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Dr. Peter Martin Calls for Consideration of Patient Preference in Mantle Cell Lymphoma Treatment

SOSS_Peter_Martin3 (1)Citing a pattern of intensive mantle cell lymphoma (MCL) treatment regimens, Dr. Peter Martin – who co-chaired the OncLive State of the Science Summit on May 4, 2017, along with Dr. John Leonard – proposed that physician-researchers become more mindful of patient preferences when determining treatment regimens. He noted that some patients might prefer to receive more broadly accessible treatments and that those decisions may not significantly impact outcomes.

High-dose cytarabine followed by an autologous stem cell transplant, for example, is an effective treatment regimen for patients with MCL, at times inducing remission durations of 10 years. But people with MCL, who tend to be in their mid-sixties, are rarely keen to take the requisite six months away from work in order to receive treatment. Because fewer than 25 percent of MCL patients are eligible for intensive regimens, more practical treatment strategies are needed.

Dr. Martin also stressed the need to find a way to help patients who are destined to have poorer outcomes due to the presence of multiple risk factors as defined in the combined Mantle Cell Lymphoma International Prognostic Index (MIPIc). These factors include: age, white blood cell count, performance status, lactate dehydrogenase (LDH), and Ki67, a marker of tumor cell proliferation.

In a comparison of two clinical trials from the European Mantle Cell Lymphoma Network, one in which patients less than 65 years of age were treated intensively with an autologous stem cell transplant, and another wherein a set of older patients received R-CHOP or fludarabine-based therapy followed by rituximab maintenance, Dr. Martin pointed out that patients with similar MIPIc scores had similar outcomes no matter their treatment regimen.

Dr. Martin highlighted that multiple clinical trials are underway to determine the best drug to combine with the MCL treatment backbone of bendamustine rituximab, to investigate ibrutinib combinations in the relapsed setting, and to evaluate the necessity of intensive treatments like stem cell transplantation.

Watch this OncLive clip for more of Dr. Martin’s thoughts on patient preference:

Is Cutaneous T-Cell Lymphoma Hereditary?

Patients often question whether various lymphoma types run in families, concerned that their own diagnosis may indicate cancer risk for their loved ones, as well. When an inquiry regarding the possibility of genetic predisposition in cutaneous T-cell lymphoma (CTCL) recently came through our clinic, we sat down with expert Jia Ruan, MD, PhD, to break down what we know and what we don’t know about the cause of this rare and complex condition.Dr. Ruan at computer

T-cell lymphomas are a form of non-Hodgkin lymphoma caused by abnormal growth of mature T-cell lymphocytes, a type of white blood cell found in the immune system. In healthy people, T-cell lymphocytes are responsible for attacking foreign antigens and viruses, and aiding B-cell lymphocytes in antibody production – but by the process of clonal evolution, the T-cell lymphocytes mutate and produce abnormal offspring that become lymphoma. When T-cell lymphomas affect the skin, they are known as cutaneous T-cell lymphomas (CTCL).

The most common subtype of CTCL, mycosis fungoides (MF), occurs when malignant cells develop from CD4+CD45RO+ T-lymphocytes and migrate to the skin. Symptoms include scaly and itchy rash-like patches that may thicken over time and develop into a plaque or a tumor. If the cancer then makes its way from the skin to the lymphatic and blood system, MF becomes the more aggressive Sézary syndrome (SS). MF patients with limited skin symptoms do very well with skin-directed treatment, such as light therapy and topical medicines including steroids, while those with more extensive skin involvement or SS often require systemic treatment.

Although mycosis fungoides and Sézary syndrome are the most common types of cutaneous T-cell lymphoma, they are still quite rare, occurring in only 4-5 percent of non-Hodgkin lymphoma cases, with about 3,000 new diagnoses per year. The median age at diagnosis is 50-70, with a prevalence in men and African Americans.

It is in part due to their rarity that doctors and researchers have yet to understand what causes MF/SS. While there is no definitive evidence of familial risk of CTCL, scientists are continually evaluating whether genetics play a role in the disease formation.

Human leukocyte antigen (HLA) genes, which enable the immune system to discern between proteins native and foreign to the body, possess specific variations, or alleles, that are inherited via the family germline and passed through generations. When a certain HLA class II allele (specifically DQB1*04) was measured in a study of six families, each with occurrences of mycosis fungoides in two first-degree relatives, researchers found the allele to appear more frequently in patients than in the healthy control population, thus suggesting an association of the allele with familial MF. It is worth noting, however, that although some familial clusters of MF have been reported, the vast majority of CTCL cases occur without a familial link.

Additionally, deep genetic sequencing (whole exome) of mycosis fungoides samples, in which the patients’ DNA was analyzed to identify genetic variants, revealed recurrent mutations that seem to be acquired during a lifetime, rather than inherited – also known as somatic mutations. Somatic mutations are believed to be a leading factor in the unchecked cell division in most cancers. The examples of alterations included genes involved in: T-cell activation and programmed cell death (apoptosis), NF-κB signaling that plays a role in cell proliferation and survival, remodeling of chromatin (the DNA and proteins from which chromosomes are derived), and DNA damage response.

Without any strong scientific evidence of hereditary susceptibility, CTCL will likely continue to be thought of as an acquired disorder. Those with skin rash who are concerned about risk and family history are encouraged to see a dermatologist, who can refer to an oncologist or other specialist if the CTCL diagnosis is confirmed.

References:

Journal of the American Academy of Dermatology, 2005 Mar; 52: 393–402.

Nature Genetics, 2015 Sep; 47(9): 1011-9.

Dr. John Leonard Comments on CAR T-Cell Therapy Outlook

Dr. John Leonard at State of the Science SummitChimeric antigen receptor (CAR) T-cell therapy is an emerging form of immunotherapy that leverages the strength of a patient’s own immune system to fight cancer.

Immune cells called T-cells are extracted from the patient’s blood and modified in the laboratory to produce chimeric antigen receptors, surface-level proteins that enable the T-cells to recognize and fight targeted antigenic tumor cells. The newly engineered T-cells are then cultivated in a lab before infusion back into the patient’s body, where they further multiply and go to work attacking cells that possess the antigen that they were programmed to destroy.

At the OncLive State of the Science Summit on Treatment of Hematologic Malignancies, Dr. John Leonard, who served as co-chair for the May 4 event, expressed promise in the use of CAR T-cell therapy for patients with acute lymphoblastic leukemia (ALL), in particular.

Dr. Leonard said that in a small group of clinical trial recipients with ALL, the immunotherapy has produced excellent, seemingly durable responses, and more data on CAR T-cells for patients with hard-to-treat lymphomas, like resistant forms of diffuse large B-cell lymphoma (DLBCL), are forthcoming.

While patient selection is a crucial part of interpreting the data and planning for the future, Dr. Leonard believes that the main challenges in the development of CAR T-cell therapy relate to factors of patient selection such age, comorbidities, and aggressive cancers with prohibitive wait times for engineered cells, which can take as long as several weeks depending on the specific CAR product being used.

 “I think there’s no doubt that some patients benefit, but at least in the near-term, it’s going to be a relatively small number of patients that will get CAR T-cells for lymphoma,” he said.

Check out what else Dr. Leonard had to say about CAR T-cells in this video from OncLive: