New NCCN Guidelines to Incorporate Approved New Treatment Options

Two recent FDA approvals have prompted the National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 21 of the world's leading cancer centers dedicated to improving the quality and effectiveness of care provided to patients with cancer, to update the NCCN Clinical Practice Guidelines in Oncology™ for Non-Hodgkin's Lymphomas to include ofatumumab (Azerra™, GlaxoSmithKline) and romidepsin (Istodax®, Gloucester Pharmaceuticals) as treatment options for select patients with two types of Non-Hodgkin's Lymphomas.

Ofatumumab was added to the NCCN Guidelines as a treatment option for relapsed/refractory disease in patients with chronic lymphocytic leukemia (CLL), with and without a 17p deletion. A 17p deletion refers to a chromosomal abnormality involving deletion of genetic material from chromosome 17. Ofatumumab was approved by the FDA on October 27, 2009 for patients with CLL, a slowly progressing cancer of the blood and bone marrow, whose cancer is no longer responding to other chemoimmunotherapy regimens.

In addition, the updated NCCN Guidelines now include romidepsin as a suggested systemic treatment option for patients with mycosis fungoides and Sezary syndrome, two of the most common types of cutaneous T-cell lymphoma (CTCL). On November 6, 2009, the FDA approved romidepsin, a histone deacetylase (HDAC) inhibitor, for the treatment of CTCL in patients who have received at least one prior systemic therapy.

These latest additions come shortly after another recent update to the NCCN Guidelines for Non-Hodgkin's Lymphomas that incorporated the FDA approval of pralatrexate (Folotyn™, Allos Therapeutics, Inc.) for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL).

The NCCN Clinical Practice Guidelines in Oncology(TM) are developed and updated through an evidence-based process with explicit review of the scientific evidence integrated with expert judgment by multidisciplinary panels of physicians from NCCN Member Institutions.

Pralatrexate Approved by FDA as the First Drug for Treatment of Peripheral T-cell Lymphoma

The U.S. Food and Drug Administration (FDA) approved pralatrexate (Folotyn®, Allos Therapeutics), the first treatment for a form of cancer known as Peripheral T-cell Lymphoma (PTCL), an often aggressive type of non-Hodgkins lymphoma.

Pralatrexate, also known as 10-propargyl-10-deazaaminopterin, is a folate analog inhibitor of dihydrofolate reductase studied for the treatment of cancer. The drug candidate was approved under the FDA's accelerated approval process, which allows earlier approval of drugs that meet unmet medical needs. It is approved for patients who have relapsed, or have not responded well to other forms of chemotherapy.

Lymphoma is a cancer of the lymphatic system, which is part of the immune system. There are many types of lymphoma: one type is called Hodgkin's disease, and the rest are called non-Hodgkin's lymphomas. PTCL involves a type of white blood cell called T-cells. It is a relatively rare disease, occurring in less than 9,500 patients each year in the United States.

“Folotyn's approval demonstrates FDA's commitment to the rapid approval of drugs for rare and uncommon diseases,” said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research.

When studying a new drug, it can take time to learn whether a drug actually provides real improvement for patients – such as living longer or feeling better. This real improvement is known as a “clinical outcome.” In 1992 FDA instituted accelerated approvals which allow earlier approval of drugs based on a surrogate endpoint, a laboratory measurement or physical sign that can serve as an indirect or substitute measurement for clinical outcomes.

In the case of pralatrexate, this meant the FDA approved the drug based on evidence that it reduces tumor size, because tumor shrinkage is considered reasonably likely to predict a clinical benefit such as extending the survival of cancer patients. Tumor shrinkage was seen on imaging scans in one study. Of 109 patients with PTCL in the trial, 27% had reduction in tumor size.
To speed the drug's availability, pralatrexate was granted priority review, ensuring a review within six months rather than 10 months for a standard review. The drug was also designated as an orphan drug, which provides a variety of financial incentives to manufacturers that develop drugs for a small number of patients with a rare disorder.

The most common adverse reactions seen with pralatrexate were irritation or sores of the mucous membranes such as the lips, the mouth, and the digestive tract, low platelet cell counts, low white blood cell counts, fever, nausea, and fatigue.

Pralatrexate can harm a fetus. Therefore, women should avoid becoming pregnant while being treated with this drug and pregnant women should be informed of the potential risk.
Patients treated with pralatrexate should take folate and vitamin B12 supplements to reduce mucous membrane irritation.

Pralatrexate is manufactured by Allos Therapeutics Inc. of Westminster, Colorado (USA). As a condition of accelerated approval, Allos will conduct studies to confirm that tumor shrinkage actually does predict that patients will live longer.

For more information:

• EMEA - Public Summary of Positive Opinion for Orphan Designation of
  pralatrexate for the treatment of peripheral T-cell lymphoma
  (nodal, other extranodal and leukaemic/disseminated)

Also read these PubMed abstracts:

• O'Connor OA, Horwitz S, Hamlin P, Portlock C, Moskowitz CH, et al. Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies. J Clin Oncol. 2009 Sep 10;27(26):4357-64. Epub 2009 Aug 3.
• Mould DR, Sweeney K, Duffull SB, Neylon E, et al. A population pharmacokinetic and pharmacodynamic evaluation of pralatrexate in patients with relapsed or refractory non-Hodgkin's or Hodgkin's lymphoma. Clin Pharmacol Ther. 2009 Aug;86(2):190-6. Epub 2009 May 27.
• Marneros AG, Grossman ME, Silvers DN, Husain S, et al. Pralatrexate-induced tumor cell apoptosis in the epidermis of a patient with HTLV-1 adult T-cell lymphoma/leukemia causing skin erosions. Blood. 2009 Jun 18;113(25):6338-41. Epub 2009 Apr 23.
• Rueda A, Casanova M, Quero C, Medina-Pérez A. Pralatrexate, a new hope for aggressive T-cell lymphomas? Clin Transl Oncol. 2009 Apr;11(4):215-20. Review.