): 3 complete and 4 partial responses. With a median follow up of 2.7 mos, 4 pts have ongoing responses and 3 pts progressed at 2, 4 and 6 mos. ALLO-501 cell expansion by qPCR was observed in 4 of 6 pts in varying degrees. Conclusions: These early data suggest that ALLO-501 and ALLO-647 have a manageable safety profile. ALLO-647 may be an effective and selective lymphodepleting agent with CD52 gene editing, and ALLO-501 shows evidence of clinical activity in pts with advanced NHL. Enrollment is ongoing, and updated safety, efficacy, PK/PD data will be presented including pts treated with increasing doses of ALLO-647. Clinical trial information: NCT03939026 .
Epcoritamab (GEN3013; DuoBody-CD3×CD20) to induce complete response in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL): Complete dose escalation data and efficacy results from a phase I/II trial.
Authors: Hutchings Martin , Lugtenburg Pieternella , Mous Rogier , Clausen Michael Roost , Chamuleau Martine , Linton Kim , Rule Simon , Lopez Juanita Suzanne , Oliveri Roberto S , DeMarco Dena , Elliott Brian , Johnson Peter
Published: May 2020

8009

Background: CD3×CD20 bispecific antibodies (bsAbs) have demonstrated promising results for the treatment of pts with R/R B-NHL. Epcoritamab is a novel subcutaneously administered bsAb with a favorable safety profile and encouraging preliminary anti-tumor activity at low doses in both aggressive and indolent B-NHL. Here we present updated safety and efficacy data from the ongoing trial (NCT03625037). Methods: Adults with R/R CD20+ B-NHL received a single SC injection of flat-dose epcoritamab in 28-day cycles (q1w: cycle 1–2; q2w: cycle 3–6; q4w thereafter) until disease progression or unacceptable toxicity. Primary objectives are determination of maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives include anti-tumor activity. Results: As of 8 Jan 2020, 41 pts with median age of 66 (range: 21–82) were enrolled. Most pts had DLBCL/HGBCL (73%) or FL (20%) and received a median (range) of 3 (1–6) and 5 (2–18) prior lines of treatment. No DLTs were observed (median follow-up: 4.7 mo; range: 3.7– 5.6). MTD has not been reached. Most common TEAEs (>35%) were pyrexia (71%), fatigue (46%), and injection site reaction (39%; all Gr 1). AEs of special interest included cytokine release syndrome (59%; all Gr 1/2; all resolved) and cytokine release-related decreased CARTOX-10 score (n=1). There was no clinical tumor lysis syndrome or treatment-related deaths. Treatment is ongoing in 13 pts. Anti-tumor activity was observed at minimal efficacy threshold (based on PK modelling) for DLBCL/HGBCL and FL (Table). Complete dose escalation data and RP2D will be presented. Conclusions: SC epcoritamab continues to demonstrate a favorable safety profile across all doses with no ≥Gr 3 CRS and no DLTs. Dose escalation data show improved efficacy as doses reach above the modeled predicted exposure threshold, inducing CRs in heavily pretreated DLBCL pts. All pts achieving CRs remain in remission. Clinical trial information: NCT03625037 . [Table: see text]
Nivolumab and brentuximab vedotin (BV)-based, response‐adapted treatment in children, adolescents, and young adults (CAYA) with standard-risk relapsed/refractory classical Hodgkin lymphoma (R/R cHL): Primary analysis.
Authors: Cole Peter D. , Mauz-Körholz Christine , Mascarin Maurizio , Michel Gérard , Cooper Stacy , Beishuizen Auke , Leger Kasey J. , Amoroso Loredana , Buffardi Salvatore , Rigaud Charlotte , Puhlmann Markus , Francis Stephen , Sacchi Mariana , Drachtman Richard A. , Harker-Murray Paul David , Leblanc Thierry , Daw Stephen , Kelly Kara M.
Published: May 2020

