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PER® Chemotherapy Foundation Symposium (CFS)

In May 2014, ASCO issued guidelines recommending the administration of adjuvant tamoxifen for 10 years in women with stage I-III hormone receptor (HR)-positive breast cancer, based on data from the collection of 5 clinical trials. This recent issuance, along with other recommendations and guidelines, served as the backdrop for the keynote address, titled “Past as Prelude: Further Dilemmas in Hormonal Treatment of Early Breast Cancer,” delivered by Norman Wolmark, MD, during the Chemotherapy Foundation Symposium on Wednesday, November 5.

“I think it’s very worthwhile reviewing the dilemmas we now face in the adjuvant therapy of breast cancer, particularly from the trials that have emerged in the last two years,” said Wolmark, a professor and chairman of the Department of Human Oncology at the Allegheny University of Health Sciences and serves as chairman and principal investigator of the National Surgical Adjuvant Breast and Bowel Project (NSABP). “This dilemma has become exacerbated. The ovary is an enigma—how are we going to address it?”

The ASCO guideline was based on findings from the large aTTom and ATLAS phase III trials, among others. In the aTTom study, women continuing tamoxifen for 10 years had a 25% lower recurrence rate and a 23% lower breast cancer mortality rate compared with those who stopped at 5 years. In the large ATLAS trial, there was a 2.8% reduction in mortality risk for continuing treatment with tamoxifen and the rate of recurrence for those receiving tamoxifen for 10 years was 25% less compared with those receiving just 5 years of treatment.

The past NCI guidelines were established in 1995 and were distributed to every oncologist at every US hospital. They were based on results from the NSABP protocol B-14, which evaluated the administration of adjuvant tamoxifen for 5 years versus 10 years in patients with HR-positive breast cancer. This study suggested that more than 5 years of adjuvant treatment was not warranted in routine clinical practice in this patient population.

“This set us back a decade. A solid decade,” Wolmark said In reference to earlier guidelines on the use of adjuvant tamoxifen. “We had not realized that there was a rebound benefit when you stopped the tamoxifen and at a 7-year preplanned interim analysis, 5 years was better than 10. And we stopped the trial because it crossed futility limits. What a mistake. The ATLAS and aTTom trials were unencumbered by interim analysis—they plotted on and went forward, so good for them.”

Looking ahead to 2015, new guidelines about AIs and GnRH agonists are on the way, said Wolmark. Additionally, further emphasis on molecular profiling should be incorporated.

“You would think we would have learned from the past,” said Wolmark, referring to the May 2014 ASCO guidelines. “Do the guidelines apply to every patient, in this age of molecular genomics? If the data are incontrovertible and absolutely definitive, then by all means go ahead and formulate guidelines. But if the guidelines don’t take into account genomic profiling, you may miss your mark. You run the risk of paying an enormous price and setting back the art by at least a decade.”

Invoking the memory of Ezra Greenspan, MD, founder of the symposium, he wondered, “What would he have thought of the consensus guidelines issued by ASCO? Would he have been in equipoise with it? I think not. He was not prone towards hyperbole. Ezra Greenspan encouraged dialogue. He encouraged discussion. He encouraged scientific discourse,” he said.

“To make that ASCO statement without taking into account genomic profiling is far too encompassing. ASCO felt the need to publish before we had the full set of information,” Wolmark said. “Ezra’s admonitions are pertinent today as they were 3 decades ago: assess the data, analyze the permutations and combinations, factor in modern advances and then speak. Otherwise, hold your peace.”

View more from the 2014 Chemotherapy Foundation Symposium

In May 2014, ASCO issued guidelines recommending the administration of adjuvant tamoxifen for 10 years in women with stage I-III hormone receptor (HR)-positive breast cancer, based on data from the collection of 5 clinical trials. 

Expert Critiques Adjuvant Tamoxifen Guideline for HR-Positive Breast Cancer

Nitin Jain, MD, assistant professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discusses lymphocytosis following treatment with a B-cell receptor inhibitor for patients with chronic lymphocytic leukemia.

The initial pattern of response following treatment with a b-cell receptor inhibitor is rapid reduction in lymphadenopathy associated with increased lymphocytosis. When patients start idelalisib and this reaction occurs, a treating oncologist should not regard this as progression — it may take 6-9 months for the white blood cell count to normalize.

Nitin Jain, MD, assistant professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discusses lymphocytosis following treatment with a B-cell receptor inhibitor.

Dr. Jain on Increased Lymphocytosis Following Treatment With a B-Cell Receptor Inhibitor

When Gail J. Roboz, MD, took the stage Wednesday to give her talk on what’s ahead in the treatment of acute myeloid leukemia (AML), she admitted feeling a little jealousy toward her colleagues in the lymphoid diseases.

“AML continues to languish at the bottom of the survival curve. The lymphoid diseases are just doing so much better,” said Roboz, associate professor of Medicine and director of the Leukemia Program at the Weill Medical College of Cornell University and the NewYork-Presbyterian Hospital.

That is not to say, however, that research into myeloid diseases is “completely languishing,” Roboz stressed in her presentation at the 2014 Chemotherapy Foundation Symposium. Real progress has been achieved in understanding AML’s biology, and new targeted agents are being explored to improve outcomes.

 (FMS-like tyrosine kinase 3) are associated with highly proliferative leukemia and adverse outcomes, while mutations in 

 (nucleophosmin 1) and biallelic mutations in 

(CCAAT enhancer-binding protein a) have significantly more favorable survival.

“Although the mechanism of action of AML is much better understood, it’s not simple, and that’s the problem,” Roboz stressed.

Another challenge in treating patients with AML—which Roboz noted results in 10,000 deaths of the approximately 13,000 cases diagnosed each year&mdash;is whether more cases will be diagnosed, as patients survive other cancers. “We know that it’s associated with chemo and radiation exposure,” as well as other known environmental risk factors, genetic abnormalities, and benign and hematologic diseases also associated with AML.

Although the current cytarabine-based 7+3 regimen remains the standard of care, “we do understand our weapon a little better, and this has certainly resulted in some survival benefit,” said Roboz, adding that this “much-worked-on regimen can be given to much older patients.”

Roboz, who will be leading an AML education session at the American Society of Hematology Annual Meeting in San Francisco next month, reviewed successive efforts by the German AML Study Group “to make chemo better,” through variations on (and additions to) the 7+3 dosing regimen, but these have led to what she described as “superimposable curves.”

“Is it in fact a triumph of hope over experience to add things on to 7+3?” This is a useful question, she elaborated, because “is it that we’re adding new things that aren’t new enough or are we adding them in the wrong place? It’s certainly concerning that all of these efforts over all of these years led to superimposable graphs.”

Other agents are pending, said Roboz, including clofarabine which, she said, “definitely works in AML, but we can’t quite get it right to be where it needs to be an approved drug for AML. We’re anxiously awaiting whether it can ‘beat’ 7+3,” she said.

 which, Roboz explained, “is taking 7+3 and trying to make it better. This is a formulation that holds cytarabine and daunorubicin in a fixed 5:1 ratio, and we’re waiting to see whether what looked like a benefit in overall survival in a very difficult-to-treat population of secondary AML patients will hold up in a randomized trial, and whether taking the best regimen that we have and making the formulation better will get the job done.”

Roboz also hopes to have data available soon from the multicenter Alliance trial, looking at decitabine versus decitabine plus bortezomib in a 10-day schedule.

Looking ahead, said Roboz, “We have epigenetics, we have targeted therapies, personalized medicine. We must be on the way to improved therapeutic options.”

“Hope springs eternal. We want these agents to work and to synergize with our ‘best regimens,’” she said.

			1. Lancet JE, Cortes JE, Hogge DE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML [published online March 31, 2014]. Blood. 2014;123(21):3239-3246.

When Gail J. Roboz, MD, took the stage Wednesday to give her talk on what's ahead in the treatment of acute myeloid leukemia (AML), she admitted feeling a little jealousy toward her colleagues in the lymphoid diseases.

Roboz Discusses Progress, Challenges in AML

The landscape in lymphoma management continues to evolve, with new therapies and approaches improving established treatment paradigms, according to Andre Goy, MD, chairman and director, and chief of the Lymphoma Division at John Theurer Cancer Center. Goy discussed recent advancements in mantle cell lymphoma and diffuse large B-cell lymphoma at the 2014 Chemotherapy Foundation Symposium.    

