Breakthroughs in T-cell physiology, new oral anticoagulants among highlights of 2012

Each January of our 13-year tenure, we have attempted to spotlight particularly intriguing work reviewed in HemOnc Today during the previous year.

Our selection of material is in no way to be construed as assessing comparative worth; rather, it relates more to our prediction that our readers will find these selections worthy of further pondering.

T-cell physiology

The two Ernest Beutler Lecturers at the recent ASH Annual Meeting and Exposition — Carl H. June, MD, and Bruce Blazar, MD — reviewed separate but related studies of T-cell physiology.

June presented a new technique for producing T cells with spectacular proclivity to destroy malignant B cells. A year ago, his team reported remarkable remissions in three massively treated, relapsed chronic lymphocytic leukemia patients with seemingly end-stage, bulky disease. In one patient, kilogram amounts of tumor rapidly and persistently disappeared.

These patients had been infused with autologous T cells that were genetically altered ex vivo, so as to contain a chimeric protein combining the CD19 antigen receptor that recognizes malignant B cells coupled to an intracellular signaling domain that promotes prolonged persistence of the transformed cells in vivo.

These so-called chimeric antigen receptor cells (CART19 cells), after expansion in culture, were reinfused into their autologous donors who entered salutary remissions — remissions that were associated with prolonged persistence of the CART19 cells in vivo.

The relatively short follow-up provided in 2011 has now been updated along with results in six other patients with refractory CLL and one child with refractory acute lymphoblastic leukemia. Six of the 10 patients have had significant remissions, including a complete remission in the child. None of those who achieved complete remission have relapsed. CART19 cells actually increased after infusion 20- to 40-fold, homed to marrow (and cerebrospinal fluid in the child with ALL) and persisted in the first-treated patient for more than 2 years at the most recent follow-up.

A major — and not surprising — side effect accompanying these dramatic tumor regressions has been a "cytokine-storm syndrome" of fever, nausea, transient hypoxia and hypotension. Associated marked increases in interferon-gamma and interleukin-6 are the likely culprits, and recent patients have been successfully ameliorated with high-dose steroids and the IL-6 antagonist tocilizumab (Actemra, Genentech).

While pondering these exciting results, we wondered whether such benefit might actually have been predictable. Consider that T cells are well-recognized professional killers of altered B cells in the common disorder infectious mononucleosis. That is, the marked proliferation of large lymphocytes in this disease consists of T cells, not Epstein-Barr virus-infected B cells, which generally are decimated by these activated T cells by the time of diagnosis. We eagerly await further results from the University of Pennsylvania group.

Blazar provided equal excitement that the scourge of allogeneic stem cell transplants, that of graft-versus-host disease (GVHD), may soon be contained by T-cell manipulation. Summarizing many of the studies published in 2012 by his University of Minnesota team, Blazar reviewed the ability of T regulatory cells (Tregs) to inhibit GVHD. New techniques for separating and expanding Tregs have advanced to the point where clinical studies using infusions of these cells have begun in allogeneic bone marrow transplantation patients and in severe diabetes. Results in animals of Treg manipulation in preventing GVHD and ameliorating autoimmune disorders have been so promising that salutary results of forthcoming clinical trials are likely.

Relapse after hematologic malignancies

In a somewhat related investigation of lymphocytes in malignant hematology, the same Minnesota BMT team has produced impressive remissions and survivals in patients — despite allogeneic-transplant failure — in relapsed hematologic malignancies.

Recognizing that virtually no therapeutic strategies are left for patients who relapse after allogeneic hematopoietic cell transplantation, this group unleashed donor cells — probably T and/or NK cells — on 35 relapsed patients, most of whom had acute myelogenous leukemia.

After lymphodepleting chemotherapy, patients were infused with expanded lymphocytes from the original donor with the surmise that a beneficial graft vs. leukemia attack might occur. An impressive 49% complete remission was attained, with a median duration of remission of 6 months (one lasted up to 6 years).

Not surprising, significant GVHD occurred.

We wonder whether these investigators, who also have shown that Tregs can inhibit GVHD, may consider providing a cocktail of transplant-donor lymphocytes plus recipient Tregs to salvage previously doomed AML patients without causing severe GVHD.

