What to Do When Cancer Comes Back after Transplant or CAR T-cell Therapy

Transcript of Presentation.

(00:01) [Steve Buechler]: Speaker Introduction. Good afternoon. Welcome to the workshop, What to Do When Cancer Comes Back After Transplant or CAR T-cell Therapy. My name is Steve Buechler, and I will be the moderator for this workshop.

(00:15): It is my pleasure to introduce today's speaker, Dr. Edmund Waller. Dr. Waller is a professor of medicine, pathology, and hematology oncology, and the Medical Director of the Hematopoietic Progenitor Cell Processing Laboratory at Emory University Hospital in Atlanta, Georgia. He specializes in bone marrow transplants for acute leukemia, myelodysplastic syndrome, myeloproliferative neoplasms, lymphoma, aplastic anemia, sickle cell disease, and the management of graft-versus-host disease. He's also an expert in CAR T-cell therapy. Please join me in welcoming Dr. Waller.

(00:52) [Dr. Edmund Waller]: Overview of Talk. Thank you. It’s a pleasure to meet you all virtually and speak at the BMT InfoNet Symposium: Celebrating a Second Chance at Life. We're going to talk today about what to do when cancer comes back after a stem cell transplant or a CAR T-cell therapy. It's a broad topic, so I'll go over it at somewhat of a high level, but I welcome questions from the audience about specific instances or any points you would like to have me clarify.

(01:36): I've been a professor at Emory for about three decades. My clinical practice has primarily been utilizing stem cell transplants and CAR T-cell therapy to help treat patients with hematological malignancies. We've recently broadened our clinical focus to include patients with solid tumor malignancies – particularly germ cell cancer – and some liver cancer patients who are eligible for either a stem cell transplant or CAR T-cell therapy.

(02:11): I’ll begin with a broad discussion about why cancer relapses. When you've been to so many doctors and you've gotten so many different types of therapies, why is cancer even still a question? The bottom line is that cancer cells are not homogeneous. They're not all the same. Within a tumor, there are a small number of cancer stem cells that can survive chemotherapy and repopulate the tumor after treatment.

(02:48): This first slide represents this idea. The cancer stem cells – shown as red – are mixed into a tumor comprised of other various cell types – shown as green or blue. If a patient with this tumor gets their first treatment, the cancer shrinks, and the volume of the tumor goes down. However, a couple of red cancer stem cells are resistant to that chemotherapy. After their second treatment, the tumor may shrink even more, but those cancer stem cells still persist. And once treatment stops, these remaining cancer cells can cause the tumor to regrow.

(03:41): The basic problem of cancer relapse is that we've not eradicated the very last tumor cell. This next graphic outlines the growth rate of tumor cells over 30 days. The horizontal axis represents the amount of days, and the vertical axis represents the number of cancer cells.

(04:09) The first panel represents treating the tumor with no therapy. The tumor starts off with a thousand cells and increases by a thousand-fold every 10 days. From day 0 to day 10, it goes from a thousand cells to a million cells. From day 10 to day 20, it goes from a million cells to a billion cells. And then from day 20 to day 30, it goes to 1012 cells.

(04:39): The second panel represents treating the tumor with one drug. This graph shows the tumor’s growth rate decreasing, with the tumor volume decreasing by 90% with every treatment. However, once those three treatments stop, the tumor regrows at the same rate.

(05:12): The third panel represents treating the tumor with two drugs. If we intensify the treatment by adding a second drug to treat in combination with the first drug, we now decrease the tumor volume by 99%. We see a greater decrease in the size of the tumor, yet, after three treatments, there are still cancer stem cells surviving, and the tumor regrows.

(05:43): The final panel represents treating the tumor with three drugs. If we intensify the therapy by adding a third drug, we now decrease the tumor by 99.9% with every treatment. With the completion of the three cycles of this therapy, we've eliminated the very last cancer stem cell, and the tumor is gone. That is what we, as oncologists, hope to achieve - the complete eradication of the tumor.

(06:16): In my experience, patients are most commonly treated with a two-drug combination therapy, and surviving cancer cells lead to relapse.