In fit patients aged ≤65 years with mantle cell lymphoma (MCL), Goy said that dose intensive and/or high-dose chemotherapy regimens followed by autologous stem cell transplantation have demonstrated superiority to standard R-CHOP, with progression-free survival (PFS) extending beyond 5 years.

Induction regimens that include a high-dose version of the chemotherapy drug cytarabine are now considered the standard of care in younger patients. Studies involving younger patients have demonstrated 5-year event-free survival rates of 56% to 65% with induction regimens containing high-dose cytarabine.

Goy said the reason for the improved outcomes with the drug is that “cytarabine brings earlier and deeper CR (complete remissions),” and, “in younger patients with MCL, achieving an early and deep response (CR and molecular CR) translates into a longer PFS and survival advantage.” This is because in MCL, there is a relatively high-risk of relapse and patients frequently become chemo-resistant in the relapsed/refractory setting.

Several targeted agents have now been approved for heavily pretreated patients with relapsed/refractory MCL, including lenalidomide, bortezomib, and ibrutinib, Goy said. Ongoing trials are examining the potential of moving these agents into the frontline setting to be used in combination with a chemotherapy backbone.

Recently, bortezomib became the first targeted agent approved for MCL in the frontline setting. In October, the FDA approved first-line bortezomib in combination with VR-CAP (rituximab, cyclophosphamide, doxorubicin, and prednisone).

Researchers are also examining the potential of incorporating targeted agents in maintenance regimens following rituximab-chemotherapy.

In older patients (aged ≥65) with MCL, for whom standard of care is R-CHOP or BR (bendamustine plus rituximab), Goy said outcomes are “disappointing,” but he has hope that outcomes can improve.

“What I find really amazing—it’s palpable really&mdash;is that we are now really able to think, in the short term, of nonchemotherapy options in some of these elderly patients that will likely replace chemotherapy.”

Goy said that the next step to improving outcomes further in MCL would likely involve exploiting the heterogeneity of the disease to better stratify patients.

In diffuse large B-cell lymphoma (DLBCL), Goy said the key research focus is moving beyond the current treatment standard of R-CHOP every 21 days for six cycles, or R-CHOP-21. While over 50% of patients are cured with this regimen, a significant number still relapse. Goy said that “relapses typically occur early, with 80% of relapses occurring in the first 3 years,” and the prognosis is poor for these patients.

To improve outcomes, researchers are examining higher intensity regimens and combination strategies with novel agents. Among the targeted agents being explored to improve on R-CHOP-21 in DLBCL are the BTK inhibitor ibrutinib, the Bcl-2 inhibitor ABT-199, IMiDs (lenalidomide), and proteasome inhibitors (bortezomib).

DLBCL is a heterogeneous disease and researchers hope to increase molecular understanding to enhance patient stratification and improve outcomes.  At this point, three distinct subtypes of DLBCL have been established: germinal center, activated B-cell (ABC), and unclassified.

“Patients with the ABC subtype clearly do worse in terms of progress-free and overall survival,” Goy said. Several ongoing phase III studies are examining targeted agents, including bortezomib, lenalidomide, and ibrutinib, in patients with this poorer ABC prognosis.

Goy said the other mechanism by which researchers hope to improve upon R-CHOP-21 in DLBCL is with better predicators/evaluators to “better appreciate the depth and the quality of patient response.” Specifically, minimal residual disease (MRD) has emerged as a new concept in large cell lymphoma. MRD refers to the small number of malignant cells that remain after therapy when the patient is in remission and shows no symptoms or overt signs of disease. “MRD-negative might become a new endpoint for measuring patient outcomes,” said Goy.

Goy hinted at a potential future option in DLBCL management with data on chimeric antigen receptor (CAR) T-cell therapy, an immunotherapeutic option that has generated recent excitement in the hematology field. In research he conducted, Goy said that 4 of 7 patients with heavily pretreated refractory DLBCL had a complete response with anti-CD19 CAR T-cell therapy. 

