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Robert and Margarita Louis-Dreyfus Professor of CLL and Lymphoma
Division of Hematology/Oncology
Department of Medicine
University of Pennsylvania
Director, Lymphoma Program and Lymphoma Translational Research
Abramson Cancer Center
Hospital of the University of Pennsylvania
Stephen J. Schuster, MD, has disclosed that he has received consulting fees from AbbVie, Aptitude Health, Celgene, Juno, Loxo Oncology, Nordic Nanovector, Novartis, and Tessa Therapeutics and funds for research support from AbbVie, Celgene, Genentech, Juno, Loxo Oncology, Merck, and Novartis.
CAR T-cell therapy provides a novel treatment approach for many patients with hematologic malignancies who were previously considered to have few viable therapeutic options. In this commentary, I will summarize key considerations with this therapeutic option and share a case from my own practice.
Identifying Candidates for CAR T-Cell Therapy
Two CAR T-cell therapies—tisagenlecleucel and axicabtagene ciloleucel—are now approved by the FDA. Tisagenlecleucel is indicated for treating patients aged 25 years or younger with acute lymphoblastic leukemia (ALL) that is refractory or in at least second relapse or for adult patients with relapsed/refractory large B-cell lymphoma after 2 or more lines of therapy. Axicabtagene ciloleucel is indicated for adults with relapsed/refractory large B-cell lymphoma after at least 2 lines of therapy.
Historically, patients with large B-cell lymphoma that is relapsed/refractory after at least 2 lines of therapy had a very poor prognosis, particularly those patients who relapsed within the first year of receiving immunochemotherapy or a stem cell transplant. In clinical trials, CAR T‑cell therapy has been associated with prolonged disease‑free survival for these patients. In patients who were enrolled in one of our institutional trials, we now have data demonstrating that at more than 4 years post treatment, almost all of the patients who achieved CR remain in remission.
Several key factors must be evaluated when considering approved CAR T-cell therapy. For a patient to be considered for treatment, he or she should have adequate performance status and general fitness. It is also critical that the patient’s disease can remain stable during the CAR T-cell manufacturing period (which can be 4-6 weeks) so that he or she can receive treatment when the CAR T-cells are ready. Several newer agents are effective as bridging therapy, including polatuzumab, ibrutinib, and PD-1 inhibitors.
Another key factor is the patient’s lymphocyte count, which determines the CAR T-cell manufacturing success rate. It is an unfortunate waste of time and resources to send a patient sample to the manufacturer only to receive word that there were inadequate T-cells or no T-cell growth. For tisagenlecleucel, an absolute lymphocyte count > 300 cells/mm3 provides approximately 95% manufacturing success, the product of which will be cryopreserved. Axicabtagene ciloleucel, which remains fresh, requires ≥ 100 cells/mm3.
After confirming that a patient meets these criteria, pheresis and cell manufacturing can proceed, with bridging therapy used as necessary in the interim. When the CAR T-cells are ready, lymphodepletion and cell infusion can be initiated.
It should also be noted that there are numerous ongoing clinical trials with approved and novel CAR T-cell therapies. Among the novel approaches being assessed, lisocabtagene maraleucel (formerly JCAR017, another CD19-targeted agent) has reached later-phase trials for patients with relapsed/refractory large B-cell lymphoma (as well as chronic lymphocytic leukemia); tisagenlecleucel is being assessed for adults with ALL and as second-line therapy for non-Hodgkin lymphoma; axicabtagene ciloleucel is in clinical trials as first-line therapy for high-risk large B-cell lymphoma; and idecabtagene vicleucel (formerly bb2121, a BCMA-targeted agent) has now reached phase III trials for treating patients with relapsed/refractory multiple myeloma. You may wish to consider a clinical trial if your patient does not fit the current indications for approved therapies.
Returning to approved therapy for patients with relapsed/refractory large B-cell lymphoma, in my experience, patients with high tumor volume—as assessed by metabolic and anatomic measures—and high serum LDH have lower rates of complete remission with CAR T-cell therapy. That is not to say you should not treat those patients; however, fewer will likely achieve CR (approximately 30% vs 40% to 50% of patients with lower tumor volumes and serum LDH). Moreover, patients with high tumor volume and high serum LDH are typically more challenging to bridge during the manufacturing period. These are important considerations when managing individual patients.
