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31 augustus 2017: Bron: FDA

Voor de eerste keer in hun bestaan heeft de U.S. Food and Drug Administration (FDA) een vorm van gentherapie goedgekeurd voor gebruik bij kinderen en jong volwassenen met een bepaalde vorm van Acute Lymfatische Leukemie (ALL) na studieresultaten uit een fase II studie (Eliana studie) waarbij 83% van de kinderen binnen drie maanden en 6 maanden in een remissie kwam.

De FDA goedkeuring werd gegeven aan de immuuntherapeutische behandeling met het 'vaccin' tisagenlecleucel (Kymriah), een vorm van immuuntherapie met bewerkte Car-T cellen gekoppeld aan tocilizumab, het medicijn dat autoimmuunreacties bij de patiënten moet voorkomen. (zie ook in gerelateerde artikelen informatie over Car-T cellen bij leukemie. In dit artikel onder beschrijving van FDA goedkeuring staan verderop ook links naar andere artikelen over CAR-T cell therapie).

In verschillende studies waren de resultaten heel goed. In een fase II studie (Eliana studie) kwam 83% van alle deelnemende patiënten (N = 63: kinderen en jong volwassenen) binnen drie maanden in een remissie.

(Tekst loopt verder onder dit schema van CAR-T cell Therapie)

CAR T-cells(2)

Tisagenlecleucel (KYMRIA) is een genetisch gemodificeerde autologe T-cel immunotherapie. Voor elke dosis tisagenlecleucel is een aangepaste behandeling gemaakt met behulp van de eigen T-cellen van een individuele patiënt. De T-cellen van de patiënt worden verzameld en verzonden naar een productiecentrum waar ze genetisch gemodificeerd zijn om een nieuw gen te ontwikkelen dat een specifiek eiwit bevat (een chimerische antigeenreceptor, - CAR) die de T-cellen stimuleert om leukemiecellen op te zoeken en te doden met een specifiek antigeen (CD19) op het oppervlak. Zodra de cellen zijn gemodificeerd, worden ze teruggegeven aan de patiënt om de kankercellen te doden. (CAR-T cell therapie is in feite ook een vorm van dendritische celtherapie maar dan met gemodificeerde T-cellen).

Behandeling met tisagenleucucel kan wel ernstige levensbedreigende bijwerkingen veroorzaken. Bv het zogeheten cytokine-release syndroom (een vorm van een autoimmuunreactie) - dat is een systemische reactie op de CAR T-cellen die hoge koorts en griepachtige symptomen en neurologische bijwerkingen kunnen veroorzaken. Zowel het cytokine-release syndroom als neurologische bijwerkingen kunnen levensbedreigend zijn en de patiënt kan eraan overlijden. Daarom ook is de FDA toestemming voor tisagenleucucel gekoppeld aan tocilizumab dat de ernstigste bijwerkingen kan voorkomen.

Bealngrijkste punten waarop de FDA de toestemming geeft:

De veiligheid en werkzaamheid van tisagenlecleucel werden aangetoond in de klinische fase II multicenter ELIANA klinische studie van 63 pediatrische en jonge volwassen patiënten met recidiverende of refractaire B-cel precursor ALL. De totale remissies binnen 3 maanden na behandeling was 83%.
De FDA heeft daarnaast ook de goedkeuring van tocilizumab uitgebreid om een soms bij CAR T-cel therapie voorkomende auto immuunziekte (cytokine-afgifte syndroom) te voorkomen en mede te behandelen bij patiënten van 2 jaar of ouder.
Vanwege het risico op cytokine-afgifte syndroom (autoimmuunziekte) en neurologische bijwerkingen wordt tisagenlecleucel goedgekeurd met een risico evaluatie en mitigatie strategie, die elementen bevat om veilig gebruik te waarborgen.
De FDA eist van de ziekenhuizen en hun bijbehorende klinieken die tisagenlecleucel mogen geven een speciale certificatie voor deze medicijnen.

In onderstaande artikelen op kanker-actueel kunt u meer informatie vinden over immuuntherapie met CAR-T cells:

https://kanker-actueel.nl/NL/dendritische-celtherapie-met-t-car-cells-wordt-als-proef-vergoed-vanuit-basiszorgverzekering-voor-melanomen-stadium-iiib-en-iiic.html

https://kanker-actueel.nl/NL/immuuntherapie-met-extra-gemoduleerde-t-car-cells-geeft-bij-zwaar-voorbehandelde-lymfklierkanker-non-hodgkin-alsnog-uitstekende-resultaten-met-33-procent-complete-remissies.html

https://kanker-actueel.nl/NL/immuuntherapie-met-t-car-cells-tumor-lymphocytic-infiltration-is-interessante-ontwikkeling-bij-verschillende-vormen-van-kanker.html

