Monitoring Minimal Residual Disease in Lymphoma: The Italian Experience

Paola Ghione, MD
paola-ghione
Dr. Ghione is a visiting hematology fellow from Torino, Italy who is working with the Weill Cornell Lymphoma Program for six months.

Minimal residual disease (MRD) detection refers to a group of techniques used to find a very small amount of disease, normally undetectable with imaging or clinical exam. Usually, this detection is performed after treatment and, in many cases, is predictive of outcomes such as whether patients will relapse, and how quickly this might happen. Often, the reappearance of MRD can anticipate recurrence of lymphoma before it becomes clinically evident. In other hematologic disorders, such as acute leukemia and chronic myeloid leukemia, MRD is used in standard clinical practice to monitor disease status or to evaluate response to treatment. In the setting of lymphoma, measurement of MRD is still considered experimental, but a lot of research is taking place around the world to find the best way to perform it.

Our laboratory in Torino, Italy, run by Dr. Marco Ladetto and Dr. Simone Ferrero, leads many MRD projects for lymphoma and is part of the EuroMRD Network, an institution born in Europe to standardize MRD techniques. Currently, we look for tumor-specific DNA alterations in the blood before and after treatment using a technique called Allele-Specific Oligonucleotide (ASO)-PCR. Depending on how much tumor DNA is present in the blood, we can figure out the relative amount of tumor left in the body. Unfortunately, ASO-PCR requires an expert laboratory team, and the method is expensive and time-consuming, which makes it hard to use outside of specialized settings. In addition, it seems more reliable if performed directly on bone marrow aspirate (blood from the interior of the bone) than peripheral blood (coming from a normal vein), making it less attractive to clinicians and people with lymphoma.

New techniques that can speed the procedure and reduce the cost are being evaluated. For example, the droplet digital (dd)-PCR is interesting because it is faster and uses less material (i.e., requires less blood for the test). Another interesting method is Next Generation Sequencing (NGS), which allows the detection of several different DNA mutations at once. NGS analysis of cell-free circulating DNA(cfDNA) (the DNA present in circulating blood outside the cells) could give a lot information. Studying cfDNA from the blood could give us a more accurate picture of the lymphoma that in theory could be even better than studying DNA derived from an open biopsy at one site of disease. This is also sometimes referred to as a liquid biopsy. The reason it might be better is that the circulating cfDNA could show us mutations coming from all the sites where the tumor is actively growing, not only the one site from which the open biopsy is taken.

In Italy, although MRD is not yet available in routine clinical practice for treating lymphoma, it is being tested in some innovative clinical trials to guide treatment decisions. In some studies MRD negativity at the end of treatment is the primary goal, while in others reappearance of MRD prompts a preemptive approach. As an example, if MRD reappears when the person is off therapy, we can give a short re-treatment in order to avoid clinical relapse. In one of our clinical trials, evaluation of MRD has been used to rule out the presence of lymphoma in the cells collected prior to autologous stem cell transplantation.

Measurement of MRD has a lot of potential uses, and experience from other diseases proves that it can be practice changing. The challenges provided by more than 50 different lymphoma subtypes as well as the rapid evolution of new laboratory techniques have delayed the adoption of a universal test for MRD. In the near future, however, we expect to see MRD analysis in standard clinical practice everywhere.


FDA Approves First-Ever Targeted Marginal Zone Lymphoma Treatment

On January 19, 2017, the United States Food and Drug Administration (FDA) approved ibrutinib to treat patients that have received at least one line of prior therapy for marginal zone lymphoma (MZL), a type of non-Hodgkin lymphoma (NHL).

MZL is an indolent B-cell lymphoma that accounts for 5-10% of all lymphomas and lacks a standard of care. Current MZL treatments include anti-CD-20 antibody therapy (e.g. rituximab) or chemotherapy. However, ibrutinib is the first-ever treatment to specifically be approved for MZL.

Ibrutinib works by inhibiting Bruton’s tyrosine kinase (BTK), an enzyme responsible for transmitting pro-growth and survival signals from the surface of a cell to its nucleus. In this way, ibrutinib may interfere with chronic stimulation arising from inflammation in the tumor microenvironment; thus slowing the growth of B-cells.

The Weill Cornell Lymphoma Program is proud to have played a role in the phase 2 trial — the largest trial to date for people with previously treated MZL of all subtypes —leading to FDA approval for ibrutinib. Roughly half of all patients had a significant response to ibrutinib, with some degree of tumor shrinkage observed in almost 80% of all patients in the trial. Roughly one-third remained on treatment 18 months after beginning treatment.

