For Mantle Zone Lymphoma: What Goes Around Comes Around
MAY 15, 2019 BY ROBERT A. NAGOURNEY, MD
Mantle zone lymphoma represents approximately 6% of all non-Hodgkin lymphomas diagnosed in the US each year.
It is named for the region in the lymph node where the malignant cell population arises. The cells characteristically express a cell surface protein known as CD5 and over-express cyclin D1 associated with a commonly identified t(11;14) chromosomal translocation.
It usually occurs in patients 60 or older and can be aggressive, with lymphadenopathy (enlarged lymph nodes), splenomegaly (enlarged spleen) and in some patients with high circulating lymphoma cells.
Case Study: Recurring Mantle Zone Lymphoma
In 2004, I consulted upon a 74-year-old gentleman with mantle zone.
The biopsy revealed activity for the drug combination R-EPOCH and he achieved a complete remission that lasted 10 years.
He then presented with lymphadenopathy and a biopsy of his axillary lymph node confirmed recurrence, but now the pattern of sensitivity favored the drug Bendamustine.
He received 6 cycles of R-Bendamustine and again achieved complete remission. He did well except for some respiratory infections that were managed with intravenous immunoglobulin.
It Comes Back Again – His Third Encounter
At year 3 he returned with a markedly elevated white blood cell count.
One concern was that he might have drug-induced acute leukemia, an uncommon but serious side effect from chemotherapy and I submitted his cells for flow cytometry. While we awaited the results he required hospitalization to manage his underlying congestive heart failure.
I then had the opportunity to review his peripheral blood smear and recognized that the white cells were indeed mantle zone cells and not leukemic blasts as I had feared. A small quantity of residual blood from his ER admission CBC was submitted to the laboratory for analysis.
His Functional Profiling Results Are Again Very Revealing
The results were extremely interesting.
Having received the EPOCH combination, the patient was now resistant to the principal agents in that combination i.e. Cytoxan, Doxorubicin, etc. He was also resistant to Bendamustine, the drug he had received most recently.
I was more intrigued by the other results.
Despite the use and appeal of the class of drugs known as Bruton tyrosine kinase inhibitors, he was completely resistant to Ibrutinib, the oral drug of this class.
Without my lab results, Ibrutinib, would probably have been my first choice as it is widely used as a salvage regimen in this setting. More unexpected was his resistance to Gemcitabine plus Oxaliplatin, 2 drugs that he had never received and that I have used to great success in other patients in the past.
Recalling My Past Work with the Assay-Directed Drug Choice
What struck me was the patient’s exquisite sensitivity to Bortezomib (Velcade), a proteasome inhibitor that disrupts nominal protein metabolism in cancer cells and has proven profoundly important for the management of another B-cell malignancy known as Multiple Myeloma.
The results for Bortezomib truly resonated.
Over fifteen years earlier, in collaboration with investigators at Millennium Pharmaceuticals in Cambridge, Massachusetts I had used our laboratory platform to identify Mantle Zone lymphoma as a target for their new small molecule Bortezomib.
I remember meeting with their principal investigator, Mark Rolfe, PhD at the ASH (American Society of Hematology) meeting in San Diego to forge a relationship for the study of Bortezomib. At that time, the drug had not received FDA approval for any indication.
Bortezomib is one of the most interesting therapeutic small molecules as its activity is based upon the atom Boron.
By disrupting the cell’s ability to clear itself of damaged proteins it unleashes one of the most potent cell death cascades, the mis-folded protein response.
While it was not surprising that our laboratory identified activity for myeloma, a disease characterized by excessive protein production in the form of antibodies, the findings for mantle zone were unexpected and ultimately led to an FDA approval of Bortezomib for this form of lymphoma some years later. Nagourney RA, Su, YZ, Horlick D, Chow C, Kollin C, Evans SS. Bortezomib (PS-341) alone and in combination with cytotoxic drugs: Ex vivo analysis in human tumor primary cultures. (3690) Amer Assoc of Canc Res 45, 2004 (abst)
Here, 15 years later, was an opportunity to take that discovery and apply it to one of my own patients.
The patient was suffering from congestive heart failure, requiring aggressive diuresis.
Confident that I could help him, once he stabilized, I transferred him to the oncology unit to begin treatment but he continued to feel poorly enough to warrant observation in the ICU overnight after only a small dose of therapy.
Let’s Not Give Up Yet!
During his stay in the ICU he was seen by the intensivist, the pulmonologist, the cardiologist, respiratory therapists and a host of other staff.
With his advanced age, the cardiologist felt it was his duty to engage in end-of-life discussions, something that I had absolutely NO intention of doing.
With only a portion of one dose completed, the patient’s white count dropped by 50% in a matter of hours.
I immediately transferred him back to the oncology ward to continue therapy and a day later his white count fell to normal as he visited comfortably with family members.
I feel a sense of particular gratification that this earlier discovery made in collaboration with investigators at Millennium (now Takeda) Pharmaceuticals may be the very thing that saves the life of my long-term patient.
How fortunate that we had access to that sample of blood the day of his admission, a sample that forged his successful therapy.
Life Starts Again
At 89 years of age, it is difficult to know whether he can be cured, but I fully expect that he will return home where he lives independently in a lovely retirement apartment.
When I spoke with him on the day of his return from the ICU, I marveled at his vigor and well-being, the cardiologist’s gloomy predictions notwithstanding. “Not bad for an alter cocker” (Yiddish term of endearment for grouchy old men) he replied.
Not bad for an alter cocker, not bad at all.
As always, I appreciate your thoughts and comments.
Dr. Robert Nagourney, has been internationally recognized as a pioneer in cancer research and personalized cancer treatment for over 20 years. He is a TEDx speaker, author of the book Outliving Cancer, a practicing oncologist and triple board certified in Internal Medicine, Medical Oncology and Hematology helping cancer patients from around the world at his Nagourney Cancer Institute in Long Beach, California. For more info go to NagourneyCancerInstitute.com