RIT takes on NHL

Advanced low-grade non-Hodgkin lymphoma (NHL) typically leads to relapse and death in patients who undergo conventional chemo and radiation therapies, but the emergence of radioimmunotherapy (RIT) in recent years has provided an encouraging alternative.

With the availability of specific monoclonal antibody targets directed at the underlying molecular pathology of the disease, there has been an increased interest in the development of treatment approaches using RIT for NHL. This increase is not only because RIT has a less toxic effect on normal tissues than chemotherapy, causes fewer side effects and requires less recovery time, but also because recent research focusing on personalized treatment approaches has indicated a certain predictability in survival rates.

One newly published study suggests that survival rates can be predicted using quantitative molecular imaging techniques to illustrate the dose uptake of the antibody target. A higher dose avidity proved to be indicative of longer, disease free survival. Despite its uncontestable benefits, however, RIT use is disturbingly not ubiquitous for various reasons. A review of the current published literature concerning RIT trials and treatment approaches, as well as perspective from practicing oncologists and thought leaders in the field shed light on potential reasons for its low utilization.

Molecular imaging guides predictability of progression free survival

Molecular imaging is responsible for facilitating yet another breakthrough in predictive personalized therapy. Newly published research finds quantitative SPECT data that illustrates dose uptake in RIT can be used to predict survival after therapy (J Nuc Med. 19 May 2014).

A team of researchers including Yuni K. Dewaraja, PhD, from the department of radiology at University of Michigan in Ann Arbor, evaluated dosimetry data and stratified curves of dose absorption within tumors to gauge patients’ progression-free survival (PFS).

“The most important finding of the present study is the clearly demonstrated separation of PFS curves when stratified by mean tumor-absorbed dose,” wrote Dewaraja et al. “This result and the robust correlation shown between predicted and delivered tumor-absorbed doses demonstrate the potential for tumor dosimetry–driven treatment planning in radioimmunotherapy of NHL.”

The authors concluded that a higher mean dose to the tumor was strongly predictive of PFS following RIT with I-131 tositumomab, also known as Bexxar. With this in mind, researchers could potentially tailor the tumor-absorbed dose prior to the start of therapy to achieve the best possible results.

“Using SPECT/CT to predict how well a patient will respond is extremely promising,” agrees Mark Kozloff, MD, clinical associate professor of medicine at the University of Chicago. “If you can show that a person is not going to do well, you can change your treatment decision earlier for that patient to something he or she may respond better to.”

NHL incidence rises, new treatments develop

Non-Hodgkin lymphoma, which includes follicular, mantle cell and other slow-growing B-cell lymphomas, is the most common cancer of the lymphatic system. The Lymphoma Research Foundation reports the incidence rate for NHL has nearly doubled since the early 1970s. According to the National Cancer Institute (NCI), there will be approximately 70,000 newly diagnosed cases of NHL in 2014, representing 4.3 percent of all new cancer cases. The NCI also estimates there will be nearly 19,000 deaths from NHL this year. Non-Hodgkin lymphoma ranks ninth in the top ten most commonly diagnosed cancers in the United States, but moves up to number seven on the list of cancers with the highest mortality rates. 

“I treat a number of lymphoma patients in my practice,” says Kozloff. “There are a number of effective treatments used for non-Hodgkin lymphoma. I have treated patients with traditional chemotherapy regimens as well as using radioimmunotherapy and have had success with both.”

Treatment for NHL is largely based on a stratification of patients into groups based on disease subtype (slow-growing or aggressive) and stage, and still relies heavily on traditional approaches based on radiation and chemotherapy. Early-stage localized disease can be effectively managed with radiation and/or a short course of chemotherapy. In cases where the disease is more advanced, patients may need a more significant course of chemotherapy and radiation therapy, and sometimes a bone marrow or stem cell transplant. The standard chemotherapy treatment used for NHL patients is CHOP—Cyclophosphamide, Doxorubicin hydrochloride, Vincristine (Oncovin) and Prednisolone. 

R-CHOP is the aforementioned CHOP regimen with the addition of the naked antibody, rituximab. Monoclonal antibodies target proteins found on the surface of cells. In NHL treatment using rituximab, the antibody targets CD20, a protein found on B cells. It attaches to the B cells and marks them so the patient’s immune system will recognize the marked cells and kill them, while leaving surrounding healthy tissue intact.

A guiding light on NHL diagnosis, staging and follow-up

Molecular imaging techniques such as PET/CT play pivotal roles in the diagnosis, staging and treatment follow-up of patients suffering from NHL. PET/CT is used as standard of care, and is the single most accurate test in the evaluation of NHL. It is used in diagnosis and treatment to determine the exact location of a tumor, the extent or stage of the disease and whether it has spread in other areas of the body. 

Throughout the progression of treatment, treating physicians use PET/CT imaging to actively monitor patients’ immediate response to specific drugs. If one treatment isn’t working well enough, PET/CT imaging can help physicians make an informed decision early on about whether or not to change the approach. After a patient reaches remission, PET/CT is used to manage ongoing care and highlight disease recurrence.

RIT makes a promising entrance

RIT is a unique and still relatively new therapeutic modality that uses a monoclonal antibody carrier labeled with a high-energy, short half–life radionuclide that is delivered directly to tumor sites with little effect on other solid organs. Up until February 2014, there were two FDA approved monoclonal antibodies that targeted CD20 on B cells: Y-90 ibritumomab tiuxetan (Zevalin; Spectrum Pharmaceuticals), Henderson, NV) and Iodine-131 tositumomab (BEXXAR, GlaxoSmithKline, Philadelphia, PA). Both RIT drugs and the naked antibody, rituximab, were evaluated in situations of relapsed disease, a familiar path in oncology therapeutics. However, given the slow growing tendencies of certain forms of NHL such as FL, some patients are placed on a “watch and wait” list instead of actively getting treatment because frequently, the growth characteristics afford that approach. The introduction of these new biological therapies offers patients a potential treatment approach that is minimally invasive in terms of side effects. For physicians, RIT offers a potential new front-line treatment for follicular non-Hodgkin’s lymphoma, and has caused some upheaval in terms of progression of treatment for doctors treating both groups of patients (newly diagnosed and relapsed); the treatment choices include CHOP alone, R-CHOP, R-CHOP followed by RIT, or possibly, RIT as the initial therapy. Several clinical trials were conducted that proved the efficacy of the RIT treatment in halting progression of disease for as long or longer than when treated with traditional treatments first. Using I-131 tositumomab and Y-90 ibritumomab tiuxetan, RIT has led to response rates of about 95 percent as a frontline treatment and 60 to 83 percent in patients who have already been treated previously with conventional therapy, generating new hope for all involved.

Unanswered questions linger

As with any advances in medical treatments, imaging technologies or surgical procedures, for example, physicians need to come together in consensus on how these new approaches, procedures or technologies will be adopted into their current standard operating procedures. RIT is no exception, however, it presents physicians with multiple levels of complexity due to the nature of the disease, the specificity of the treatment, and the overall health of the patient. In an editorial published in the Journal of Clinical Oncology in 2012, Thomas Witzig, MD of the Mayo Clinic in Rochester, Minn., summarizes the various treatment approaches used in the current published research and concludes, “The results of these studies have implications for current care and the design of future studies, but … leaves us with nagging unanswered questions.”

A simple treatment guideline or standard treatment protocol will not suffice. “The evaluation and treatment of each new case of FL is perhaps one of the better examples of the need for personalized medical care. The age, comorbid conditions, bulk, LDH, FLIPI score, presence or absence of symptoms, and patient preference all figure into the equation with the following question: Does my patient need immediate treatment or is he or she a candidate for monitoring without therapy?” Witzig writes.

