CURRENT ADVANCES IN THE TREATMENT OF AGGRESSIVE B AND T CELL LYMPHOMAS��

Sonali M. Smith, MD FASCO

Elwood V. Jensen Professor of Medicine

Chief, Section of Hematology/Oncology

Co-Leader, Cancer Service Line

The University of Chicago

Disclosures

• Consulting in past 24 months:

Genmab

Regeneron

• Spouse is employed by Caris Life Sciences
• I may discuss approved agents in unapproved settings and unapproved agents in development. I will disclose when this is the case.

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LBCL Treatment

Major milestones in DLBCL Treatment

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November 2017:

axi-cel is approved for 3L+ DLBCL followed soon by tisa-cel and liso-cel

Major milestones in DLBCL Treatment

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2021

2018

2017

2019

2022

Selinexor for RR DLBCL

Tafa-len for RR DLBCL

Axi-cel for 3L+ DLBCL

Tisa-cel for 3L+ DLBCL

Liso-cel for 3L+ DLBCL

Lonca-T for RR DLBCL

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Pola-BR for RR DLBCL

2020

Axi-cel and Liso-cel for 2L+ DLBCL

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Major milestones in DLBCL Treatment: 2023-2025 Updates

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2023

2023

Epcoritamab-bysb

Pola-RCHP

Glofitamab-

gxbm

2023

2025

BV plus len-R

Updates in LBCL

• FDA-approved

POLARIX 5-year data

BV plus len-R (ECHELON-3 trial)

• Emerging trials/data for TN LBCL

Epco plus RCHOP

Golca plus RCHOP

Fixed duration epco

• Emerging trials/data for RR LBCL

Odronextamab post CAR-T

Glofit plus pola

Mosun-pola versus R-pola

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POLARIX: a randomized double blind phase 3 trial

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PRIMARY ENDPT: PFS

Med f/u 28.2m

Tilly N Engl J Med. 2022 Jan 27;386(4):351-363

POLARIX: primary endpoint was met

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No difference in overall survival

Will Pola R-CHP become the new standard of care for 1L DLBCL?

Tilly N Engl J Med. 2022 Jan 27;386(4):351-363

POLARIX Subgroup Analysis

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Tilly N Engl J Med. 2022 Jan 27;386(4):351-363

Pola-RCHP better for

• Older pts
• PS 0-1
• Non-bulky disease
• ABC subtype
• No DHL/THL

Initial PFS benefit of Pola-R-CHP over �R-CHOP is maintained at 5 years; HR for OS is 0.85

*Data cut-off: June 28, 2021; ^†Data cut-off: June 15, 2022; ^‡Data cut-off: July 5, 2024.�CI, confidence interval; HR, hazard ratio; NE, not evaluable.

1. Tilly H, et al. N Eng J Med 2022;386:351–63.

PFS in the global ITT population

Patients treated with Pola-R-CHP required 23% fewer �subsequent therapies versus patients treated with R-CHOP

Data cut-off: July 5, 2024.

CAR-T, chimeric antigen receptor T-cell therapy; NALT, new anti-lymphoma treatment.

Δ=23.4%

Pola-R-CHP (n=440)

R-CHOP (n=439)

Δ=9.8%

Δ=4.6%

Δ=8.2%

Δ=5.7%

Δ=3.4%

Δ=1.8%

Δ=0.7%

Total number of subsequent therapies

Patterns of subsequent therapies received on study mirror routine clinical care at the time of study conduct.

Subsequent therapies in the global ITT population

Still building on R-CHOP

BsAb

CELMoD

Hughes Essays in Biochemistry (2017) 61 505–516

Castaneda-Puglianni. Drugs Context. 2021;10:2021. Bannerji. ASH 2020. Abstr 42. Budde. ASH 2018. Abstr 399. Hutchings. Lancet. 2021;398:1157. Engelberts. eBioMedicine. 2020;52:102625. Hutchings. JCO. 2021;39:1959.

Golcadomide (formerly CC-99282)

GOLCA-RCHOP in TN LBCL

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• Primary endpt: Safety/tolerability (part 1) and preliminary efficacy (part 2)
• Patient Characteristics: med age 62y, 80% high-risk

Amzallag Blood (2024) 144 (Supplement 1): 579.