The landscape in lymphoma management continues to evolve, with new therapies and approaches improving established treatment paradigms

New Strategies Explored in B-Cell Malignancies

As the targeted therapy era in chronic lymphocytic leukemia (CLL) continues to unfold, two next-generation agents are generating responses with improved safety profiles as single agents and in combination regimens, according to Howard A. “Skip” Burris III, MD.

TGR-1202 is a PI3K-delta inhibitor administered in once-daily oral dosing while ublituximab (TG-1101) is a glycoengineered anti-CD20 monoclonal antibody, explained Burris during the hematologic malignancies session as the 2014 Chemotherapy Foundation Symposium opened Wednesday.

Notably, ublituximab will be evaluated in combination with ibrutinib (Imbruvica) in patients with previously treated high-risk CLL in a phase III trial expected to be launched this year. The trial aims to enroll approximately 330 patients who harbor 17p or 11q chromosomal deletions, or 

The new regimens are being developed as part of an emerging therapeutic landscape in CLL in which it is “not unrealistic to talk about, if not a cure for patients, certainly [patients] living long enough to die of other causes and from natural means,” said Burris.

Burris specializes in early-phase clinical trials at the Sarah Cannon Research Institute in Nashville, Tennessee, where he is chief medical officer and executive director of the Drug Development Program. He was honored earlier this year with a Giants of Cancer Care™ award, a program that the Intellisphere Oncology Specialty Group launched to recognize oncology specialists who have made significant contributions to cancer care.

The structures of both TGR-1202 and ublituximab offer potential advantages, Burris noted.

He said TG-1202’s structure “contributes to a favorable pharmacokinetic profile which enables once-daily dosing and a differentiated safety profile” from other PI3K-delta inhibitors such as the recently approved idelalisib (Zydelig) and IPI-145 still in development. He said hepatic toxicities have been “noticeably absent,” and that there have not been colitis events.  

Ublituximab binds to a unique epitope on the CD20 antigen and is glycoengineered for enhanced affinity for FcγRIIIa receptors, resulting in enhanced antibody-dependent cell-mediated cytotoxicity, said Burris.

“Both TGR-1202 and ublituximab have displayed single-agent activity in a variety of relapsed/refractory hematologic malignancies,” said Burris.

The favorable safety profile that each drug has demonstrated as monotherapy has also been evident when the two novel agents were combined in a phase I involving 21 patients with CLL, diffuse large B-cell lymphoma, Richter, and follicular lymphoma. Overall, 14 of 15 evaluable patients achieved stable disease ≥12 weeks with manageable neutropenia and infusion-related reactions as thre most frequently reported adverse events, according to results presented at the Pan Pacific Lymphoma Conference held in Hawaii in July (Lunning et al).

In his symposium abstract, Burris presented findings for evaluable patients with CLL who received the drugs across all studies, which he said constituted the largest patient population whose experiences could be analyzed.

In the most advanced regimen under study, investigators will seek to determine whether the addition of ublituximab improves upon outcomes delivered by ibrutinib, a first-in-class Bruton tyrosine kinase inhibitor that the FDA approved this year in combination with chlorambucil for patients with previously untreated CLL and as monotherapy for patients with 17p deletions.

In a phase II trial, all of the 20 patients who were among the first group enrolled in the study responded to the combination, said Burris. Findings were presented at the 19th Congress European Hematology Association held in Italy in May (Sharman et al).

The phase III study involving ublituximab and ibrutinib was designed under a special protocol agreement (SPA) between the FDA and TG Therapeutics, which is developing both TGR-1202 and ublituximab. Burris said patients will be stratified by prior lines of therapy and then randomized to receive either ublituximab and ibrutinib in combination or ibrutinib alone.

The overall response rates for the first 200 patients to be treated will be analyzed as the basis for an accelerated approval for ublituximab. Progression-free survival will be evaluated for all 330 participants in the trial as the primary endpoint for a full approval, said Burris.

"It’s certainly a novel way to approach this,” Burris said.

As the targeted therapy era in chronic lymphocytic leukemia (CLL) continues to unfold, two next-generation agents are generating responses with improved safety profiles as single agents and in combination regimens

TGR-1202 and Ublituximab Show Promise in CLL

The combination of a FLT3L-primed in situ vaccine, low-dose radiotherapy, and a toll-like receptor 3 (TLR) 3 agonist has been shown to be feasible, safe, and immunologically and clinically effective in a phase I/II study for patients with low-grade lymphoma, according to a presentation by Joshua Brody, MD, during the 2014 Chemotherapy Foundation Symposium.