(06:32): Stem cell transplants were developed as a treatment option for patients with leukemia or lymphoma ,with the ultimate goal of eradicating every last cancer cell. There are autologous stem cell transplants (auto-transplants), where patients receive their own stem cells, and allogeneic transplants (allo-transplants) where patients receive donor stem cells. The incidence in relapse differs between the two.

(07:05): During an auto-transplant, all the work to destroy the cancer cells is done by the intensity of the chemotherapy treatment given before transplant. In contrast, with allogeneic transplants, the donor T-cells – the immune cells – are infused and then seek out and destroy cancer cells that may have been resistant to chemotherapy the patient received prior. You can think about it as an auto-transplant being like a ‘one punch’ with your right hand, and the allo-transplant is a ‘one-two punch’ that includes both the benefit of the conditioning regimen – the chemotherapy received prior to the transplant – in addition to the activity of the donor T-cells from the transplant.

(07:58): The pre-transplant conditioning regimen – the chemotherapy we give before transplant – varies in intensity. In this slide, I've included a publication that lists all of the different usual regimens of chemotherapy that are given before transplant, ordered according to their intensity.

(08:28): A combination treatment regimen of Busulfan, Cyclophosphamide, and total body irradiation (TBI) is the most intensive treatment plan, and a treatment plan consisting solely of low dose TBI, is the least intensive. More intensive chemotherapy is given with the hope of completely eradicating the cancer stem cells, but it comes with the cost of increasing the risk of toxicity.

(08:59): While most conditioning regimens are done in the inpatient setting, low dose TBI can be given outpatient due to its less intensive nature. If you received low dose TBI as your conditioning treatment prior to transplant and never got the stem cells, you would still survive. Your blood counts might go down for a few days, but they would bounce back to where they were before. It's a well-tolerated and non-toxic therapy, but it is not as strong or effective in completely eradicating the cancer stem cells.

(09:38): In general, as doctors and oncologists, we try to give patients the most intensive regimen that we think they will be able to tolerate. This is based upon results from a randomized clinical trial done by the Bone Marrow Transplant Clinical Trials Network. Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) were randomized to receive either a more intensive pre-transplant conditioning regimen called MAC – myeloablative conditioning – or a less intensive conditioning regimen called RIC – reduced intensive conditioning. They then had their allo-transplant; either stem cells from a brother or sister or from an unrelated donor.

(10:25): This graph shows data published a couple of years ago, indicating that the overall probability of surviving without relapse is significantly higher in the group that received the myeloablative conditioning regimen compared to the group that received the reduced-intensity conditioning regimen. So, more chemotherapy given before transplant leads to a higher probability of maintaining a relapse-free survival state.

(11:06): That high-dose chemotherapy, though, comes with the increased risk of toxicity and increased risk of non-relapse mortality. There is a risk of the chemotherapy doing more harm than good. A lot of clinical decision-making is done when we take people to a stem cell transplant, regarding how much chemotherapy to give before transplant, and it's a discussion that usually takes place between patients and their doctor.

(11:49): In an allo-transplant, it's that one-two punch with chemotherapy to reduce the cancer stem cells and then donor T-cell immunotherapy to eliminate the cells that may be resistant to chemotherapy.  

(012:12): There are multiple ways that leukemia cells can evade the immune system after transplant. One way is that they fail to express on their cell surface the immune recognition molecules that are necessary for them to be seen by donor T-cells. In addition, they can express extra molecules that incapacitate the ability of the immune system to attack them. They can also produce soluble molecules called cytokines that also slow down the immune system or reduce the secretion of cytokines that accelerate the immune system. They can make enzymes that degrade the constituents of the amino acids necessary for the donor immune cells to function, or they can grow too fast for the immune system to catch up.

(13:18): In lieu of a very technical description, we can think about leukemia cells as having a ‘cloak of invisibility’. They can become ‘non-sticky,’ allowing them to slip away from the immune cells. They can blend in so that the immune cells can't see them. They can ‘hide in the dark’, and they can grow too fast so that the immune cells can't catch up. These are all strategies that leukemia cells can use to evade immune surveillance after an allo-transplant.

