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1328 Part X: Malignant Myeloid Diseases Chapter 86: Primary Myelofibrosis 1329

STAT3 and STAT5, inhibit colony growth of cells harboring JAK2 and Hydroxyurea can, inconsistently, decrease the size of the spleen and
MPL mutations, and to have therapeutic effects in a nude mouse model liver, decrease or eliminate constitutional symptoms of night sweats or
of JAK2 V617F -induced myeloproliferative disease. The effects of several weight loss, and occasionally lead to an increase in hemoglobin con-
415
JAK2 inhibitors have been described. 416–418 Although their effects are centration, a decrease of platelet counts, and a decrease in the degree
somewhat different, the most striking and consistent effect with each of marrow fibrosis. Patients with myelofibrosis often do not have the
agent is a decrease in spleen size and reversal of constitutional symp- marrow tolerance to chemotherapy of patients with other chronic mye-
toms. They often suppress blood cell counts, and thrombocytopenia can loproliferative diseases. Hydroxyurea can be administered in doses of
be dose-limiting. At least initially, the anemia worsens although this 0.5 to 1.0 g/day or 1 to 2 g orally two to three times per week, depending
laboratory deterioration may be transient, lasting only for few months. on the level of pretreatment blood cell counts. Patients should be evalu-
Typically, in spite of progression of anemia, most treated patients report ated for dose adjustment at least every week for 1 month and, if appro-
decreased fatigue. The reduction in large spleen size and the improve- priate, eventually extended to evaluation every 3 months. Although
ment in the quality of life of many patients have been dramatic and were alkylating agents, especially busulfan and other cytotoxic agents, have
similar in those with and without a JAK2 mutation. This effect may be been used successfully, they have largely been replaced by hydroxyurea.
explained by the drug’s ability to inhibit JAK1 and JAK2 isoforms, the Use of alkylating agents has resurfaced with the suggestion that melpha-
former having a role in cytokine elaboration. These agents may decrease lan or busulfan may be useful as therapy. 427,428
morbidity and mortality, prolonging survival (see “Course and Progno-
sis” below). 419–423 Thalidomide and Lenalidomide
In 2011, ruxolitinib, an oral JAK2 inhibitor, was approved by the Thalidomide is poorly tolerated at optimal doses of approximately
FDA for use in patients with intermediate or high-risk myelofibrosis. It 800 mg/day. Most patients receive about half that amount and are
decreases spleen size, fatigue, night sweats, pruritus, and red cell trans- tapered to the lowest effective dose. One study of 14 patients found
fusion requirements, and can result in weight gain in a significant pro- the drug was not beneficial and had high toxicity rates. Other stud-
429
portion of patients. The principal dose-limiting side effect is a decreased ies found some decrease in spleen size and improvement in blood
platelet count. Although some patients may have worsened anemia or hemoglobin and platelet counts in a minority of patients receiving up
neutropenia, the net effect often was beneficial, with improvement in to 600 mg/day. 430,431 In subsequent studies, lower doses of thalidomide
fatigue and other symptoms. Headache, dizziness, and diarrhea also (50 mg/day) coupled with prednisone were more tolerable and resulted
may occur but are usually manageable without discontinuing the drug. in improvement of anemia and thrombocytopenia in about half of
After 6 months of treatment approximately 40 percent of treated patients patients, with sustained improvement in some patients after treatment
have a significant decrease in spleen size and constitutional symptoms. was stopped. The thalidomide congener lenalidomide may supersede
432
The initial drug trials were limited to patients with a platelet count at the thalidomide use. Lenalidomide has provided responses in a significant
9
initiation of ruxolitinib therapy of 100 × 10 /L; however, newer studies minority of patients. 433–436 The drug can result in marked improvement
using lower starting doses of ruxolitinib and gradually incrementing in hemoglobin concentration or avoidance of a requirement for trans-
those doses have indicated that patients with platelet counts of between fusion (22 percent of patients treated), improvement in platelet count
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50 and 100 × 10 /L may receive similar benefits from carefully incre- (50 percent of patients treated), and decrease in spleen size (33 percent
mented drug doses. Table 86–4 shows a suggested approach to initial of patients treated). Neutropenia and thrombocytopenia were the most
dosage. Of all available therapeutic modalities for primary myelofibro- troubling side effects. The drug has also been useful in patients with
433
sis, ruxolitinib is the only therapy that has shown benefit in clinical tri- primary myelofibrosis who have a 5q– cytogenetic abnormality. 435,436
als that included a comparison group given a placebo. Another thalidomide congener, pomalidomide, has completed a phase
3 trial and has not been shown to decrease transfusion requirements. 437
Hydroxyurea
Hydroxyurea is a commonly used agent for exaggerated accumulation Cyclosporine, Etanercept, Imatinib Mesylate, and Tipifarnib
of platelets, occasional very high leukocyte counts, troublesome areas Cyclosporine has been used to achieve a serum level of 100 to 200 ng/
of extramedullary hematopoiesis, and symptomatic splenomegaly. 424–426 mL in severely anemic patients with evidence of immune abnormalities
(positive Coombs test, antinuclear antibodies). Three of six patients
438
responded with an increased hemoglobin concentration. Cyclosporine
TABLE 86–4. Guideline for Initial Oral Ruxolitinib Dose in has been used with apparent success in a single patient with myelofibro-
439
Primary Myelofibrosis sis and red cell aplasia.
TNF-α has been proposed as a target to inhibit its possible effects
Platelet Count Dose in the pathogenesis of primary myelofibrosis. Of 20 patients treated
440
>200 × 10 /L 20 mg twice daily with soluble TNF-α receptor (etanercept), 12 had improvement in con-
9
stitutional symptoms (fever, night sweats, fatigue, weight loss), and four
9
100–200 × 10 /L 15 mg twice daily
had improved blood counts and decreased spleen size. 441,442
50–100 × 10 /L 5 mg twice daily (increasing each month Imatinib mesylate for treatment of myelofibrosis has been exam-
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by 5 mg daily until maximal splenic size ined on empirical grounds and has been largely ineffective in influenc-
reduction, only if platelet count stays ing the disease course. 442,443 Modest doses have not been well tolerated,
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above 40 × 10 /L) *
and responses have been infrequent and insubstantial.
444
* Drug not FDA approved for starting platelet counts of 50 to 100 × 10 /L. The farnesyl transferase inhibitor tipifarnib is not well tolerated.
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If platelet count decreases while on ruxolitinib therapy, dose reduc- Although it may decrease spleen size, it has shown no advantages over
hydroxyurea.
tion should be made in relation to level of platelet count. The drug
should not be administered if platelet counts falls to less than
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50 × 10 /L. Therapists should consult more detailed guidelines, Pre- Interferons
scribing Information, published by Incyte, for use of ruxolitinib (Jakafi) Interferon-α and interferon-γ act synergistically to inhibit myeloprolif-
(revised November 2011). eration. Interferon-α has been used extensively for treatment of CML
445
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