Blood transfusion management

An important study in blood transfusion management was presented during the plenary session at ASH.

A well-accepted guideline for dealing with severely thrombocytopenic patients, particularly those on chemotherapy, has been to platelet-transfuse virtually all if platelet levels fall below 10,000/mcL. However, rigorous evidence is lacking that this prophylaxis is worthy.

Researchers from the United Kingdom and Australia randomly assigned 600 patients, primarily those undergoing chemotherapy or stem cell transplantation for various disorders. Half underwent prophylactic platelet transfusions. The other well-matched group did not. During 30 days, grade 2 or higher bleeds were not statistically different between groups, although the time to bleed was slightly shorter in the non-transfused patients.

Although one might come away from this presentation concluding that prophylactic platelet transfusions for therapy-associated severe thrombocytopenia is not required — not so fast. As noted in the post-presentation discussion, careful perusal of the data indicates that the subgroup of patients with AML — in contrast to patients with other malignancies — were, in fact, significantly protected from catastrophic bleeds if transfused when counts fell to 10,000 or lower.

In a HemOnc Today perspective that accompanied an article about this study, this dichotomy was hypothesized to reflect the deleterious effect of previously elevated circulating myeloid cells in AML. Such cells have a propensity to adhere to endothelium and cause vascular wall injury — thus, possibly predisposing thrombocytopenic AML patients to excessive hemorrhage.

FDA approves Iclusig

The FDA approved ponatinib (Iclusig, Ariad Pharmaceuticals) — a promising new therapy for chronic myeloid leukemia — in December under its priority review program.

Ponatinib can target CML cells that have a particularly deadly mutation in their abnormal BCR/ABL-generated tyrosine kinase, the T3151 gene mutation. Patients with this mutation fail to respond to the several tyrosine kinase inhibitors, such as imatinib (Gleevec, Novartis), that have been spectacularly beneficial in most patients who lack the mutation.

The FDA approval was based on results of a trial that included 449 patients with various phases of CML and Philadelphia chromosome-positive ALL. Ponatinib produced major cytogenic responses in 54% overall, and an extraordinary 70% in those with the previously untreatable T3151 mutation. In addition, the trial demonstrated that 52% of patients with accelerated phase CML, 31% of those with blast-crisis CML and 41% of those with Ph+ALL experienced major hematologic responses that persisted for months.

The FDA also approved bosutinib (Bosulif, Pfizer) and omacetaxine mepesuccinate (Synribo, Cephalon) in 2012 for treatment of CLL. The agency also approved vincristine sulfate liposome injection (Marqibo, Talon Therapeutics) for Ph+ALL.

The durability of these drug-responses will be important to monitor in the coming months.

New oral anticoagulants

The excellent efficacy and probable safety of new oral anti-Xa and anti-thrombin anticoagulants were validated in numerous publications.

The fact that they are not inferior to warfarin and are far easier to use — requiring no laboratory monitoring — suggest they might provide a major advance, especially in patients who require prolonged therapy, such as those with non-valvular atrial fibrillation or thromboembolisms.

In addition, interest has greatly intensified regarding the anti-Xa drug rivaroxaban (Xarelto, Janssen Pharmaceuticals), which the FDA approved in November for treatment of deep vein thrombosis and pulmonary embolism. The drug had been previously approved for prophylaxis in patients after hip or knee replacement surgery.

In a Nov. 25 article, A. Koneti Rao, MD, FACP, a HemOnc Today Editorial Board member, outlined reasons that the drug might revolutionize the DVT/pulmonary embolism field: It is a single agent given orally without need for subcutaneous or IV administration; it requires no repeated cumbersome and expensive laboratory monitoring; and its rapid onset of action and short half-life allows it to be administered and discontinued with great ease.

But clouds on the horizon should be perceived. The phase 2 RE-ALIGN trial of the oral anti-thrombin dabigatran (Pradaxa, Boehringer Ingelheim) in patients with artificial heart valves had to be discontinued because interim data were not achieving optimal results — at least with the dosing regimen utilized. Moreover, the safety of these new agents is under continual review.

