A review of some of the year’s breakthroughs in hematology

Our tradition of briefly discussing some of the most interesting hematology and oncology papers of the past year continues. Dr. Bertino and I, assisted by suggestions from our HemOnc Today subeditors, provide the following with the caveat that we may have missed a meritorious article or two.

In the hematology arena, few would disagree that the recent FDA approval of dabigatran (Pradaxa, Boehringer Ingelheim) for prevention of atrial fibrillation-associated strokes has been long awaited and is welcomed (see related story here.) From results presented on the plenary session of last December’s American Society of Hematology meeting, it seems likely that this anti-thrombin oral medication will soon be approved for treatment of venous thromboembolism. The drug is at least as efficacious as warfarin, is well-tolerated (but at half-doses in patients with renal impairment) and possibly less likely to cause catastrophic cerebral hemorrhage. Its cost (at least in England and Canada) at approximately $400 for a month’s supply has been considered a cost-effective alternative to warfarin in a just published article in the Annals of Internal Medicine; of course, this will depend on pricing in the United States. Clearly, patient acceptance is likely to be exuberant, as constant international normalized ratio monitoring and concerns about dietary and drug interactions will no longer be a problem for those choosing the medication.

Romiplostim for immune thrombocytopenia

In our Nov. 15 issue of HemOnc Today we offered our rapid take on another pharmaceutical breakthrough in the treatment of hemostatic disorders. In the Nov. 11 issue of The New England Journal of Medicine, Kuter and colleagues from several countries reported that romiplostim (Nplate, Amgen), a thrombopoietin mimetic, provides major benefit to adult non-splenectomized patients with immune thrombocytopenia. An effective platelet count of more than 50,000 was achieved twice as often than in randomly assigned patients receiving the standard of care. Moreover, the need for splenectomy in these patients, who were treated for many months with weekly subcutaneous injections of the drug, was greatly diminished (9% vs. 36%), as were bleeding events and the need for blood transfusions. In addition, greater improvements in quality of life were registered while serious adverse effects were lower in the romiplastim-treated patients.

Harry S. Jacob

The ultimate cost of the synthetic peptide is unknown at this time and will need to be compared with periodic infusions of immunoglobulin G, which can be highly efficacious in patients with infrequent relapses and are approved in pregnant patients as well. The durability of the beneficial response after cessation of the drug will also need to be assessed in future studies. Notwithstanding, the Amgen folks are to be congratulated for their innovative prowess in producing this thrombopoietin “peptibody,” comprising a human IgG1 Fc domain linked to two 14-amino-acid peptides that bind to and stimulate the thrombopoietin receptor.

Myeloma combination treatments

Among the treatment modalities for hematologic malignancies, myeloma seems to be the most tweaked in the past few months. So many combinations and permutations have been presented that we thought it appropriate to present a large review of the subject in an October HemOnc Today issue. For those embarking on therapy for new patients with this disease, I urge a careful perusal of the opinions presented therein by our interviewed experts: Paul Richardson, MD, A. Keith Stewart, MB, ChB, William Bensinger, MD, James Berenson, MD, Brian Durie, MD, and our own subsection editor, Morton Coleman, MD.

The stimulus for this review came from recent papers that demonstrated for the first time good-to-complete response rates of nearly 100% along with favorable tolerability profiles in multiple myeloma patients — patients who were provided with various three- or four-drug combinations of bortezomib (Velcade, Millennium Pharm), dexamethasone, melphalan, cyclophosphamide, thalidomide (Thalomid, Celgene) or lenalidomide (Revlinid, Celgene.) This embarrassment of riches with various drug combinations makes it all the more important to tailor therapy for individual patients. Moreover, the need for autologous or allo transplants after successful induction therapy in younger patients (approximately 65 years or younger) will again become a matter of judgment, rather than mandate, as complete responses approach 50% with drug therapy alone.

New debate over upfront use of all the “big drug guns” such as bortezomide, melphalan and thalidomide (or lenalidomide) in previously untreated patients vs. saving drugs for later relapse is also presented in our review. One comes away with the sense that results in this incurable disease are improving significantly. However, careful tailoring of patient to regimen and sensitive awareness of the significant, and often painful, neuropathy associated, especially with boratezomib, continues to be paramount.

What does not seem to be in doubt, is the great benefit of long-term use of bisphosphonates (particularly zoledronic acid) in inhibiting bone involvement and its miseries while significantly extending lifespan; — results were presented in June to the European Hematology Association in Barcelona.

Rituximab for follicular lymphoma

The role of rituximab (Rituxan; Genentech, Biogen Idec) maintenance therapy in follicular lymphomas (and I suspect, ultimately, in chronic lymphocytic leukemia) has been intensively studied this year and now seems likely to achieve standard-of-care status.

