Approval of treatments for Hodgkin’s lymphoma, myelofibrosis, prostate cancer among highlights of 2011

Every December, we ask members of the HemOnc Today Editorial Board for their suggestions about the most important developments in the fields of hematology and oncology during the past year.

The following is our distillation of their suggestions, with the caveat that we may have missed a meritorious article or two.

AAV vector-mediated gene transfer

A few years back, Katherine A. High, MD, and colleagues excited us with the following findings: A modified serotype 2 adenovirus-associated vector fashioned to express the Factor IX gene could induce that protein in patients with hemophilia B (Christmas disease) and do so at levels likely to be therapeutic.

The correction was short-lived due to immunologic destruction of the viral carrier. However, persistence in this arena has again rekindled great enthusiasm as noted in a highlight plenary session paper at last month’s 53rd American Society of Hematology Annual Meeting, along with its accompanying full publication in an article in the December issue of The New England Journal of Medicine.

A large international collaboration of scientists, including Dr. High, produced a new adenoviral vector containing the transgene, this time using a serotype 8 virus that is not endemic in the population and, thus, predictably far less immunogenic.

Harry S. Jacob

A single IV infusion of the vector into six patients successfully induced therapeutically relevant Factor IX levels that have remained stable for up to 20 months. No toxicity has been noted, the need for prophylactic infusions of the factor has abated in four patients — with an estimated annual savings of more than $100,000 per patient — and no spontaneous bleeding has occurred in any of the six patients.

A minimal immune response to the vector was successfully inhibited by brief steroid administration in two of the patients. Similar techniques to treat Factor VIII-deficient hemophiliacs likely are in the works and will be awaited with high hopes.

Effect of NACS in TTP

Although these results represent a supreme example of bench-to-bedside translation, basic studies in thrombotic thrombocytopenic purpura (TTP) — described in an editorial in the July 10 issue of HemOnc Today — have not yet been clinically pounced upon, but I suspect they will be soon.

That is, the extra-large polymers of von Willebrand’s factor (VWF) that underlie catastrophic blood vessel occlusions in TTP have been shown to depolymerize when exposed to a simple FDA-approved amino acid, N-acetylcysteine (NACS).

In fact, at doses routinely used in patients with cystic fibrosis or those overdosed with acetaminophen, NACS splits the disulfide bonds that form the toxic, huge VWF polymers that, in turn, agglutinate platelets. In a mouse model of TTP, NACS prevented production of VWF polymers generated by injured endothelium and, thereby, inhibited platelet-associated occlusion of visualized mesenteric vessels.

Surprisingly, although these studies by Chen and colleagues were published 10 months ago in The Journal of Clinical Investigation, no relevant ASH poster appeared in San Diego last month — but wait until next year.

CML therapeutics

Several papers presented at the recent ASH meeting suggest that the wonder drug imatinib (Gleevec, Novartis) may no longer be the initial go-to medication for chronic phase chronic myeloid leukemia.

The international Evaluating Nilotinib Efficacy and Safety in Clinical Trials (ENEST) demonstrated that nilotinib (Tasigna, Novartis) 400 mg twice daily achieved more rapid and more durable cytogenetic and molecular responses and lower rates of progression to advanced phase and blast crises than imatinib given at 400 mg daily.

Confirmatory studies from The University of Texas MD Anderson Cancer Center showed that nilotinib 400 mg twice daily as first-line therapy produced rapid complete cytogenetic recovery in 80% of patients within 3 months. At 12 months, approximately 90% of patients were in major molecular and cytogenetic recovery. OS at 4 years was an astounding 96%. Toxicity was modest and no different than historical levels with imatinib, although some believe that cytopenias may be more troublesome with nilotinib.

A new player in CML therapeutics is now in play. The phase 3 BELA study randomly compared bosutinib (Pfizer) — an orally active, dual inhibitor of Src and Abl tyrosine kinases — with imatinib in patients with newly diagnosed chronic phase CML.

Joseph R. Bertino

Bosutinib resulted in a higher rate of major molecular responses at 12 months, faster times to major molecular and cytogenetic responses, fewer events of transformation to accelerated or blast-phase CML, and fewer overall and CML-related deaths compared with imatinib.

The researchers suggest that bosutinib may be an equal, and possibly superior, therapy in those with newly diagnosed chronic phase CML.