(13:51): Signs of Relapse. If patients are suspecting relapse, they may notice increased fatigue, weight loss, night sweats, swollen lymph nodes, bone pain, or abnormal lab tests. When they see their doctor, the doctor will examine them for physical signs of cancer, such as increased lymph nodes under the neck or arms, and may order various diagnostic tests.

(14:26): Testing for Relapse. These tests may include a bone marrow aspirate, where a needle is inserted into the hip bone and collects bone marrow cells for analysis in the laboratory. They may also order a PET scan, where the image can indicate any detectable cancer in the lymph nodes.

(14:59): Doctors may also run molecular tests, where we can identify a different set of DNA molecules within cancer cells, compared to normal cells. Those differences can be detected by sophisticated testing involving PCR (polymerase chain reaction) or DNA sequencing, so that even very low levels of residual disease can be detected and help anticipate a clinical diagnosis of relapse.

(15:41): Testing done early on after transplant can help determine whether patients might benefit from a strategy to prevent clinical relapse from occurring called maintenance therapy. This therapy is something doctors can do after a stem cell transplant or CAR T-cell therapy to keep the patient in remission and prevent relapse.

(16:14) Maintenance therapy has been quite effective for a number of different disease diagnoses and different types of transplant. This slide shows the benefit of utilizing lenalidomide (Revlimid®) as a maintenance drug for patients with multiple myeloma who underwent an autologous stem cell transplant. The upper curve shows that the group that was randomized to receive lenalidomide (Revlimid®) had a higher percentage of patients who remained progression-free with no detectable relapse. This is compared to the curve representing the group randomized to receive a placebo, indicating a lower percentage of patients who are alive without disease progression.

>Relapse in myeloma does not mean bad things are going to happen immediately, and indeed, the overall survival of patients randomized to lenalidomide (Revlimid®) or randomized to placebo was the same. But we might anticipate, if we were to look at the survival curve for a longer period of time, not just four years, but 10 years, we would expect to see a greater survival rate for patients who received lenalidomide (Revlimid®) maintenance after stem cell transplant.

(17:38): In lymphoma, B-cell lymphoma, and mantle cell lymphoma, we have seen benefits in patients receiving rituximab (Rituxan®) maintenance after an autologous stem cell transplant. In this line graph, the red line represents patients diagnosed with mantle cell lymphoma, who were randomized to receive rituximab (Rituxan®), and saw no disease progression. This is compared to the blue curve representing those randomized to observation only, who saw no disease progression or relapse. The overall survival rate is not as distinct, but we see that rituximab (Rituxan®) maintenance reduced the risk of disease progression at 4 years from 45% to 20%. This is another example of a maintenance strategy to keep patients in remission.

(18:51): Here is data from an allogeneic transplant setting. These are patients with acute myeloid leukemia (AML),  who had a particular genetic mutation called FLT3, that causes leukemia cells to grow faster. We have a drug called gilteritinib (Xospata®) that selectively inhibits the enzymatic activity of the FLT3 gene. We participated in a randomized clinical trial for patients with FLT3 positive AML undergoing an allogeneic transplant. About two months after their transplant, patients in remission were randomized to receive the maintenance drug, gilteritinib (Xospata®), or a placebo drug.

(19:48): The blue curve in this first graph indicates a greater survival rate and reduction of relapse in the group of patients who received maintenance gilteritinib (Xospata®), compared to the red curve indicating those who did not. Patients who had some measurable residual disease (MRD) also showed a clear benefit from getting maintenance gilteritinib (Xospata®).

>(20:19): This second graph indicates patients who were MRD[-] – meaning the patients had no detectable evidence of leukemia in their blood after the stem cell transplant – saw no difference in relapse-free survival whether they received gilteritinib (Xospata®) or a placebo. This tells us that maintenance treatment should be driven by the disease status of each patient.

(20:53): Maintenance therapy comes with its own potential toxicities, so we want to reserve it for the patients who will experience the greatest benefit from it.  These are patients who have detectable disease utilizing those very sophisticated molecular tests, but below what would be called a clinical relapse.

(21:19): We can also use immunotherapy to treat relapse. CAR T-cells are commonly used to treat a relapse of leukemia or lymphoma after either an autologous or an allogeneic transplant.

