Non-Hodgkin Lymphoma Stories
Here's a story of successful CAR-T response for a Shahzad Bhat, who'd been diagnosed with stage IV Non-Hodgkin Lymphoma (Diffuse Large B-Cell) and given three months to live. That's when his wife, Nicole, championed for him to get this new line of treatment. He was actually the first to undergo a commercial CAR-T drug at Stanford Medical Center.
Here's the incredible Bhat Family story as told by Nicole.
“The doctor called and said, "I’m sorry your husband has relapsed, he’s refractory, he’s no longer responding to chemo,
there’s nothing we can do.""
Table of Contents
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1.Before CAR T-cell Therapy
What was the initial diagnosis?
Shahzad was stage IV with non-Hodgkin Lymphoma Diffuse Large B-Cell by the time he needed CAR-T.
How did first line treatment end?
Due to an initial misdiagnosis of Mantle Cell Blastoid, Shahzad underwent R+B and then R-ICE. When he was properly diagnosed, he underwent dose-adjusted R-EPOCH but miscommunication led to three cycles of that chemo instead of six. He relapsed and we were told by doctors that there was nothing that could be done.
How did you know about CAR T?
In February 2017, my son and I attend the Leukemia and Lymphoma Foundation Conference in San Francisco. The break out group we chose, naturally, was for Diffuse Large B-Cell. The presenter was Dr. Babis Andreadis of UCSF. He could have chosen any subject to present. Lucky for us, he chose CAR-T.
He said it was still in clinical trials and fairly new, so it would be another two years before the Food and Drug Administration (FDA) would approve it. Sigh. Two years is a very long time to a stage IV cancer patient.
From that moment on, I began researching. I taught myself about clinical trials and what to look for: inclusions and exclusions. Insurance didn't seem too committed to covering it, so I had to search for financial assistance which was difficult because our 2016 income disqualified us on paper. But I continued to follow the progress. Kymriah, the Novartis CAR-T for pediatrics Acute Lymphoblastic Leukemia (ALL) was approved in August of 2017, several months earlier than expected. Then an independent committee voted unanimously to recommend approval to the FDA for Yescarta (commercial CAR-T drug).
The FDA approved Yescarta on October 18th, 2017. On October 19, 2017, Shahzad had a biopsy because doctors could not agree on the PET scan images. I remember feeling conflicted. Of course I didn't want him to have disease.
Or did I? In order to qualify for Yescarta, you must have some disease for the T-cells to work. I felt relieved, because I knew that regardless of the outcome, we would be okay.
I never wanted the stem cell transplant. My gut just felt it was not in his best interest. The following week when the doc told me, "The biopsy was positive. He is now considered Relapsed/Refractory, disqualified for stem cell transplant, out of options, and has three months to live."
I piped in with, "What about CAR-T?" She said that he's an excellent candidate for CAR-T but her facility won't be ready until February, and he doesn't have until February.
That is when I turned to Kite to find out who nearby is ready. I wrote to Dr. Miklos at Stanford. He said he had over a hundred referrals waiting, but given my husband's timeline, he put Shahzad at the top of the list.
How did you get him approved for CAR T-cell therapy?
Once I knew that Stanford was a viable option, I began a campaign strategy in my head with two objectives:
I had to gather what I thought would be compelling information for the insurance.
I had to find a way to appeal on a personal level.
Compelling Information: I obtained Letter of Statement from three separate oncologists, all of whom had evaluated Shahzad, stating that he was indeed a qualified candidate for this treatment, that he only had three months to live, and that this was his only option for survival. I printed off the Yescarta brochure so there was clear understanding of what the therapy involved. And I obtained literature that demonstrated a cost savings of Yescarta versus an allogeneic stem cell transplant with graft-versus-host disease (GVHD) life long side effects. Now they can't argue the price.
Personal Appeal: I called our case manager, whom I had never seen, only spoken to over the phone. I asked for a face-to-face meeting because what I needed to discuss was too important to be discussed over the phone. She agreed. I prepared a simple timeline from symptoms, to diagnosis, to treatments, to now. I reminded her where and what he's been through, where he stands now (with three months to live), and [that] there is one option left. Can we do this?
Had she said no, I was prepared to make this public. I had obtained the names and phone numbers and email of each of the Board of Trustees. I was going to make flyers and postcards and social media pleas to flood their voicemails and emails! I was going to send them each a party invitation, asking them if they had the chance to save someone's life, would they? I was going to contact local media and stage picket lines. I was not taking no for an answer. I was going to fight, fight, fight, and even if they didn't change their mind, the negative publicity does not do a local union good. Thankfully, Stanford's finance department and our insurance were able to come to a financial agreement very quickly.
There are different "exceptions" for different kinds of CAR T-cell therapy drugs?
CAR T-cell is the therapy, immunotherapy, which targets CD19 protein. Shahzad had that but he also was positive for CD5.
Clinical trials have a huge list of inclusions, what is required to be accepted into the trial, as well as a huge list of exclusions, which disqualify you from a trial. During the clinical trial phase, since Shahzad was predominantly CD19 positive qualified him for the trial. The fact that he was also CD5 positive excluded him from trial, because the trial was only targeting CD19. The CD5 was an unknown.
However, when the FDA approved Kite’s Yescarta as a third line therapy, they did not make CD5 positive an exclusion. That means a patient mostly CD19 positive, even with a CD5 positive, made him qualified to accept the commercial brand.
What were your questions for doctors about CAR T-cell therapy after he was approved?
I had been following CarT for the year. The only question I had to the doctors were:
If CAR T fails, how will we know if CD5 was a factor? A blood test would reveal what protein(s) remain.
