The Right Treatment at the Right Time: Double-Hit Lymphoma
On February 5th, 2018 I was asked to consult on a 53-year-old patient who was admitted to the hospital with a one month’s history of low back pain. An MRI of the lumbar spine a few days earlier revealed a mass impinging on the spinal canal extending down to the pelvis.
I arrived to find a strapping, healthy, vigorous gentleman complaining of pain.
Diagnosis: B-Cell Non-Hodgkin's Lymphoma (NHL)
He had no evidence of neurological deficit and was able to stand and walk without difficulty. The differential diagnosis of a mass in the lower spine includes metastatic disease from a distant site i.e. lung, etc. versus a primary tumor such as chordoma versus lymphoma.
A needle biopsy confirmed B-cell non-Hodgkin’s lymphoma (NHL).
As NHL is generally responsive to therapy we opted against surgery in favor of radiation. Although I would gladly have used the EVA-PCD platform to treat him, I suggested he move forward with radiation as I awaited completion of staging, flow cytometry and special studies.
Late Friday evening, 2 days after admission, the patient lost the ability to move his lower extremities and emergency surgery was undertaken that night. My colleagues in neurosurgery kindly provided a sterile portion of tissue to my laboratory for analysis.
While I awaited final pathology, we set up a broad array of cytotoxic drug combinations, targeted agents and synergy studies. The patient slowly recovered but with impingement on the lower spinal cord it was uncertain whether he would regain the full use of his legs.
Functional Profiling Results
A few days later the results of the EVA-PCD analysis returned.
Though B-Cell NHL is considered highly drug sensitive, this patient’s cells could not have been more drug resistant.
I was surprised by the degree of resistance to almost every drug and combination tested in the lab. Adriamycin, Vincristine, Corticosteroids, and Fludarabine were all inactive.
I was puzzled. Isn't B-cell lymphoma one of the success stories of modern oncology? Isn't this tumor supposed to melt away with treatment? Was there a mistake?
I reviewed his findings with our hematopathologist. What gives, I wondered?
Not Your Typical Non-Hodgkin's Lymphoma
A week later, the answer to my question became clear.
This was not a run-of-the-mill B-cell NHL.
This was not one of those cancers you treat with conventional combinations.
Quite to the contrary – this was a double-hit lymphoma, with over-expression of both the c-MYC oncogene and the Bcl-2 oncogene and a proliferation rate of more than 80%.
This was a B-cell lymphoma that was not going to play by the rules.
As I examined my laboratory findings one result stood out, the clear and unequivocal activity and synergy for Gemcitabine and Cisplatin, used clinically as R-GemOx.
We had studied these combinations in my laboratory for two decades and previously published our findings (Deoxynucleoside Analogs in Cancer Therapy, Humana Press, 2006). We had pioneered their use in ovarian cancer, triple negative breast, bladder, and other cancers.
Today these doublets are used around the world.
However, R-GemOx the one we found for this gentleman is never, ever used in the first line (newly diagnosed) setting. Never!
I returned to meet with the patient, now bedridden, as a physical therapist worked to recapture the use of his lower extremities. We sat and had a long heart-to-heart discussion.
Contrary to the guidelines, the literature and the NCCN (National Comprehensive Cancer Network), I was recommending that this patient take a “so called” salvage regimen as his first-line therapy.
It was more than uncomfortable, as I could easily be criticized for failing to provide the patient potentially "curative therapy" with R-CHOP, R-EPOCH, CODOX, hyper-CVAD or others. What would possess me to use my EVA/PCD laboratory studies to make changes in a patient's management when everyone knew that R-CHOP or modified R-EPOCH were the standards of care?
Thinking Out of the Box
The answer was not all that hard to find. One need only read the literature more closely to see that double-hit lymphoma requires out of the box thinking.
It is now well-recognized that conventional treatments like R-CHOP are inadequate.
One investigator from the Wilmot Cancer Institute at Rochester University said “…it is clear that R-CHOP is not sufficient induction therapy for this group of patients, since the majority of patients will have disease progression after standard therapy “ (Jonathan Friedberg, MD BLOOD 2016).
None-the-less, in 2018 and in the absence of controlled clinical trials, physicians continue to give these patients R-CHOP, R-EPOCH and related regimens. If I were to diverge from these standards of care, say to provide first-line R-GemOx, would I be viewed as compromising his well-being?
