Bruce D. Cheson, MD; Myron S. Czuczman, MD


June 16, 2014

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Bruce D. Cheson, MD: Hello. I am Bruce Cheson, Deputy Chief of Hematology/Oncology and Head of Hematology at Georgetown University Hospital and the Lombardi Comprehensive Cancer Center in Washington, DC. Welcome to this edition of Medscape Oncology Insights in hematologic malignancies, coming to you live from the 2014 annual meeting of the American Society of Clinical Oncology (ASCO®).

Joining me today is Myron Czuczman, Professor of Medicine at the State University of New York at Buffalo, and Professor of Oncology and Chief of the Lymphoma/Myeloma Section at the Roswell Park Cancer Institute in Buffalo, New York. Which presentations do you think were outstanding at the lymphoma section?

Eye Toxicities Accompany New CD19 Conjugates

Myron S. Czuczman, MD: There were a couple of very interesting presentations[1,2] about antibody-drug conjugates, and in particular for the CD19 target, which is broadly expressed on B-cell malignancies, but not on the progenitor cells, stem cells, or plasma cells. Of the 2 presentations, one of the agents was SGN-CD19A,[1] which used not quite monomethyl auristatin (MMA) but MMAF, which is basically still a tubulin toxin.

This study was opened for patients with relapsed/refractory B-cell malignancies, but most of the patients were relapsed large cell lymphoma patients. The prognosis for these patients is dismal. They have perhaps a 4-month survival if they fail upfront therapy. There were 37 of these individuals, who were not candidates for transplant or had failed an autologous stem cell transplant.

There was a 30% objective response rate, including 16% complete response and 14% partial response rates. They saw visual changes, which is quite interesting because some of these novel agents are showing toxicities that we would not have expected on the basis of other trials. They demonstrated that patients developed microcysts of the cornea, but they were reversible. They were thinking about premedicating patients in the future with steroid drops.

The other CD19 conjugate, coltuximab ravtansine, is an anti-CD19-DM4 conjugate, a different drug.[2] Most of these agents are tubulin toxins and they lead to apoptosis. CD19 is the target because when CD19 binds to antibody, it internalizes whatever is on it. In the group of patients with relapsed/refractory large cell lymphoma, 41 were evaluable, and they saw a 44% objective response rate with about a 15% complete response rate. This is just the beginning; it's just a signal. Here again, about 20% of the patients experienced eye toxicities, so that is a little strange as a common thread. We don't know why, because there is no CD19 within the chamber of the eye. We are going to be seeing further development of these antibody-drug conjugates, not only in chronic lymphocytic leukemia and in follicular lymphoma, but now data are emerging that in large cell lymphoma they will have some potential as well.

SEXIE Results of Elderly Men on Rituximab

Dr. Cheson: Those were interesting, but was there anything at the session that was really "sexy"?

Dr. Czuczman: Yes. A trial was presented by Michael Pfreundschuh and the German Large Cell Lymphoma Research Group.[3] It was called "Increased Rituximab Doses and Effect on Risk of Elderly Male Patients With Aggressive CD20+ B Cell Lymphomas: Results From the SEXIE-R CHOP Trial." There have been some investigations by German researchers, led by Michael Pfreundschuh, that showed that older male patients, perhaps because they tend to be overweight, don't maintain a high enough blood level of rituximab compared with women, who do better.

One hypothesis is that because women maintain higher levels, they do not metabolize it or clear it as quickly. So the idea was that a higher dose (instead of 375 mg, using a 500 mg/m2 dose) or 8 loading doses very early (not spreading them out over a period of 6-8 cycles of R-CHOP14) might result in better outcomes. There appears to be some difference, but it didn't look earth-shattering. When I looked at the numbers, they weren't statistically significant with respect to improvement; they were very similar.

We were always taught that when rituximab is given, it binds to its target, and the excess is in the circulation. We are not seeing that excess in these elderly men, but we don't know what to make of that. Is that just an observation or is it a cause-and-effect phenomenon? Future ideas include giving even higher doses of rituximab and monitoring drug levels.

Dr. Cheson: Does the difference make sense?

Dr. Czuczman: The data are not overwhelming. I would not start giving more rituximab to my elderly male patients than I am giving them right now.

Blood Test to Identify Minimal Residual Disease?

Dr. Cheson: We cure most patients with large cell lymphoma. Whereas PET scan is a good predictor of who is not going to do well, there was an interesting study from Stanford[4] and Australia investigators about a novel assay that might be a predictor of minimal or molecular residual disease.

Dr. Czuczman: That was very interesting. It was presented by David Kurtz[4] and was titled "Noninvasive Monitoring of Cellular versus Acellular Tumor DNA From Immunoglobulin Genes for Diffuse Large B-Cell Lymphoma." It was a proof-of-principle study; it did not involve a large number of patients. The idea was whether they could monitor clonotypic circulating DNA in the bloodstream from an original tumor. By looking at the immunoglobulin genes, they found it was more common to be able to take out a section and identify an area of heavy chain gene rearrangement. If a marker can be identified, we could study the peripheral blood, using either leukocytes or plasma. Plasma seems to be more informative than leukocytes. This method may not be good in predicting a cure, but it appeared that when looking for molecular residual disease, even before you have a positive PET or CT scan, if you see a positive signal in the serum with respect to the heavy chain rearrangement in the clonotypic genes, and if they find the DNA, you can predict that a good number of those patients would relapse.

This can be validated in a larger number of patients prospectively. It would be very interesting if we will be able to use a simple blood test to monitor our patients for risk for relapse, and maybe we can do away with a lot of the standard CT and PET scans that we are doing today.

Dr. Cheson: It would be nice to know that if you reacted to a positive test, it could make a clinical difference.

PET Project: Assessing Response in Follicular Lymphoma

Dr. Cheson: Speaking of PET scans, Judy Trotman[5] presented an interesting conglomerate analysis of 3 trials supporting the value of PET scans in assessing response in follicular lymphoma.

Dr. Czuczman: They did a study in which they used data from PRIMA, FOLL05, and the PET Folliculaire studies, and there was a fair number of patients (246). Most of the patients had received R-CHOP.

Dr. Cheson: It was 75%, wasn't it?

Dr. Czuczman: Yes. They have additional trials that will look at R-bendamustine and other drugs that are commonly used now. It looked as though the PET scan was predictive of progression-free survival, the difference being that if the patient was PET-negative, the 4-year progression-free survival was 63%, but in patients who were PET-positive, it was only 23%. The 4-year overall survival was 97% if patients were PET-negative but only 87% if patients were PET-positive.

Moreover, it was more meaningful in patients whose Follicular Lymphoma International Prognostic Index(FLIPI)indicated 3-5 risk factors; these patients had PET positivity about 23% of the time. Patients whose FLIPI had only 1-2 risk factors had only a 30% chance of being PET-positive. So it may be more valuable in patients who had an intermediate- or high-risk FLIPI score. The question is, if the patient is PET-positive after completing the induction therapy, could we change the natural history by giving further therapy? Can we convert patients to PET-negative? That question has not been answered yet but will lead to the logical next step.

Dr. Cheson: Last week, a patient's PET scan for follicular lymphoma was rejected by his insurance company. I started telling the physician from the insurance company of the results of all of these trials, but he still wouldn't buy it. Now new staging and response criteria are coming out, the so-called "Lugano classification," which will be in the Journal of Clinical Oncology shortly. It includes all FDG-avid lymphomas as subject to PET for staging and for restaging.

Unconvincing Results in Mantle Cell

Dr. Cheson: That takes care of large cell and follicular lymphoma. An abstract was presented by Franco Cavalli[6] on mantle cell lymphoma. What do you think?

Dr. Czuczman: It's very interesting. It was a randomized phase 3 study looking at patients receiving either R-CHOP or R-CHOP without the vincristine and replacing vincristine with bortezomib. They called it VR-CAP. These are patients with newly diagnosed mantle cell lymphoma who were ineligible for bone marrow transplantation. Several trials have looked at these proteasome inhibitors with respect to their activity in cells that are driven by nuclear factor-kappaB. Several trials in large cell lymphoma are looking at the combination of bortezomib and R-CHOP. This trial was looking at mantle cell lymphoma because bortezomib is already US Food and Drug Administration (FDA)-approved in the relapsed/refractory setting.

This was looking at whether we can move bortezomib to the upfront setting. Even though there was an increase in toxicity with respect to platelet count suppression and a need for platelet transfusions, there appeared that in a study of almost 490 patients, progression-free survival was basically doubled. It was 14 months with R-CHOP, and patients who received R-CHOP with bortezomib had a 25-month progression-free survival. That was significant. The percentage of complete responses was 42% with R-CHOP, but with VR-CAP, complete responses occurred in 53% of the patients. Overall survival was 56 months with R-CHOP upfront in mantle cell lymphoma. This endpoint was not reached with VR-CAP.

The toxicity was significant, and many of the patients are elderly, so there was no rituximab maintenance therapy. It's not clear whether this is the way to go. The drug was given on days 1, 4, 8, and 11, so the audience asked about using a subcutaneous administration, perhaps with less toxicity, and considering a weekly dose instead of giving it 4 times in 2 weeks. Those questions are unanswered, but the study gives us a signal that it might have better activity.

Dr. Cheson: This is with R-CHOP as a comparator, and in the randomized trials R-bendamustine has been better, so the jury is still out. Did any other data resonate with you?

Ibrutinib Results RESONATE in Refractory CLL

Dr. Czuczman: Perhaps the RESONATE trial?[7] Patients with refractory chronic lymphocytic leukemia were randomly assigned to receive either ofatumumab (an FDA-approved, second-generation CD20 antibody) or ibrutinib. Can you guess which one did better?

Dr. Cheson: It's why we used to use chlorambucil, because it was easy to beat up on it.

Dr. Czuczman: Ofatumumab was FDA-approved for a reason. We now realize that ofatumumab had activity in the blood and marrow, but it wasn't evaluated with respect to bulky or nodal disease. Now we are looking at ibrutinib, which has a major advantage in that it starts working in patients with bulky nodal disease and hepatosplenomegaly, and then it begins to clear up the disease within the blood. It is not surprising that there was about a 40% objective response rate, including some patients with minimal residual disease clearing with ibrutinib, compared with a 4.1% response rate for ofatumumab.

Dr. Cheson: Ofatumumab was approved with a response rate of 45% or 50%, and this randomized trial was 4.1%.

Dr. Czuczman: It is because we are measuring nodal disease.

Dr. Cheson: We are doing a better job of assessing response.

Thank you for joining us in this edition of Medscape Oncology Insights. This is Bruce Cheson, reporting from ASCO 2014.


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