Golca-RCHOP Results

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Amzallag Blood (2024) 144 (Supplement 1): 579.

Epco-RCHOP (n=47) phase 2

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Falchi Blood (2024) 144 (Supplement 1): 581.

Eligibility:

TN DLBCL

incl TFL, DHL/THL

IPI > 3

PS 0-2

Key patient characteristics:

Med age 64y

IPI 3 47%

IPI 4-5 53%

DHL/THL 21%

Bulky disease 34%

Epco-RCHOP Results: high ORR and DoR/DoCR

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Falchi Blood (2024) 144 (Supplement 1): 581.

Epco-RCHOP Results

• Avenio used for MRD assessment

91% MRD negativity at any point

83% by C3D1

• 2-yr PFS 82%
• 2-yr OS 87%
• No new safety signals (neutropenia is dominant event)

2 cases of ICANS (grade 1 and grade 2)

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Falchi Blood (2024) 144 (Supplement 1): 581.

Epco fixed duration monotherapy in older adults: EPCORE DLBCL-3 (randomized ph 2)

• Assumption is that 10% of newly diagnosed pts are ineligible for anthracyclines and have worse outcomes

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Treatment up to 1y

Primary endpoint: CR

Morschhauser Blood (2024) 144 (Supplement 1): 867.

EPCORE DLBCL-3 (n=120 screened but only 88 randomized; 45 to epco monotherapy)

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Reasons for contraindication for anthracyclines:

• 78% with HTN
• 71% increased enzymes
• 16% with a.fib

Morschhauser Blood (2024) 144 (Supplement 1): 867.

EPCORE DLBCL-3

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Med f/u 6m

6-m PFS 73%

6-m OS 81%

9 deaths: 6 pts with PD and AE in 3 pts

High CRS but low grade and manageable

7 pts with ICANs (16%) with med age 79-92yo

CNS hemorrhage, capillary leak syndrome

Morschhauser Blood (2024) 144 (Supplement 1): 867.

What’s next in TN DLBCL?

• Should anthracycline-based chemo still be the SOC for all patients?

(stuck in the R-CHOP plus X mode)

• If cure rates are improving, what is the demand for 2L+ treatments?
• Are precision approaches on the horizon?

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Proposed Lymphomatch schema for US Intergroup

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REL/REF LBCL

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Bartlett J Clin Oncol. 2025 Jan 7:JCO2402242

BV + R2

Pbo + R2

Primary endpt: OS

Patient demographics

Bartlett J Clin Oncol. 2025 Jan 7:JCO2402242

OS was improved with BV+Len+R vs placebo+Len+R in both age groups

Aged ≥65 years

Aged ≥75 years

Bartlett J Clin Oncol. 2025 Jan 7:JCO2402242

PFS was improved with BV+Len+R vs placebo+Len+R in both age groups

^a PFS is the time from randomization to the earliest occurrence of progressive disease per Lugano 2014 or death. PFS is estimated using the Kaplan-Meier method.

^b Hazard ratio and 95% CI are based on an unstratified Cox regression model.

^c Two-sided P value from an unstratified log-rank test.

Aged ≥65 years

Aged ≥75 years

Bartlett J Clin Oncol. 2025 Jan 7:JCO2402242

STARGLO: RP3 Trial of GEMOX vs. glofit-GEMOX in rel/ref LBCL

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Primary endpoint: OS

Med f/u 20.7m

Med OS 25.5m vs 12.9m

(HR 0.62)

Abramson EHA 2024 LB3438

Final 5-year analysis: tafasitamab-lenalidomide in rel/ref LBCL (med f/u 44m)

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Duell Haematologica 2024 Feb 1;109(2):553-566

• Depth of response matters more than line of therapy
• Some durable responses
• Toxicity: cytopenias

DR by line of therapy

OS by CR vs PR

Loncastuximab teserine: Final analysis of LOTIS-1 trial in rel/ref LBCL (n=145)

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Caimi Haematologica. 2024 Apr 1;109(4):1184-1193

• Lonca 0.15mg/kg q21d x 2 cycles, then 0.075mg/kg q21d up to 1 year
• Median f/u 7.8m all pts, >35m for responders
• Toxicity: increased GGT, cytopenias

BsAB plus Pola

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Phase Ib/II Study of glofit plus pola in RR DLBCL

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Hutchings Blood (2023) 142 (Supplement 1): 4460.

