CAR T-Cell Therapy Shows Promise for Patients With Hairy Cell Leukemia

For patients with hairy cell leukemia whose cancer returns after multiple treatments, researchers are investigating whether CAR T-cell therapy could provide longer-lasting remissions and potentially lead to a cure.

Dr. Robert J. Kreitman, a researcher at the National Institutes of Health (NIH), has spent decades studying hairy cell leukemia, a rare type of blood cancer. His work has included the development of targeted treatments, including Lumoxiti (moxetumomab pasudotox), and more recently, research involving CAR T-cell therapy.

The investigational approach uses a patient's own immune cells, which are modified to recognize and attack cancer cells. In one patient who previously received several treatments, Kreitman reported no detectable hairy cell leukemia for more than two and a half years following CAR T-cell therapy.

Kreitman discussed how the treatment works, the risks patients should understand and why researchers are hopeful about its future.

CURE: What have patients entering your CAR T-cell therapy trial typically experienced before receiving this treatment?

Kreitman: The patients have been through a lot. Many have received cladribine, sometimes combined with rituximab, or pentostatin. Some have received both drugs through several different treatment regimens.

Other patients have received treatments targeting BRAF, if their disease is eligible for those therapies. Some have also undergone a splenectomy, which is the surgical removal of the spleen.

The patients receiving CAR T-cell therapy have generally been heavily pretreated, meaning they have already received multiple treatments for their disease.

How does CAR T-cell therapy work, and why are you targeting CD22?

CD22 is a very good target for hairy cell leukemia because it is strongly expressed on the leukemia cells.

Our approach involves collecting a patient's T cells and engineering them to recognize CD22 on malignant cells. Once the modified T cells are returned to the patient, they can recognize and attack those cells.

Another advantage of CD22 is that it does not interfere with rituximab, which targets CD20. Rituximab does not prevent CD22-directed CAR T cells from binding to hairy cell leukemia cells.

CD22 has also been targeted successfully in research involving children with acute lymphoblastic leukemia at the NIH.

How does CAR T-cell therapy compare with Lumoxiti, a treatment you previously helped develop?

The two approaches appear to work well in different circumstances.

Lumoxiti has worked particularly well in patients with high numbers of malignant cells in the blood or enlarged spleens. It can also eliminate measurable residual disease, or MRD, which refers to very small amounts of cancer that remain after treatment.

However, Lumoxiti has not worked as well for patients with large lymph nodes or substantial masses of leukemia cells outside the blood, bone marrow and spleen.

CAR T-cell therapy appears to have a different pattern. Patients with large numbers of leukemia cells in their blood can experience significant toxicity because of the many interactions between the engineered T cells and cancer cells. These interactions can lead to cytokine release and serious complications.

By contrast, we have seen CAR T cells gradually clear masses of leukemia cells in other parts of the body with little significant toxicity in some patients.

The treatments could complement one another, and we hope both approaches may be available to patients in the future.

Can hairy cell leukemia eventually be cured?

We think it can be, but determining whether a patient is truly cured takes many years.

One patient who received BL22, an earlier drug that helped lead to Lumoxiti, more than 25 years ago still has no detectable evidence of hairy cell leukemia. We use highly sensitive tests that can detect extremely small numbers of malignant cells in the blood and bone marrow.

We also have patients who have remained without detectable disease for more than 15 or 20 years following other treatments.

Our goal is not only to achieve complete remission, but also to eliminate measurable residual disease. We have seen that remaining disease can eventually lead to relapse, even if it takes many years.

The longer patients remain without detectable disease, the more hopeful we become about the possibility of a cure.

One patient has shown no detectable leukemia for more than two and a half years following CAR T-cell therapy. What makes this case significant?

This patient had already received multiple treatments, including repeated courses of purine analogs such as cladribine, as well as vemurafenib and rituximab. He had also undergone a splenectomy.

His disease eventually developed into a large mass between the bladder and prostate, which obstructed the drainage of urine from his right kidney.

Previous treatments provided only temporary responses.

After receiving CAR T-cell therapy, however, we have found no detectable evidence of hairy cell leukemia for more than two and a half years.

We cannot say he is cured. We also do not know whether the CAR T cells are still present in his body and controlling any remaining leukemia cells.

But we are very excited about the response. It raises the possibility that CAR T-cell therapy could eventually produce cures in some patients.

What risks should patients understand before considering CAR T-cell therapy?

One of the major concerns is toxicity in patients who have very high numbers of leukemia cells in their blood.

When the engineered T cells encounter large numbers of malignant cells, the immune response can become intense. Patients may develop fever, elevated ferritin levels and serious inflammatory complications.

We have seen patients experience substantial toxicity when their leukemia burden is very high, even when treatment eliminates nearly all detectable malignant cells.

Neurological side effects have also been reported with CAR T-cell therapy in other cancers, although we have not observed them in our hairy cell leukemia patients.

This is one reason we believe CAR T-cell therapy should be considered before patients develop an extremely high burden of disease.

Could CAR T-cell therapy eventually be used earlier in treatment?

I think it could.

In the future, CAR T-cell therapy might be considered after initial treatment with chemotherapy-free regimens, particularly for patients whose disease returns or continues to progress.

For patients who relapse after BRAF-directed treatment, repeating the same approach may not lead to a long-lasting remission.

That may be an appropriate point to consider CAR T-cell therapy rather than waiting until the disease becomes much more advanced.

We are also studying other treatments, including venetoclax, which targets BCL-2, and BTK inhibitors. These approaches may expand the options available to patients.

How does CAR T-cell therapy differ from a stem cell transplant?

CAR T-cell therapy is very different from a transplant.

With the CAR T-cell approach we are studying, we take the patient's own T cells and engineer them to recognize and attack malignant cells.

We are not transferring cells from another donor, so we do not have the same concerns about graft-versus-host disease that can occur following an allogeneic stem cell transplant.

CAR T-cell therapy still carries risks, but it is an important treatment approach that is being investigated across leukemias, lymphomas, solid tumors and even autoimmune diseases.

I think it is something patients should consider when appropriate.

What gives you the most hope for the future of hairy cell leukemia treatment?

We hope that some of these investigational treatments will eventually receive FDA approval so physicians can offer them to their patients.

Our goal is to continue developing treatments that provide longer-lasting remissions and, potentially, cures for people with hairy cell leukemia.

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