8013

Background: Outcomes for younger patients (pts) with R/R cHL are poor, particularly for those without complete metabolic response (CMR) before autologous transplant (auto-HCT). Nivolumab + BV has shown 67% CMR and a high 2-y PFS rate as first salvage in adults with R/R cHL. CheckMate 744 (NCT02927769) is an ongoing phase 2 study for CAYA with R/R cHL, evaluating a risk-stratified, response-adapted approach using nivolumab + BV and, for pts without CMR, BV + bendamustine. In the initial analysis of the standard-risk cohort (R2), the regimen was well tolerated with high CMR rates before consolidation with high-dose chemotherapy plus auto-HCT. We report data from the primary analysis. Methods: Pts were aged 5–30 y and had first-line treatment (tx) without auto-HCT. Risk stratification has been described previously (Harker-Murray, ASH 2018). Pts received 4 induction cycles of nivolumab + BV; pts without CMR by blinded independent central review (BICR) received BV + bendamustine intensification. Pts with CMR at any time could proceed to consolidation off study. Response was per Lugano 2014 criteria. Primary endpoint: CMR rate (Deauville ≤3) per BICR any time before consolidation. Results: At database lock, 44 pts were treated in R2 (median follow up: 20.9 mo); 43 received 4 induction cycles and 11 received intensification. Median age was 16 y (range 9–30); 24 (55%) pts had primary refractory cHL and 20 had relapsed cHL. CMR rates and ORR any time before consolidation and after induction are shown in Table. 1-y PFS rate by BICR was 91% (90% CI 77–96). During induction, 8 (18%) pts experienced grade (G) 3–4 tx-related adverse events (TRAEs); the most common any grade TRAEs were nausea and hypersensitivity (20% each). 1 TRAE led to discontinuation (G3 anaphylaxis). Most tx-related immune-mediated AEs were G1–2 (1 pt had 2 G3 infusion-related reactions). Conclusions: This risk-stratified, response-adapted approach offers a well-tolerated salvage strategy with high CMR rates and no new safety signals for CAYA with R/R cHL. Most pts avoided alkylator exposure prior to consolidation. Further follow up may confirm durability of disease control. Clinical trial information: NCT02927769 . [Table: see text]
Acalabrutinib in treatment-naïve chronic lymphocytic leukemia: Mature results from phase II study demonstrating durable remissions and long-term tolerability.
Authors: Byrd John C. , Woyach Jennifer Ann , Furman Richard R. , Martin Peter , O'Brien Susan Mary , Brown Jennifer R. , Stephens Deborah Marie , Barrientos Jacqueline Claudia , Devereux Stephen , Hillmen Peter , Pagel John M. , Hamdy Ahmed M. , Izumi Raquel , Patel Priti , Wang Min Hui , Jain Nitin , Wierda William G.
Published: May 2020

8024

Background: The next-generation Bruton tyrosine kinase inhibitor acalabrutinib was approved in patients (pts) with treatment-naïve (TN) and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) based on two complementary phase 3 studies, ELEVATE-TN and ASCEND. This report of ACE-CL-001 (NCT02029443), the first phase 2 study of acalabrutinib, provides the longest safety and efficacy follow-up to date in symptomatic TN CLL pts. Methods: Adults with TN CLL/SLL were eligible if they met iwCLL 2008 criteria for treatment, were inappropriate for/declined standard chemotherapy and had ECOG performance status 0–2. Pts received acalabrutinib 100 mg BID or 200 mg QD, later switching to 100 mg BID, until progressive disease (PD) or unacceptable toxicity. Primary endpoint was safety. Events of clinical interest (ECI) were based on combined AE terms for infections, bleeding events, hypertension, and second primary malignancies (SPM) excluding non-melanoma skin, and on a single AE term for atrial fibrillation. Additional endpoints included investigator-assessed overall response rate (ORR), duration of response (DOR), time to response (TTR), and event-free survival (EFS). Results: Ninety-nine pts (n = 62 100 mg BID; n = 37 200 mg QD), were treated [median age: 64 years, 47% Rai stage 3–4 disease, 10% del(17p), 62% unmutated IGHV]. At median follow-up of 53 months (range, 1–59), 85 (86%) pts remain on treatment; most discontinuations were due to AEs (n = 6) or PD (n = 3 [n = 1 Richter transformation]). Most common AEs (any grade) were diarrhea (52%), headache (45%), upper respiratory tract infection (44%), arthralgia (42%), and contusion (42%). All-grade and grade ≥3 ECIs included infection (84%, 15%), bleeding events (66%, 3%), and hypertension (22%, 11%). Atrial fibrillation (all grades) occurred in 5% of pts (incidence: 1% in years 1, 2, 4; 3% in year 3). SPMs excluding non-melanoma skin (all grades) occurred in 11%. Serious AEs were reported in 38% of pts; those in > 2 pts were pneumonia (n = 4) and sepsis (n = 3). ORR was 97% (7% complete response; 90% partial response). Median TTR was 3.7 months (range, 2–22). Response rates were similar across high-risk groups. Median DOR and median EFS were not reached; 48-month DOR rate was 97% (95% CI, 90%–99%), and 48-month EFS rate was 90% (95% CI, 82%–94%). Conclusions: Long-term data from ACE-CL-001 further support the favorable results with acalabrutinib in phase 3 studies and demonstrate durable responses with no new long-term safety issues. Clinical trial information: NCT02029443 .
First-line immunochemotherapy for follicular lymphoma in the GALLIUM study: Prognostic value of PET-CT status after long-term follow-up.
Authors: Nielsen Tina , Barrington Sally , Meignan Michel , Sahin Deniz , Knapp Andrea , Kinkolykh Anastasiia , Herold Michael , Hiddemann Wolfgang , Marcus Robert , Trotman Judith
Published: May 2020