Although conventional chemotherapy for lymphoma has advanced greatly, most cases of lymphoma are incurable, demonstrating the need for novel therapies with less toxicity and more specific targeting of tumor cells. TLR agonists work as immune cell stimulants to activate dendritic cells. An earlier version of the treatment utilized a TLR9 agonist; however, further research suggested that a TLR3 inhibitor would induce higher rates of dendritic cell activation, specifically those impacted by FLT3L. TLRs are involved in tumorigenesis and have potential in immunotherapeutics or vaccine adjuvants.

“TLR9 would not be the right agonist to use because the dendritic cells express more TLR3. That’s the rationale for using a TLR3 agonist,” said Joshua Brody, MD, an assistant professor of Medicine, Hematology, and Medical Oncology at Mount Sinai Hospital.

In the phase I/II study, patients were treated with an intratumoral injection of the FLT3L-primed vaccine therapy followed by low-dose radiotherapy along with an intratumoral injection of the TLR agonist poly-ICLC. At the time of the presentation, 6 patients had been enrolled into the study, with 2 completing the treatment. Treated patients had 2- to 200-fold increases in BDCA1 and BDCA3 intratumoral dendritic cells after FLT3L administration and marked immune cell activation after radiation therapy and poly-ICLC, suggesting an antitumor response.

Both treated patients have had partial remissions of untreated sites per Cheson criteria, persisting or improving for >6 months after vaccination. Patients who responded experienced regressions of bulky lymph nodes, as well as peripheral blood and bone marrow disease. Brody said that 1 patient with significant peripheral blood tumor burden experienced >10-fold decrease in malignant B cells with concurrent increase in nontumor B cells, suggesting a degree of cell specificity in the tumor-killing mechanism. Adverse effects have been mild said Brody.

“These new results are way too preliminary to say if this will lead to an FDA-approved therapy,” said Brody. “But it’s fair to say that some more targeted immune therapies will have an effect on community oncologists—those somewhat less specific, but promising immune therapies like PD-1 blockade or PD-L1 blockade will affect community oncologists today.”

Research into the combination regimen using the TLR9 agonists also demonstrated early success. In this study, 60 patients were treated with the in situ vaccine in trials for low-grade B-cell and T-cell lymphoma and it induced partial and complete remissions, some lasting for years. Brody said that this previous therapy regimen became more powerful with repeated use, as is expected with vaccines.

This approach and the long last remissions are a contrast to chemotherapy; however, the treatment can still be made even more effective, said Brody. One likely limitation is that there are very few dendritic cells at the tumor site constraining the ability to prime the antitumor T-cell response.

In preclinical studies, FLT3L induced tumor leukocyte infiltration and regression of lymphoma. A new formulation of this cytokine, CDX-301, has been shown to mobilize dendritic cell subsets BDCA-1 and BDCA-3. These dendritic cell subsets respond to TLR agonists more effectively than plasmacytoid dendritic cells (the CpG-responsive dendritic cell subset).

“We now have a way to bring more dendritic cells to the tumor with a clinical-grade recombinant FLT3L,” said Brody. “It’s known that dendritic cells are better at presenting antigens than other types of antigen-presenting cells.”

The combination of a FLT3L-primed in situ vaccine, low-dose radiotherapy, and a toll-like receptor 3 (TLR) 3 agonist has been shown to be feasible, safe, and immunologically and clinically effective in a phase I/II study for patients with low-grade lymphoma

PER® Chemotherapy Foundation Symposium (CFS) | Conference

Expert Critiques Adjuvant Tamoxifen Guideline for HR-Positive Breast Cancer

Dr. Jain on Increased Lymphocytosis Following Treatment With a B-Cell Receptor Inhibitor

Roboz Discusses Progress, Challenges in AML

New Strategies Explored in B-Cell Malignancies

TGR-1202 and Ublituximab Show Promise in CLL

New Vaccine Formulation Effective in Low-Grade Lymphoma