The most common side effects included fatigue, diarrhea, and anemia. These side effects were manageable, and consistent with previous research, although some cases required the discontinuation of treatment with ibrutinib.

Results from this study support the use of ibrutinib as an effective well tolerated chemotherapy-free option for the treatment of previously treated MZL. However, some questions remain. MZL is a heterogeneous group of lymphomas, and it is unclear which subtypes might respond best to ibrutinib. With only half of all previously treated MZL patients responding to ibrutinib, improvements might be realized by combining ibrutinib with other drugs and/or using it earlier in the treatment of MZL.

At Weill Cornell, we are currently studying ibrutinib in combination with the immunotherapy drug durvalumab in people with previously treated indolent non-Hodgkin lymphoma, including MZL.


Living with Lymphoma: Updates in Treatment

Join us for a special event as the Lymphoma Program faculty host a discussion on the latest updates in the treatment of lymphoma with our partners at the Leukemia & Lymphoma Society. Details are below. To attend the event you must register here with the LLS.

patient-edu-flyer-digital-161025

 

 


Dr. Kristy Richards and Comparative Research for Lymphoma

Splitting her time between the main Cornell campus in Ithaca and the Weill Cornell Medical campus in New York City, Dr. Kristy Richards has developed a unique plan to research new lymphoma treatments. Lymphoma is a common form of cancer in humans and also the most common form of cancer found in dogs. So as human oncologist, Dr. Richards thought that treatments for canine patients could lead to advances in the treatment of human lymphoma patients,

“Dog and human lymphoma patients share many biological similarities, as well as the unfortunate fact that rates of the disease are rising for both species. “We don’t know why this is,” Richards says. “It could be something in the environment, which both dogs and humans share. So in a way, dogs could be a canary in the coal mine.”

“Richards plans to test cutting-edge approaches such as immunotherapy, which harnesses the body’s natural defenses to fight off cancer cells, in dogs suffering from lymphoma. This September, she was awarded a supplement grant from the National Cancer Institute, in partnership with the Roswell Park Cancer Institute in Buffalo, to further explore canine immunotherapy with veterinary patients that come to the Cornell University Hospital for Animals.”

The full article can be read here. More information about Dr. Richards work and the practical benefits so far accrued for both two and four legged lymphoma patients can be found in the below video.


Join a Twitter Chat with Dr. John Leonard

Get your questions ready because two weeks from now Dr. John Leonard will join the Lymphoma Research Foundation for a Twitter chat to answer questions about the latest treatment options and research for lymphoma. Just follow the hashtag #EdForumChat on Saturday, October 29th at 1:45pm.

Full details are below.

edforumchat_flyer_description


Taking a Pie in the Face for Lymphoma

The results are in and the first annual Pie-in-the-face event was a smashing success! We raised $3500 for the  The Leukemia and Lymphoma Society as part of the 2016 Light The Night campaign.

Obviously the highlight of the event was Lymphoma Program Director, Dr. John Leonard receiving a pie in the face from his esteemed colleague Dr. Peter Martin. Look at that fakeout!

Asked about his pie throwing heroics after the event Dr. Martin said, “Sometimes this job requires us to make tough decisions, like should I throw the pie with my left hand or right hand? At first I was nervous about throwing a pie at my boss…just kidding, it was awesome.”

http://gph.is/2cRTvNNgiphy

More pics of the event can be found here. Thanks to the Meyer Cancer Center & Englander Institute for Precision Medicine for organizing this event. Additional donations can be made on our Light the Night team page.


Who Would You Pie?

leonard-pie

The Meyer Cancer Center & Englander Institute for Precision Medicine are hosting a friendly competition to raise money for The Leukemia and Lymphoma Society as part of the Light The Night campaign.

Pick who you want to get pied by donating to their “pie fund”. If the fund reaches its $250 goal, that person will get pied. The biggest donors get the honor of launching the pies.

…HOWEVER…

The pie recipients can save themselves by doling out their own dough, matching the money raised in their fund. They can then designate someone else to get the pie.

The date and site

Wednesday, Sept. 21 at 5:00 P.M.

Belfer Research Skylight Terrace (2nd floor)

So let’s make the stakes as high as possible, and have some fun while we are at it!