8025

Background: The prognostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) response assessment following first-line immunochemotherapy for advanced-stage symptomatic follicular lymphoma (FL) was previously demonstrated for patients (pts) enrolled in the Phase III GALLIUM study (NCT01332968; Trotman et al. ICML 2017). Here, we evaluated the association between PET complete metabolic response (CMR) and survival after longer follow-up in this patient population. Methods: In the GALLIUM study, 1202 pts with previously untreated FL were randomized 1:1 to induction therapy of 1000mg obinutuzumab (G; Days 1, 8, 15 of Cycle 1 then Day 1 of subsequent cycles) or 375mg/m2 rituximab (R; Day 1 of each cycle), in combination with chemotherapy (CHOP, CVP, or bendamustine) (Marcus et al. New Engl J Med 2017). PET-CT scans were mandatory, where available, at baseline and end-of-induction (EOI) for the first 170 pts enrolled, and optional thereafter. For this response analysis, the Lugano 2014 criteria were applied by an independent review committee (IRC) (Cheson et al. J Clin Oncol 2014). Associations between EOI PET complete metabolic response (PET-CMR) status and progression-free survival (PFS) and overall survival (OS) were evaluated, with hazard ratios (HR) stratified according to chemotherapy regimen and FL International Prognostic Index. Results: Of the 609 pts with a baseline PET scan, 595 (98%) had detectable lesions. Of these, 519 pts had an EOI PET evaluable by Lugano 2014 criteria. At EOI, per IRC assessment, 450/595 (76%) pts had achieved CMR. Pts with non-available scans were considered as non-responders and were excluded from the landmark (LM) analyses. Pts who died or progressed (CT-based progression assessment) before or at EOI were excluded from the PFS LM analysis; pts who died before EOI were excluded from the OS LM analysis. After a median follow-up of 76.5 months, EOI PET status was highly prognostic for both longer investigator-assessed PFS (non-CMR vs CMR: HR 3.40; 95% CI: 2.33–4.97; p < 0.0001) and longer OS (HR 3.34; 95% CI: 1.81–6.17; p < 0.0001). Six-year investigator-assessed PFS from EOI was 62.6% (95% CI: 57.0–67.6) for CMR pts compared with 23.4% (95% CI: 12.2–36.7) for non-CMR pts; the corresponding OS was 91.3% (95% CI: 88.1–93.6) vs 79.6% (95% CI: 68.0–87.4). Conclusions: With more than 6 years of follow-up, this analysis confirms that after first-line chemoimmunotherapy for FL, achieving CMR on PET-CT is an early and strong predictor of increased PFS and OS. Clinical trial information: NCT01332968 .
Brentuximab vedotin and bendamustine as first-line treatment of Hodgkin lymphoma in the elderly (HALO Trial).
Authors: Schiano de Colella Jean Marc , Viviani Simonetta , Rapezzi Davide , PATTI CATERINA , Clement Filliatre Lauriane , Rossi Andrea , Bijou Fontanet , Cantonetti Maria , Borel Cécile , Thamphya Brice , Schiappa Renaud , Chamorey Emmanuel , Debaigt Colin , Gastaud Lauris , Thyss Antoine , Gallamini Andrea
Published: May 2020

