Personalized and costly, but new ALL treatment offers hope

A breakthrough treatment for acute lymphoblastic leukemia (ALL), one of the most common childhood cancers, offers new hope for patients who have not responded to standard therapies.

The new treatment, developed by Novartis AG (Basel, Switzerland), involves removing cells from affected patients, programming them to attack cancer cells, then returning those cells to the patients. Access to the highly personalized treatment is somewhat limited at this point and very expensive, but oncology experts are still touting the therapy as revolutionary in the field.

Gwen Nichols, MD, chief medical officer of the Leukemia and Lymphoma Society, says CAR-T cell therapy is a “remarkable breakthrough” for treating children and adults aged younger than 25 years who have relapsed or not responded to standard therapy for B-cell ALL. Nichols notes that the treatment has not been approved by the US Food and Drug Administration (FDA) as a first-line treatment, and can only be used after traditional treatment methods have failed.

“While the CAR-T cells do not last for all patients who receive this treatment, those patients who have experienced a lasting remission have been able to go on to enjoy their normal lives, returning to school and regular activities within a few months after the single in-hospital treatment,” Nichols says, adding that physicians should remember that the treatment is not widely available at this time. “Doctors should be aware that for now the treatment is only available at major cancer treatment facilities, so patients may need to travel from their homes in order to have access to this treatment.”

Scourge of ALL

Acute lymphoblastic leukemia makes up about a quarter of all cancer diagnoses in children aged younger than 15 years and is the most common childhood cancer in the United States. It appears most often between the ages of 3 and 5 years, and affects slightly more boys than girls, according to St. Jude Children’s Research Hospital, Memphis, Tennessee.

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Standard treatment options have traditionally been limited and involve a combination of chemotherapy and radiation lasting roughly 2 to 3 years. This regimen works well for about 90% of ALL patients, Nichols says, with younger patients responding better than adolescents and young adults. In those cases where treatment works, the patients are considered cured, although they still may suffer from some long-term or late-term effects from their treatments. Patients who relapse after standard treatment may receive stem cell transplants, but it’s an intensive procedure that requires long hospitalizations with limited exposure to other people.

“Children undergoing treatment for ALL miss many days of school,” Nichols says.

The benefit of CAR-T cell therapy, she says, is that the treatment can generally be done with a one-time infusion following some chemotherapy to prepare for the procedure. This is not to say that CAR-T cell therapy is easy, however. Nichols says it can sometimes be followed by an intense reaction called cytokine release syndrome. This involves a high fever, tachycardia, and other serious adverse effects. Nichols says some of these adverse effects can be mitigated and often pass within a few days, but the reaction also can be life threatening. Still, for patients who have exhausted other therapy options, the new treatment offers a lot of hope.

“This new approach to therapy provides a very promising option for patients who before this had a very poor prognosis,” Nichols says. “Whereas the vast majority of patients respond well to standard therapy, those who do not had very limited options and typically had very poor outcomes. This new therapy is likely to save many hundreds of lives.”

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Trials show promise

The therapy, also known as tisagenlecleucel (Kymriah), was given priority review by the FDA and approved in August 2017. The approval of tisagenlecleucel was based on a trial of 63 patients with ALL, including 35 patients who had a prior hematopoietic stem-cell transplantation. Patients in the study received a single dose of tisagenlecleucel intravenously 2 to 14 days after lymphodepleting chemotherapy. Participants in the study experienced an 82.5% remission rate after therapy-63% with complete remission and 19% with complete remission with incomplete hematologic recovery.

David Lebwohl, MD, senior vice president and franchise global program head, CAR-T Program, Oncology Global Development at Novartis, says tisagenlecleucel is the first-ever FDA-approved chimeric antigen receptor T cell (CAR-T) therapy. It has shown high rates of remission and durable response in children and young adults with relapsed or refractory ALL, he adds. It is currently the only FDA-approved CAR-T cell therapy, and no similar therapies are currently under review, either.

“CAR-T cell therapy represents a novel treatment option that is the embodiment of personalized medicine. Each dose is tailored individually to, and manufactured for, each patient using the patient’s own blood cells,” Lebwohl says. “The therapy, which is not a pill or traditional chemotherapy, is produced via pioneering technology and a sophisticated manufacturing process.”

Lebwohl says the therapy is developed by extracting a patient’s own white blood cells including T cells through a specialized filtration process called leukapheresis. After the cells are collected, they are reprogrammed to recognize and fight cancer and other cells that express a specific antigen. Engineering takes place at a Novartis plant in New Jersey, and the process includes cryopreservation of the harvested cells so that physicians will have the flexibility to reintroduce the engineered cells based on the individual patient’s condition. Chemotherapy is given before the reprogrammed cells are returned to the patient to reduce the level of white blood cells and help the body accept the reprogrammed cells, Lebwohl says.

The therapy can be completed in the inpatient or outpatient setting at certified cancer treatment centers, and patients should remain within a 2-hour distance of the treatment center for up to 4 weeks for posttherapy monitoring, Lebwohl says.

This can be a challenge considering that tisagenlecleucel is not widely available and patients may have to travel far for treatment. Use of the therapy is limited by the highly specialized nature of the therapy, he says, adding that Novartis is working to improve access.

“Given the sophisticated and individualized nature of Kymriah, we expect a gradual ramp-up compared to traditional small molecules, and we are establishing a network of treatment centers to offer Kymriah. We are actively onboarding treatment centers across the country, which includes training and finalizing relevant agreements, as we progress toward our goal to have 32 centers fully operational by the end of the year in order to be able to collect patients’ cells for Kymriah manufacturing and, subsequently, administer the product,” Lebwohl says. “As of early October 2017, 32 centers have been certified and 10 centers are fully operational. We are helping to ensure that the needs of eligible patients are being met and treatment can be administered through one of the fully operational centers.”

High cost of treatment

Another consideration for the therapy is the cost. Lebwohl says that external estimates and Novartis’ own quantitative assessments indicate a cost-effective price tag for the therapy could be $600,000 to $750,000, but the company has set the price at $475,000.

“Novartis is committed to doing everything we can to help children and young adults who can benefit from Kymriah have access to the therapy, and we are working with stakeholders to discuss Kymriah clinical efficacy and safety, patient population, and burden of illness to ensure they fully understand the value of this therapy and provide coverage for patients accordingly,” Lebwohl says.

Lebwohl could not offer specifics on how commercial insurers would cover the therapy, but says Kymriah will be provided free of charge to eligible underinsured or uninsured patients. He says Novartis is also working with the Centers for Medicare and Medicaid Services (CMS) to develop novel pricing for the therapy, which may include value-based arrangements or indication-based pricing depending on the clinical outcomes achieved.

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Commercial plans will evaluate Kymriah on its clinical and economic benefits and make an independent decision for coverage. Costs will vary from patient to patient and treatment center to treatment center, based on the level of care each patient requires and the patient’s insurance coverage. In addition, for the uninsured or underinsured, Kymriah will be provided free of charge to eligible patients.

“Novartis is also working to make an outcomes-based approach available that would allow for payment only when pediatric and young adult ALL patients respond to Kymriah after 1 month,” Lebwohl says. “In other words, for patients treated at centers that have opted in to the outcomes-based approach, there is no charge if the patient doesn’t respond in this time frame. We are working through specific details with stakeholders to put this new pricing model in place as soon as possible. There are many hurdles, and Novartis is committed to continue working with our partners to make this happen as quickly as possible. When it comes to future potential indications, the most relevant approach will be reviewed depending on the data and other considerations.”