https://kanker-actueel.nl/NL/lymfklierkanker-jami-lijkt-alsnog-genezen-dmv-immuuntherapie-met-t-car-cells-immuuntherapie-van-haar-zwaar-voorbehandelde-vergevorderde-lymfklierkanker-non-hodgkin.html

https://kanker-actueel.nl/NL/immuuntherapie-gentherapie-afdeling-in-umc-gaat-trial-doen-met-leukemie-en-extra-ingebrachte-t-cellen-met-zelfmoordcommando-gen.html

https://kanker-actueel.nl/NL/layla-een-baby-met-ongeneeslijke-vorm-van-all-acute-lymfatische-leukemie-lijkt-alsnog-te-genezen-door-immuuntherapie-met-t-cellen-van-een-donor-via-t-cell-enginering-therapie.html

https://kanker-actueel.nl/NL/gen-therapie-bij-leukemie-blijkt-succesvol-bij-enkele-patienten-toeval-of-doorbraak-in-immuuntherapie.html

De officiële tekst van de FDA toestemming staat onder in een persbericht van de FDA. Daaronder het persbericht over de Eliana studie van Novartis de producent van deze behandeling: Novartis pivotal CTL019 6-month follow-up data show durable remission rates in children, young adults with r/r B-cell ALL

FDA approval brings first gene therapy to the United States! CAR T-cell therapy approved to treat certain children and young adults with B-cell acute lymphoblastic leukemia

This release was updated on Aug. 30, 2017 to correctly identify the FDA designations granted to Kymriah.

The U.S. Food and Drug Administration issued a historic action today making the first gene therapy available in the United States, ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases.

The FDA approved Kymriah (tisagenlecleucel) for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL).

“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” said FDA Commissioner Scott Gottlieb, M.D. “New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses. At the FDA, we’re committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving.”

Kymriah, a cell-based gene therapy, is approved in the United States for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.

Kymriah is a genetically-modified autologous T-cell immunotherapy. Each dose of Kymriah is a customized treatment created using an individual patient’s own T-cells, a type of white blood cell known as a lymphocyte. The patient’s T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.

ALL is a cancer of the bone marrow and blood, in which the body makes abnormal lymphocytes. The disease progresses quickly and is the most common childhood cancer in the U.S. The National Cancer Institute estimates that approximately 3,100 patients aged 20 and younger are diagnosed with ALL each year. ALL can be of either T- or B-cell origin, with B-cell the most common. Kymriah is approved for use in pediatric and young adult patients with B-cell ALL and is intended for patients whose cancer has not responded to or has returned after initial treatment, which occurs in an estimated 15-20 percent of patients.

“Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER). “Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that has shown promising remission and survival rates in clinical trials.”

The safety and efficacy of Kymriah were demonstrated in one multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within three months of treatment was 83 percent.

Treatment with Kymriah has the potential to cause severe side effects. It carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T-cells causing high fever and flu-like symptoms, and for neurological events. Both CRS and neurological events can be life-threatening. Other severe side effects of Kymriah include serious infections, low blood pressure (hypotension), acute kidney injury, fever, and decreased oxygen (hypoxia). Most symptoms appear within one to 22 days following infusion of Kymriah. Since the CD19 antigen is also present on normal B-cells, and Kymriah will also destroy those normal B cells that produce antibodies, there may be an increased risk of infections for a prolonged period of time.

The FDA today also expanded the approval of Actemra (tocilizumab) to treat CAR T-cell-induced severe or life-threatening CRS in patients 2 years of age or older. In clinical trials in patients treated with CAR-T cells, 69 percent of patients had complete resolution of CRS within two weeks following one or two doses of Actemra.

Because of the risk of CRS and neurological events, Kymriah is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring that hospitals and their associated clinics that dispense Kymriah be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of Kymriah are required to be trained to recognize and manage CRS and neurological events. Additionally, the certified health care settings are required to have protocols in place to ensure that Kymriah is only given to patients after verifying that tocilizumab is available for immediate administration. The REMS program specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Kymriah.

To further evaluate the long-term safety, Novartis is also required to conduct a post-marketing observational study involving patients treated with Kymriah.

The FDA granted Kymriah Priority Review and Breakthrough Therapy designations. The Kymriah application was reviewed using a coordinated, cross-agency approach. The clinical review was coordinated by the FDA's Oncology Center of Excellence, while CBER conducted all other aspects of review and made the final product approval determination.