8029

Background: Hodgkin Lymphoma (HL) treatment in the elderly is a challenge, as standard ABVD is able to cure no more than 60% of the patients (p.). Bendamustine (Be), and Brentuximab Vedotin (BV), are well-tolerated and effective drugs in relapsing HL, but only preliminary data exist in 1st line treatment of the elderly (Evens AM 2018). Methods: HALO is a prospective international multicenter open-label phase I/II study (NCT02467946) to assess the safety and efficacy of Be-BV in advanced-stage elderly HL p. Briefly, BV 1.2 mg/kg on D1, and Be 90 mg/m2 on D1-2 were administered Q3W for 6 cycles. The primary endpoint was the feasibility and the efficacy of Be-BV. Results: Between July 2015 and February 2019, 59/60 p. consecutive enrolled received at least 1 Be-BV cycle, and are valuable for primary endpoint. One p. was excluded because a histological review showing angioimmunoblastic T-Cell Lymphoma. The mean age was 70.32 (62-79), and M/F ratio 41/18. The Ann-Arbor stage was IIB in 12, III in 14 and IV in 33 patients, B-symptoms (y/n) 40/19. IPS was 0-2 in 19 and ≥ 3 in 40 p., P.S. (ECOG) was 0-1 in 53, 2 in 6 p., nonetheless most of them were frail, as ADL was ≥ 6 in 47 (79%) and IADL was ≥ 8 in 42 (71%) p. Most frequent co-morbidities were cardio-vascular disease (45) metabolism disorders (31) prostatic adenoma (11). 163 treatment-related adverse events (WHO 3-4) were recorded: neutropenia and lymphopenia, (134), infections (7), cutaneous reactions (5), liver toxicity (2). No case of grade > 2 peripheral neuropathy was recorded. Out of 59 p., 41 concluded and 18 interrupted the treatment for toxicity (8), progression (5), treatment failure (2), CMV reactivation (3). The latter was recorded in 17 p., 12/17 received valgancyclovir. 4 p. died with CMV viremia. After a mean follow-up of 20.6 (0.3-46.5) months, 37/59 (63%) were in CR, while 22 (37%) have progressed (5) or relapsed (17). The 2-y OS and PFS in ITT analysis were 83% (95% CI 71-96) and 54% (95% CI 41-72) and in PP 89% (95%CI 75-100) and 78% (95%CI 64-96), respectively. 22 p. had a PFS event: 5 progression (2 deaths), 17 relapse (8 deaths). 10 p. died for recurrent HL (5), sepsis (1), secondary malignancy (2), respiratory insufficiency (1) and unknown (1). Conclusions: The Be-BV combination, a novel anthracycline-free regiment for first line treatment of HL in elderly, proved effective in unselected, frail, poor-risk, HL p. aged more than 60 in daily hospital real life. The CMV reactivation is frequent and should be treated with preemptive antiviral therapy upon detection of CMV DNA in plasma. Clinical trial information: NCT02467946 .
Frontline brentuximab vedotin as monotherapy or in combination for older Hodgkin lymphoma patients.
Authors: Yasenchak Christopher A. , Bordoni Rodolfo Eduardo , Patel-Donnelly Dipti , Larson Tim , Goldschmidt Jerome H. , Boccia Ralph V. , Cline Vivian Jean M. , Forero-Torres Andres , Sims Robert Brownell , Newhook Trevor , Friedberg Jonathan W.
Published: May 2020

