June 2020 Clinical case of the month
Title: Consolidation Therapy in Immunocompetent Host with PCNSL
Submitted by: Syed Ali Abutalib and Nicolaus Kröger
Physicians expert perspective: Gerald Illerhaus
A 55-year-old man presented with complaints of newly developed neurologic symptoms over the course of 2 weeks. He stated that he had been getting lost driving while performing his job driving taxi, which he has had been doing for the past 10 years. He has also experienced abulia, an inability to make decisions or lack of will, while listening to sports on the radio, and he found himself singing while driving, both of which were atypical behaviors for him and a substantial variation from his normal baseline. He reported no headaches or visual symptoms and is otherwise healthy, with no medical or surgical history. He denied travel outside of his city for the past 5 years.
The Karnofsky score is 90%. The neurologic exam was normal. The complete blood cell count (CBC) and complete metabolic profile were also normal. The hepatitis panel and HIV test were negative. These constellations of new symptoms led to brain imaging. Magnetic resonance imaging (MRI) with contrast demonstrated a homogeneously enhancing lesion in the left frontal lobe. A similar, smaller, noncontiguous lesion was also noted in the right frontal lobe. The staging is unremarkable for disease outside the CNS. The diagnosis of primary central nervous system lymphoma is secured after uneventful stereotactic brain biopsy. After four cycles of methotrexate-based induction therapy, he underwent restaging, which confirms complete remission (CR1).
Which of the following is the most likely diagnosis?
A. High-dose chemotherapy with hematopoietic stem cell rescue
B. Whole-brain irradiation therapy
C. Nonmyeloablative cytarabine based chemotherapy
D. All of the above are reasonable options
E. A and B
Expert Perspective by Professor Gerald Illerhaus
Primary CNS lymphoma (PCNSL) is a rare aggressive Non-Hodgkin lymphoma confined to the cerebral parenchyma, eyes, leptomeninges, and spinal cord. Median survival in untreated patients is limited to a few months. Despite the high complete remission rate after methotrexate (MTX)-based chemotherapy, more than 50% of patients will relapse within 2 years. Therapeutic approach in younger patients (<65-70 years of age) usually consists of a high-dose (HD)-MTX (> 3 g/m²) based induction immunochemotherapy followed by consolidation treatment. The addition of additional drugs like HD-cytarabine and alkylating agents like thiotepa, procarbazine or temozolomide showed a benefit on overall survival (OS) . A promising chemotherapeutic regimen comprising HD-MTX, HD-cytarabine, thiotepa and rituximab (MATRix) showed a 2-year progression-free-survival (PFS) of 62% and OS of 67% as well as a benefit in treatment response regarding the addition of rituximab . Whole-brain radiation therapy (WBRT) following induction HD-MTX-based chemotherapy has shown to be an effective consolidation therapy associated with 2-year PFS of 63-72% and OS of 85-86% . However, there is a considerable risk of severe neurotoxicity as long-term effect after WBRT especially in patients older than >60 years of age. Severe dementia, gait disorder and incontinence are the most common symptoms caused by post-therapeutic leukoencephalopathy and are associated with a significant 30% mortality rate. In order to reduce neurocognitive impairment, investigators proposed different consolidating strategies; hence high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HDT-AHSCT) or non-myeloablative chemotherapy  gained importance. An ongoing phase III trial is currently validating another regimen comprising rituximab, dexamethasone, etoposide (VP-16), ifosfamide and carboplatin (R-DeVIC for 2 cycles every 3 weeks) in comparison to HDT-AHSCT for consolidation treatment [(NCT02531841).
Besides a beneficial effect on neurocognitive impairment and quality of life , HDT-AHCT also appeared superior to WBRT concerning the 2-year PFS of 87% vs. 63%  along with a low transplantation-associated mortality of 3-5%. Conditioning protocols should be thiotepa-based due to poor blood-brain barrier penetration of other commonly used regimens.
Correct Answer – A - High-dose chemotherapy with hematopoietic stem cell rescue
- Omuro A, Chinot O, Taillandier L, et al. Methotrexate and temozolomide versus methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial. Lancet Haematol. 2015;2(6):e251‐e259.
- 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 2 trial.
- Ferreri AJM, Cwynarski K, Pulczynski E, et al. Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase
- Rubenstein JL, Hsi ED, Johnson JL, et al. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol. 2013;31(25):3061‐3068.
- Houillier C, Taillandier L, Dureau S, et al. Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients 60 Years of Age and Younger: Results of the Intergroup ANOCEF-GOELAMS Randomized Phase II PRECIS Study. J Clin Oncol. 2019;37(10):823‐833. doi:10.1200/JCO.18.00306
Syed Ali Abutalib, MD
Associate Director, Hematology and Cellular Therapy Program
Director, Clinical Apheresis Program
Cancer Treatment Centers of America, Zion, Illinois
Associate Professor, Rosalind Franklin University of Medicine and Science
Nicolaus Kröger, MD
Professor and Medical Director of the Department of Stem Cell
Transplantation at the University Hospital Hamburg-Eppendorf, Germany
University Hospital Hamburg, Hamburg, Germany
Correspondence: Nicolaus Kröger, MD
Gerald Illerhaus, MD
Professor and of Hematology and Oncology
Medical Director, Dept. of Hematology, Oncology, Stem Cell Transplantation and Palliative Care
Klinikum Stuttgart, Stuttgart Cancer Center / Tumorzentrum Eva Mayr-Stihl
Future Clinical Case of the Month
If you have a suggestion for future clinical case to feature, please contact Nicolaus Kröger.