Those who treat chronic lymphocytic leukemia (CLL) are commonly asked if we can cure the disease. It is what every patient wants to know. The majority of patients are told the usual answer, “CLL is not a curable malignancy”. While CLL may not be cured with standard treatment approaches, we do know that CLL can provide long-term survival without relapse for some patients with aggressive disease who undergo stem cell transplantation. The next question patients ask is “why don’t we do more stem cell transplants and cure this disease?” To address this question it is first important to understand the concepts that define stem cell transplantation and the rationale for its use.
Stem cell transplants are largely separated into two groups, either using a patient’s own stem cells, termed autologous transplantation, or using another person (i.e., a donor) to provide stem cells, defined as an allogeneic transplant. Autologous transplantation is centered on the rationale that the dose of treatment makes a difference. In other words, if we just get a higher dose of treatment into a patient we can kill more malignant cells and control disease. The key to autologous transplantation is therefore to deliver escalated doses of chemotherapy, sometimes even combined with high doses of radiation treatment, to eradicate every last cancer cell possible. Of course when we deliver these high doses of chemotherapy we also kill all of the normal blood forming cells in the bone marrow. We accept ablation of normal blood progenitor cells because we first collect stem cells from the patient (i.e., autologous or “auto” cells) and store them in the freezer for subsequent reinfusion to rescue the bone marrow and recover normal blood cell production. Autologous stem cells are collected using a procedure where patients have their blood circuited through a specialized machine that separates out the stem cells that are stored and returns the remaining blood back to the patient. After cells are collected and frozen, the patient will then receive the high-doses of therapy followed by thawing the stem cells and infusing them back into the patient so that they can go on to make normal red blood cells, white blood cells, and platelets. Autologous transplantation does impart significant morbidity to the patient, however, the risk of having a serious life-threatening complication is relatively low, perhaps 1-2%. Despite the morbidity and the often prolonged hospitalizations, we know that this approach can be often highly successful with long-term survival benefits. Autologous transplantation has been considered the standard of care in select hematologic malignancies, in particular for patients who have relapsed Hodgkin lymphoma or diffuse large cell lymphoma. So if an autologous transplant can be so successful with acceptable risk, then why don’t more CLL patients undergo this procedure? Autologous transplantation has not been widely used for CLL patients simply because it is not curative and invariably all CLL patients will relapse. Relapses are largely due to fact that collected autologous stem cells are “contaminated” with malignant cells. Specifically, the CLL cells cannot be sorted out from the normal stem cells and therefore malignant cells are reintroduced to the patient as part of the transplant procedure, which leads to a subsequent relapse in the vast majority of CLL patients. Alternatively, allogeneic transplants use a healthy donor to provide “clean” stem cells and eliminate the risk of delivering contaminated stem cells back to the patient.
Allogeneic transplantation has proven to be curative and critically important for many patients with acute leukemia, such as those with acute lymphoblastic leukemia or acute myeloid leukemia. High dose allogeneic transplants have also been associated with a significant risk of major complications that has limited this approach to younger patients who can tolerate the procedure. Given that most CLL patients are above the age of 55, however, a high dose allogeneic strategy has been rarely utilized. More often allogeneic transplantation employs a reduced-intensity approach that relies on the donor’s immune system cells to eradicate the disease. In particular, a reduced-intensity allogeneic transplant does not use high doses of chemotherapy or radiation, but uses just a little bit of therapy to suppress the patient’s immune system and allow the donor cells to engraft. It is these powerful donor immune cells that eradicate the disease by generating a graft-versus-leukemia (GVL) effect, with the graft being the donor immune cells. Unfortunately the relative low intensity of this procedure does not eliminate risk. A major risk centers on these donor immune system cells that also can attack the patient’s normal organs and potentially cause significant complications, in particular a disease termed graft-versus-host disease (GVHD). Moreover, these transplants use essential medications to suppress the patient’s immune system to control GVHD. However, a deeply suppressed immune system can lead to severe infections that can be life-threatening. In general, it is recognized that about 1 of 3 patients who receive an allogeneic transplant for relapsed aggressive CLL might be cured, with about a third dying of a transplant-related complication, and the remaining one-third tolerating the transplant relatively well yet still relapsing from their disease. So given these risks, while recognizing the curative potential of the procedure, which CLL patients, if any, should we consider for an allogeneic transplant?
As with any clinical scenario, understanding the risks and benefits of a proposed therapy formulate the basis for making complex medical decisions. Clearly we have had a dramatic emergence of novel and highly active therapies, including new antibody approaches and targeted kinase inhibitors that have changed the landscape for how we treat CLL. However, we know that the disease remains incurable with the standard treatments and there are select fit patients who may benefit from an allogeneic transplant. Overall these transplant candidates have been largely considered to be those with very poor-risk disease with limited or no further meaningful therapeutic options. These have been CLL patients who have either not achieved a response or relapsed very rapidly (i.e., within 6-12 months) after cytotoxic regimens such as fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR), or those with the most high-risk genetic aberrations including 17p deletion or the presence of a TP53 mutation. In addition, appropriate patients with a Richter transformation (RT) have been considered for an allogeneic transplant due to the aggressive biology. To transplant RT patients, however, should show an objective response to on-going therapy that would be anticipated to be durable enough to allow for time to generate the GVL effect.
In summary, allogeneic transplants are typically reserved for CLL patients who really have few alternative options and still are considered to be appropriate candidates for the procedure. Clearly, we need better understanding of the biologic, molecular, and genetic features of each individual patient’s CLL to better determine the appropriate utilization of allogeneic transplantation. We still have a long way to go to routinely cure CLL, but the good news is that most patients will not ever need to be considered for a stem cell transplant. While there likely always will be a role for this ultimate immune therapy, its utilization in CLL will continue to decline given the multitude of new available therapies and the continued further development of novel therapies.
Dr. John Pagel is Chief of the hematologic malignancy program at the Swedish Cancer Institute in Seattle, WA.