8032

Background: Older patients with classical Hodgkin lymphoma (cHL) have poor outcomes relative to younger patients, often due to comorbidities and toxicities related to standard first-line (1L) chemotherapy (5-yr PFS: 30%–45% vs 75%–80%) (Evens 2008; Proctor 2009). Brentuximab vedotin (BV, ADCETRIS®), a CD30-directed antibody-drug conjugate, has robust activity in patients refractory to several lines of chemotherapy. Methods: This phase 2, open-label study, SGN35-015 (NCT01716806), evaluated efficacy and tolerability of BV alone or combined with single-agents in treatment-naive cHL patients ≥60 yr. The full-analysis set (FAS) includes all patients who received BV (1.8 mg/kg IV). Patients in Part A received BV monotherapy on Day 1 of every 3-week cycle (n = 26); Part B: BV+dacarbazine (DTIC; 375 mg/m2; n = 19); Part C: BV+bendamustine (benda; 70 mg/m2; n = 20); and Part D: BV+nivolumab (nivo; 3 mg/kg; n = 20). The efficacy evaluable (EE) set includes all patients who had at least 1 post-baseline response assessment (n = 25, 19, 17, 19). Results: Demographic characteristics were generally similar: median age 78, 69, 75, and 72 yr in Parts A, B, C, and D, respectively, and 62% of patients (range 45%–70%) reported impaired physical functioning at baseline. Most patients had disease stage III/IV (62%, 68%, 75%, 80%), were ECOG 0/1 (77%, 74%, 80%, 95%), and male (54%, 68%, 50%, 75%). Median time from diagnosis was 1.2 to 1.5 mo (FAS; 10 Jan 2019 data cutoff). ORR were high (92%, 100%, 100%, 95%) at a median follow-up of 59.4, 58.6, 51.3, and 19.4 mo in the EE data set. Median OS in the FAS set was 77.5 mo with monotherapy; 64.0, 46.9, and not reached in the combination parts. Treatment-related AE ≥ Grade 3 occurred in 50%, 37%, 70%, and 60% of patients; peripheral neuropathy (PN) was most common (35%, 26%, 20%, 35%). Treatment-related SAEs occurred in 12%, 11%, 40%, and 5% of patients. Part C enrollment (BV+benda) closed early due to multiple acute toxicities. There were no treatment-related deaths in any part of the study. The median treatment cycles per patient were 8.0, 12.0, 5.0, and 14.5. Treatment discontinuation due to related AEs occurred in 42%, 42%, 40%, and 30% of patients, most commonly due to PN (38%, 37%, 30%, 20%). Conclusions: Older patients with cHL and multiple comorbidities have very high response rates with BV as monotherapy or combined with other single agents and improved tolerability versus combination chemotherapy. Median overall survival exceeded 6 yr with BV monotherapy. BV+nivo or BV+DTIC appeared to be the most reasonable combination treatment options in this study. Clinical trial information: NCT01716806 .
Lisocabtagene maraleucel (liso-cel) for treatment of second-line (2L) transplant noneligible (TNE) relapsed/refractory (R/R) aggressive large B-cell non-Hodgkin lymphoma (NHL): Updated results from the PILOT study.
Authors: Sehgal Alison R. , Hildebrandt Gerhard , Ghosh Nilanjan , Godwin John E. , Wagner-Johnston Nina D. , Hoda Daanish , Licitra Edward J. , Munoz Javier , Trede Nikolaus S. , Wang Lei , Thorpe Jerill , Gordon Leo I.
Published: May 2020

8040

Background: Patients (pts) with aggressive large B-cell NHL who are R/R after first-line immunochemotherapy and not eligible for high-dose chemotherapy and HSCT have a poor prognosis and no established standard of care. The ongoing, open-label phase 2 PILOT study is the first to assess the safety and efficacy of liso-cel, an investigational, CD19-directed, defined composition, 4-1BB CAR T cell product infused at equal target doses of CD8+ and CD4+ CAR+ T cells, as 2L therapy in TNE pts (NCT03483103). Methods: Eligible pts had aggressive R/R diffuse large B-cell lymphoma NOS (de novo or transformed follicular lymphoma [FL]), high-grade B-cell lymphoma, or FL grade 3B with 1 line of prior therapy containing an anthracycline and anti-CD20 agent. Pts were deemed TNE by meeting ≥1 criteria: age ≥70 y, ECOG PS 2, or impaired organ function (DLCO ≤60% [but SaO2 ≥92% and CTCAE ≤1 dyspnea], LVEF ≥40% to < 50%, creatinine clearance > 30 to < 60 mL/min, or AST/ALT > 2 to ≤5 × ULN). Liso-cel (100 × 106 CAR+ T cells) was administered 2–7 days after lymphodepletion (LD) with fludarabine/cyclophosphamide. The primary endpoint is ORR; key secondary endpoints are AEs and CR rate. Results: At data cutoff, 25 pts had LD followed by liso-cel infusion. Pt characteristics are summarized in the Table. Overall, 48% (n = 12) had high tumor burden and 48% were primary refractory. 18/25 (72%) pts had grade ≥3 treatment-emergent AEs, 40% of which were cytopenias. No grade 5 AEs occurred within the first 30 days after liso-cel. Five pts (20%) had cytokine release syndrome (CRS) and 3 (12%) had neurological events (NEs). No grade 3/4 CRS was observed; 2 pts (8%) had grade 3/4 NEs. Five pts (20%) received tocilizumab and/or dexamethasone for CRS/NEs. At a median follow-up of 3.5 mo, the ORR was 80% (95% CI, 59–93; n = 20); 48% of pts (n = 12) achieved CR. Conclusions: These interim data suggest that elderly and/or comorbid pts with R/R aggressive large B-cell NHL, who are not eligible for high-dose chemotherapy and HSCT, can receive 2L liso-cel with similar safety and efficacy to 3L+ pts as previously reported (Abramson, ASH 2019 #241). Updated data with longer follow-up will be presented. Clinical trial information: NCT03483103 . [Table: see text]
MAGNIFY phase IIIb interim analysis of induction R2 followed by maintenance in relapsed/refractory indolent NHL.
Authors: Andorsky David Jacob , Coleman Morton , Yacoub Abdulraheem , Melear Jason M. , Fanning Suzanne R. , Kolibaba Kathryn S. , Lansigan Frederick , Reynolds Chris , Nowakowski Grzegorz S. , Gharibo Mecide , Ahn Jung Ryun , Li Ju , Rummel Mathias J. , Sharman Jeff P. ,   on behalf of the MAGNIFY Trial Investigators
Published: May 2020

