Page 1302 - Hematology_ Basic Principles and Practice ( PDFDrive )

1148 Part VII Hematologic Malignancies

of clinical activity that is associated with enhanced histone acetyla- IFN are anticipated to lead to significant clinical improvements in
tion. A report of the results of long-term administration of low-dose the outcomes of PMF patients. The evaluation of these combination
panobinostat in MF patients demonstrated the potential to alleviate therapies will certainly require the use of novel strategies for the
constitutional symptoms, reduce splenomegaly, improve anemia, design of clinical trials that will evaluate the effects of several active
eliminate peripheral blood leukoerythroblastosis, reduce BM reticulin agents administered either simultaneously or sequentially. Overall,
and collagen fibrosis, and restore normal BM morphology in a small the implementation of any therapeutic approach by the practicing
number of patients. A phase II study of panobinostat at a dose of community of hematologists should only occur after evidence is
25 mg orally thrice weekly is currently ongoing, and studies combin- provided by the completion of well-planned and adequately powered
ing this agent with ruxolitinib are ongoing, and the results are highly phase III trials comparing the experimental approach to the standard
anticipated. The therapeutic potential for the use of chromatin- of care. aSCT with RIC and PBSC grafts remains the only potentially
modifying agents for the treatment of PMF patients is an exciting curative therapy available for patients under 70 years of age with
approach and requires further careful evaluation in ongoing, well- an acceptable performance status and a suitable available donor.
designed clinical studies. Although there is a reluctance to expose PMF patients to the risks
A novel and exciting therapeutic approach to the treatment of MF of aSCT, if their underlying disorder is associated with a sufficiently
was recently reported by the Mayo Clinic group, in which a pilot poor prognosis, this risk appears to be warranted. Because early
study at this single institution was conducted evaluating an infusional forms of PMF are associated with survival of well over a decade,
telomerase inhibitor. Imetelstat is a 13-mer lipid conjugated oligo- many individuals have been even more reluctant to expose such
nucleotide competitive inhibitor of telomerase RNA (hTR) resulting patients to experimental therapeutic agents or aSCT. Unfortunately,
in telomere shortening and cell cycle arrest and apoptosis. Thirty progression to more advanced forms of MF is anticipated in younger
three patients were treated either with weekly infusion and then every patients. Exploration of therapeutic agents that can delay or even
3 weeks infusion or every 3 weeks from the start. The majority of prevent disease progression or identification of the appropriate role
patients discontinued due to suboptimal response or progressive of SCT in this low-risk group will require additional study. Such
disease, and three patients died on study. However, after a median of trials will be time consuming due to the prolonged survival of such
five cycles of treatment, seven responses were documented (four patients with low-risk disease. The decision to proceed to transplant
complete response and three partial response; three complete molecu- requires a detailed discussion of the risks and benefits of such a
lar responses) and appeared to be durable for a median of >9 months). high-risk but potentially curative procedure. The recent establish-
Additionally, anemia responses (n = 4) and 50% reduction in spleen ment of multiinstitutional cooperative groups to evaluate such novel
size (n = 9) were reported. The occurrence of transaminitis was a therapies and treatment strategies for PMF patients has met the
cause initially for temporary study hold and now a large multicenter need of insuring rapid evaluation of candidate therapeutic agents.
phase II trial will evaluate imetelstat in MF patients and molecular No single institution has sufficient numbers of patients to perform
determinants of therapy response will be prospectively assessed. this ever-growing number of required investigative efforts. Only with
the completion of such rigorous evaluations of individual therapeutic
strategies will one be able to determine the value of a continu-
FUTURE DIRECTIONS ously growing number of potentially active agents used alone or in
combination. Each new therapy will likely be evaluated using not
More rational therapies for PMF are evolving from increased only a number of clinical endpoints, but also surrogate biomarkers
understanding of the cellular and molecular biologic abnormali- and consideration of the immediate and long-term toxicities associ-
ties underlying PMF. Studies defining the relative contributions of ated with their use documented. Independently developed objective
acquired genetic mutations, epigenetic events, as well as the influence criteria by which responses to experimental therapeutic agents can be
of the BM and splenic microenvironment on the origins of PMF, judged must be implemented for the evaluation of promising agents.
disease progression, and events leading to leukemic transformation Furthermore, quality-of-life tools have become more widely used
are ongoing. Because PMF originates at the level of the HSC, the in the evaluation of such experimental therapeutic agents. Because
identification of novel drugs that eliminate such malignant stem cells it is likely that a large number of such agents will be evaluated in
is likely the most direct route to potentially curative pharmacologic patients with PMF in the future, it is recommended that a uniform
strategies. Also, further delineation of the therapeutic potential standard be adopted so that the relative efficacy of any new thera-
of IFN as well as histone deacetylase inhibitor therapies must be peutic approach can be more easily judged. The integration of these
pursued to define their potential use in the management of PMF new classes of agents can also be incorporated into the conditioning
patients. The evaluation of the use of combinations of active agents, regimens that are used before aSCT; this approach will also likely
including the JAK2 inhibitors, TGF-β inhibitors, IMiDS, histone contribute to significant improvements in outcomes in PMF patients
deacetylase inhibitors, telomerase inhibitors, and pegylated forms of undergoing aSCT.

How Should PMF Patients With Thrombocytopenia Be Treated?
Platelet Count 50–100 × 10 /L: phase III trial, pomalidomide failed to meet the primary endpoint of
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It is important to be certain that vitamin B 12 or folate deficiencies and/ anemia response (transfusion independence: ≥84 days), but the platelet
or sustained suppression from prior chemotherapeutic agents have not response rate was 22% in the treatment arm. This finding supported the
contributing to the development of a low platelet count. Chemothera- previous phase II findings of a response rate of 58% in increasing the
peutic agents such as hydroxyurea can be used in patients with marked baseline platelet count by greater than 50% in patients with baseline
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splenomegaly, which can result in an improvement in the platelet count platelets above 50 × 10 /L. This second-generation IMiD has not been
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as the spleen volume is reduced. Patients can also be treated with evaluated in patients with platelet counts below 50 × 10 /L. A course
thalidomide or lenalidomide in combination with prednisone. These first- of prednisone therapy should also be considered, since 30–40% of
generation immunomodulatory drugs (IMiDs) can sometimes improve patients have been reported to respond to this agent alone. Ruxolitinib
cytopenias and reduce splenomegaly in primary myelofibrosis (PMF) has more recently been shown to be safe and effective in patients
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patients, and in some cases, this response can persist even after drug with baseline platelet counts as low as 50 × 10 /L, and the FDA label
discontinuation. Lenalidomide can induce cytopenias to a greater extent has been expanded to include such myelofibrosis patients. Sustained
than thalidomide, which needs to be taken into consideration before thrombocytopenia with ruxolitinib therapy is an indication for a dose
this agent is used in the thrombocytopenic patient. In a randomized reduction or discontinuation of the drug. Patients can also be enrolled