Heartening are studies from members of the Karolinska Institute presented at ASH. Researchers analyzed reports of 1,121 major bleeds occurring in a large number of patients — primarily with atrial fibrillation or DVT — in the RE-LY trial and three others that compared outcomes in warfarin- vs. dabigatran-treated patients. Thirty-day mortality favored dabigatran (P=.007), and patients who used dabigatran experienced significantly shorter stays in the ICU.

This suggests that, despite absent specific antidotes, the shorter half-lives of the newer agents may produce less catastrophic outcomes in anticoagulated patients who develop major hemorrhages — about 5% per patient/year.

WARFASA, ASPIRE trials

Two other somewhat-related studies provide optimism that we can rationally take patients with an initial, unprovoked thromboembolism off chronic anticoagulants.

Results of the WARFASA and ASPIRE trials published in The New England Journal of Medicine demonstrate a 32% reduction in the rate of recurrence of venous thromboembolism with simple addition of aspirin to patients after withdrawal from warfarin.

In an editorial, Ted Warkentin, MD, said these results require a caveat: It is important to treat patients after a single unprovoked thromboembolism for at least 3 months with effective anticoagulation before weaning to daily 100 mg aspirin. He also noted that aspirin is far cheaper than monitored warfarin; it is not affected by renal insufficiency as is dabigatran and rivaroxaban; and if unwanted bleeding occurs, platelet transfusions can counter aspirin’s antiplatelet effects.

In the latter regard, I suggest that we also should consider switching many patients from aspirin to the adenosine diphosphate (ADP)-receptor antagonist ticagrelor (Brilinta, AstraZeneca). It is already popular in Europe, it is a more potent platelet inhibitor, and its antiplatelet effects are significantly shorter than aspirin’s — a real asset if bleeding occurs, and also a boon for patients who may require surgery without requiring a 4- to 5-day washout of aspirin.

These results, coupled with the aforementioned data that oral rivaroxaban can be used alone to treat DVT/pulmonary embolism, means that thromboembolisms can now be handled without the patient ever seeing a needle. Amazing — if, as hoped, these results hold up in the future.

Radiation in Hodgkin’s disease

A study by Meyer and colleagues again called into question the need for adjunct radiation therapy in early-stage Hodgkin’s disease.

Almost all studies that compare PFS suggest a benefit to adding irradiation.

The Meyer study compared four to six cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) with two cycles of ABVD followed by irradiation in patients with early-stage, unfavorable disease. Although combined treatment resulted in an increase in PFS (94% vs 86%), survival was better with ABVD alone at long-term follow-up. However, imbalances in causes of death in the combined treatment arm not attributable to either disease or treatment may explain this difference in survival. Six patients in the combined treatment group developed a malignancy vs. only one in the ABVD arm, but all of these malignancies were outside of the irradiated field.

As subtotal irradiation and 35 Gy were used in the Meyer study, smaller fields and lower doses of radiation could lead to reduced long-term effects. By decreasing the cycles of chemotherapy needed when radiation is used, lung and cardiac toxicity produced by bleomycin and doxorubicin also may be lessened.

The strongest arguments for eliminating radiation therapy are that the long-term effects of radiation would be eliminated. Additionally, the few relapses that occur may be salvaged with chemotherapy and autologous stem cell transplant. Also, there are no data to suggest that the 20 Gy dose of irradiation is safe.

Although the jury is still out, the use of PET scans may play an increasing role in the decision of whether to add radiation to chemotherapy. A presentation at ASH by the U.K. cooperative group showed that a negative PET scan after three cycles of ABVD in patients with early-stage good risk Hodgkin’s disease was as good as the arm in which radiation was added.

Another game changer may be the drug-antibody conjugate brentuximab vedotin (Adcetris, Seattle Genetics), shown to have impressive effects in relapsed and refractory patients. Studies are on the way to combine it with ABVD or use it to replace bleomycin and/or doxorubicin, with the goal of increasing efficacy while decreasing long-term side effects.

Ibrutinib for lymphoma

The understanding of the role of Bruton’s tyrosine kinase (BTK) in downstream signaling from the B-cell receptor (BCR) — described by Louis M. Staudt, MD, PhD, at ASH — has led to development of inhibitors of this enzyme.

Ibrutinib (PCI-32765, Pharmacyclics), an orally available irreversible inhibitor of BTK, leads to interruption of receptor signaling in cells dependent on this pathway for survival and, thus, causes apoptosis.