Toxicities and Monitoring
The primary toxicities associated with CAR T-cell therapy are cytokine-release syndrome and a neurotoxicity syndrome, both of which have been well described by the American Society of Transplant and Cell Therapy in recommendations published in December 2018. I will not go in to detail about these toxicities here except to say that these are manageable and are rarely lethal unless they are not recognized or managed appropriately. It is important to be familiar with these phenomena when managing a patient undergoing CAR T-cell therapy. CCO has developed an interactive online tool into which you can enter your patient’s CAR T-cell therapy history and adverse event characteristics to get consensus recommendations from 5 multidisciplinary experts on how to manage patients who experience an adverse event. To access the tool, please click here.
It is important to note that most patients who fail CAR T-cell therapy will progress within the first 3 months. As such, it is important to monitor patients closely during this period. If they are progressing, obtain biopsies to make sure you understand what is happening in the tumor and what the therapeutic options might be. It is critical that the clinical team responds quickly. If patients can achieve CR and maintain it for 1 year, they have a very good probability of maintaining long‑term, durable CR.
Case: 42-Year-Old Woman With Transformed Follicular Lymphoma
To bring these details to life, let’s look at an example of a patient from my clinic. A 42‑year‑old woman with large‑cell transformed follicular lymphoma presented with a very large abdominal mass that was palpable and measured 9 cm x 10 cm x 22 cm. The tumor caused some renal obstruction, for which she had stents placed. She had received several previous therapies for follicular lymphoma and then developed large‑cell transformed lymphoma and was refractory to salvage therapy. As part of her 11 previous therapies, she had received an allogeneic stem cell transplant. At the time I first saw her, she had stable disease on carboplatin/gemcitabine and had no evidence of graft‑vs‑host disease. We felt confident that we would be able to treat her with CAR T-cells, even though we assumed that most of the harvested lymphocytes would be of donor origin.
We harvested T-cells, and when her CAR T-cells were available in July, we administered a lymphodepleting chemotherapy followed by the CD19 CAR T‑cell infusion. She had an excellent response; every week I could measure her tumor by palpation, and by early October, it had reached a nadir of approximately 50% reduction by physical examination.
On subsequent visits, the mass began to enlarge. Imaging showed that the abdominal mass was now 10 cm x 10 cm and was metabolically active. We performed a biopsy and found that her large‑B‑cell lymphoma was active with minimal T‑cell infiltration. Of interest, FISH analysis showed that her tumor harbored both C‑MYC and BCL2 rearrangements, so it was a double‑hit lymphoma. Moreover, her tumor cells showed high PD‑L1 expression compared with her baseline biopsy, which was likely driving her disease progression. Based on this finding, we treated her off‑study with nivolumab. and she went on to have a CR by March 2016. We resected the entire residual mass, including anything that had been suspicious on scanning and found extensive necrosis but no viable tumor; she had achieved an anatomic/surgical CR. She did very well after that and required no further therapy. Unfortunately, she had renal insufficiency from her past obstruction that ultimately required her to begin dialysis. However, at her last follow‑up at 3 years post treatment (she later moved out of state), she remained in CR.
This patient had been through multiple previous therapies, including a donor allotransplant, and we were able to achieve CR with pathologic confirmation and a prolonged disease‑free survival with CAR T‑cell therapy, in this case together with PD-1 blockade. Although she required some additional therapy because of the early development of resistance, in most cases of patients who ultimately achieve CR, they have done so with CAR T-cells alone.
What are your experiences with CAR T-cell therapy in patients with leukemia and lymphoma? Answer the polling question and join the discussion by posting a comment or question below.
Attending the ASH annual meeting in Orlando this year? Sign up here to attend CCO’s satellite symposium, “CAR T-Cell Therapy for Leukemia, Lymphoma, and Myeloma: Where We Are and Where We Are Going,” on the evening of Friday, December 6, during which I will discuss patient case studies and current and emerging strategies in CAR T-cell therapy with our esteemed panel, including Matthew Frigault, MD; James K. Kochenderfer, MD; and Jae H. Park, MD.
Not attending ASH but still want to view this exciting educational event? Sign up here to watch the live simulcast from your computer.