Page 1256 - Hematology_ Basic Principles and Practice ( PDFDrive )

1102 Part VII Hematologic Malignancies

and in 14% and 6% of PV and ET patients, respectively, in the differential diagnosis of patients being treated with any formulation
United States study after about 2 years’ median follow-up. Combin- of IFN. The role of pegylated IFN therapy versus hydroxyurea
ing both studies, 12 out of 64 (19%) PV patients achieved a molecular therapy or pegylated IFN versus ruxolitinib will be defined only after
complete response (MCR). Of note, many of these MCRs occurred the performance of a randomized phase III trial in newly diagnosed
after the 12th month of treatment, but hematologic responses high-risk ET and PV patients. Two randomized multicenter trials
occurred within a few weeks. Prolonged exposure (>12 months) to comparing IFN and hydroxyurea are currently ongoing and will
peg-IFNα-2a seems to be an important factor in achieving MCR. hopefully establish differences in terms of efficacy and tolerability of
The reduction in the JAK2V617F allele burden was not influenced the two medications.
by the cumulative dose of peg-IFNα-2a in the PVN-1 study, but The use of small-molecule inhibitors of JAK1/2 ruxolitinib was
toxicity was clearly dose dependent in the United States study. Taken first approved in the United States in 2011 for the treatment of
together, these results indicate that peg-IFNα-2a therapy is best initi- advanced forms of MF, and most recently in 2015 was approved for
ated at very low doses that are gradually increased until hematologic the treatment of patients with PV that are intolerant or resistant to
response is achieved; this strategy avoids cessation of therapy and HU. In a phase III study (RESPONSE trial), hydroxyurea resistant
allows sufficient exposure to the drug to allow for the achievement or intolerant patients were randomized to receive either ruxolitinib
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of a molecular response. These results are in agreement with studies or standard care. To be eligible for the study entry patients had to
3
from Denmark, showing major molecular responses in PV after long- have splenomegaly with a spleen volume of at least 450 cm and
term treatment with IFNα-2b that could persist after IFN-α was ongoing phlebotomy requirements, and be resistant to or intolerant
discontinued. Finally, several who achieved MCR in the PVN-1 study of hydroxyurea according to the standardized criteria. Standard care
have maintained this response after peg-IFNα-2a was discontinued was selected by the investigator and included hydroxyurea. Patients
(≤30 months after discontinuation), with none experiencing hema- receiving standard therapy were able to cross over to ruxolitinib if
tologic relapse. Such long-term clinical and molecular responses after they failed to achieve the primary end point by 32 weeks. The
the discontinuation of treatment have previously been reported after primary end point was achievement of hematocrit control and reduc-
IFN-α therapy in MPN patients, an effect that has not been reported tion in spleen size (at least 35% by MRI). This was achieved in 21%
with other currently available therapies. It is important to emphasize of patients in the ruxolitinib arm versus 1% of patients in the standard
that the elimination of JAK2V617F in this setting is not necessarily therapy arm. Hematocrit control was achieved in 60% of patients
indicative of cure of the MPN, and that clinical implications of these receiving ruxolitinib and 20% of patients receiving standard therapy,
molecular responses remain uncertain and require validation. It has and 38% of patients in the ruxolitinib arm met the reduction in
been shown that molecular relapse can rapidly occur after IFN-α spleen end point versus 1% of patients in the standard therapy arm.