(21:40): Immune-checkpoint blockade therapy uses antibodies to reactivate T-cells to treat relapse after allogeneic transplant, but they may cause very severe graft-versus-host disease (GVHD).

(21:53): Hypomethylating drug therapies – such as azacitidine (Vidaza®) or decitabine (Dacogen®) – may make the leukemia cells more recognizable and susceptible to the immune system by stripping away some of those leukemia cells’ shielding strategies that make them invisible to the immune system. The hypomethylating drug therapies can ‘shine a light’ on the leukemia cells, allowing the T-cells to seek them out and destroy them.

(22:28) In some cases, we may give additional donor immune cells or a second allogeneic transplant if patients have relapsed after an initial allo-transplant.

(22:39): Chimeric antigen receptor T-cells – or CAR T-cells – are clearly a breakthrough for patients with relapsed lymphoma or multiple myeloma. These are FDA-approved products that use patients' own lymphocytes to manufacture a population of cancer-targeting killer T-cells.

(23:02): This slide shows the evolution of CAR T-cells over time. We've made them more effective by making them a little bit more complex. This slide shows the first generation, second generation, and third generation of CAR T-cells. I won't try to teach you all about which co-signaling domain is more effective, but I will simply say that many people around the world have worked hard to understand how to engineer T-cells to be more effective in fighting lymphoma and myeloma. By engineering new molecules that are expressed on the T-cell, called chimeric antigen receptors – or CAR – with specific DNA sequences, we can create a CAR T-cell that expands a thousand-fold, or maybe a million-fold, in the patient that can attack and eradicate a disease.

(24:13): Engineering CAR T-cells is a complex process that some of you have gone through, so you'll recognize the different steps. First, we must harvest normal lymphocytes from the blood of the patient or a volunteer donor. We then select the cells that are going to be used for CAR T-cell manufacturing. This often involves purifying the T-cells – and in some cases NK (natural killer) cells – and then genetically modifying them. We want to insert a new piece of DNA into the T-cell or NK cell that will reside permanently within the cell nucleus and instruct the cell to express that CAR on its cell surface.

(25:00): On the previous slide, the green structure outside the cell is the recognition molecule that the CAR uses to identify the tumor cell. Once those T-cells have been manufactured over a one to two week time period, they're packaged up in a bag, frozen, and then shipped back to the hospital. After the patient has received a sequence of drugs to deplete their own lymphocytes, creating new space for the CAR T-cells to grow, the manufactured cells are infused into the patient. Those CAR T-cells then hone in on the disease sites and eradicate the cancer. This approach has been very effective against certain diseases

(25:51): A CAR T-cell study that included pediatric patients with acute lymphoblastic leukemia led to the FDA approval of the first CAR T-cell product. The recipients in this study were children with a median age of 11. Most had received a prior allogeneic transplant and had relapsed, and many of them had experienced two or more relapses. Most of them had detectable leukemia at the time of CAR T-cell infusion.

(26:29): The adult patients that were included in this study consisted of patients with a median age of 47 who had not undergone an allogeneic transplant, and most had primary refractory disease that had not responded to any therapy. Despite their very poor prognosis, half of these patients were long-term survivors after a CAR T-cell infusion.

(26:57): This CAR-T product is called tisa-cel (Kymriah), and has also been used to treat lymphoma patients. In a lymphoma study we participated in at Emory, about 40% of the patients were long-term survivors without recurrent lymphoma. If the patients had an initial response of their lymphoma to the CAR T-cell infusion, two-thirds of them remained lymphoma-free at two years. This therapy was really life-changing for the patients and revolutionary from our perspective as doctors. However, it must be noted that half the patients or more were not cured with CAR T-cell therapy.

(27:50): This image shows one of our patients at Emory who received tisa-cel (Kymriah®) to treat their lymphoma. In the image taken prior to receiving their CAR T-cell infusion, you can see the lymphoma is in the black areas highlighted by the red bars, including a very large black circle in the groin. In the image taken six months later, after receiving their CAR-T infusion, that black circle is gone. The remaining black areas on the PET scan represent the bladder and the heart, which are normal. You actually can see the vocal cords lighting up as two little black wings right below the chin that are metabolically active because the patient was talking. So clearly, CAR T-cells can offer curative therapy for patients even with significant bulk disease.