8046

Background: Patients (pts) with relapsed iNHL have limited standard treatment options. The immunomodulatory agent lenalidomide shows enhanced activity with rituximab (ie, R2), which recently reported 39.4-mo median PFS in R/R iNHL pts (AUGMENT; J Clin Oncol. 2019;37:1188). Methods: MAGNIFY is a multicenter, phase IIIb trial in pts with R/R FL gr1-3a, MZL, or MCL (NCT01996865) exploring optimal lenalidomide duration. Lenalidomide 20 mg/d, d1-21/28 + rituximab 375 mg/m2/wk c1 and then q8wk c3+ (R2) are given for 12c followed by 1:1 randomization in pts with SD, PR, or CR to R2 vs rituximab maintenance for 18 mo. Data presented here focus on induction R2 in efficacy-evaluable FL and MZL pts (MCL not included) receiving ≥ 1 treatment with baseline/post-baseline assessments to analyze the primary end point of ORR by 1999 IWG criteria. Results: As of June 16, 2019, 393 pts (81% FL gr1-3a; 19% MZL) were enrolled with a median follow up of 23.7 mo (range, 0.6-57.8) for censored pts (n = 335). Median age was 66 y (range, 35-91), 83% had stage III/IV disease, with a median of 2 prior therapies (95% prior rituximab-containing). ORR was 69% with 40% CR/CRu (Table). Median DOR was 39.0 mo, and median PFS was 40.1 mo. 199 pts (51%) have completed 12c of R2, and 188 (48%) have been randomized and entered maintenance. 139 pts (35%) prematurely discontinued both lenalidomide and rituximab, primarily due to AEs (n = 52, 13%) or PD (n = 45, 11%). Most common all-grade AEs were 48% fatigue, 43% neutropenia, 36% diarrhea, 31% nausea, and 30% constipation. Grade 3/4 AE neutropenia was 36% (9 pts [2%] had febrile neutropenia); all other grade 3/4 AEs occurred in < 7% of pts. Conclusions: R2 is active with a tolerable safety profile in pts with R/R FL and MZL, including rituximab-refractory, double-refractory, and early relapse pts. Clinical trial information: NCT01996865 . [Table: see text]
Immunohistochemical characterization of anaplastic large cell lymphoma using tissue microarray.
Authors: Desai Poorvi Kirit , Zhang Ling , Mo Qianxing , Sokol Lubomir
Published: May 2020