discontinuation in some cases. In one patient with a biclonal By week 80, almost 60% of patients treated with ruxolitinib had
JAK2V617F/TET2-mutated PV, peg-IFNα-2a treatment did not normalization of their platelet counts. Patients on ruxolitinib enjoyed
affect the TET2-mutated cells, but the JAK2V617F clone was eradi- improvement in such PV-related symptoms as pruritus, headaches,
cated. Nevertheless, prolonged periods of time (≤40 months, personal fatigue, and night sweats. The mean change in JAK2V617F allele
unpublished data) during which the patient remained in complete burden from baseline to week 32 was 12.2% in the ruxolitinib group
hematologic remission without any cytoreductive therapy after peg- and 1.2% in the standard therapy group. Based on an analysis after
IFNα-2a withdrawal was observed in several patients of the PVN-1 80 weeks of follow-up, there was a suggestion that those patients
study even though low levels of the JAK2V617F allele (≈5%) were receiving ruxolitinib had a reduced incidence of serious thrombotic
still detected. Such results suggests that despite the disease not being events but that ruxolitinib therapy did not affect progression to MF
eradicated, long-term exposure to peg-IFNα-2a was sufficient to and AML; these conclusions are not well substantiated since the study
modify the clinical expression of the MPN for a sustained period of was not powered to examine these events. It also did not provide
time. information on correction of the BM histopathological findings and
In addition to clinical, hematologic, and MCRs achieved in a chromosomal abnormalities in patients treated with ruxolitinib. In
significant proportion of PV and ET patients, IFN-α therapy has also general, ruxolitinib was well tolerated with 85% of patients remain-
been shown recently to reverse BM histopathologic abnormalities in ing on ruxolitinib at 81 weeks. The most common nonhematological
selected cases of both PV and PMF. Thus, IFN-α seems to be a drug adverse event was diarrhea, while the hematological toxicity included
able to deplete PV stem cells, and induce complete resolution of all anemia, lymphopenia, and thrombocytopenia. In addition the rates
clinical, biologic, and morphologic abnormalities in selected MPN of nonmelanoma skin cancer were higher in the ruxolitinib arm
patients, raising the hope that a curative outcome might be possible compared with those patients receiving standard therapy. An increase
in a limited subset of such patients. These observations lead one to in infectious complications was observed on ruxolitinib treatment,
question the validity of the current therapeutic strategies for PV and specifically herpes zoster infection. This has also been observed in MF
ET patients in which myelosuppressive therapy is exclusively used in patients treated with ruxolitinib. Cases of tuberculosis activation,
subpopulations of patients at high risk for developing additional toxoplasmosis, and other atypical infections have been reported in
thrombotic events ruxolitinib-treated patients. The increased number of infections has
IFN is not a leukemogenic drug but it is also not an innocuous been attributed to the inhibition of both T- and NK-cell function by
agent, necessitating careful follow-up of patients receiving such treat- ruxolitinib.
ment. Initially, many patients experience flu-like symptoms, which Pruritus in PV patients occurs on exposure to sudden body
are controllable with acetaminophen or aspirin. Such symptoms cooling, especially after a warm bath, and is experienced by as many
usually resolve spontaneously after several months of therapy. More as 40–60% of patients treated with phlebotomy. Aquagenic pruritus
serious side effects, including excessive suppression of blood counts, in MPN patients and in patients without an associated malignancy
irritability, high fevers, severe asthenia, reversible lower extremity has been associated with lactose intolerance. In some instances,
bilateral neuritis, retinopathy, hypothyroidism, depression, sarcoid- multiple family members are affected, suggesting that genetic factors
osis, and left-sided heart failure have been reported and may require might predispose individuals to this symptom. In some studies,
cessation of IFN-α therapy. Exacerbation of depression and other basophils and mast cells have been shown to be involved with
psychiatric manifestations are serious potential side effects of IFN, JAK2V617F in patients with aquagenic pruritus and PV, likely
and it should probably not be used in patients with history of clini- leading to the elaboration of mediators that lead to itching. The
cally significant psychiatric conditions. Patients and family members frequency of pruritus appears to be somewhat lower in patients
should be counseled to watch for subtle evidence of depression, mood treated with myelosuppressive agents. This observation is related to
swings, and personality changes and to immediately report their the probable relationship between pruritus and degranulation of
concerns to the treating physician. The use of IFN should also be tissue mast cells and circulating basophils. Aged transgenic mice
avoided in patients with any history of autoimmune diseases and new expressing JAK2V617F suffer from pruritis and the massive accumu-
development of autoimmune disorders should be high on the lation of mast cells in the skin. Cultured mast cells from these mice