Dr. Jason Westin:
Welcome to The ASCO Post Roundtable Series on Treatment Strategies for Transplant-Ineligible Relapsed/Refractory Diffuse Large B-Cell Lymphoma. I'm Dr. Jason Westin, Professor at MD Anderson Cancer Center, where I'm the Director of Lymphoma Clinical Research. Joining me today are two of my colleagues and we'll start off by introducing Dr. Caron Jacobson. They'll introduce themselves and then we'll go into the case.Dr. Jacobson?
Dr. Caron Jacobson:
Hi, I am Caron Jacobson. I'm a lymphoma specialist at the Dana-Farber Cancer Institute in Boston, and it's a pleasure to be here today.
Dr. Westin:
Dr. Chihara?
Dr. Dai Chihara:
Hello, I'm Dai Chihara. I'm an Assistant Professor at MD Anderson Cancer Center. I'm also a lymphoma expert at Anderson, and it’s a pleasure to be here too.
Dr. Westin:
Wonderful. Well we're thrilled to have both of you.
Today, we'll be discussing the treatment and management of relapse refractory diffuse large B-cell lymphoma or DLBCL with three patient case studies. Our first installment will focus on the treatment of a patient with early relapsed or refractory DLBCL.
This patient is Mr. R.G. and he's 76 years old with a history of hypertension and hyperlipidemia. He was diagnosed with DLBCL, non-GCB or non-germinal center subtype with no translocation of MYC or MYC. He has an international prognostic index score of 4 at diagnosis, representing high-risk disease.
He was treated with six cycles of R-CHOP and achieved a complete response on his interim PET/CT scan, but unfortunately had progressive disease at the end of the treatment scan. He tolerated treatment relatively well and has a performance status of 1. A biopsy after the end of treatment scan showed he's got refractory DLBCL. You reassess him and find that he's got adequate organ function based on labs, a repeat echocardiogram and pulmonary function testing. Unfortunately, he was told by his local team that he was "too old for stem cell transplant" and he's come now to see Dr. Jacobson to ask her what are the standard-of-care options in this situation?
Dr. Jacobson:
Thanks Jason. So this is a case of primary refractory large B-cell lymphoma. At 76, he may have just made on the cusp of our considering him for an autologous stem cell transplant, but based on two randomized studies looking at CAR T-cells vs standard-of-care salvage chemotherapy with the intention to an autologous stem cell transplant in chemoresponsive disease, we now know that that is not the most standard of care or the best treatment option for patients like this.
So specifically for patients with primary refractory or early relapsing large B-cell lymphoma within 12 months of front-line chemoimmunotherapy, there were two randomized studies, the ZUMA-7 study for axicabtagene ciloleucel , which of course Dr. Westin is a lead author for and has presented a lot of this data as well as the TRANSFORM study for lisocabtagene maraleucel that both showed that the experimental CAR T-cell arms, axicabtagene ciloleucel and lisocabtagene maraleucel were superior in terms of event-free survival over standard-of-care salvage chemo and an autologous transplant.
And despite the fact that more than 50% of patients on both studies in the standard-of-care arm did receive CAR T-cells in the third line, either off of the study as commercially available CAR T-cells for the ZUMA-7 study or actually on study on the TRANSFORM study, we actually see both a statistically significant overall survival benefit to getting CAR T-cells in the second line on the ZUMA-7 study and a trend towards an improved overall survival on the TRANSFORM study. And so I think what that really tells me is that waiting to give patients like this CAR T-cells in the third line actually loses some of the survival advantage and loses some of the curative potential of CAR T-cells. So I think the most appropriate standard of care for this patient would be to move on to either axicabtagene ciloleucel or lisocabtagene maraleucel at this point.
Dr. Westin:
Excellent. Well said.
Dr. Chihara, is there a maximum age for CAR T-cell therapy in your practice?
Dr. Chihara:
I think it's a tricky question. Probably yes and no.
The chronological age is probably not the major issue. I quickly looked up our database at Anderson at the maximum age we treated for large cell lymphoma was 88. When I looked up the SEER-Medicare database to describe the outcome of CAR T-cell therapy in older patients, the maximum age in that database was 90.
Obviously I don't know if we want to treat the patient with CAR T-cell therapy if they're 100, but I do believe there is no clear age cutoff. The EBMT guideline also doesn't set age limits for consideration of the CAR T.
So to answer that question, I don't think there's any maximum age limit for CAR T-cell therapy as long as they're fit by the assessment. And I think the question is how to assess that fitness. But if we think they're fit for CAR T-cell therapy, the chronological age is probably not the most important factor for consideration of the CAR T-cell therapy.
Dr. Westin:
I think that's critically important, especially for doctors in practice who have a history of knowing what stem cell transplant looks like and having a filter saying this patient is not going to tolerate platinum based chemotherapy, therefore I'm not even going to send them for an evaluation at the transplant center.