8048

Background: Anaplastic Large Cell Lymphoma (ALCL) is a subtype of mature T-cell lymphoma comprised of systemic (ALK+ or ALK-) and primary cutaneous (PCALCL) forms. ALK+, usually associated with NPM1-ALK gene, has a favorable prognosis. PCALCL is usually indolent. Despite worse prognosis for ALK-, pts with DUSP22 rearrangement have favorable outcomes similar to ALK+ while those with p63 aberration have poor outcomes. We hypothesize that other genetic alterations in ALCL could aid in diagnosis and prognosis. We compared protein expression levels of selected signaling molecules (JAK1, STAT3, DUSP22, ERBB4/HER4, PRDM1/BLIMP1 and SOCS3) among the subtypes and correlated to outcomes. Methods: Of 50 pts with ALCL at Moffitt (MCC) from 2000-2019, 27 tissue samples (6 ALK+, 10 ALK-, 8 PCALCL, 3 controls) met eligibility criteria. Tissue microarrays (TMAs) were constructed from formalin-fixed, paraffin-embedded lymph node biopsies. Up to 3 replicate cores were taken from each block. Immunohistochemistry was performed with antibodies to the selected proteins. Stained TMA slides were scanned using the Aperio™ ScanScope XT2 to determine % positive biomarker stain within each core per established algorithm. Statistics: ANOVA was used to compared protein expression levels, with pairwise tests when significant. T-test compared PCALCL to systemic ALCL. Boxplots were created for differences in protein expression levels and time to event outcomes (OS and RFS) using Log rank test and Cox proportional hazards models. Kaplan-Meier curves were used for clinical time-to-event outcomes and quartiles of the protein expression levels. Results: The 3 subgroups had a significant difference in SOCS3 expression with mean and std respectively: 42.4% (0.153), 17.4% (0.089), and 21.0% (0.155), p = 0.008. Among all pairs, ALK+ and PCALCL groups were statistically different (P = 0.011). Patients with high BLIMP1 (≥28.5%) across 3 ALCL subgroups were associated with better median OS (not reached) in comparison to pts with lower expression (27.3 mos) (Log rank test p = 0.014, HR = 0.17, 95% CI 0.034-0.829). The same was seen for median RFS (81.1 vs. 12.5 mos). (Log rank test p = 0.009, HR 0.23, 95% CI 0.069-0.755). Conclusions: High BLIMP1 suggests favorable prognosis in ALCL and could potentially be a positive prognostic marker. High SOCS3 appears more prevalent in PCALCL than systemic and could aid in differential. Larger samples should be used to validate results. Secondary markers like Bcl-2 can be considered in the future to correlate expression levels to targeted treatments like venetoclax.
Atezolizumab + obinutuzumab + venetoclax in patients with relapsed or refractory diffuse large B-cell Lymphomas (R/R DLBCL): Primary analysis of a phase II trial from LYSA.
Authors: Herbaux Charles , Casasnovas Olivier , Feugier Pierre , Damaj Gandhi , Bouabdallah Reda , Guidez Stephanie , Ysebaert Loic , Tilly Herve , Le Gouill Steven , Fornecker Luc , Daguindau Nicolas , Morineau Nadine , Haioun Corinne , Gyan Emmanuel , Sibon David , Gressin Rémy , Houot Roch , Salles Gilles A. , Morschhauser Franck , Cartron Guillaume
Published: May 2020

