Evolution of Lymphoma Staging and Response Evaluation

Evolution of lymphoma staging and response evaluation:

Current limitations and Dr Joel Cunningham Haematology Specialty Registrar future directions East of England [email protected]

With thanks to Dr B Sharma & Dr S Iyengar • What does the past evolution of lymphoma staging tell us about current limitations and future directions?

• How do current national and international guidelines relate to current practice in haemato-oncology multidisciplinary teams?

• What is the role of functional metabolic imaging in the interim assessment of lymphoma treatment?

• How might novel techniques provide accurate and dynamic assessment of lymphoma staging and Overview treatment response?

2 1. Why is any medical investigation performed?

2. How will the result of an investigation change patient management?

3 3. What is your department’s current practice in lymphoma staging and response assessment?

4 "A valid staging classification for a neoplastic disease is important for at least four reasons: (1) to provide important prognostic information for different sites and extent of the disease, (2) to assist the physician in selecting the most appropriate therapeutic program, (3) to provide a standardized system which permits comparisons of therapeutic results, and (4) to provide an accepted descriptive system Why stage which communicates the extent of the disease.“ lymphoma? Rosenberg, S. A. Validity of the Ann Arbor staging classification for the non-Hodgkin’s lymphomas. Cancer Treat. Rep. 61, 1023–1027 (1977). 5 Facilitate Improve communication prognostication within MDT

Why stage lymphoma? 6 Guide treatment Aid research choices 1971 1989 Evolution of lymphoma staging 7

2009 2014 Cunningham J, Iyengar S, Sharma, B. 2017. Evolution of lymphoma staging and response evaluation: current limitations and future directions. Nat Rev Clin Oncol. Jun 13. doi: 10.1038/nrclinonc.2017.78. Cunningham J, Iyengar S, Sharma, B. 2017. Evolution of lymphoma staging and response evaluation: current limitations and future directions. Nat Rev Clin Oncol. Jun 13. doi: 10.1038/nrclinonc.2017.78. Cunningham J, Iyengar S, Sharma, B. 2017. Evolution of lymphoma staging and response evaluation: current limitations and future directions. Nat Rev Clin Oncol. Jun 13. doi: 10.1038/nrclinonc.2017.78. Ann Arbor

IMAGE: https://www.lls.org/lymphoma/hodgkin-lymphoma/diagnosis/hodgkin-lymphoma-staging “...therefore, 2 systems of classifications are presented.

Clinical staging (CS), while recognized as incomplete, is easily performed and should be reproducible from one center to another.

The second, called pathological staging (PS), takes into account all the extrapathological data obtained from vigorous staging procedures and has a higher degree of precision but is restricted in its application..." Ann Arbor Rosenberg, S. A. Validity of the Ann Arbor staging classification for the non-Hodgkin’s lymphomas. Cancer Treat. Rep. 61, 1023–1027 (1977). 12 Ann Arbor Rosenberg, S. A. Validity of the Ann Arbor staging classification for the non-Hodgkin’s lymphomas. Cancer Treat. Rep. 61, 1023–1027 (1977). 13 Ann Arbor

14 Cunningham J, Iyengar S, Sharma, B. 2017. Evolution of lymphoma staging and response evaluation: current limitations and future directions. Nat Rev Clin Oncol. Jun 13. doi: 10.1038/nrclinonc.2017.78. Cunningham J, Iyengar S, Sharma, B. 2017. Evolution of lymphoma staging and response evaluation: current limitations and future directions. Nat Rev Clin Oncol. Jun 13. doi: 10.1038/nrclinonc.2017.78. Cunningham J, Iyengar S, Sharma, B. 2017. Evolution of lymphoma staging and response evaluation: current limitations and future directions. Nat Rev Clin Oncol. Jun 13. doi: 10.1038/nrclinonc.2017.78. Deauville score

18 • PET/CT promoted as tool of choice to stage lymphoma in majority of circumstances – PET/CT should be used for staging in clinical practice and clinical trials (in FDG-avid lymphomas) – PET/CT can help select biopsy sites – PET/CT is superior to CT alone for interim imaging

• Use of Deauville criteria recommended Lugano – Generally, score of 1,2 or 3 represents ‘complete metabolic response’. classification • Bone marrow staging considered virtually redundant in high grade lymphomas 19 Limitations of modern imaging PET positive does not PET negative does not Lymphoma subtypes techniques = active lymphoma = “cure” which are not FDG avid

Difficult anatomical Assessment of Radiation risk to sites (CNS, abdomen) response to novel patients therapies 20 Meta-analysis of 11 studies, 139 patients.