Updated results of a large expanded phase 1/phase 2 study showed remarkable activity in CLL/ small cell lymphoma and mantle cell lymphoma, including responses of 70% to 80% and PFS of more than 1 year, as well as substantial activity in follicular lymphoma (about 50% partial responses and complete responses). Common grade 1 and 2 toxicities included diarrhea, fatigue and nausea, whereas grade 3 and 4 toxicities were uncommon.

Although responses in diffuse large cell lymphoma were less (27%), a presentation by Wyndham Wilson, MD, showed that the activated B-cell subtype showed responses (40%) while the drug was not effective in the germinal center subtype.

As Staudt noted, it may be possible to predict response to this drug by examining the BCR pathway utilized by the lymphoma. As this agent has substantial activity with minimal marrow toxicity, ibrutinib is already being tested in combination with other effective anti-lymphoma drugs. If effective, it may be a major advance for the treatment of these B-cell malignancies.

Prostate cancer: More options, more questions

The FDA approved enzalutamide (Xtandi, Medivation Inc.) and a new indication for abiraterone acetate (Zytiga, Janssen Biotech) for treatment of prostate cancer, and it likely will approve cabozantinib (Cometriq, Exelixis) in 2013.

Enzalutamide binds to the androgen receptor with greater affinity than bicalutamide (Casodex, AstraZeneca). The FDA approved enzalutamide based on results of a trial that compared the drug to placebo in patients with metastatic disease who previously were treated with docetaxel. Both PFS and survival were significantly prolonged in the enzalutamide arm.

Just as abiraterone was approved this past year for treatment of patients who had not received docetaxel, enzalutamide likely also will be used in docetaxel-naive patients in the future.

Given the increased binding affinity for the androgen receptor as compared to bicalutamide, studies likely will examine the use of enzalutamide alone or combined with luteinizing hormone-releasing hormone (LHRH) agonists in early and advanced disease. Sequential use or combination use of enzalutamide with abiraterone likely also will be on the docket for future investigations.

Androgen deprivation

The standard treatment for patients with metastatic prostate cancer, and also for patients after surgery or irradiation with a rising PSA, has been treatment with a combination of an LHRH agonist and bicalutamide. Because of side effects of testosterone depletion caused by these agents, intermittent therapy has been investigated.

In a large randomized study presented at ASCO, 1,535 patients who achieved a PSA level of ≤ 4 ng/mL after combined androgen blockade were randomly assigned to remain on continuous androgen deprivation treatment or undergo intermittent therapy. After 9.2 years of follow-up, the difference in median OS between the two arms did not reach statistical significance but trended toward benefit for the continuous arm.

The subset of patients with minimal disease benefited from continuous treatment to a greater degree than patients with extensive disease. Clearly, patients would prefer having time off from androgen blockade, and this may be an option for patients. The authors plan to document the toxicities of the two regimens in a future publication, and lessened side effects of the intermittent regimen could argue for intermittent treatment.

Advances in melanoma

Progress in melanoma continues.

Tarhini and colleagues tested the combination of interferon plus the anti-CTLA4 tremelimumab (Pfizer) and reported promising results from the phase 2 study. Thirty-five patients were evaluable. Researchers reported four complete responses, five partial responses and 14 patients with stable disease. Median PFS was 6.4 months and median OS was 21 months.

There finally are several effective drugs available to treat melanoma, and finding effective combinations and understanding acquired resistance will be key to further progress.

Role of mTOR inhibitors

Based on studies that showed that the oral mTOR inhibitor everolimus (Afinitor, Novartis) restored the sensitivity of breast cancer cells to endocrine therapy and also demonstrated activity in early-phase, metastatic breast cancer, Bachelot and colleagues performed a randomized phase 2 study that compared tamoxifen to tamoxifen plus everolimus in patients with breast cancer who had hormone receptor–positive, HER-2–negative metastatic breast cancer who were resistant to aromatase inhibitors.

The median time to progression was 8.6 months in the combination arm vs. 4.5 months in the tamoxifen arm. The toxicities were consistent with that expected for everolimus. This study adds to the spectrum of activity seen with mTOR inhibitors, particularly in combination with other agents.

Progress in colorectal cancer

Progress continues in colorectal cancer, but no giant steps were made.