CAR T-cell therapy is a different animal and has different toxicities and can be tolerated by different patients. Historically, patients that would have been transplant ineligible might still be CAR T-cell eligible and the best way to know is to refer a patient to see somebody at a CAR T-cell center to ask that question. So you've heard clearly that CAR T-cell is superior to what was the old standard of chemotherapy first and then save CAR T-cell for third line and that patients who do receive a CAR T-cell can do so even if they're a significantly advanced age, as long as they've got significant fitness and the logistical ability to travel to a CAR T-cell center, the social support that goes along with that.
And along those lines, we've now updated our algorithm where previously we used to ask “does the patient have eligibility for yes or no?” Now we ask “did the patient relapse within 1 year?” And if the answer is yes, then we ask are they eligible for CAR T-cells? And we think that thankfully the number of patients who the answer will be yes eligible for CAR T-cells is a significant growth from what we used to say for patients who'd be eligible for stem cell transplant. Thankfully offering hopefully curative intent therapy for more and more of our patients.
So back to our case, this patient was treated with CAR T-cell therapy, either axicabtagene or lisocabtagene and had a grade 2 CRS and grade 1 ICANS. So CRS is cytokine-release syndrome and ICANS is immune effector cell–associated neurologic syndrome, both of which resolved within 5 days of onset. A PET/CT scan 1 month after CAR T-cell therapy shows a complete response to treatment.
Dr. Jacobson, are there any special considerations or prophylactic medications for patients who receive CAR T-cell therapy?
Dr. Jacobson:
Yeah.
So I think obviously with the thing that we're the most worried about are those acute toxicities of cytokine-release syndrome and neurologic toxicity. It sounds like this patient did very well, which is great to see. But then there are some long-term side effects that we need to be mindful of both ourselves and then also when we refer these patients back to the community in order to make sure they're mindful of them as well.
First is an on-target off tumor effect of B-cell aplasia. So of course these CAR T-cells are targeting CD19, which will lead to attack of normal healthy B cells as well as the cancerous B cells. And so these patients can have B-cell aplasia that lasts for months to more than a year in certain circumstances. Of course we can measure the output of these B cells by measuring IgG levels and different institutions have different practices of repleting IgG levels empirically when they fall below 400 or waiting until patients have frequent infections. I think for community practices they would generally take their cues from the general practice of the treating CAR T-cell treatment center.
Along those lines of immune suppression, I think we've also realized that many of our patients have prolonged T-cell lymphopenia, specifically CD4 lymphopenia. And so we keep all of our patients on PJP and herpes virus prophylaxis. We do that for at least a minimum of 6 months and then we start measuring CD4 counts in these patients and only when they rise to over 200 do we stop those medications. I will say with the caveat that we have had some cases of PJP pneumonia in patients with a CD4 count over 200 even after stopping PJP prophylaxis. So I do think it's very important to at least hit that threshold of a CD4 count of 200 before stopping and to be cognizant of the fact that some patients don't recover their CD4 count for even 18 or 24 months after CAR T-cell therapy.
And then the last thing is that some of these patients can have prolonged cytopenias. About a quarter of patients will have cytopenias that recur around 1 month and on average they last for about 6 months. Although some patients they can last quite a bit longer to varying extents. So patients, they can have transfusion-dependent cytopenias and severe neutropenia and require GCSF and transfusions. In those patients we would try to treat with some anti-inflammatory therapies because we do think this is immunomodulatory and we will try things like IVIG or TPO mimetics in these patients. Other patients can have very sort of mild cytopenias that will eventually recover. I think anybody who doesn't have cytopenias that recover within 6 months, we would typically get a bone marrow biopsy to assess for other causes of cytopenias. But to that end, when we have patients like that, it's reasonable I think to do screening therapies. So thinking about not necessarily prophylactic medications, but prophylactic serologies for things like fungal infections and CMV reactivation and things like that.
Dr. Westin:
Thank you, Dr. Jacobson. A lot for doctors in practice to be aware of and pay attention to for infectious risks after these patients are successfully treated.
So for the key clinical takeaways for this case, in patients in second-line treatment with refractory or early relapse DLBCL, CAR T-cell therapy, specifically axicabtagene ciloleucel or lisocabtagene maraleucel, are the preferred treatments over platinum chemotherapy as they've been shown to improve outcomes including overall survival. In patients over age 70, outcomes with CAR T-cell therapy for refractory or early relapse patients are similar to younger patients and there's really no maximum chronologic age; it's more to do with the physiology, the fitness of the patient. And along those lines, patients who historically have been considered transplant ineligible may be eligible for CAR T-cell therapy and therefore should be referred for an evaluation at a center with CAR T-cell experience.
So in conclusion for case one, this brings us to the end of that case. Please see the other segments for further discussions about the latest research in DLBCL or visit ascopost.com.
