You Make the Call: What is the best consolidation therapy for this patient with primary central nervous system lymphoma?

Erin Reid, MD
Professor of Medicine; Vice Chair, Lymphoma Working Group, Moores Cancer Center, UC San Diego Health

This month, Erin Reid, MD, discusses treatment of primary central nervous system lymphoma.

And don’t forget to check out next month’s clinical dilemma – send in your responses for a chance to win an ASH Clinical News-themed prize!

CLINICAL DILEMMA

What is the best consolidation therapy for a newly diagnosed transplant-eligible primary central nervous system lymphoma (PCNSL)? The patient is in first complete remission.

EXPERT OPINION

Given the rarity of PCNSL, it has not been feasible to perform the phase III randomized trials needed to determine the best regimen in the setting of immunocompetent PCNSL. There are even fewer data about PCNSL management in persons living with HIV, although long-term survival has been demonstrated after methotrexate-based therapy in the era of high active anti-retroviral therapy.1 Whenever possible, referral to well-designed clinical trials should be encouraged to improve our understanding and exploration of novel therapies for PCNSL.

In general, for immunocompetent PCNSL, thiotepa-based consolidation with autologous hematopoietic cell transplant (AHCT) appears the most encouraging as consolidation therapy.

Below are brief summaries of a few manuscripts supporting my opinion.

IELSG32: This prospective randomized phase II trial conducted by the International Extranodal Lymphoma Study Group addressed the tolerability and efficacy of adding rituximab with or without thiotepa to methotrexate-cytarabine combination therapy (the MATRix regimen) in immunocompetent patients with PCNSL.2 Patients received 4 courses of methotrexate and cytarabine with or without rituximab, or the three-drug combination plus thiotepa. In 219 assessable patients, those treated with the rituximab combination plus thiotepa had a complete remission (CR) rate of 49%, versus 23% of those treated with methotrexate-cytarabine alone and 30% in those treated with methotrexate-cytarabine plus rituximab. Infectious complications were similar in the three groups. Treatment-related deaths occurred in 13 patients (6%). A randomization comparing consolidation with whole brain radiation versus AHCT is ongoing.

Adult Lymphoma Working Group of the Japan Society for Hematopoietic Cell Transplantation: In this retrospective study conducted in Japan, thiotepa-containing high-dose therapy with AHCT was associated with better progression-free survival (PFS; p=0.019), lower relapse (p=0.042), and a trend toward a survival benefit than other regimens used when thiotepa was not available. In multivariate analysis, thiotepa-containing conditioning remained significant for PFS (hazard ratio=0.42; p=0.038).3

Freiburg ZNS-NHL Study (2016): This prospective, multicenter, single-arm, phase II trial conducted in Germany recruited 79 immunocompetent patients aged 18 to 65 years with newly diagnosed PCNSL who were eligible for analysis.4

Patients received 5 courses of intravenous rituximab, high-dose methotrexate, then 2 courses of intravenous rituximab, cytarabine, and thiotepa, followed by conditioning with rituximab, carmustine, and thiotepa and AHCT. Sixty-one of 79 participants (77%) experienced complete response. There were 4 treatment-related deaths.

Freiburg ZNS-NHL Study (2017): This prospective single-arm trial conducted by the German Cooperative PCNSL study group enrolled patients with immunocompetent PCNSL <66 years who were refractory to high-dose methotrexate-based chemotherapy.5 Induction consisted of 2 courses of rituximab, high-dose cytarabine, and thiotepa with collection of stem cells in between, followed by conditioning with rituximab, carmustine, and thiotepa. Patients commenced AHCT regardless of response after induction. Of 39 patients, 22 responded to induction and 32 received AHCT, with 22 (56%) experiencing a CR after AHCT. Patients not achieving CR after AHCT received whole-brain radiotherapy. In this initially refractory population, the 2-year PFS rate was 46% (median = 12.4 months) and the 2-year overall survival rate was 56% (median = not reached).

References

  1. Gupta NK, Nolan A, Omuro A, et al. Long-term survival in AIDS-related primary central nervous system lymphoma. Neuro Oncol. 2017;19:99-108.
  2. Ferreri AJ, Cwynarski K, Pulczynski E, et al. Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase II trial. Lancet Haematol. 2016;3:e217-e227.
  3. Kondo E, Ikeda T, Izutzu K, et al. High-dose chemotherapy with autologous stem cell transplantation in primary central nervous system lymphoma: data from the Japan Society for Hematopoietic Cell Transplantation Registry. Biol Blood Marrow Transplant. 2019;25:899-905.
  4. Illerhaus G, Kasenda B, Ihorst G, et. al. High-dose chemotherapy with autologous haemopoietic stem cell transplantation for newly diagnosed primary CNS lymphoma: a prospective, single-arm, phase 2 trial. Lancet Haematol. 2016;3:e388-e397.
  5. Kasenda B, Ihorst G, Schroers R, et. al. High-dose chemotherapy with autologous haematopoietic stem cell support for relapsed or refractory primary CNS lymphoma: a prospective multicentre trial by the German Cooperative PCNSL study group. Leukemia. 2017;31:2623-2629.

How did readers respond? Check out You Make the Call – Readers’ Response.

NEXT MONTH'S CLINICAL DILEMMA

I have a frail 84-year-old male patient who presented with an elevated white blood cell count (70,000/mm3), anemia, and a low platelet count in May 2019. The results of his bone marrow biopsy were consistent with hairy cell leukemia variant (HCLV). A BRAF genetic test was negative. He experienced a good response with standard-dose cladribine, but because this was HCLV rather than classical HCL, we expected the remission to be short lived. He has now relapsed approximately 5.5 months after completion. I am reluctant to use cladribine again after such a short disease-free period. My plan was to start with rituximab to get a response and then consider low-dose bendamustine. Are there any other drugs I should consider for relapsed HCLV with remission within 6 months?

Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.