Obinu pretreatment

24h admission for C1D8

Glofit plus pola: Results (ORR)

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Hutchings Blood (2023) 142 (Supplement 1): 4460.

Glofit plus pola: DR and PFS

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No unexpected AE’s

Hutchings Blood (2023) 142 (Supplement 1): 4460.

RP2 trial of mosun sc plus pola in RR DLBCL

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Budde Nat Med. 2024 Jan;30(1):229-239

No mandatory admission

Mosun—pola vs. R-pola: Results�(med f/u 18m)

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Budde Nat Med. 2024 Jan;30(1):229-239

Key Takeaways for Advances in DLBCL/Aggressive B-Cell Lymphoma Excluding CAR T

• TN DLBCL:

Adding new agents to RCHOP vs. R-polaRCHP remains a standard approach for new trials

BsAbs are feasible as an additive agent

MRD may be useful going forward

What will be the demand for 2L+ treatments in 5 years?

Older adults remain without good options

• R/R DLBCL:

BsAbs are active after initial treatment and after CAR-T

What is the best backbone for RR setting? Pola? Len-R? other?

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Trials available via NCTN/NCORP in rel/ref LBCL

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S2114: post-CAR-T optimization

S2207: RP2 in rel/ref LBCL

Rel/ref LBCL

• COO
• Rel vs. ref

Tafa-len + zanu

Tafa-len

Tafa-len + taz

www.clinicaltrials.gov

Advances in T-cell Lymphomas

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T-cell Lymphoma updates at ASH 2024

• 464 Autologous and Allogeneic Stem Cell Transplantation for Major T-Cell Lymphoma Entities: An Analysis of the EBMT Lymphoma Working Party (Shumilo)
• 463 Dual-Targeted Therapy with Ruxolitinib Plus Duvelisib for T-Cell Lymphoma (Moskowitz)
• 984 Romidepsin, Azacitidine, Dexamethasone, and Lenalidomide (RAdR) for Relapsed/Refractory T-Cell Lymphoma (Gordon)

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T-NHL: rare, heterogeneous, chemoresistant

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Hsi et al. Clin Lymph Myel Leukemia 2017

ALCL

• CD30 positive
• ALK+ or ALK-
• Large anaplastic cells

AITL/Nodal PTCL with TFH features/Follicular T-cell lymphoma

• 2 of the following: BCL6, CD10, PD1, CXCL13, ICOS

PTCL NOS

• Grab bag term

Slide courtesy of Neha Mehta-Shah

Expected outcomes with PTCL: Swedish National Registry

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Ellin F et al. Blood 2014;124:1570-1577

Most PTCL

ALK+ ALCL

Overall Survival

Progression Free Survival

Most PTCL

ALK+ ALCL

NORDIC: Prospective autoSCT in CR/PR1 in PTCL <67yo (AILT, ALK(-) ALCL, PTCL-NOS, EATL)

Curves represent an ITT population and include primary refractory cases

Background: autoHCT consolidation

Dutch Patients 18-64 with Stage II-IV PTCL (AICL, ALCL, PTCL-NOS)

Mirian Brink et al. Impact of etoposide and ASCT on survival among patients aged 65 years with stage II to IV PTCL: a population-based cohort study, Blood, 2022,

Background: autoHCT consolidation

ASH 2024: EBMT analysis of first autoHCT and alloHCT in PTCL (2002-2022, ~10K patients) �

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• Median age 56 years (18-85)
• Male/female: 63%/37%
• Number of therapy lines prior to auto-SCT
• one line 61%

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• Remission status at auto-SCT
• CR1/PR1 72%
• CR2/PR2 and beyond 10%
• SD/PD 8%

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• Conditioning regimen
• BEAM 74%

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Shumilov EHA abstract S245 2024; Shumilov ASH abstract 464

EBMT analysis of first autoHCT in PTCL (2002-2022) patients)

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Shumilov EHA abstract S245 2024; Shumilov ASH abstract 464

Untreated PTCL

- CD30 expression <10% by IHC (excludes ALCL)

