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CLINICAL DILEMMA
We have a 51-year-old male patient in Belgium who was diagnosed with blastoid mantle cell lymphoma (MCL) four months ago. The presentation was aggressive with spleen, lymph node, and bone marrow involvement, constitutional symptoms, and a very high C-reactive protein level. We treated him with three cycles of R-CHOP, after which his disease progressed, though we planned to add three cycles of R-cytarabine if his disease responded. We tested his diagnostic sample and found the presence of a TP53 mutation. Instead of R-cytarabine, we treated with R-DHAX (rituximab, dexamethasone, cytarabine, and oxaliplatin) and started a donor search. After two cycles, his disease progressed again. We started ibrutinib, lenalidomide, and rituximab, but after one month of therapy, the lymphoma continues to progress. We are looking for chimeric antigen receptor (CAR) T-cell therapy trials, as well as other types of therapy being tested in clinical trials. However, there is a possibility that he cannot be included in a trial because of the speed of his disease progression and because liver invasion has led to a high bilirubin concentration.
If clinical trials are not available, is there anything we can do? One option may be to try to reduce the tumor burden and proceed to allogeneic transplant. For example: Dexa-BEAM (dexamethasone, carmustine, etoposide, cytarabine, and melphalan) followed by stem cell collection, autologous transplant after BEAM conditioning, and then allotransplant. Or bendamustine instead of Dexa-BEAM? We don’t think that bortezomib or temsirolimus will lead to a response, nor that venetoclax would work because the disease is refractory to ibrutinib. Do you agree?
EXPERT OPINION
For this patient with ibrutinib-resistant MCL, unfortunately options are limited. Clinical trial remains the best option if the patient is a candidate at this time or becomes one in the future.
Off clinical trial, venetoclax is associated with a response of 50% in ibrutinib-refractory disease and thus may be considered, alone or in combination with an anti-CD20 antibody, such as rituximab.1
Liver toxicity will be an issue with chemotherapy, such as bendamustine, depending on the level of impairment. Furthermore, chemotherapy is typically less efficacious in Bruton tyrosine kinase (BTK) inhibitor–relapsed setting.
VLS-101, an antibody drug conjugate targeting receptor tyrosine kinase–like orphan receptor 1 (ROR1) or mosunetuzumab, a CD20-targeted bispecific antibody, have demonstrated encouraging preliminary data and may be considered on a compassionate use basis if patient is not a trial candidate.
CAR T-cell therapy could be the most effective approach in this setting, if available. In a recent phase II study of the KTE-X19 CAR T-cell therapy, 93% of patients achieved a response, and 67% had a complete response.2 All patients on study had previously received a BTK inhibitor.
References
- Zhao S, Kanagal-Shamanna R, Navsaria L, et al. Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) – outcomes and mutation profile from venetoclax resistant MCL patients. Am J Hematol. 2020;95:623-9.
- Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382:1331-42.
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NEXT MONTH'S CLINICAL DILEMMA
A 76-year-old woman was referred for anemia. Her hemoglobin level was 8.5 g/dL, her mean corpuscular volume was 88 fL, and she had normal white blood cell and platelet counts. There was no evidence of hemolysis, and her ferritin level was 33 ng/mL. She was repleted with iron, but her anemia persisted with a hemoglobin level of 10 g/dL. She underwent a biopsy, and her bone marrow was normocellular (60% cellularity) with normal trilineage hematopoiesis and no dyspoiesis. Her iron stores were absent on iron stains of the aspirate. She has a normal metaphase karyotype, and fluorescence in situ hybridization (FISH) was negative for -5/5q31-, -7/7q31-, +8, and 20q12-. Next-generation sequencing (NGS) noted several variants: DNMT3A, TET2, U2AF1, IKZF1, and MPL.
In retrospect, I’m not sure what to do with this NGS data, aside from continued observation and repeating bone marrow biopsy if worsening cytopenias develop. Should I have ordered the NGS?
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