Pooled FDG-PET false-positive proportions:

• Interim FDG-PET in NHL 83.0% (95% CI: 72.0%–90.2%) • End of treatment FDG-PET in HL 23.1% (95% CI: 4.7%–64.5%) • End of treatment FDG-PET in NHL 31.5% (95% CI: 3.9%–83.9%)

Infection / Inflammation / Necrosis

21 22 DISEASE RELAPSE

MISSED MICROSCOPIC/MINIMALLY RESIDUAL DISEASE?

23 24

Barrington, S. F. et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J. Clin. Oncol. 32, 3048–3058 (2014).

43 patients with relapsed/refractory HL receiving anti-PD1 treatment. ORR 72%, with PET/CT imaging revealing response at 8weeks. Physiological FDG uptake:

Central nervous system

Breasts

Cardiac (blood glucose dependent)

Liver (& spleen)

Renal tract

Bowel

Bone marrow (e.g. GCSF)

Active muscle

Testicular

Ahmad Sarji, S. Physiological uptake in FDG PET simulating disease. Biomed Imaging Interv J. 2:e49. (2014).

Current practice in lymphoma What - disease-specific imaging

How – modality-specific

When - circumstance-specific Histopathological subtype:

– Guidelines

– Evidence base

Clinical urgency VS. Resource availability

Relative contraindications:

Imaging in – Ongoing/recent chemotherapy lymphoma – Concurrent infection – Patient factors (diabetes, age, mobility, claustrophobia, allergy status, renal function) • Pre-treatment PET/CT will upstage a minority of patients and aid interpretation of subsequent PET/CT imaging • Assess response using Deauville criteria, 1/2 = negative, 4/5 = Hodgkin positive (3 = interpret in clinical context) guidelines • Biopsy PET-positive residual lesions where possible • Interim PET imaging is highly predictive of outcome, but (BSH - 2014) optimal management is “uncertain” • End of treatment PET/CT is recommended for all patients who have not achieved interim PET-negativity • Staging CT N/C/A/P should be performed in all patients • Where possible, staging PET/CT is recommended DLBCL • PET is “very valuable” in assessing bone marrow involvement • “The PPV of an interim PET scan is variable with insufficient guidelines evidence at present to change standard treatment based on the result of interim PET-CT scan alone. A routine interim PET scan is (BSH - 2016) therefore not recommended” • An end of treatment PET scan is “strongly recommended” • Offer PET/CT to confirm staging in: – Stage 1 DLBCL – Stage 1 or 2 FL(e.g. if radiotherapy considered) – Stage I or II Burkitt lymphoma with low risk features • Consider PET/CT for other stages/subtypes of NHL if results NHL guidelines will alter management • Offer PET/CT imaging to assess response at completion of (NICE – 2016) planned treatment for DLBCL/Burkitt lymphoma • Consider PET/CT to assess response prior to autologous stem cell transplantation in high grade NHL NHL guidelines (NICE – 2016) How can we best utilise interim imaging?

35 Response- RAPID Stage Ia/IIa disease: involved field adapted therapy radiotherapy vs no in Hodgkin further treatment 94.6% vs 90.8% 3 year Lymphoma PFS for patients with negative PET/CT after 3 cycles of ABVD (NOT non-inferiority) Response- adapted therapy H10 Can radiotherapy be in Hodgkin omitted in stage I/II disease (favourable Lymphoma and unfavourable groups) on basis of interim PET? Response- adapted therapy in Hodgkin Lymphoma • Stopped early due to interim analysis – increased number of events in experimental arm. RATHL: Negative PET/CT after two cycles allows de-escalation Response- to AVD (3y PFS of 85.7% vs 84.4%) in advanced Hodgkin’s adapted therapy Lymphoma (Stage ≥ 2B, or stage 2A with adverse features). in Hodgkin Lymphoma BEACOPP used in patients with positive interim PET/CT at 2#, Response- with good outcome (3-year PFS 67.5%). adapted therapy in Hodgkin Lymphoma Response- adapted therapy HD0801 Use of an ifosfamide/ in Hodgkin gemcitabine/vinorelbine salvage + HSCT in interim Lymphoma PET+ve advanced stage HL provides good PFS. Response- adapted therapy in aggressive NHL? Response- adapted therapy in aggressive NHL? Novel lymphoma • Novel PET radiotracers • Diffusion weight magnetic resonance assessment imaging techniques • Radiogenomics

• MRD monitoring

• Combined reporting / template approach… Novel PET • 18F-fluoromethylcholine (FCH)–PET choline kinase is upregulated radiotracers in tumour cells: high lesion-to-CNS background ratio • 3ʹ-deoxy-3ʹ-[18F]fluorothymidine (FLT) is retained in proliferating cells by the actions of thymidine kinase 1

