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When Not to Watch and Wait: Emerging Strategies in the Treatment of Indolent Lymphoma

Christopher Flowers, MD, MS, FASCO

Division Head Division of Cancer Medicine

Chair, Professor Department of Lymphoma/Myeloma

Research at MD Anderson

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Disclosures

Consultant: Abbvie, Bayer, BeiGene, Celgene, Denovo Biopharma, Foresight Diagnostics, Genentech/Roche, Genmab, Gilead, Karyopharm, N-Power Medicine, Pharmacyclics/Janssen, SeaGen, Spectrum.

Stock Options: Foresight Diagnostics, N-Power Medicine

Research Funding: 4D, Abbvie, Acerta, Adaptimmune, Allogene, Amgen, Bayer, BostonGene, Celgene, Cellectis EMD, Gilead, Genentech/Roche, Guardant, Iovance, Janssen Pharmaceutical, Kite, Morphosys, Nektar,Novartis, Pfizer, Pharmacyclics, Sanofi, Takeda, TG Therapeutics, Xencor, Ziopharm, Burroughs Wellcome Fund, Eastern Cooperative Oncology Group, National Cancer Institute, V Foundation, Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research

​

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Learning Objectives

  • Describe the settings for watchful waiting in FL

​

  • Delineate the options for first line therapy in FL

​

  • Define the novel agents and combinations emerging for FL

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Current standard treatment landscape for FL

Courtesy of Dai Chihara MD, PhD

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Treatment naive

Radiation

Low tumor burden

Surveillance

Rituximab

Limited disease

Advanced disease

High tumor burden

Observation

Rituximab

Observation

Rituximab

BR/R-CHOP

R2

Rituximab

1L treatment

2L treatment

3L treatment

R2

?

R2/CIT

Mosunetuzumab

Epcoritamab

CAR T-cell therapy

Zanubrutinib

Tazemetostat

MD Anderson Department of Lymphoma/Myeloma

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Low tumor burden: Considering watch and wait vs. R

  • 10-15% spontaneous regression

Northend et al. ASH 2022

Median follow-up duration: 12.7 years

Median not reached

Median 9.9 years (5.7-N/A)

Median 2.7 years (2.2-4.0)

Arm

10-year TTNT

10-year 2nd

10-year CSS

W&W

29%

78%

87%

RI

49%

85%

88%

RM

64%

86%

90%

Arguments for W&W

  • Treatment does not impact OS

​

  • 15-20% not received treatment after 10 years

​

  • Median time to start treatment: 2.5 years

​

  • Psychological impact/QoL

​

MD Anderson Department of Lymphoma/Myeloma

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RWE for Watch and wait (Australia)

  • 267 patients from 8 centers
  • Median age: 64 years (range: 24-88)
  • Median follow up: 5.5 years
  • 10.5% met GELF criteria

​

  • 10% can developed organ dysfunction
  • Surveillance imaging before treatment in 20%
  • ↑LDH or >4 nodal sites at diagnosis risk factors for shorter time to treatment

Tobin et al. ASH 2024

49% continued WW at 5 years

30% WW at 10 years

MD Anderson Department of Lymphoma/Myeloma

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Treatment option for advanced stage/high tumor burden disease

Department of Lymphoma/Myeloma

​

STiL

BRIGHT

GALLIUM

RELEVANCE

Agent

Bendamustine

Bendamustine

Obinutuzumab

Lenalidomide

Eligibility

FL G1-2

Stage III or IV

FL G1-2

HTB

FL G1-3a

Stage III or IV

HTB

FL G1-3a

Stage II to IV

HTB

Treatment

BR x 6

BR x 6

O-chemo + maintenance

R2 + 2-yr maintenance

Primary endpoint

PFS

CR rate

PFS

CR30, PFS

Design

Non-inferior

Non-inferior

Superior

Superior

CR rate

40% (CT)

31% (CT)

20% (CT), 78% (PET)

48% (CT)

