First-line Treatment of Stage III or IV Classical Hodgkin Lymphoma Approved

First-line Treatment of Stage III or IV Classical Hodgkin Lymphoma Approved

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Highlights:
  • Previously untreated stage III or IV classical Hodgkin lymphoma can now be treated with brentuximab vedotin (Adcetris) in combination with chemotherapy
  • Patients who took the combination of Adcetris plus chemotherapy of adriamycin (doxorubicin), vinblastine and dacarbazine were able to survive for a longer period without the disease than those who received the standard treatment
The US Food and Drug Administration (FDA) has approved the antibody-drug conjugate, Adcetris as a first-line treatment in stage III or IV classical Hodgkin lymphoma in combination with chemotherapy.

Adcetris - brentuximab vedotin

Adcetris is an antibody-drug conjugate, that consists of the chimeric monoclonal antibody brentuximab connected via linkers to the antimitotic (an agent that stops cell division) known as monomethyl auristatin E / MMAE. Vedotin refers to MMAE plus its linking structure.
First-line Treatment of Stage III or IV Classical Hodgkin Lymphoma Approved

Brentuximab, also known as cAC10 primarily targets the cell-membrane protein CD30 present on lymphoma cells. MMAE is highly toxic and hence stably linked to brentuximab so that the drug is not easily released from the antibody in physiological conditions lest it imparts its toxicity to healthy cells. This binding also ensures that the dosage of the drug is maintained till it enters the target cells.

CD30 is predominantly present only on diseased cells and rarely on normal tissues. Once the conjugate reaches the tumor cells, the antibody cAC10 part binds to CD30 on the surface of malignant cells. The conjugate is then internalized by endocytosis and forms a vesicle which fuses with lysosomes. MMAE is rapidly and efficiently cleaved, releasing the drug into the tumor environment.

Before this trial, Adcetris was approved by the FDA to treat cHL after relapse, cHL after Stem cell transplant when a patient is at high risk of relapse or progression, and for systemic anaplastic large cell lymphoma (ALCL) and primary cutaneous ALCL after failure of other treatments.

ECHELON-1 Phase 3 clinical trial

A total of 1334 patients who had not been previously treated for Hodgkin's lymphoma enrolled in the trial. They were assigned to 2 groups and received an average of six 28-day cycles of treatment.
  • A group of 664 patients received A+AVD (Adcetris plus chemotherapy of adriamycin (doxorubicin), vinblastine and dacarbazine)
  • The second group of 670 patients received the standard-of-care / chemotherapy-only regimen (AVD plus bleomycin, also known as ABVD)
The primary endpoint was progression-free survival (mPFS) which takes into account the time taken for
  • The disease to progress
  • Death to occur
  • New therapy to be initiated in patients with incomplete response

Results

  • Those treated with A+ AVD were 23 percent less likely to experience disease progression, death or begin new therapy compared to those receiving ABVD
  • There were 82 percent of patients in the A+AVD who did not experience disease progression, death or begin new therapy compared to 77 percent in the ABVD group
  • Adverse events like low levels of white blood cells (neutropenia) and nerve damage causing numbness or weakness in the hands and feet (peripheral neuropathy) occurred more commonly in the A+AVD group than in the ABVD group.
Neutropenia and peripheral neuropathy are listed among the common side effects of Adcetris along with anemia, nausea, fatigue, diarrhea and fever.

Due to the risk of neutropenia, patients taking Adcetris plus chemotherapy are recommended to take a growth factor, G-CSF as a preventive treatment to make the bone marrow produce more white blood cells.

Serious risks of Adcertis include allergic or infusion-site reactions, damage to the blood, lungs, and liver, metabolic abnormalities and severe skin and gastrointestinal complications.

Adcetris has a boxed warning that highlights the risk of John Cunningham virus infection that can result in a rare but potentially fatal brain infection known as progressive multifocal leukoencephalopathy or PML.

"Today's approval represents an improvement in the initial treatment regimens of advanced Hodgkin lymphoma that were introduced into clinical practice more than 40 years ago," said Richard Pazdur, M.D., director of the FDA's Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. "This approval demonstrates our commitment to approving advancements in treatment that give prescribers and patients' different options for care."

Classical Hodgkin Lymphoma (cHL)

Hodgkin lymphoma or Hodgkin disease is a type of lymphoma, a cancer that begins in the lymph system, which is part of the immune system. Lymphoma can begin almost anywhere in the body and can spread to nearby lymph nodes. The other main type of lymphoma is the non-Hodgkin lymphoma. Most people with Hodgkin lymphoma have the classical type that is characterized by large, abnormal lymphocytes (a type of white blood cell) in the lymph nodes called Reed-Sternberg cells. If early intervention is given, patients with Hodgkin lymphoma can usually experience long-term remission.

As of 2018, the number of new cases of cHL in the United States is about 8,500, and the number of deaths from this cancer is about 1,050.

References:
  1. FDA expands approval of Adcetris for first-line treatment of Stage III or IV classical Hodgkin lymphoma in combination with chemotherapy - (https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm601935.htm)
  2. Brentuximab vedotin - (https://en.wikipedia.org/wiki/Brentuximab_vedotin)
Source: Medindia
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