In the past year, the FDA approved two new drugs — regorafenib (Stivarga, Bayer HealthCare Pharmaceuticals) and ziv-aflibercept (Zaltrap, Sanofi-Aventis) — for the treatment of colorectal cancer.

Regorafenib was approved for previously treated metastatic colorectal cancer based on results of the international, multicenter, randomized, placebo-controlled phase 3 CORRECT trial. Patients were randomly assigned to receive regorafenib (n=505) or placebo (n=255). Median OS was 6.4 months in the regorafenib arm vs. 5 months in the placebo arm (HR=0.77; 95% CI, 0.64-0.94).

Treatment-related adverse events occurred in 465 (93%) patients assigned to regorafenib and 154 (61%) assigned to placebo. The most common grade 3 or higher adverse events related to regorafenib were hand-foot skin reaction (17%), fatigue (10%), diarrhea (7%), hypertension (7%), and rash or desquamation (6%).

Although survival benefits were modest, this is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer that has progressed after all standard therapies. Questions now relate to the possible role of this agent in upfront or second-line therapy.

Ziv-aflibercept, a novel recombinant fusion protein, is an angiogenic factor trap that blocks the binding of VEGF-A, VEGF-B and placental growth factor to its receptors.

The FDA based its approval on results of a trial in which patients were randomly assigned to receive ziv-aflibercept 4 mg/kg intravenously or placebo every 2 weeks combined with FOLFIRI.

The addition of ziv-aflibercept to FOLFIRI significantly improved OS (13.5 months vs. 12.1 months; HR=0.817; 95.34% CI, 0.713-0.937) and PFS (6.9 months vs. 4.7 months; HR=0.758; 95% CI, 0.661-0.869). The response rate was 19.8% with ziv-aflibercept vs. 11.1% with placebo (P=.0001).

Adverse effects observed in patients assigned to the ziv-aflibercept regimen included the characteristic anti-VEGF effects and also reflected an increased incidence of some chemotherapy-related toxicities.

Although not a major step forward, ziv-aflibercept represents a potential new treatment option for patients with metastatic colorectal cancer.

The other important study was the documentation of the value of second-line continuation of bevacizumab (Avastin, Genentech) plus chemotherapy. These studies validate the value of continued VEGF suppressive therapy in colorectal cancer.

References:

Arnold D. Abstract #CRA3503. Presented at: ASCO Annual Meeting; June 1-5, 2012; Chicago.

Bachelot T. J Clin Oncol. 2012;30:2718-2724.

Becattini C. N Engl J Med. 2012;366:1959-1967.

Brighton TA. N Engl J Med. 2012;367:1979-1987.

Hussain M. Abstract #4. Presented at: ASCO Annual Meeting; June 1-5, 2012; Chicago.

Majeed A. Abstract #19. Presented at: ASH Annual Meeting and Exposition; Dec. 8-11, 2012; Atlanta.

Meyer RM. New Engl J Med. 2012;366:399-408.

Porter DL. N Engl J Med. 2011;365:725-733.

Porter DL. Abstract #717. Presented at: ASH Annual Meeting and Exposition; Dec. 8-11, 2012; Atlanta.

Stanworth SJ. Abstract #1. Presented at: ASH Annual Meeting and Exposition; Dec. 8-11, 2012; Atlanta.

Tarhini AA. J Clin Oncol. 2011;30:322-328.

Warlick ED. Biol Blood Marrow Transplant. 2012;18:480-486.

Wilson W. Abstract #686. Presented at: ASH Annual Meeting and Exposition; Dec. 8-11, 2012; Atlanta.

For more information:

Joseph R. Bertino, MD, is Associate Medical Editor of HemOnc Today. He can be reached at The Cancer Institute of New Jersey, 195 Little Albany St., Room 3034, New Brunswick, NJ 08901-1914; email: bertinoj@umdnj.edu.

Harry S. Jacob, MD, FRCPath(Hon), is Chief Medical Editor of HemOnc Today. He can be reached at Hematology, Oncology and Transplantation Office, MMC 480 Mayo, 420 Delaware St., Minneapolis, MN 55455; email: jacob002@umn.edu.

Disclosure: Bertino and Jacob report no relevant financial disclosures.