A major, multi-country study of high tumor-burden follicular lymphoma patients demonstrated a significant reduction in progression risk for patients randomly assigned to rituximab maintenance. The results analyzed after a 2-year median follow-up were presented at ASCO 2010 and a further year follow-up were to be provided at ASH 2010 this month. The latter robust results indicate complete and near-complete remissions sustained in 75% of rituximab-maintained patients as compared with 55% in patients similarly induced with immunochemotherapy but without maintenance treatments.

In a similar study of 465 patients by a European consortium (EORTC 20981) published in June in the Journal of Clinical Oncology, of those achieving significant remission after immunochemotherapy, rituximab maintenance significantly improved PFS compared with observation only (median, 3.7 years vs. 1.3 years). Moreover, 5-year OS increased as well (74% vs. 64%). The ever-present caveat: Maintenance therapy significantly increases grade 3-4 infection, approaching a 10% incidence over a median of 6 years. It should be noted that rituximab was provided as 375 mg/m² intravenously once every 3 months in the maintenance arm, and that no cases of encephalopathy were reported.

These studies in pre-induced patients more to be expanded this month (at the ASH meetings) in studies of treatment-naïve patients with asymptomatic, but advanced-staged, follicular lymphomas. In the plenary session, results from a multi-country trial demonstrated a remarkable benefit of rituximab without chemotherapy given at the time of diagnosis, followed by maintenance every 2 months for 2 years compared with watchful waiting, which has been preferred historically for asymptomatic patients. At 4 years, more than 70% of treated patients are progression-free and on no therapy compared with only 30% of watched patients. These results suggest to the authors that their findings “may change the management of patients with newly diagnosed asymptomatic follicular lymphoma.” I’m inclined to agree.

JAK2 inhibitors for myelofibrosis

The discovery that a tyrosine kinase, JAK2, is mutated in the myeloproliferative disorders — polycythemia vera, essential thrombocythemia and inmost primary myelofibrosis patients — has sparked a flood of papers this year. These mainly examine newly synthesized JAK inhibitors for myelofibrosis therapeutic efficacy in mouse models, as well as in human trials. A Medline search provides an astounding 100 or so such original and review articles in 2010 alone.

To date, significant benefit, particularly reduction of splenomegaly and improvement in constitutional symptoms (with concomitant decrease in inflammatory cytokines in myelofibrosis patients) has been noted with at least two different compounds by American, Italian and Australian investigators. Of interest are findings that significant benefit is observed in patients with or without the originally described JAK2V17F mutation, and that inhibitors studied to date affect JAK1 as well as JAK2.

In that regard, a NEJM paper in September from The University of Texas M.D. Anderson Cancer Center and Mayo Clinic investigators notes that approximately 50% of primary patients, as well as post-polycythemia vera or essential thrombocytosis-myelofibrosis patients, enjoy marked and durable clinical benefits from the oral drug, INCB018424, a potent and selective JAK1 and JAK2 inhibitor. Mutant JAK2 was irrelevant in responding patients. Adverse effects, mainly myelosuppression, were modest and observed in only 10% of patients; those with debilitating symptoms such as weight loss, sweats and pruritus were remarkably benefitted. Although improvement in splenomegaly (and associated early feeding satiety) was common, it is still too early to determine whether marrow fibrosis will also abate.

These salutary results were to be buttressed this month at the ASH meetings with studies that demonstrate INCB018424 also stabilizes some refractory myeloid leukemias (including markedly diminishing blasts), particularly in AML that develops as a post-myeloproliferative disorder and in chronic myelomonocytic leukemia. The authors suggest that combining a JAK inhibitor with chemotherapy may become a worthwhile stratagem for patients with post-myeloproliferative AML.

Also at the ASH meetings, an Australian pharmaceutical company reports on another newly formulated oral JAK1-2 inhibitor, CYT387, that also reduces spleen size and controls constitutional symptoms in myelofibrosis patients while significantly improving anemia and reducing transfusion requirements in nearly half the treated patients. For those of us who have observed the disastrous post-splenectomy complications attending splenectomy in myelofibosis/myeloid hyperplasia patients (mainly extreme thrombocytosis with thromboembolism), these new spleen-reducing agents are welcome indeed. All in all, worthwhile therapies are evidently in the pipeline for this previously neglected arena.

For more information:

• Freeman J. Ann Intern Med E-289 [epub ahead of print, Nov. 1, 2010].
• Kuter DJ. N Engl J Med. 2010; 363:1889-1899.
• Van Oers, MHJ. J Clin Oncol. 2010; 10:2854.
• Verstovsek S. N Engl J Med. 2010; 363:1117-1127.