8053

Background: R/R DLBCL treatment remains challenging. Atezolizumab (ATE) and obinutuzumab (OBI) are monoclonal antibodies acting respectively to inhibit T-lymphocyte exhaustion or by inducing lymphoma cells cytotoxicity, whereas venetoclax (VEN) is a small molecule inhibiting BCL-2. Combining tumor-targeted therapies with agents that enhance anti-tumor immunity represents an attractive treatment paradigm. This LYSA sponsored multicenter phase 2 trial (NCT03276468) evaluate the combination of ATE, OBI and VEN in R/R B lymphomas, we present here primary efficacy and safety data fromthe DLBCL cohort. Methods: Patients ≥18 years with biopsy-confirmed R/R DLBCL who failed at least one line of therapy were eligible. OBI was given IV at the dose of 1 g on day (D) 1, 8 and 15 of cycle (C) 1 and on D1 from C2 to C8 every 3 weeks. ATE was given IV, 1.2 g every 3 weeks, started at D2 of C1, then administered at D2 of each cycle for 24 cycles. VEN was given orally at 800 mg/D at full dose, started on D8C1 for 24 cycles. The primary endpoint wasthe Overall Metabolic Response Rate (OMRR) by Lugano criteria at the end of induction (EOI) after 8 cycles of ATE, OBI and VEN (M6) or at premature treatment discontinuation. Results: At the time of the primary analysis (03 Jan 2020), 58 pts were enrolled and the median follow-up was 9 months [6.9-11.8]. Baseline characteristics were: median age, 70 years; male, 53.4%; Ann Arbor Stage IV, 84.5%; aaIPI (≥2), 63.2%; > 2 prior lines of therapy, 83.6%; and refractory to last line of prior regimen, 63.6%. The OMRR at EOI was measured at 23.6% [14.58%-34.93%], including 18% of CMR. To date, these responses seem durable with only 3 reported relapses. According to the highest diameter mass, OMRR was 38.5% versus 10.3%, < 5cm and > 5cm respectively; P = 0,02. All three treatments were stopped in 78% of patients, mostly for progressive disease. At the time of analysis, a median of 4 cycles [1-8] has been administered. A total of 48 (84.2%) pts experienced grade 3–4 adverse event (AE) and 6 (10.5%) had an AE that led to discontinuation of any drug.AE of grade 3 or more reported in at least 20% of patients were neutropenia (33.3%) and lymphopenia (35.1%). Of note, a grade 3 autoimmune colitis and a grade 1 hypothyroidism were reported during induction. Conclusions: The ATE, OBI and VEN combinationappears to be well tolerated. The OMRR rate at EOI is comparable with currently available treatment options in this population, with durable responses. The OMRR seems better in patients with a low tumor burden. Clinical trial information: NCT03276468 .
Multi-omics analysis of mantle cell lymphoma reveals an immune-cold tumor microenvironment associated with ibrutinib resistance.
Authors: Nomie Krystle , Jain Preetesh , Kotlov Nikita , Segodin Vitaly , Cai Qingsong , Liu Yang , Navsaria Lucy , Svekolkin Viktor , Bagaev Alexander , Frenkel Felix , Ataullakhanov Ravshan , Fowler Nathan Hale , Wang Michael
Published: May 2020

8055

Background: Mantle cell lymphoma (MCL) is an aggressive and incurable B-cell lymphoma. Although the role of the MCL tumor microenvironment (TME) in survival and therapeutic response has been studied, greater knowledge regarding the tumor-immune interaction is needed to develop MCL immunotherapeutic strategies. Methods: Whole exome sequencing (WES; n = 41) and RNA-seq (n = 93) were performed on fresh peripheral blood, apheresis, or biopsy MCL patient primary samples. Joint WES and RNA-seq mutation calling, expression analysis were performed by BostonGene. Results: Both tumor and TME molecular signatures were characterized based on ibrutinib response. Concurrent analysis of MCL biopsy samples with an additional previously published cohort (n = 122; Scott et al., JCO, 2017) identified 4 MCL microenvironment signatures (Nomie et al., Blood, 2019) in which the ibrutinib-resistant MCL samples primarily belonged to the “stroma-enriched” subtype (29%; 6/8 resistant, non-immune with increased stromal signature and tumor-promoting cytokines), whereas most of the ibrutinib-sensitive samples were assigned to the “immune-hot” subtype (53%, 9/9 sensitive; anti-tumor infiltration, high immune and checkpoint molecule expression with low stromal expression, Chi-square test p-value = 0.001). NOTCH1 gain-of-function mutations (25%, 3/12 resistant) in the PEST domain were found exclusively in the ibrutinib-resistant cohort associated with the microenvironment-depleted subtype. Frequent recurring inactivating mutations in the epigenetic modifier KMT2D (30%) were identified in MCL cells associated with the ‘immune-suppressed” subtype (p < 0.05). Loss-of-function mutations in epigenetic modifiers have been tied to immune evasion. PD-L1 was significantly downregulated in the ibrutinib-resistant MCL tumors (p = 0.03), indicating that targeting the PD-L1 and PD-1 immune checkpoint axis may not be beneficial. Conclusions: Ibrutinib sensitivity and resistance were defined by immune-hot and immune-cold TME portraits, respectively, suggesting that the TME has a prominent role in mediating ibrutinib response. Ibrutinib has been suggested to activate the immune TME through its off target inhibition of interleukin 2–inducible T-cell kinase (ITK). The immune activation by ibrutinib suggests that anti-tumor activity of ibrutinib may be better harnessed by combining ibrutinib with immunotherapy.