(28:51): There are three different brands of CAR T-cells for lymphoma: axi-cel (Yescarta®), liso-cel (Breyanzi®), and tisa-cel (Kymriah®). They've been compared to each other in retrospective studies, and it appears that axi-cel and liso-cel are more effective than tisa-cel. Therefore, the specific constructs of the CAR – the DNA sequences used to modify the T-cell – make a difference in terms of how effective the CAR will be in eradicating disease.

(29:33): Both axi-cel (Yescarta®) and liso-cel (Breyanzi®) are more effective than an auto-transplant for patients with relapsed lymphoma. Patients with diffuse large B-cell lymphoma typically receive a chemotherapy regimen called CHOP (cyclophosphamide, hydroxydaunorubicin or doxorubicin, vincristine, and prednisone), or R-CHOP (CHOP with the addition of rituximab), given every two or three weeks.

(30:02): If patients relapse after R-CHOP, our next line of therapy in the past was a high dose chemotherapy regimen and a stem cell transplant, referred to as standard-of-care (SOC). When patients with diffuse large B-cell lymphoma relapsed, they were randomized to either receive CAR-T or SOC therapy, and the progression-free survival was clearly superior for those patients randomized to the CAR-T group. Therefore, CAR T-cell therapy has now replaced an autologous transplant as treatment for most patients with relapsed lymphoma.

(30:47): In a similar vein, using CAR T-cells to target myeloma is superior to the standard-of-care for patients with relapsed myeloma. These graphs compare the standard-of-care treatment to treatment with ciltacabtagene auto-cel (Carvykti®) and ide-cel (Abecma®). In particular, cilta-cel (Carvykti®) is able to produce long-term remissions in over half of the patients with relapsed myeloma. Because they're receiving a CAR T-cell that selectively attacks their myeloma, we think some of these patients will be cured.

(31:34): Acute lymphoblastic leukemia (ALL) is another area of great interest for CAR T-cells. In adult patients, obe-cel (Aucatzyl®) was able to produce durable remissions in more than 40% of patients, and the CAR T-cells persisted in the blood to a greater extent, and with a lower toxicity, than the initial Kymriah CAR T-cell product. By improving the design of CAR T-cells, and the specific DNA sequences which are introduced into the T-cell, we hope to continue to improve the efficacy of CAR T-cells.

(32:17): There are a number of different therapies that may be effective for myeloma or lymphoma patients who've relapsed after CAR T. Bispecific antibodies can reactivate the T-cells in the patient's blood. A second transplant could be performed with a new donor graft, with the hope that those donor T-cells will eliminate the residual disease. Patients can sometimes receive a second infusion of CAR T-cells that targets a different lymphoma or myeloma specific antigen.

(33:06): This graph shows the survival rate of patients who received a bispecific antibody compared to patients who received another standard-of-care therapy for disease relapse after CAR T. The red curve represents lymphoma patients who relapsed late and received a bispecific antibody, and the yellow curve represents patients with late relapsed disease who received standard-of-care therapy. The bispecific antibody was notably more effective in patients who had a late relapse of their disease after their initial therapy.

(33:56): An allo-transplant for patients with relapsed lymphoma after CAR T-cell has shown an overall survival of about one third of patients. However, this comes with some cost as non-relapse mortality occurred in 25% of patients, and continued disease progression and lymphoma growth occurred in 40% of patients. We still have more work to do to improve the management of patients whose disease has relapsed after CAR T.

(34:44): The later a relapse occurs, the better the survival rates. Patients whose lymphoma relapsed more than three months after CAR T-cell infusion had much better survival rates than patients whose disease relapsed very early.

(35:14): A second CAR T may also be used. This is a somewhat complex slide, but it tells us that a third of patients who don't respond to initial CAR T may achieve a durable remission by getting a second CAR T-cell infusion, particularly if it's targeting a different antigen.

(35:36): These are all different strategies that can be used to manage relapses after CAR T.

