Canterbury DHB

Management of Non-Trial Patients

There are many guidelines and expert reviews for management and treatment of non-Hodgkin’s lymphoma which often describe approaches using newer drugs that may not necessarily be available or funded in NZ.

For expert reviews, see:

• Armitage, J. O., et al. (2017). "Non-Hodgkin lymphoma." The Lancet 390(10091): 298-310.
• Reagan, P. M. and A. Davies (2017). "Current treatment of double hit and double expressor lymphoma." Hematology Am Soc Hematol Educ Program 2017(1): 295-297.
• Martin, P. (2017). "Optimizing therapy for mantle cell lymphoma." Hematology Am Soc Hematol EducProgram 2017(1): 304-309.
• Broccoli, A. and P. L. Zinzani (2017). "Peripheral T-cell lymphoma, not otherwise specified." Blood 129(9): 1103.
• Grommes, C. and L. M. DeAngelis (2017). "Primary CNS Lymphoma." J Clin Oncol 35(21): 2410-2418.
• Schiff, D., Hong, F. (2016). "Defining optimal initial therapy for primary CNS lymphoma." Lancet Haematol 3: e206-7.
• Johnson, P.et al. (2015). "How I treat advanced classical Hodgkin lymphoma." Blood 125: 1717-23.
• Sehn LH, Salles G. Diffuse Large B-Cell Lymphoma. New England Journal of Medicine 2021;384(9):842-858. DOI: 10.1056/nejmra2027612.
• Crombie J, LaCasce A. The treatment of Burkitt lymphoma in adults. Blood 2021;137(6):743-750. DOI: https://doi.org/10.1182/blood.2019004099.
• Brice P, de Kerviler E, Friedberg JW. Classical Hodgkin lymphoma. Lancet 2021;398(10310):1518-1527. DOI: 10.1016/S0140-6736(20)32207-8.
• McNamara C, Montoto S, Eyre TA, et al. The investigation and management of follicular lymphoma. Br J Haematol 2020;191(3):363-381. DOI: 10.1111/bjh.16872.
• Dimopoulos MA, Kastritis E. How I treat Waldenström macroglobulinemia. Blood 2019;134(23):2022-2035. DOI: 10.1182/blood.2019000725.
• Cwynarski K, Marzolini MAV, Barrington SF, et al. The management of primary mediastinal B-cell lymphoma: a British Society for Haematology Good Practice Paper. British Journal of Haematology 2019;185(3):402-409. DOI: 10.1111/bjh.15731.

Assessment of Response

See Cheson, B. D., et al. (2014). "Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification." Journal of Clinical Oncology 32(27): 3059-3067 and Cheson, B.D., Ansell, S. (2016). "Refinement of the Lugano Classification lymphoma response criteria in the era of immunomodulatory therapy." Blood 128: 2489.

Re-assessment is often performed after 3-4 cycles of therapy to confirm a response. All patients will be systematically re-evaluated to assess response 3-4 weeks following final chemotherapy administration.

Re-evaluation Investigations

1. Full history and physical examination.
2. FBC, biochemical profile, LDH level.
3. Repeat CT of all sites found to be abnormal pre-chemotherapy.
4. Bone marrow trephine + aspirate, if abnormal pre-chemotherapy.

PET and PET/CT

Positron emission tomography using ¹⁸F-fluorodeoxyglucose when combined with CT scanning can improve the detection of lymphoma and measure disease activity. It may be used for staging, early therapy response, and end of treatment evaluation. It is helpful in determining the nature of residual masses after therapy. PET/CT is available at Christchurch Radiology Group for the following DHB-Approved indications in lymphoma:

Complete both sides of the PET/CT Imaging Request Form and give the form to Anne Quick, Clerical Supervisor (ext 80399).

Suggested Follow-Up

There is no standardised follow-up for patients who have completed therapy. This will depend on the:

• side effects which the patient has experienced from chemotherapy (which usually resolve within a few weeks of completion)
• ability of follow-up to detect treatable disease recurrence. (Disease recurrence in curable lymphomas—e.g. DLBCL, BL—is unlikely after 3 years but can occur after much longer periods in low grade lymphomas with the highest incidence in the first 3 years.)

In practice it is reasonable to follow patients 2-3 monthly for the first 6 months after treatment has finished, then less often, and to consider discharge after 3-5 years.

CNS Directed Therapy

Secondary CNS involvement occurs more commonly in high grade than low grade lymphoma. Relapse in the CNS may occur following complete remission and the prognosis is extremely poor. Risk factors for CNS involvement include:

• high age-adjusted IPI
• advanced stage disease
• elevated LDH
• more than one extra-nodal site and disease involving the testes, breast, paranasal, or epidural space.

There is no consensus about which patients should receive prophylactic CNS-directed therapy or which regimen is the most effective. However, a valuable and practical approach is based on risk assessment and use of intravenous methotrexate after systemic chemotherapy (usually RCHOP) in high risk patients with DLBCL. See Calimeri T, Ferreri A. Prevention of CNS relapse in diffuse large B-cell lymphoma: common sense prevails when science fails. British Journal of Haematology 2020.

Here is the Christchurch Hospital algorithm for selecting which patients with DLBCL should receive CNS prophylaxis. It is based on the German NHL CNS study group international prognostic index.

Use of acetazolamide during high dose methotrexate improves diuresis and maintains better renal function, especially in older females. See Ku M, Bazargan A, Tam C. Addition of low dose acetazolamide as an adjunct in patients undergoing high dose methotrexate is safe and beneficial. Intern Med J 2020;50(3):357-362. DOI: 10.1111/imj.14468.

Treatment of Lymphoma

It goes without saying that wherever possible patients should be offered treatment in any studies for which they may be eligible.

There are many very promising new drugs at an advanced stage of development for the treatment of all subtypes of lymphoma. In some cases these are licensed in NZ and more generally overseas. None is funded in NZ as of 2018. Patients may wish to purchase these drugs at their own expense.

Some treatment studies available in Christchurch may include some of these newer agents.

These drugs include:

• Second generation anti-CD20 monoclonal antibodies, e.g., obinutuzumab
• B cell receptor inhibitors e.g., ibrutinib, acalabrutinib, zanubrutinib
• BNL2 inhibitors e.g., venetoclax
• PI3K inhibitors e.g., idelalisib
• Antimetabolites e.g., pralatrexate (T cell NHL)
• HDACs e.g., Romidepsin (T cell NHL)
• Anti-CD30 monoclonal Ab e.g., brentuximab (Hodgkin Lymphoma, ALTCL)
• PD or PD Ligand inhibitors e.g., nivolumab, pembrolizumab (Hodgkin Lymphoma)

All treatments below are available in NZ. Some require special authority (rituximab, bendamustine, vinorelbine, gemcitabine, GCSF, and pegfilgrastim) which may be limited to use in certain NHL or to particular stages of disease.

Topic Code: 5949