For patients whose disease stage directs them down the path of “watch and wait,” the debate is ongoing about whether these patients could be treated with RIT as a first line of defense. Studies have shown going with RIT as the primary NHL treatment achieved improved efficacy in terms of PFS (J Clin Oncol. 2013 Jan 20;31(3):308-13).

From the patient’s perspective, there are many who would benefit from, and prefer RIT as a frontline treatment because they are poor candidates for chemotherapy. Unfortunately, RIT is only FDA-approved for patients who have failed other treatments first. 

“Radioimmunotherapy was probably used a lot more when it was first released, and there are still many physicians who use it, but it depends on the patient you’re treating,” Kozloff explains. “I don’t believe there are accessibility issues. It’s not something that’s only available at larger university hospitals. It depends on the physician, and also the individual patient.  I have used it in my practice, for example, when a patient with recurring disease didn’t respond well to other treatments, and the treatment was effective for that patient.”

Little utilization of RIT prompts probe, discontinuation of promising drug

According to the Society of Nuclear Medicine and Molecular Imaging (SNMMI), it is estimated that only 5 to 10 percent of patients who are eligible for RIT are actually receiving it, a statistic that is difficult to believe, considering the success of the treatment in trials in the published literature. So what’s behind the low utilization?

“It’s not on the forefront of physician’s minds as an alternative treatment—they may not be familiar with the most current literature; and while the treatment is still relatively new, some of the literature is dated,” Kozloff suggests. “It hasn’t been directly compared to other treatments. More importantly, since its approval, other new drugs have been developed for the treatment of NHL. So, while RIT is promising, it’s not the only game in town. I am currently participating in a study where, using a pill, we’re seeing lymphoma in the patient one day and no disease the next. As a physician, what would you do? Despite the encouraging results of RIT, there are a lot of opportunities for patients to participate in current clinical trials that may hold even better potential. Additionally, one always has to be sensitive to reimbursement; you have to consider the treatment compared to other effective treatment options that may be available.” 

Survey says RIT is not an obvious choice

A survey published in May 2011 in the Journal of Nuclear Medicine investigated the opinions and patterns about the use of RIT by nuclear physicians, affiliated researchers, nuclear medicine technologists, and radiation oncologists and to identify possible barriers to the use of RIT.

Validating the—until now—unsubstantiated lackluster RIT utilization, nearly 40 percent of survey respondents said they do not treat NHL patients using RIT. Respondents who did not administer RIT for NHL also thought it took too much time to administer RIT, and had concerns about the dosimetry procedure and radiation safety. Though RIT was viewed positively in general by the survey base, the results indicated a preference to treat patients with nonradioactive compounds, rather than refer patients out for RIT. The treatment can only be prepared and administered by pharmacists, oncologists and hematologists who are licensed to mix/administer radiopharmaceuticals. Those are a tiny minority of all the practicing pharmacists/oncologists/hematologists, so they must refer their patients to another practice to get RIT if they are not licensed themselves. (J Nucl Med. 2011 May;52(5):830-8).

When the business side fails to thrive

Due to lack of use, manufacturer GlaxoSmithKline (GSK) discontinued production and sales of its RIT iodine-labeled antibody, BEXXAR, in February 2014. Fewer than 75 patients in the U.S. received BEXXAR in 2013, according to a GSK spokesperson at the time of the announcement. BEXXAR had been approved for use by the FDA for about a decade, and usage peaked in 2006, but sales had dropped 30 percent annually since then, according to GSK.

Many physicians were disappointed with GSK’s decision to discontinue BEXXAR. In an article published on Xconomy.com, Anas Younes, the chair of the lymphoma service at Memorial Sloan-Kettering Cancer Center in New York writes: “It’s a shame to see this being pulled off the market. If you look at this drug, it has about a 70 percent response rate, in one shot.”

Watch and wait

Zevalin continues to be produced and sold in the U.S., and antibodies that target other cells are currently in development, but it remains to be seen whether RIT will gain momentum, armed with an ever-increasing clinical body of evidence to support widespread use and adoption as a frontline treatment for NHL.