5-year PFS

58%

66%

70%

63%

​

​

​

​

​

44 N Eng J Med. 2018; 379-947

Lancet. 2013; 381: 1203-10

Blood. 2014; 123:2944-52

N Eng J Med. 2017; 377: 1331-1344

Courtesy of Dai Chihara MD, PhD

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Ibrutinib +R2�Similar outcomes with ↑ toxicity

​

Grade 1

No. (%)

Grade 2

No. (%)

Grade 3

No. (%)

Grade 4

No. (%)

Nonhematologic AEs

Arthralgia

11 (22.9)

2 (4.2)

​

​

Chills

12 (25)

3 (6.3)

​

​

Constipation

13 (27.1)

​

​

​

Cough

5 (10.4)

4 (8.3)

​

​

Diarrhea

17 (35.4)

6 (12.5)

6 (12.5)

​

Dizziness

4 (8.3)

1 (2.1)

​

​

Dry skin

9 (18.8)

1 (2.1)

​

​

Dyspnea

5 (10.4)

2 (4.2)

1 (2.1)

​

Edema, limbs

13 (27.1)

5 (10.4)

​

​

Fatigue

23 (47.9)

12 (25)

2 (4.2)

​

Fever

9 (18.8)

2 (4.2)

​

​

Headache

16 (33.3)

1 (2.1)

​

​

Mucositis

9 (18.8)

3 (6.3)

​

​

Myalgia

30 (62.5)

7 (14.6)

​

​

Nausea

13 (27.1)

3 (6.3)

​

​

Rash,

13 (27.1)

3 (6.3)

24 (50)

​

Vomiting

3 (6.3)

2 (4.2)

​

​

Hematologic AEs

Anemia

2 (4.2)

2 (4.2)

1 (2.1)

​

Leukopenia

​

​

2 (4.2)

​

Neutropenia

2 (4.2)

1 (2.1)

3 (6.3)

4 (8.3)

Department of Lymphoma/Myeloma

Safety and efficacy of ibrutinib in combination with rituximab and lenalidomide in previously untreated FL and MZL: An open label, phase 2 study

Gordon et al. Cancer, 2024

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Treatment schema

Cycle 1

Acalabrutinib 100 mg PO BID

Lenalidomide 20 mg PO D 1-21

Rituximab 375 mg/m2 IV weekly X 4, then monthly

​

For 13 cycles

For 12 cycles

Cycle 2

Pre-C2

6 months

response

13 months

response

PB

PB

PB

Baseline

PB/tissue

PB/tissue at PD

3 months

response

Strati et al. ASH 2023 Abstract #983

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Efficacy results: Response rates

Primary endpoint: best CR rate > 80%

Observed best CR rate: 92%

3M 6M EOT BEST

N=24 N=24 N=24 N=24

62.5

92

92

87.5

Strati et al. ASH 2023 Abstract #983

Median follow-up 29 months (95% CI, 28-32 months)

N PD/dead 2-y PFS

24 9 79%

1 PD at 16 months (d/c acalabrutinib)

3 tFL at 5, 7 and 12 months (baseline tFL?)

POD24 rate 17%

# at risk 24 (0) 23 (0) 22 (0) 19 (0) 19 (0)

(#censored)

Progression-free survival

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Treatment-emergent adverse events

Patients (N=24)

Grade 1-2

Grade 3-4

Neutropenia

8 (33)

14 (58)

ALT elevation

7 (29)

4 (17)

AST elevation

6 (25)

3 (12.5)

Infection

8 (33)

3 (12.5)

Anemia

18 (75)

2 (8)

Skin rash

10 (42)

2 (8)

Fatigue

18 (75)

1 (4)

Nausea

6 (25)

1 (4)

Infusion-related reaction

5 (21)

1 (4)

Peripheral neuropathy

4 (17)

1 (4)

Lymphopenia

3 (12.5)

1 (4)

Atrial fibrillation

0 (0)

1 (4)

Patients (N=24)

Grade 1-2

Grade 3-4

Thrombocytopenia

16 (67)

0 (0)

Headache

14 (58)

0 (0)

Diarrhea

10 (42)

0 (0)

Pruritus

7 (29)

0 (0)

Arthralgia

7 (29)

0 (0)

Bruising

6 (25)

0 (0)

Myalgia

6 (25)

0 (0)

Dizziness

5 (21)

0 (0)

Dry skin

4 (17)

0 (0)

Sinus bradycardia

3 (12.5)

0 (0)

Dysgeusia

2 (4)

0 (0)

Strati et al. ASH 2023 Abstract #983

MD Anderson

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Single agent bispecific antibody therapy

Department of Lymphoma/Myeloma

Falchi et al. ASH 2024

MD Anderson

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Single agent bispecific antibody therapy

Department of Lymphoma/Myeloma

Falchi et al. ASH 2024

MD Anderson

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Single agent bispecific antibody therapy

Department of Lymphoma/Myeloma

Falchi et al. ASH 2024

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Single agent bispecific antibody therapy

Department of Lymphoma/Myeloma

Falchi et al. ASH 2024

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R/R FL: POD24 is associated with inferior survival

Biopsy recommended to detect histologic transformation of FL, which is reported to occur at a rate of 2% per year1

    • If concerned for clinical transformation and biopsy is not pursue, would treat as DLBCL2

Early progression of disease (≤2 years) after frontline chemoimmunotherapy (POD24) occurs in approximately 20% of patients

Worse OS �in patients �with early POD

Time from Risk-Defining Events (months)

No. at risk

Early POD

Reference

110

420

82

408

66

387

56

363

50

344

42

253

32

145

14

34

3

0

12

24

36

60

48

72

84

96

0.4

0.8

0.6

1.0

0.2

Survival (probability)

0

Early POD

Reference

Casulo C, et al. J Clin Oncol. 2015;33:2516.

    • Associated with a poor prognosis3
    • Represents a population that should be targeted for trials.

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1L FL What’s next? – Value of MRD Assessment

GALLIUM: Mid induction PCR-based assessment of MRD predicts PFS for treatment of 1L FL

​

Pott, et al. J Clin Oncol. 2024

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1L FL What’s next? – FLIPI24

Aim: Develop a FL clinical prognostic index using early events as the primary endpoint

Harmonized individual pt data from >9,000 pts with FL from 11 international registries

4743 1L FL pts Dx 2002-2018;vtreated with R-CHOP, B-R, R-CVP

    • Model build on 80% (N=3793)
    • Testing on 20% (N=950)

​

​

Maurer M, et al. ASH Ann Meeting. 2023

Final Model

EFS Across Models

Test

Build

FLIPI 24 Risk

High

Low

Variable

Input Range

Effect

Age

18-90

Linear 60-90

Inflection at age 75

LDH/ULN

0.5-5

Linear

B2M

1-10

Linear

HGB

8-17

Linear

WBC

4-11

Linear

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Core Infrastructure and Methodological Research for Cancer Epidemiology Cohorts

Jim Cerhan MD, PhD

Chris Flowers MD, MS

AIMS:

  1. Recruit 12,900 newly diagnosed NHL pts

including 3,600 DLBCL and 3,100 FL

  • Build a NHL tumor bank w/ TMA, tumor DNA and RNA
  • Central biorepository: PB, serum, plasma, DNA
  • Collect clinical, epidemiologic, pathology and treatment data
  • Prospectively follow patients for clinical and patient-reported outcomes

GOAL:

To Facilitate research that uses LEO infrastructure and supports

Interaction with lymphoma NCTN

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LEO Geography and Comparison of to SEER

Cerhan et al, AJH 2024

Residence of LEO participants enrolled 2015-2020 by Rural Urban Code

(n=7735)

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Take Home Points & Future Directions

  • Anti-CD20 + chemotherapy remains the standard first line therapy

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  • R2 – not superior to R-chemo, but appears comparable, potential option if the goal is to avoid chemotherapy

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  • Novel agents and combinations are emerging

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  • New prognostic models may help risk stratify patients

…and guide treatment selection

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Christopher Flowers, MD, MS, FASCO

Division Head Division of Cancer Medicine

Chair, Professor Department of Lymphoma/Myeloma

​

Contact: crflowers@mdanderson.org

Questions?

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