The FDA granted approval of Kymriah to Novartis Pharmaceuticals Corp. The FDA granted the expanded approval of Actemra to Genentech Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines, and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Related Information

83% of patients achieved complete remission (CR) or CR with incomplete blood count recovery within 3 months of treatment with CTL019; consistent with interim ELIANA data

Novartis pivotal CTL019 6-month follow-up data show durable remission rates in children, young adults with r/r B-cell ALL

Jun 23, 2017

83% of patients achieved complete remission (CR) or CR with incomplete blood count recovery within 3 months of treatment with CTL019; consistent with interim ELIANA data
Data evaluating 63 patients demonstrate relapse-free survival and probability of survival in a majority of patients at six months
Advances in CTL019 and ELIANA result from global CAR-T cell therapy collaboration with the University of Pennsylvania
CTL019 is manufactured using cryopreserved leukapheresis which, in the ELIANA trial, enabled the treatment of patients in 25 sites across four continents

Basel, June 23, 2017 - Novartis today announced updated results from the ELIANA clinical trial demonstrating CTL019 (tisagenlecleucel) remission rates are maintained at six months in relapsed/refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL). These data from this pivotal trial of CTL019 show that 83% (52 of 63; 95% confidence interval : 71%-91%) of patients achieved complete remission (CR) or CR with incomplete blood count recovery within three months of infusion. No minimal residual disease (MRD) was detected among responding patients[1]. MRD, which measures the elimination of residual disease in the blood and bone marrow at the molecular level following treatment, is important because it may be an indicator of potential relapse[2]. Results from this study of CTL019 - an investigational chimeric antigen receptor T cell (CAR-T) therapy - will be presented at the European Hematology Association (EHA) Annual Meeting (Abstract #S476; Saturday, June 24, 4:00 PM CEST).

The ELIANA study also showed that the relapse-free probability was 75% (95% CI, 57%-87%; median duration of response not reached) at six months and 64% (95% CI, 42%-79%) at 12 months among responders. In addition, the probability of survival was 89% (95% CI, 77%-94%) at six months and 79% (95% CI, 63%-89%) at 12 months. The median time from infusion to data cutoff was 8.8 months[1].

"The updated CTL019 ELIANA data illustrating early observed response rates that have held steady over six months' time are exciting findings. Durability is an important measure for children and young adults with relapsed or refractory B-cell ALL, and we are truly encouraged by the results of this study," said lead investigator Stephan Grupp, MD, PhD, the Yetta Deitch Novotny Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania (Penn), and Director of the Cancer Immunotherapy Frontier Program at the Children's Hospital of Philadelphia (CHOP).

Forty-seven percent of patients in ELIANA experienced grade 3 or 4 cytokine release syndrome (CRS), a known complication of the investigational therapy that may occur when the engineered cells become activated in the patient's body. CRS was managed globally using prior site education on implementation of the CRS treatment algorithm. There were no deaths due to refractory CRS and no incidents of cerebral edema were reported. Fifteen percent of patients experienced grade 3 neurologic events, with no grade 4 events seen[1].

The ELIANA trial enrolled 88 patients. Of the 88, 16 patients discontinued before infusion and the majority (nine patients) did so due to rapid progression of their disease or deterioration in their clinical status. This reflects the acute and progressive nature of this disease. Of the 16 patients who weren't infused, seven were a result of insufficiently formulated CAR-T cell product. Additionally, five infused patients had not reached three-month follow-up and four patients were pending infusion at the time of data cutoff.

"These positive, updated ELIANA data help us better understand the ability for CTL019 to maintain durable responses in r/r ALL," said Vas Narasimhan, MD, Global Head of Drug Development and Chief Medical Officer, Novartis. "The results, including relapse-free survival findings at six and 12 months, reaffirm our confidence in CTL019 to potentially become an effective treatment for pediatric and young adult patients with r/r ALL in need of more options."

ELIANA (NCT02435849) is the first pediatric global CAR-T cell therapy registration trial, with study enrollment having occurred across 25 centers in the US, Canada, EU, Australia and Japan. The single-arm, open-label, multicenter Phase II study included patients aged three to 23 years who were primary refractory, refractory to chemotherapy after their first relapse, relapsed after second line therapy or ineligible for an allogeneic stem cell transplant (SCT). Patients in the trial received a median of three prior lines of therapy and 59% of patients had a prior SCT.

CTL019 was first developed by Penn and uses the 4-1BB costimulatory domain to enhance cellular responses. In 2012, Novartis and Penn entered into a global collaboration to further research, develop and then commercialize CAR-T cell therapies, including CTL019, for the investigational treatment of cancers.>>>>>>Read more:

tisagenlecleucel (Kymriah), gentherapie, CAR T-Cell therapie, ALL, Acute Lymfatische Leukemie, FDA goedkeuring