This was a crisis, a dilemma.
I knew that the patient needed R-GemOx. My instincts told me that he should receive it, but I was clearly veering off the standard guidelines and about to commit the most heinous of all crimes, diverging from "community standard."
The patient's wife had brought her husband to me in the first place because she was the close friend of one of my longest surviving lung cancer patients, a delightful young woman who lived nearly a decade with highly aggressive non-small-cell.
Based on that experience, she was determined that her husband be treated under my care, no matter what. As a nurse and someone who knew my work, the treatment that I recommended was going to be the treatment her husband would receive, regardless of guidelines or protocols.
We agreed to move forward with the laboratory-identified R-GemOx.
The patient required radiation and we arranged one course of chemotherapy before it began. As this chemotherapy combination is too toxic to combine with radiation, I had to bide my time until the 10 days of radiation were complete. The next day, I again instituted R-GemOx.
How the Patient Responded
Slowly, the patient's lower extremity strength improved. He began to use a walker.
Every two weeks, I treated the patient, shepherding him from the rehabilitation hospital to the acute care hospital and back each time. Two cycles later, he was able to be discharged
Once discharged, the patient continued physical therapy as I treated him every two weeks. At first, he came with a walker, then with a cane and then recently, walking without assistance.
I had known from the start that a "double-hit lymphoma" would require bone marrow transplantation. I wrote a letter of referral to a colleague at a large transplant center but anticipated that the response might be one of dismay at my choice of therapy.
After all, we had diverged from protocol; we had used a non-standard salvage regimen, as his first-line therapy. We had not applied the standard of care and had instead veered off the path, using the laboratory to guide our drug selection. I was concerned that he might be disqualified.
Despite my concerns, it was obvious that with each cycle, the patient's condition improved.
I was buoyed by his physical well-being and improving parameters of his disease. The PET/CT revealed near complete resolution of all measurable disease after only 3 doses.
Time had come. He was ready for his consultation at the transplant center.
Just before he departed, I repeated all of his laboratory measures of his disease and had them forwarded to my colleague. All were completely normal. I waited with some trepidation, anticipating a critical review of my unconventional therapy recommendation.
This week, the patient and his wife returned.
They had met with the trans-planters. The conversation had proven quite jovial.
This accomplished consultant smiled when she looked at the patient's PET/CT and lab results.
She pointed out that this was not the standard of care.
But then went on to say that she knew my work, and that although I had veered off the path, she very impressed with the good result. She would indeed accept the patient into the transplant program. He will undergo, what I hope will prove to be, a curative bone marrow transplant in July.
This story is emblematic of my philosophy in medicine, that patients should receive the right treatment the first time, every time. But it represents a broader collection of issues.
First, in medicine today, we do not reward physicians for success but we punish them severely for failure.
Had this patient had less than a perfect response, I would have been pilloried for not administering standard treatment; despite their well-recognized lack of benefit. In this environment, physicians are increasingly afraid to do the right thing. I must admit my own concern when I followed what I knew to be the right course of therapy for this patient, fearing the consequences of failure.
Second, there are no right treatments, even for the most treatable malignancies.
Each patient is a unique story unfolding in real time. I am gratified by this patient's good outcome and feel a particular sense of accomplishment in that the patient's referral was predicated on the good outcome of one of my longest surviving lung cancer patients who received laboratory directed therapy as well.
Finally, the key to each patient’s diseases lies within their own tissue. Failing to use each patient’s tumor to select treatments relegates them to protocol therapies that may be very wrong for them.
I will await the patient's final PET/CT scan with anticipation but look forward to the very real likelihood of curing this patient with, what many oncologists might consider, an incurable lymphoma.
As always, I appreciate your thoughts and comments.
UPDATE - June 29, 2018:
It is with a particular sense of pleasure that I report the findings of today’s PET/CT: “No evidence of residual lymphoma”.
I am more than pleased by this result. His outcome is the very essence of what we do and why we do it. It is a vindication for the use of unconventional approaches when the conventional ones won’t do.
It is a life saved; a family reunited and, in the end, has proven to be a relatively simple solution to a very complex problem. I am sure that the readership will join me in congratulating this patient on his splendid outcome.
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