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• stratify for:
• TFH-PTCL/AITL
• CHOP/CHOEP backbone therapy
• CHOP: age >60
• CHOEP (age≤60)

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Duvelisib-CHO(E)P x 6 cycles (n=53)

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• CHOP/CHOEP given standardly
• With GCSF support
• Duvelisib 25mg BID days 1-21

CHOP or CHOEP x 6 cycles (n=53)

R (1:1:1)

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• Primary Objective:
• To compare the PET CR rate of duvelisib or 5-azacitidine in combination with CHOP/CHOEP compared to CHOP/CHOEP

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• Primary Endpoint:
• 25% difference PET CR rate

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• Correlative Studies:
• Monitoring MRD
• Alizadeh
• Gene Expression Profiling and Custom Capture Sequencing
• Dave
• Patient Reported Outcomes
• Thanarajasingam
• PET/CT Evaluation
• Schoder and Wright

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CC-486-CHO(E)P x 6 cycles (n=53)

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• CHOP/CHOEP given standardly
• With GCSF support
• CC486 300mg QD
• Cycle -1: days -6 to 0
• Cycles 1-5: days 8-21

Cycle =21 days

EA4232: Enrolling now!!!

NCCN Guidelines for rel/ref T-NHL: laundry list of options

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https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf

Duvelisib consistently efficacious in T-cell lymphomas

Encouraging activity in PTCL in phase I

Horwitz, et al. Blood 2018;131:888-98

Phase II PRIMO study confirms activity:

Mehta-Shah N, et al. Abstract 3061

**Poster session tonight

JAK/STAT mutations enriched among non-responders to PI3K inhibition

JAK/STAT mutations enriched among non-responders to duvelisib-based therapy

Horwitz, S.M., Nirmal, A.J., Rahman, J. et al. Duvelisib plus romidepsin in relapsed/refractory T cell lymphomas: a phase 1b/2a trial. Nat Med 30, 2517–2527 (2024)

Dose Escalation

n=8

Evaluable for DLT analysis

Dose Expansion at DL1

Rux 20mg BID plus Duv 25 mg BID

n=41

Evaluable for Efficacy and Safety analysis

n=49

n=2*

JAK/STAT activation

n= 24

No JAK/STAT activation

n= 17

JAK/STAT activation

n= 32

No JAK/STAT activation

n= 17

DL1

n=6^

DL2

DL3

*progressed during DLT period

^2 DLTs: grade 4 thrombocytopenia

grade 4 neutropenia

^

Dual-targeted therapy with ruxolitinib plus duvelisib for T cell lymphoma

Related Adverse Events ≥ 10% of Patients

4% grade 3 AST/ALT increase compared to 3% grade ≥3 AST/ALT increase with duvelisib alone¹

0% grade 3 rash compared to 2% grade ≥3 rash duvelisib alone¹

2% grade 3 diarrhea compared to 12% grade ≥3 colitis duvelisib alone¹

¹From Phase III study of duvelisib 25mg BID vs ofatumumab in CLL.

Flinn, et al. Blood. 2018;132(23):2446-2455

No pneumonitis observed compared to 3% grade ≥3 pneumonitis duvelisib alone¹

Ruxolitinib plus duvelisib: Efficacy by histology

TFH lymphomas

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T-PLL

RAdR for RR CTCL/PTCL (NCI study)

• Phase I dose escalation (28d cycles x 6)

Len 5-20mg/d D1 through D10

Romidepsin 12mg/m2 D1 and D10

Azacitidine 300mg D1 through D10

Dexamethasone 40mg D1 and D10

• N=26 with med age 61y (42% Black)
• Histology: 31% PTCL NOS, 19% AITL, 23% MF
• Results:

ORR 63%

CR 19%

1y PFS 11.1%

1y OS 71.4%

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1 PTCL NOS and 1 MF in remission >36m

PTCL and CTCL Summary

• Anthracycline-based chemotherapy plus autoHCT consolidation remains the SOC

What is the “true” added value of transplant?

• Current spectrum of targeted approaches

PI3K

JAK/STAT

Epigenetic deregulation—hypomethylating agents, HDACi

Monoclonal antibodies (not discussed—mogamulizumab)

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LYMPHOMA PROGRAM:

The University of Chicago

cancer@uchospitals.edu

THANK YOU

Opening 2027