(35:46): Treatment options for relapse after an allogeneic bone marrow transplant. We can flip the sequence of therapies and give a CAR T for certain diseases that have relapsed after an allogeneic transplant, such as with B-cell acute lymphoblastic leukemia. We also can perform a second allogeneic bone marrow transplant for patients with a late relapse, or give hypomethylating drug therapy for patients with minimal detectable residual leukemia or myelodysplastic syndrome following allogeneic transplant.

(36:27): Let’s discuss some of these strategies. This figure is one I showed earlier with the data from the trial that led to FDA approval of tisa-cel (Kymriah®) for acute lymphoblastic leukemia. It makes the point that nearly three quarters of the pediatric patients who received this therapy had relapsed after allogeneic transplant, so CAR T is still a curative therapy option.

(37:02): A second allogeneic transplant can be used for patients with myeloma. It's not very effective for patients with an early relapse, but it can prolong survival and cure about a quarter of the patients who had a late relapse of their disease after an allogeneic transplant.

(37:24): Hypomethylating drug therapy can reawaken the ability of immune cells to see leukemia, and can improve survival for patients with relapsed AML after an allo-transplant. Giving additional donor lymphocytes is often used in this setting, as well.

(37:46): Hypomethylating drug therapy increases the activity of the donor T-cells. And that increasing frequency of donor T-cells implies an increased ability of those cells to attack leukemia.

(38:14): A second transplant, or a donor leukocyte infusion, is most effective when the disease burden is low. This graph indicates that patients with a low blast count of less than 5% had better survival outcomes than patients whose bone marrow had greater than 5% blasts.

(38:36): Strategies families and patients can utilize to help manage relapse. We've talked a lot about different chemotherapy strategies and cell strategies. What about the human aspects of this? What can patients do? What can families do to help manage relapse?

(38:51): Diet is important. We know a diet that promotes a diverse microbiome in the intestines – the gut microbiome – has been associated with less gut inflammation and better anti-cancer immunity. Many patients ask me, "What diet should I eat?”. I always tell them to eat a varied diet with lots of different fiber and nuts, because that may help their immune system fight cancer.

(39:20): Managing stress is also important. Psychological stress may increase inflammation and impede the success of donor T-cells.

(39:30): We know that the fear of relapse is inevitable, and there's a limit to what we can do as doctors or patients to prevent relapse. Fear is a big issue for patients who have gone through CAR T or a stem cell transplant. Some of it is really beyond our control. I advise patients to try and enjoy the days they are feeling well to the greatest extent possible, while recognizing that we don't know what will happen in the future. Patients cannot control their outcomes, and I encourage them not to rely on scans or marrow biopsies to have hope.

(40:14) Hope should always be available to patients, and we don't need to wait for a good scan result to be optimistic.

(40:24): Family and support are important. Nutrition, exercise, and stress management all can be combined to improve patients' emotional state, physical state, and even the ability of their immune system to fight cancer.

(40:43): Caregivers are important. They provide emotional and practical support. They can help discuss test results with the doctors and ask, "Well, if plan A doesn't work, what will plan B be? What are the options if the disease does relapse?"

(41:00): Patients and families are encouraged to seek a second opinion at a center that may have a higher volume of patients, or that may have a clinical trial available which offers a new therapy that might be more effective.

(41:19) Fear of relapse is also stressful for caregivers, so I advise family members to seek out support as well.

(41:27): I'll end and summarize with a couple of takeaway messages.

(41:34): An ounce of prevention is worth a pound of cure. The more the doctor can control and reduce the disease before patients undergo a stem cell transplant or CAR T-cell therapy, the less the risk of relapse and maintenance therapy.

(41:52): Targeted maintenance therapy after transplant, and most likely after CAR T-cell as well, may help prevent relapse.

(42:01): CAR T-cells are more effective than auto-transplant for relapsed lymphoma, and CAR T-cells can be given after allo-transplant and still cure up to half of patients with relapsed B-cell lymphoblastic leukemia.

(42:17): Allo-transplants can be given after CAR T-cell and cure another third of patients. Even though these therapies are intensive, they may be given in sequence, in the appropriate setting, to eradicate disease that has relapsed after initial cell therapy.