The 18-month estimates for event-free survival and OS currently favor bosutinib, but longer follow-up will be required to confirm this dichotomy. Bosutinib and imatinib each were associated with acceptable but distinct toxicity profiles, so individualizing the drugs to variously affected patients would seem a reasonable possibility in the future.

CLL, B-cell derived ALL

Another bench-to-bedside translation is reported in August issues of The New England Journal of Medicine, Science Translational Medicine and Blood from two sets of investigators at the University of Pennsylvania and at Memorial Sloan-Kettering Cancer Center.

The studies show immense promise in treating multiply relapsed CLL patients and B-cell derived acute lymphoblastic leukemia.

Using different viral vectors, but both expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19 — coupled with co-stimulatory molecules for T cells — these investigators report astonishing complete remissions in several previously recalcitrant CLL patients.

The ex vivo modified T cells, when reinfused, expanded more than 1,000 times and lysed kilogram amounts of tumor. Not surprisingly, tumor lysis syndromes were manifest but successfully treated.

The engineered lytic cells persisted at high levels for more than 6 months in blood and bone marrow, and remissions in several patients continue. Hypogammaglobulinemia and B cell depletions, but not other blood cell losses, have been the expected chronic side effects of this new and exciting technology.

Hodgkin’s lymphoma, myelofibrosis

The FDA approved two drugs that have shown significant benefit in Hodgkin’s lymphoma and myelofibrosis.

The antibody drug conjugate brentuximab vedotin (Adcetris, Seattle Genetics) has produced unprecedented objective response (75%) and complete response (34%) rates in relapsed or refractory Hodgkin’s lymphoma.

The drug conjugates a monoclonal antibody to CD30, present especially on malignant Hodgkin’s and anaplastic large-cell lymphoma cells, with an antimicrotubule drug.

Toxicities have been minor. The CD30 antigen also may be exhibited by dendritic cells, suggesting that the drug might find use in other, rarer CD30+ malignancies in the future.

The FDA approved ruxolitinib (Jakafi, Incyte) for myelofibrosis. This JAK2 inhibitor’s major beneficial impact has been to ameliorate constitutional symptoms and reduce splenomegaly size.

Several papers at ASH from numerous countries attest to its efficacy in improving overall quality of life, and collaborative studies from Italy and MD Anderson Cancer Center demonstrate a twofold increase in OS of high-risk patients (with an estimated 3-year survival of 67% vs. 33% in a historical well-matched control group).

One should be aware, however, that Ayalew Tefferi, MD, a HemOnc Today section editor, and colleagues at the Mayo Clinic in Rochester, Minn., provided caveats in a recent NEJM correspondence.

Thus, although ruxolitinib is effective in alleviating constitutional symptoms, its activity in reducing spleen size is only modest and may not be durable. In addition, OS may not be increased, according to Mayo Clinic investigators, and nearly 90% of their patients have discontinued the drug because of toxicity or lack of response.

Sickle cell disorders

Perhaps Stuart H. Orkin, MD, and colleagues from Harvard Medical School provided the most exciting basic science paper of the year — one that may alter our treatment of sickle cell disorders. Their September paper in NEJM uncovered a 3.5-kilobase (kb) intergenic region in the beta gene locus that is necessary for gamma-globin silencing and, thereby, fetal hemoglobin diminution after birth.

The factor critical for fetal hemoglobin silencing was shown to be a protein — BCL11A. Recognizing that persistence of fetal hemoglobin in adults markedly decreases sickle disease severity, the Harvard investigators recently published in Science remarkable evidence that the hematologic and pathologic effects of sickle disease can be corrected.

Thus, inactivation of the BCL11A repressor of gamma-globin induced in sickle disease transgenic mice marked increases in pancellular fetal hemoglobin and “cured” their sickle manifestations. Their modest conclusion — that “interference with [fetal hemoglobin] silencing by manipulating a single target protein is sufficient to reverse sickle cell disease” — is truly evocative.

Prostate cancer

The long-awaited FDA approval of abiraterone (Zytiga, Centocor Ortho Biotech) for treatment of metastatic castration-resistant prostate cancer and the demonstration that treatment of patients with bone metastasis with cabozantinib (Exelixis) results in pain relief, marked regression and even healing of bone metastasis were highlights of the past year.

Abiraterone, an inhibitor of the CYP17 enzyme complex and testosterone biosynthesis, is approved for use in combination with prednisone for men who have received prior chemotherapy with docetaxel. Studies showing that resistance to androgen ablation was in some patients due to androgen synthesis by prostate tumors prompted development of this drug.