I know there was a death during this trial. What caused it and is it a risk or what steps have you taken to prevent it?
The death was caused by cerebral edema, which they did not expect as a severe adverse side affect. Now they know how to recognize the signs and bring in the neurologist immediately, so it will never get to that stage again.
What were the biggest hurdles?
At that point, the insurance approved the consultation, which was done in November. That bought a little more time for the rest of the contract to be negotiated. One site gave me a little trouble about getting records sent over quickly, but I just went up the chain until I got someone compassionate and empowered to help me.
There was an error made on the initial contract which I found out about as I stayed on top of the timeline. I knew when something fell through the cracks and just helped to keep it moving along. Once the contract was finalized, Stanford enrolled Shahzad with [the pharmaceutical company] and it makes the schedule, based on lab production. We were lucky that it was so soon after FDA approval and not many sites were certified, so the calendar was pretty open for us. As a result, Shahzad was the first patient to be treated with Yescarta at Stanford. Compared to everything else, the hurdles were really minor.
2. CAR T-cell Treatment & Results
What happens during CAR T-cell therapy?
Once [the pharma company] makes the calendar, the first part of the process is called leukapheresis. It is the process in which the T-cells are extracted from the body and separated from the rest of the blood. It is much like collection for a stem cell transplant. One tube goes from the body into an ATM looking machine where it gets separated and the T-cells are collected. Another tube takes the remaining parts of the blood from the machine and sends it back into the body. That process takes about four hours.
As soon as the T-cells at collected, staff and a [drug company] rep triple-verify all of the information (very comforting to know his T-cells won't get mixed up with someone else's in the lab by mistake!). Once that is done, the bag is placed into this ultra modern Styrofoam cooler and sealed. The [drug company] rep immediately takes it to the airport so it can be sent to the lab immediately. The T-cells are frozen, so it is time- and temperature-sensitive. The T-cells spend about 17 days in the lab (including travel time).
Shahzad went back to work for two weeks. On December 21, he was taken into surgery to have his two-year old internal port removed and replaced with an external Hickman line. Then on December 22, he began the preconditioning chemo known as Cy/Flu for short. It is done outpatient and took a few hours each day, for three consecutive days. Everyone responds differently. He had some fatigue and nausea and vomiting. He had Christmas day free to recover. On December 26th he was admitted to the hospital and prepped. On December 27th, that infamous cooler was again retrieved at the airport and brought to the hospital by the [drug company] rep. Again, everything was triple-verified before removing the bag from the cooler.
Was there physical pain during CAR T-cell therapy?
There was absolutely no pain involved for him, whatsoever. But the only pain he ever had was in the beginning when the lymphoma decided to go into his foot bone and he couldn't walk. Compared to the harsh chemo he went through, and what a stem cell transplant has been described as, this was the easiest piece of cake ever! He was ready to return to work in five weeks.
What were the side effects?
Typically, nothing happens for the first three days but that's an average and everyone is different. There are two major side effect potentials: Cytokine Release Syndrome (CRS) also known as the Storm. This is where the T-cells are working, but the body is kind of like whoa, what's going on? One may develop flu-like symptoms including weakness, fever, etc.
The other is neurotoxicity, where the cytokines mess with the brain. This can cause confusion, loss of memory, seizures, or cerebral edema. They can be very serious, but 20% in trial never experienced any.
Once discharged, the patient must remain in the immediate area for 21 days for observations and daily blood counts. There are several medications prescribed. Some start prior to infusion, some start at infusion, some end at post-30 days, some may start at post-30 days, and one is for a minimum of six months, Acyclovir, which is the only one Shahzad is currently on. Some take with food, some on empty stomach - you really must be very organized to manage this. There are also several "as needed" but he never needed them. On the days that he did not visit the outpatient clinic, he did need to flush his PICC line with Heprin. Low white blood counts and low potassium are common after infusion, and are treated. There will be a PET scan sometime around Day +30. In many cases with Yescarta, patients are seeing complete metabolic response!
Were there any surprises?
The only part that was difficult was when he had an episode that was originally thought to be a seizure. They did everything they told me would be done- brought in a neurologist, gave tocilizumab, ran a CT scan, etc. It turned out not to be neurotoxicity, but for the hours that we thought it was, it was petrifying. I was warned and knew to expect it, but I don't think there is anyway a human can really prepare for the emotions that come when actually seeing it happen.
What do you wish you had known before CAR T-cell therapy began?
For me, nothing other than the emotions from the episode. Everything else went exactly as planned. I wouldn't change it and have absolutely no regrets!
3. CAR T-Cell Therapy: Quality of Life
"Be your own advocate"
You need to be on your own best advocate. You can't rely on others to hand you information. You need to go out and look for it yourself. There are so many out there and free resources to help you.
Do your research. Learn as much as you can and question everything because people do make mistakes, even doctors and nurses. I would definitely suggest a second opinion to be 100% sure. And... each patient is different, each subtype is different, each experience is so different. You can’t compare yourself to a graph or statistics - it just doesn’t add up.
Did your husband work during CAR T-cell therapy?
No, but he was ready for work five weeks later. Also, law prohibits a patient from driving for 60 days after infusion, so we waited until he could drive to return to work, but by then his counts were normal and healthy.
Your biggest disappointment involved friends
Dealing with friends who didn’t engage. It took me a really long time to understand why. Cancer isn’t contagious, so there was no physical risk. They are not people who are “fair-weather friends," so why the lack of interest? I truly believe they haven’t encountered this type of illness in their life, so it’s just too painful to acknowledge it. I believe it’s merely self preservation. And I get it.
Thank you, Nicole and Shahzad, for sharing your story!