Primary Cutaneous T-cell Lymphoma is a rare type of non-Hodgkin’s lymphoma (approximately 0.8 in 100,000 in Western countries). They are complex, heterogeneous and characterised by localisation of neoplastic T-lymphocytes to the skin. CD30 positive T-cell lymphoma encompasses anaplastic large cell lymphoma (ALCL) at the malignant end and lymphomatoid papulosis at the benign end. Borderline lesions lie somewhere in between, with overlapping clinical and histopathological features. Mycosis fungoides is the most common type of primary cutaneous T-cell lymphoma and can be co-morbid with CD30 positive T-cell lymphoma.
CD30 positive primary cutaneous T-cell lymphoma refractory to standard treatment has some evidence for systemic therapies, such as described below. However, due to the rare nature of primary cutaneous T-cell lymphoma, other randomised clinical trials are lacking. Although multi-agent cytotoxic regimens may be palliative, there is no proven survival benefit.
Treatment options for relapsed disease are limited, and this led to the study comparing brentuximab and physician’s choice from 2012 to 2015 for CD30 positive primary cutaneous T-cell lymphoma that failed at least one treatment.
Brentuximab is an anti-CD30 antibody that is conjugated to an anti-microtubule agent, monomethyl auristatin E (MMAE). The binding of brentuximab to the CD30 receptor results in the internalisation of the whole molecule to the lysosomal compartment. The monoclonal antibody is then cleaved from the MMAE through proteolytic cleavage inside the cell and results in apoptosis by interrupting the microtubule network inside the cell.
In this international, open-label, randomised, phase 3 trial brentuximab was compared with physician’s choice in patients who were previously treated with CD30 positive cutaneous T-cell lymphoma. CD30 positive patients were defined as those with greater than 10% CD30 positive cells or lymphoid infiltrate. Treatment in the physician’s choice arm was methotrexate 5 to 50mg orally ONCE per week or bexarotene 300mg/m2 orally per day. Brentuximab was given at a dose of 1.8mg/kg and treatment was continued until progression or unacceptable toxicity for a maximum of 16 cycles.
The primary endpoint was an objective response for a minimum of four months (ORR4) as defined by an independent panel. All patients who finished treatment were followed every 12 weeks for a minimum of 24 months. The objective response is a more appropriate measurement of outcome than progression-free survival (PFS) in cutaneous T-cell lymphoma as PFS may still include those who are symptomatic and progress to other therapies. ORR4 was chosen as a measurement that measures not only the proportion of response but also the length of response.
The ORR4 was 56.3% vs 12.5% in favour of brentuximab over physician’s choice. This strong response was seen in both subgroups of primary cutaneous ALCL and mycosis fungoides. In all subgroups, there was an improvement in response and across all ranges of CD30 levels. Benefit was shown for all key secondary endpoints, and the median duration of response was 15.1 months.
The most common side-effect is peripheral neuropathy, which is not surprising given MMAE is an anti-microtubule agent. Nine out of 66 patients (13%) ceased brentuximab due to peripheral neuropathy. 67% of patients experienced some form of peripheral neuropathy, however, the majority were mild cases being Grade 1 or 2. Peripheral sensory neuropathy was the most common form of peripheral neuropathy seen in 45% of patients. There was also one patient whose death was attributed to brentuximab due to tumour lysis syndrome on sites of visceral lymphoma involvement.
Patients with CD30 greater than 10% were included in this trial. However, other trials have been conducted in patients with lower CD30 counts and high Sezary cell count, another exclusion criteria, and were shown to respond to treatment with brentuximab.
Pralatrexate is a potent anti-folate molecule that is designed to be efficiently internalised by the reduced folate carrier (RFC) and folylpolyglutamyl synthetase (FPGS). This causes accumulation in lymphoma cells. Upon internalisation, it inhibits dihydrofolate reductase and thereby inhibits DNA replication and cell division.
The PROPEL study treated patients with peripheral T Cell Lymphoma (PTCL) with 30mg/m2/week every six out of seven weeks. Patients included had been treated with at least one treatment and progressed after treatment. Treatment was continued until disease progression, unacceptable toxicity or stopped at the physician’s discretion.
The primary endpoint for PROPEL was an objective response (ORR), and a secondary outcome was the length of response. ORR was assessed by central review.
One hundred eleven patients received treatment, and 29% had an ORR, the primary outcome for PROPEL. 11% had complete remission, and 19% had stable disease. For patients who did not respond to their most recent therapy, 25% of those patients had a response, and 24% of patients treated with prior methotrexate, a drug with a very similar mechanism of action had a response.
The median duration of response was 10.1 months, and median overall survival was 14.5 months.
Mucositis is the most common reason for dose reduction with pralatrexate (23% of patients). Other reasons in PROPEL included abnormal liver function tests (LFTs), thrombocytopenia, fatigue, Herpes Zoster, Neutropenia and pruritic rash.
Grade 3 or 4 adverse reactions included thrombocytopenia, mucositis and neutropenia and 5% of patients experienced a case of febrile neutropenia. One death was potentially attributed due to pralatrexate, a cardiopulmonary arrest while being hospitalised with mucositis and febrile neutropenia.
Four patients that received autologous stem-cell transplantation (ASCT) post-pralatrexate remained in remission at the time of the article being published, and the authors suggested this is a potential bridge to stem cell transplantation for pralatrexate.
As stated above, mucositis is the most common troublesome side-effect with pralatrexate treatment. A study gave folinic acid 25mg three times daily for two days, starting 24 hours after pralatrexate treatment to look at whether this helps with mucositis associated with pralatrexate. The primary endpoint was Grade 2 or greater mucositis in cycle one of pralatrexate treatment (six doses). At the time of analysis, all 30 patients met the primary endpoint. This is now included as standard treatment for patients receiving pralatrexate treatment. Another study has shown giving five days of leucovorin 25mg every six hours, stopping at a minimum 48 hours prior to the next pralatrexate dose ameliorated mucositis in patients receiving pralatrexate, and it has been reported as standard practice in one centre to give leucovorin 15mg four times daily for every day except the day before, day of, and the day after chemotherapy. In patients with mucositis despite two days of leucovorin, extended leucovorin treatment could potentially be an option.
Refractory primary cutaneous T-cell lymphoma, as discussed, is a disease with very poor prognosis and these treatment options are now available in this difficult to treat population. Mucositis is no longer as debilitating as it was with pralatrexate, given the standard prophylactic treatment with two days of leucovorin or at the physician’s discretion even a longer period of leucovorin treatment to prevent mucositis.
- Adcetris® (brentuximab vedotin) Australian approved product information. Sydney: Takeda Pharmaceuticals. Approved April 2020.
- Duvic M, Tetzlaff MT, Gangar P, Clos AL, Sui D, Talpur R. Results of a phase II trial of Brentuximab vedotin for CD30 positive cutaneous T-cell lymphoma and lymphomatoid papulosis. J Clin Oncol. 2015; 33(32): 3759-65.
- Peripheral T-cell lymphoma pralatrexate. Alexandria: NSW Government; 2019.
- Folotyn® (pralatrexate) Australian approved product information. Sydney: Mundipharma. Approved February 2020.
- Kim YH, Tavallee M, Sundram U, Salva KA, Wood GS, Li S, et al. Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides and Sézary syndrome with variable CD30 expression level: a multi-institution collaborative project. J Clin Oncol. 2015; 33(32): 3750-8.
- O’Connor OA, Amengual J, Colbourn D, Deng C, Sawas A. Pralatrexate: a comprehensive update on pharmacology, clinical activity and strategies to optimize use. Leuk Lymphoma. 2017; 58(11): 2548-57.
- O’Connor OA, Pro B, Pinter-Brown L, Bartlett N, Popplewell L, Coiffier B, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011; 29(9): 1182-9.
- Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P, et al. Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet 2017; 390: 555-66.
- Shuslov et al Management of mucositis with the use of leucovorin as adjunct to pralatrexate in treatment of peripheral T-cell lymphoma (PTCL) – results from a prospective multicenter Phase 2 clinical trial. Blood 2018; 132(1): 2910.
- Willemze R, Hodak E, Zinzani PL, Specht L, Ladetto M. Primary cutaneous lymphomas: ESMO clinical practice guidelines. Ann Oncol. 2018; 29(4): iv30-iv40.