Abiraterone was approved based on the results of a phase 3, randomized, placebo-controlled, multicenter study that showed the drug was associated with a significant increase in median OS. Patients (n=1,195) were assigned to once-daily abiraterone combined with prednisone or placebo twice daily combined with prednisone.

At prespecified interim analysis, OS was 14.8 months in the experimental group vs. 10.9 months for placebo. Risk for death decreased by 35% in the experimental group (HR=0.646; 95% CI, 0.543-0.768). An updated analysis showed a 4.6-month difference in OS favoring abiraterone, 15.8 months vs. 11.2 months (HR=0.74).

The optimal role of this drug has not been defined as yet. Questions such as its use as first-line treatment in castration-resistant prostate cancer, as well as its use in combination with other drugs and vaccines, will be addressed in future trials.

The investigational drug cabozantinib — which targets two proteins, MET and VEGFR2, that play a role in the development and progression of many types of cancer — showed striking results in the treatment of metastatic, hormone-refractory prostate cancer, with particularly notable results among patients with bone metastases.

Maha Hadi Hussain, MD, FACP, and colleagues conducted a phase 2 clinical trial of 171 patients with progressive prostate cancer. More than three-quarters of the men had bone metastases. All patients were initially treated with 12 weeks of cabozantinib. Treatment after 12 weeks depended on how the patients had responded to initial treatment.

Among the patients with bone metastases, 76% had partial or complete disappearance of the bone metastases on bone scan. Among patients who had been taking narcotics for bone pain, 67% had a reduction in pain, and 56% decreased or stopped their narcotic use. More than two-thirds of patients had some reduction in metastases outside of the bone. Adverse effects of cabozantinib included fatigue, gastrointestinal symptoms and high blood pressure.

A phase 2 study from Memorial Sloan-Kettering Cancer Center enrolled 51 patients with castration-resistant prostate cancer that was metastatic to bone and had progressed on prior docetaxel therapy.

The investigators also noted a high rate of pain reduction and improvement of bone metastatic disease. These unexpected and striking results, likely due to targeting both MET and VEGFR2, indicate that cabozantinib is active against hormone-refractory prostate cancer and may be particularly beneficial for patients with bone metastases.

Additional studies of the drug, including a large phase 2 study, are under way.

These new therapies — after the approval of vaccines and the taxanes docetaxel and cabazitaxel (Jevtana, Sanofi-Aventis) last year for treatment of castration-resistant disease — now provide many treatment options for patients and opportunities for combining drugs to improve outcomes.

Metastatic melanoma

After years without progress for treatment of metastatic melanoma, the FDA approved two drugs.

Vemurafenib (Zelboraf, Genentech), a small molecule inhibitor targeted to BRAF V600E–positive metastatic or unresectable melanoma, present in 50% to 60% of tumors, was approved under the FDA’s priority review program. The approval comes in combination with the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems), a companion diagnostic to help determine BRAF V600E status.

The safety and efficacy of vemurafenib, as well as the cobas diagnostic test, were established in a single international trial of 675 treatment-naive patients with metastatic melanoma with the BRAF V600E mutation. Patients were assigned to vemurafenib or dacarbazine. The trial was designed to measure OS.

Patients assigned to vemurafenib have not reached median survival — 77% are still living — and median survival among those who received dacarbazine was 8 months.

Of concern, about 25% of patients developed cutaneous squamous cell carcinoma, which can be managed with surgery. The FDA recommends that patients treated with vemurafenib avoid sun exposure.

The approval includes a medication guide to inform health care professionals and patients of the drug’s potential risks.

Although an important advance, this treatment is not curative, and patients eventually become resistant to this drug. Efforts to understand resistance, as well as to develop strategies to prevent or treat resistant tumors, are under way.

Ipilimumab (Yervoy, Bristol-Myers Squibb), a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte antigen 4 (CTLA-4), was the second drug approved by the FDA in 2011 for the treatment of patients with advanced melanoma.

Anti–CTLA-4 antibodies enhance T-cell responses in vitro and in vivo, activate proliferation of tumor-specific T cells and lead to immune-mediated tumor regression.

A phase 3, randomized, double blind, multicenter trial showed a significant improvement in OS in patients with advanced melanoma treated with ipilimumab.

