Lymphoma Patients Being 'Hit' With Aggressive Disease

September 5, 2014

Article

She came in with her husband for a consultation, and to receive information on potential clinical trials.

The patient had the indolent (slow-growing) kind of lymphoma that needed a new form of treatment every couple of years. The bulge of lymph nodes in her groin was now causing pain. She was started on an experimental tyrosine kinase inhibitor, which is now approved for indolent lymphomas, and was doing well for a period of time. Upon returning from a trip, she became fiercely weak and was found to have stopped making most of her blood cell lines. Her bone marrow biopsy showed large lymphoma cells that are generally associated with the aggressive kind of lymphoma. This demonstrates how indolent lymphomas can become much more serious.

With indolent lymphomas, there have been many new advances that provide treatment options for patients who have this type of lymphoma. But, for the patient with aggressive lymphoma that must be treated immediately, treatment options have not advanced as rapidly. In fact, after the addition of rituximab to CHOP, the next advance would be a rearrangement of basically the same drugs by administering them in a different order which is the regimen EPOCH .

The targeted therapy rituximab was probably the first real advance in treatment, but there have been numerous agents, with the most recent being perhaps idelalisib, a PI3KÎ´ inhibitor. There is a touch of irony here since the favored treatment with most indolent lymphomas is a "wait and watch" approach whereas aggressive lymphomas need to be treated urgently and emergently in some cases.

The treatment protocol for the largest group of lymphoma (diffuse large B-cell), which happens to be an aggressive subtype, consists of CHOP plus rituximab, and then a few salvage regimens and autologous transplant if or when there is a relapse. In the age of rituximab, survival has increased markedly-so much so that older prognostic indicators are no longer accurate, and depending on the prognostic group, the vast majority is surviving for many years to decades. This improvement in survival is mostly due to rituximab, early transplant, diligent follow-up, and supportive care.

Not all aggressive lymphomas are considered equal. Although the treatment is not as sophisticated like in many targeted therapies for indolent lymphomas, there are certain sophisticated markers of aggressiveness which are thought to drive the lymphoma forward. The markers are gene rearrangement or protein expressions involving MYC, BCL2, or BCL6 genes, and when two are positive, it is known as a "double-hit" lymphoma, and when three are positive, it is known as a "triple-hit" lymphoma. The lymphoma morphology is usually diffuse large B-cell lymphoma (DLBCL). These various "hit" lymphomas were historically considered very rare, but the gene rearrangements or protein expressions were infrequently tested in the past.

The fact that our patient transformed from an indolent lymphoma and had a dramatic presentation with no blood cell production, led the inpatient hematology team to obtain the cytogenetic information needed to diagnosis her with a triple-hit lymphoma. Thankfully, she was able to quickly get a bone marrow transplant and has now been free of disease for over a year and is doing wonderfully. Were it not for a transplant, she would not have been able to survive the disease course after her transformation since there are no additional adequate therapies.

This case highlights some of the key issues even with diseases that have benefited from targeted therapies. Often, there is a subgroup of patients who will not respond or do as well clinically, so it is important to direct research efforts to these areas. Secondly, the role of using tumor or biomarkers as a way to characterize various subgroups within a disease population is incredibly important. A couple of months later, we saw a similarly dramatic presentation of a female patient with newly diagnosed lymphoma. She did not receive timely treatment since she was trying to establish herself as a patient in the United States. Her cytogenetic testing revealed the same triple-hit lymphoma abnormality, but she was not able to benefit from transplantation given the lateness and seriousness of her disease progression.

I am not sure of the best way to help patients psychologically deal with these sorts of dilemmas in cancer medicine. We don’t have adequate treatment regimens for all of the variations within a common disease theme. It's unsettling to screen for something for which there is not a dedicated treatment-which may lead to a worse prognosis. At our institution, we now routinely screen for these hit lymphomas in any patient who has the associated lymphoma morphology.

Perhaps, one way to help patients is to assure them that we are assessing for these kinds of biomarkers early on. It certainly takes a tremendous amount of courage and trust for a patient to undergo a transplant based on molecular findings and her physicians’ recommendation. It is also much easier to assure patients about your prescribed testing when you know there will be an acceptable form of treatment available. The catch-22 here is that on a larger scientific level, attention needs to be drawn to these areas where it turns out that hit lymphomas are not quite as rare as what was first thought. The more we describe the prevalence, the more pressure there is to find better treatment options for these aggressive subtypes.

Disclosures:

Daniel McFarland is a clinical fellow in hematology and medical oncology at Mount Sinai Medical Center in New York City and a member of the American Psychosocial Oncology Society. He is dually trained in internal medicine and psychiatry. As part of the American Psychosocial Oncology Society, Dr. McFarland is currently collaborating with Dr. Jimmie Holland at Memorial Sloan Kettering Cancer Center in an effort to bring psychosocial issues to the attention of oncologists as they treat patients in the new era of personalized medicine. The views expressed are his own.