Dr. Richard Furman Examines Future of CLL Risk Assessment

At OncLive’s State of the Science Summit on Hematologic Malignancies, Dr. Richard Furman, director of the Chronic Lymphocytic Leukemia (CLL) Research Center at Weill Cornell Medicine, discussed how medical oncologists should be using prognostic markers to make risk assessments in order to determine individualized treatments for their patients with CLL.

SOSS_Richard_FurmanDr. Furman noted that current CLL therapies are effective, but they often lead to complications. CLL patients treated with standard chemotherapy drug combination fludarabine, cyclophosphamide, rituximab (FCR) are often prone to developing treatment resistance or Richter’s transformations (RT), in which their CLL transforms into a more aggressive diffuse large B-cell lymphoma (DLBCL). They may also succumb to infectious complications, adverse events, or secondary malignancies.

Because of the risks associated with FCR treatment, Dr. Furman suggested a movement toward treatment agents that are not as toxic, such as ibrutinib. But even with ibrutinib, patients can develop resistance to treatment. For example, in cysteine481-to-serine mutations, the amino acid in Bruton’s tyrosine kinase (BTK) that ibrutinib binds to is changed from a cysteine to a serine, prohibiting ibrutinib from continuing to bind. This results in inadequate ibrutinib coverage and enables CLL cells to escape treatment and survive.

According to Dr. Furman, a large number of CLL patients will have excellent responses and enjoy very long progression free survivals. What is important is to identify those who will not and to devise a treatment strategy that can improve their outcomes. Currently, interphase FISH (demonstrating deletion 11q or 17p), NOTCH1 mutation, or certain V genes help identify those patients who will progress on currently novel agents or have a risk of Richter’s transformation. In the future, stimulated karyotyping, or evaluating changes in the chromosomes after stimulation of the CLL cells, will also be of great importance.

The CLL team at Weill Cornell Medicine and NewYork-Presbyterian is currently investigating an early intervention trial in which patients at risk of developing Richter’s transformation or resistance to BTK inhibitors receive intervention before the mutations have a chance to develop. Our team is also looking into the use of combination therapies, such as ibrutinib and venetoclax, in treatment of CLL patients.

Additionally, Dr. Furman pointed out that prognostic markers are dependent upon the setting in which they’re used. Those used for FCR, such as minimal residual disease (MRD), don’t necessarily apply to ibrutinib. He said that prognostic markers are traditionally based upon responses, but we now need to start looking at them from a progression-free survival (PFS) perspective.

To hear more from Dr. Furman about the outlook of CLL prognostic markers, check out this short OncLive clip:

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.