Cunningham J, Iyengar S, Sharma, B. 2017. Evolution of lymphoma staging and response evaluation: current limitations and future directions. Nat Rev Clin Oncol. Jun 13. doi: 10.1038/nrclinonc.2017.78. O'Flynn, E. A., & DeSouza, N. M. 2011. Functional magnetic resonance: biomarkers of response in breast cancer. Breast cancer research . 13, 204. doi:10.1186/bcr2815

DW-MRI • Non-FDG avid lymphoma subtypes? • Assessment of bone marrow disease? • Residual mass assessment? • Radiation-free? CD15/CD20/CD30 + Gray Zone Lymphoma – PET imaging DW-MRI suggestive of disease relapse. DW-MRI: anterior mediastinal mass with minimal fat, large volume of unimpeded water, low cellularity. 47

Diagnosis: thymic hyperplasia Jansen, RW et al. Non-invasive tumor genotyping using radiogenomic biomarkers, a systematic review and oncology-wide pathway analysis. Oncotarget. 9(28):20134-20155 (2018)

• Correlation of imaging ‘phenotypes’ with tumour ‘genotypes’ • Extraction of spatial and temporal radiological data Radiogenomics from multi-parametric imaging studies • Evidence in solid organ tumours (e.g. liver cancers) • In lymphoma… • 57 patients with DLBCL treated with R-CHOP • Cell of origin: (p=0.02)

– GCB Median SUVmax =20.8

– ABC medin SUVmax = 15.2 Radiogenomics • Interim scoring system predicts overall survival: COO + iPET* + aaIPI

*Fast response = ∆SUVmax >70% How could we dynamically assess response to chemotherapy?

“...2 systems of classifications are presented.

Clinical staging (CS), while recognized as incomplete, is easily performed and should be reproducible from one center to another.

50 Changing technology may facilitate ‘liquid biopsies’

• Multicolour flow cytometry – Limited to ‘leukaemic’ disease

• PCR quantification (e.g. IGH/BCL2 translocations in FL) – Susceptible to failure from poor breakpoint coverage

• Next-generation sequencing of circulating tumour DNA – Track somatic mutations , monitor mutation evolution

Luminari, S. Positron emission tomography response and MRD monitoring minimal residual disease impact on progression-free survival in patients with follicular lymphoma. A subset analysis from the FOLL05 trial of the Fondazione Italiana Linfomi. Haematologica; 101(2):e66-8 (2016) Cunningham J, Iyengar S, Sharma, B. 2017. Evolution of lymphoma staging and response evaluation: current limitations and future directions. Nat Rev Clin Oncol. Jun 13. doi: 10.1038/nrclinonc.2017.78. Take home points:

• What is your department’s routine staging practice? • Novel imaging and molecular technique will change guidelines again! • PET +ve lesions do not always equate to lymphoma activity. • Only request imaging when it will change management… • MDT discussion is vital at each point, particularly when imaging is indeterminate. …use imaging ‘wisely’!

“Limit surveillance computed tomography (CT) scans in asymptomatic patients following curative-intent treatment for aggressive lymphoma.”

“Don’t perform baseline or routine surveillance computed tomography (CT) scans in patients with asymptomatic, early-stage chronic 53 lymphocytic leukemia (CLL).” • Barrington, S. F. et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J. Clin. Oncol. 32, 3048–3058 (2014). • Cheson, B. D. et al. Refinement of the Lugano classification lymphoma response criteria in the era of immunomodulatory therapy. Blood 128, 2489–2496 (2016). • Cunningham J, Iyengar S, Sharma, B. 2017. Evolution of lymphoma staging and response evaluation: current limitations and future directions. Nat Rev Clin Oncol. 14, 631-645 (2017). • Dührsen, U. et al. Positron Emission Tomography–Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL): A Multicenter, Randomized Phase III Trial. J. Clin. Oncol. 36, 2024-2034 (2018). • Johnson, P. et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N. Engl. J. Med. 374, 2419–2429 (2016). • Radford, J. et al. Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N. Engl. J. Med. 372, 1598–1607 (2015). • Raemaekers, J. M. M. et al. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an Selected increased risk of early relapse: clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J. Clin. Oncol. 32, 1188–1194 (2014). references • Younes, A. et al. International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017). Ann Oncol. 28, 1436–1447 (2017).

54 Evolution of lymphoma staging and response evaluation:

Current limitations and Dr Joel Cunningham Haematology Specialty Registrar future directions East of England [email protected]

With thanks to Dr B Sharma & Dr S Iyengar