(42:40): I'll end there for some questions from the audience, and I'd be happy to answer those as they're made available to me.

Question and Answer Session

(42:53) [Steve Buechler]: Thank you, Dr. Waller, for this excellent presentation. We will now begin the question and answer session.

(43:07): “What is the current relapse time for Mantle Cell Lymphoma (MCL)? I had standard care treatment from Hopkins in 2021, followed by a stem cell transplant. Then only four rounds of rituximab maintenance due to many fevers of unknown origin and other issues. I was supposed to be on it for three years."

(43:28) [Dr. Edmund Waller]: Mantle cell lymphoma is heterogeneous. Some types of mantle cell lymphoma grow very quickly while some may be more indolent. We believe that there's a fraction of mantle cell lymphoma patients who can be cured by transplant and by maintenance therapy.

(43:53): If I skip quickly to the slide that I showed earlier on mantle cell lymphoma, you can see that the group that got rituximab (Rituxan) for up to six years, three-quarters of those patients remain in remission. While disease relapse may occur late, I congratulate you if your disease is still in remission, and I would be optimistic that it stays in remission.

(44:36): The good news for mantle cell lymphoma is that even disease that has relapsed after a stem cell transplant can be effectively treated with a lot of different strategies. Bruton tyrosine kinase (BTK) inhibitors are very effective for mantle cell lymphoma, as are a variety of CAR T-cells.

(44:56) [Steve Buechler]: "Are cancer stem cells particularly dependent on glucose for growth? If so, would a ketogenic diet that minimizes glucose and insulin be beneficial?"

(45:09) [Dr. Edmund Waller]: That's an area of active investigation. Cancer stem cells have long been known to utilize glucose as their primary energy source. There's no clear evidence from randomized clinical trials that a ketogenic diet is going to have a major effect, in part because even with a ketogenic diet, the level of glucose in the blood stays in a normal range. It's not as if you can survive with no glucose at all, because the brain cells need glucose to stay alive. But certainly, I advise patients that having a diet which is relatively free of refined carbohydrates and relatively rich in vegetables and nuts makes sense from a general health perspective and I believe makes sense from a cancer perspective.

(46:14) [Steve Buechler]: "How long do AML patients have to stay on Xospata® (gilteritinib) after transplant?"

(46:21) [Dr. Edmund Waller]: Maintenance therapy is usually measured in years and can be monitored by PCR tests. Sometimes we stop early if patients remain PCR negative and they have toxicities from the maintenance therapy. So that question really is something to discuss with your doctor.

(46:48) [Steve Buechler]: "How do CAR T-cells become cancerous cells in some cases?"

(46:55) [Dr. Edmund Waller]: Manufacturing CAR T-cells involves inserting new pieces of DNA into an existing T-cell. Occasionally – rarely – there is an abnormal T-cell in the blood during CAR T-cell manufacturing, so that when the new DNA is inserted into that cell's nucleus, it can create a new lymphoma cell. That happens quite infrequently – at a low rate – and, in my opinion, should not dissuade patients or doctors from prescribing CAR T-cells, because the number of cases in which that's occurred of the tens of thousands of people receiving CAR T-cells is less than a dozen. But it's still something to be aware of as a potential side effect and risk.

(47:57) [Steve Buechler]: "What are your thoughts on intermittent fasting after CAR T therapy? Is there a way to metabolically reset?"

(48:07) [Dr. Edmund Waller]: It’s an interesting idea, intermittent fasting. My wife does that and sometimes makes me miss a meal or two. It certainly is a great way to lose weight. It's unclear whether we'll have a significant long-term benefit for patients who received CAR T-cell therapy. As long as your weight is staying in a normal range, I don't believe it's dangerous. But I would let your doctor know that you're doing intermittent fasting because it can cause some abnormalities in routine blood tests that your doctor may find confusing if they are not aware that you're fasting.

(48:52) [Steve Buechler]: "What role does psychological stress play in cancer cells? Does this increase the chance of recurrence?"

(49:01) [Dr. Edmund Waller]: Psychological stress does affect the immune system, and we know the immune system has an important role in controlling cancer cells. I think life is better when experiencing less stress, so I think strategies to manage stress are advised for cancer patients, as well as everyone.