The study compared ipilimumab combined with an experimental melanoma peptide vaccine (gp100), and gp100 monotherapy in HLA-A*0201-positive patients with previously treated unresectable stage III or IV melanoma. Ipilimumab, with or without the gp100 peptide vaccine, improved OS in patients with previously treated metastatic melanoma compared with gp100 alone.

Adverse events can be severe, long-lasting or both, but most are reversible with appropriate treatment.

Anti–CTLA-4 antibody treatment is also being evaluated in patients with prostate and lung cancer.

A phase 3 trial showed there was a significant improvement in OS among patients with previously untreated metastatic melanoma who received ipilimumab plus dacarbazine compared with dacarbazine plus placebo. Adverse events other than those typically seen with dacarbazine or ipilimumab therapy were not identified.

An increase in liver-function toxicity was observed more frequently than expected with the combination therapy. Enterocolitis and endocrinopathy, ipilimumab-associated adverse events, were observed, albeit at a rate lower than expected.

Combinations of these drugs with different mechanisms of action may further improve outcomes, and perhaps delay or abrogate resistance that occurs to each of these drugs. The use of one or more of these drugs in the adjuvant setting also may be of potential usefulness.

Childhood tumors

Medulloblastoma is the most common pediatric malignant brain tumor. During the past year, a series of articles — primarily written in the Journal of Clinical Oncology — documenting that medulloblastoma is made up of multiple different molecular subsets of the disease, and these subsets carry a variable prognosis and responsivity to therapy.

Genomic sequencing has shown that medulloblastoma comprises four distinct molecular and clinical variants: WNT, sonic hedgehog (SHH) and two less well-defined subtypes (groups C and D). Inhibitors of hedgehog signaling have shown promise in the SHH subgroup of patients. Children with WNT medulloblastoma have improved survival, whereas those with group C medulloblastoma have a dismal prognosis. These latter cases should be considered for experimental therapy.

Setback for Avastin

A great deal of controversy surrounded the FDA’s decision to revoke approval of bevacizumab (Avastin, Genentech) for treatment of patients with metastatic breast cancer.

The FDA granted accelerated approval for bevacizumab in 2008 based on the strength of results from the E2100 trial, which showed bevacizumab treatment led to a 5.5-month improvement in PFS. However, as the drug was associated with serious cardiotoxicity and the development of perforations in the nose, stomach and intestines, Genentech was ordered to produce further results showing a survival benefit for the drug.

Two subsequent studies submitted to FDA showed only a slight effect on tumor growth without demonstrating that patients lived any longer or had a better quality of life compared with standard chemotherapy.

In July 2010, The Oncologic Drugs Advisory Committee voted to remove the indication. Bevacizumab is still approved for colon, lung and kidney cancers and glioblastoma multiforme.

Harry S. Jacob, MD, FRCPath(Hon), is Chief Medical Editor of HemOnc Today. Joseph R. Bertino, MD, is Associate Medical Editor of HemOnc Today. Disclosure: Drs. Jacob and Bertino report no relevant financial disclosures.

For more information:

• Basch E. Abstract #B57. Presented at: 2011 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; Nov 12-16, 2011; San Francisco.
• Chapman P. Abstract #LBA4. Presented at: 2011 ASCO Annual Meeting; June 3-7, 2011; Chicago.
• Chen J. J Clin Invest. 2011;121:593-603.
• Cortes JE. Abstract #455. Presented at: 53rd Annual Meeting of the American Society of Hematology; Dec. 10-13, 2011; San Diego.
• de Bono JS. N Engl J Med. 2011;364:1995-2005.
• Hodi FS. N Engl J Med. 2010;363:1290.
• Hussain M. J Clin Oncol. 2011;29:4516.
• Nathwani AC. N Engl J Med. 2011;365:2357-2365.
• Quintás-Cardama A. Abstract #454. Presented at: 53rd Annual Meeting of the American Society of Hematology; Dec. 10-13, 2011; San Diego.
• Robert C. N Engl J Med. 2011;364:2517-2526.
• Saglio G. Abstract #452. Presented at: 53rd Annual Meeting of the American Society of Hematology; Dec. 10-13, 2011; San Diego.
• Sankaran VG. N Engl J Med. 2011;365:807-814.
• Tasi M. J Clin Invest. 2012;122:408-418.
• Tefferi A. N Engl J Med. 2011;365:1455-1457.
• Verstovsek S. Abstract #793. Presented at: 53rd ASH Annual Meeting and Exposition; Dec. 10-13, 2011; San Diego.
• Xu J. Science. 2011;334:993-996.