by Dr. C.H. Weaver M.D. updated 5/2021
Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia (SLL/CLL) is considered a very indolent or slowly growing cancer, occurring predominantly in older individuals. Because the cancer grows slowly, it is very hard to cure with traditional cancer chemotherapy or radiation therapy treatments, which only destroy rapidly growing cells. Although curing patients is very difficult, patients may live a very long time with their disease. In fact, the average patient with SLL/CLL lives 6-10 years from diagnosis.
For patients under the age of 50-60 with SLL/CLL, allogeneic stem cell transplantation or CAR T Cell Therapy may be treatment options. For a general overview of the process of allogeneic stem cell transplants and CAR T Cell therapies select
Allogeneic Stem Cell Transplantation for SLL/CLL
Allogeneic stem cell transplantation is a potentially curative treatment for patients with SLL/CLL. Until ten years ago, SLL/CLL had been considered an incurable slowly growing cancer of the elderly requiring chemotherapy only to treat symptoms or delay disease progression. In parallel with the growing evidence of safety and effectiveness of stem cell transplantation for the treatment of other leukemias, there was emerging interest in using this approach to treat younger patients with SLL/CLL. About 40% of patients with SLL/CLL are younger than 60 years and about 10% are younger than 50 years at the time of the diagnosis.
In spite of several new drugs and new drug combinations, or precision cancer medicines, there is no current evidence that any of these strategies can cure patients with SLL/CLL. The average duration of survival for younger patients with SLL/CLL remains around 5 years from the initiation of therapy. The most useful predictor for decreased survival is the history of prior treatment. Patients with SLL/CLL who fail any kind of therapy (cancer returns or progresses after treatment) have an average life expectancy of 30 months. Patients who are refractory to treatment with chemotherapy have an average survival of only 9 months. These outcomes have resulted in consideration of more aggressive and potentially curative approaches, such as stem cell transplantation. Two transplantation strategies have been evaluated for patients with SLL/CLL: autologous stem cell transplantation and allogeneic stem cell transplantation. For more information on autologous transplantation, go to autologous stem cell transplant.
Allogeneic stem cell transplantation has two main advantages. One advantage is that the stem cells collected from a donor are free of leukemia. The other advantage is that the donor lymphocytes facilitate the killing of SLL/CLL cells by an immunologic graft-versus-leukemia effect. These two features of an allogeneic stem cell transplant act in concert with high doses of chemotherapy and irradiation to contribute to the cure of some patients with SLL/CLL.
Several hundred patients with SLL/CLL have received allogeneic bone marrow or blood stem cell transplants. The main disadvantage of an allogeneic stem cell transplant is the side effects, which may result in death in up to 20% of patients although those continues to improve. This is mainly due to complications related to graft-versus-host disease. Leukemia recurrence is unusual and 45-65% or patients survive beyond 3 years from treatment and may be cured.
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CAR T Cell Therapy for CLL
Combining the kinase inhibitor Imbruvica (ibrutinib) with an investigational personalized cellular therapy known as CTL119 can lead to complete remission in patients with high-risk CLL, according to new research from the Perelman School of Medicine at the University of Pennsylvania and Penn’s Abramson Cancer Center (ACC). The team presented the results from its pilot study of this combination therapy during the 2017 American Society of Clinical Oncology Annual Meeting.
The team will present on the first 10 patients in the trial, each of whom had been taking Imbruvica for at least six months but had not achieved a complete remission. They were then infused with their own engineered “hunter” T cells. Eight of nine patients who are evaluable for response had no evidence of disease in their bone marrow at three months, and all remain in remission after a median follow-up period of six months, with a range from 0.5 to 9 months. One patient was found to have a partial response in their marrow.“
Combining Imbruvica with the CTL119 therapy achieved very powerful results for these patients, and with limited toxicity,” Gill said. “This newer, coupled approach gives us hope that personalized cell therapies could be an important option for high-risk CLL patients on these types of drugs.”CTL119 manufacturing begins with a patient’s own T cells, some of which are removed and then reprogrammed in Penn’s Clinical Cell and Vaccine Production Facility with a gene transfer technique designed to teach the T cells to target and kill tumor cells.
The engineered cells contain an antibody-like protein known as a chimeric antigen receptor (CAR), which is designed to bind to a protein called CD19 found on the surface of cancerous B cells. The modified “hunter” cells are then infused back into the patient’s body, where they multiply and are believed to attack the cancer cells.Patients in the trial had been on Imbruvica for a minimum of six months and had not achieved a complete response when they received an infusion of engineered cells split over three consecutive days. All had abnormalities of TP53 or ATM – two mutations associated with high-risk disease – and two patients had increasing BTK C481S clones, also a high-risk marker.The new data builds off several preclinical studies supporting the use of Imbruvica with CAR therapy. In March 2016, Penn researchers published a study in Blood that showed long-term Imbruvica treatment reverses the dysfunction of T cells in CLL and that combining CAR therapy with Imbruvica enhanced engineered T cell proliferation in mice.CAR therapy alone has led to complete remissions and responses in some CLL patients, but not all patients respond, findings that led the Penn team to seek combination therapies that might enhance efficacy of the therapy. In 2015, Penn Medicine researchers reported in Science Translational Medicine an overall response rate of 57 percent in CLL patients treated with CAR therapy, and a complete remission rate of 29 percent.Imbruvica is a well-tolerated, oral drug that improves symptoms and survival in high-risk CLL patients, but is not curative and requires continuous treatment for life. It rarely induces complete remissions by itself. That first year on the drug may provide an optimal window to collect T cells from patients and subsequently administer a potentially curative T cell therapy, the authors said.“These patients had a lower disease burden and were treated earlier in the course of their disease, which distinguishes it from other studies,” Gill said. “One of the challenges in treating CLL patients with personalized cellular therapy is not having healthy enough cells to manufacture. The results suggest that Imbruvica restored T cell activity in the patients.All 10 patients who received the CTL119 cells experienced mild cytokine release syndrome (CRS), a known potentially lethal type of toxicity, within a few days after receiving their infusions; however, none required treatment with tocilizumab, an immunosuppressant drug that blocks the effects of the inflammatory cytokine IL-6. All recovered from their CRS.CRS can include varying degrees of flu-like symptoms, with high fevers, nausea, and muscle pain, and temporary neurologic symptoms, including delirium, and in more severe cases, low blood pressure and breathing difficulties which may require treatment in an intensive care unit. One patient in the study developed tumor lysis syndrome and recovered.Longer follow-up will reveal the durability of these results, the authors said, and may support the evaluation of a first-line approach with Imbruvica and CAR therapy in an effort to remove the need for chronic therapy.