(49:25): However, I don't think that patients should feel responsible – that they did something wrong – if their cancer recurs. We don't have a clear signal as to what level of stress might increase the risk of relapse, and we certainly can't point to patients as being responsible for their relapse if they were not able to manage stress effectively.

(49:53): I can tell you from personal experience, there's a lot of stress during my workday. Dealing with phone calls, dealing with sick patients, dealing with insurance company denials. Stress is a fact of life, so it's not a question of eliminating stress, it's a question of managing stress to enjoy one's life to the greatest extent possible.

(50:20) [Steve Buechler]: "Do menin inhibitors figure into your thinking about relapse treatment?"

(50:27) [Dr. Edmund Waller]: Menin inhibitors are really exciting drugs that can be used both for ALL and AML and should be considered as maintenance in this setting. Absolutely.

(50:40) [Steve Buechler]: "How long on average do CAR T-cells remain active after initial infusion?"

(50:47) [Dr. Edmund Waller]: It varies by the brand of CAR T-cells. One of those earlier slides I showed indicated first generation, second generation, and third generation of CAR-T cells. It is the inside-the-cell part of CAR T that helps determine how long it remains active.

(51:08): For axi-cel (Yescarta®), CAR T-cells remain active for months. For liso-cel (Breyanzi®) and tisa-cel (Kymriah®), the CAR T-cells may remain active for years, to the extent that patients who received tisa-cel (Kymriah) may not have recovery of normal B-cells.

(51:28): Emily Whitehead, the first pediatric patient treated with CAR T-cell therapy more than 10 years ago, is still alive with no detectable leukemia, but also no normal B-cells, because there are enough CAR T-cells still in her system to eliminate the B-cells in her bone marrow. So, she needs to get immunoglobulin infusions every month or so. And I have patients in my clinic six years out from CAR T-cells for lymphoma, who still have sufficient CAR T-cells in their body to prevent normal B-cells from recovering. It varies a lot by the brand of CAR T-cell, and it varies a lot from patient to patient.

(52:17) [Steve Buechler]: "How long should I continue maintenance in high-risk FLT3 NPM1 positive AML? I had an early relapse after the first transplant and underwent a second one 11 months later."

(52:29) [Dr. Edmund Waller]: The studies have looked at maintenance for two years. I think it's a discussion to have with your doctor if you've relapsed after initial therapy. If you're getting a FLT3 inhibitor and you're tolerating it well, I would repeat those highly sensitive PCR tests. And in my practice, I would probably treat for three years to give a little margin of extra drug exposure, and maybe longer if relapse had already occurred from a prior transplant.

(53:10) [Steve Buechler]: "For multiple myeloma, if the relapse comes five to six years after transplant, would a patient normally move to CAR T or a second transplant? What are the criteria for deciding the course of treatment?"

(53:25) [Dr. Edmund Waller]: That's been a question addressed by prospective clinical trials. The results are not finalized, but I think the activity of CAR T-cells is quite striking, particularly cilta-bel (Carvykti®). Transplants can sometimes be used to debulk the disease. And both therapies may be given in tandem to achieve optimal disease control.

(53:56) [Steve Buechler]: "If a patient receives an allogeneic transplant and then relapses, would you suggest a CAR T from the donor's T-cells instead of the patient's?"

(54:08) [Dr. Edmund Waller]: Typically, in that setting, we have used the patient as the source for the CAR T, recognizing that they are engrafted with donor T-cells. It's been difficult to collect the T-cells from the unrelated donor for CAR T-cell manufacturing, since the process of getting insurance approval for CAR T typically specifies that we collect the cells from the patient with cancer. Those T-cells are donor-derived and, in my experience, can be quite potent in their anti-leukemic activity– even in patients with relapsed disease. I think collecting and manufacturing CAR T-cells from the donor directly is of interest, but would probably need to be done in a clinical trial.

(55:06) [Steve Buechler]: On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Waller for a very helpful presentation, and also thank the audience for your questions. Please contact BMT InfoNet if we can help you in any way, and enjoy the rest of your day.