Page 1295 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 70 Primary Myelofibrosis 1141

chromosome 1q, which occurs in 22% of PMF patients, has been degree of splenomegaly and alleviating systemic symptoms, therapy
reported to be associated with disease progression, and jumping 1q for PMF patients has become much more effective. The therapeutic
translocations have been observed to be associated with imminent strategies employed for an individual patient are currently based on
transformation to AML. In PMF, the region on chromosome 1 that an assessment of the patient’s clinical characteristics, performance
is most frequently duplicated or occurring in trisomy is between status, and prognosis estimated using one of the prognostic scoring
1q21-32 and 1q32-44 band regions (see Fig. 70.5). The 5-year sur- systems described above. A conservative approach to management is
vival for patients with an unfavorable karyotype, including trisomy generally recommended for low-risk patients, with observation of
8, abnormalities of chromosomes 5 or 7, inversion of chromosome asymptomatic patients and therapeutic intervention reserved for
3, isochromosome 17q, deletion 12p or 11q23 rearrangement, as well patients with intermediate/high-risk disease or individuals with
as two abnormalities including an unfavorable abnormality and a especially burdensome symptoms. 10
complex karyotype, was 8% with a median survival of 2 years. In general, therapy is indicated for PMF patients with the follow-
Moreover, multivariable analysis demonstrated that karyotype and ing conditions: symptoms attributable to anemia, pressure symptoms
9
platelet count (<100 × 10 /L) but not the IPSS status predicted related to splenomegaly, bleeding problems, life-threatening throm-
leukemia-free survival. The 5-year leukemic transformation rates for bocytopenia, significant hyperuricemia, bone pain, systemic symp-
patients with an unfavorable versus favorable karyotype were 46% toms (fevers, night sweats, and weight loss), and portal hypertension
and 7%, respectively (p < .0001). The widespread implementation of and life-threatening gastrointestinal bleeding. Hyperuricemia should
this cytogenetically-based scoring system requires more extensive be aggressively treated in all patients with PMF. Hydration and
validation. A new cytogenetic risk category, monosomal karyotype chronic administration of allopurinol (300 mg/day) are suggested.
(MK), also defines an unfavorable risk category. An MK is defined Patients with the prefibrotic form of MF or low-risk MF, par-
as having two or more autosomal monosomies or a single autosomal ticularly if they are young, are particularly challenging for most
monosomy associated with at least one structural abnormality. This physicians. These patients are largely asymptomatic but are at a risk
is a rare cytogenetic change associated with median survival of 6 of their disease eventually evolving to a symptomatic form of MF
months and a 2-year leukemic transformation rate of 29.4%. At or acute leukemia. Many patients are eager to entertain options that
diagnosis of PMF, detection of MK is associated with extremely poor might prevent the evolution of such disease but at present there
overall and leukemia-free survival. is no data to indicate that any approach can successively achieve
The mutational profile of a MF patient has also been shown to this goal. Also aSCT is not an option for such patients due to the
have prognostic significance. Four risk groups based on mutational morbidity and mortality associated with its implementation. During
status of the driver mutations involving JAK2, MPL, and CALR have the last decade several investigators have promoted IFN-α therapy
been shown to predict different overall and leukemia-free survival. as an agent that might be capable of delaying disease progression by
MF patients with CALR-positive, JAK2V617F-positive, MPL- decreasing the rate of fibrosis if administered chronically during the
positive, or “triple-negative” disease have a mean OS of 17.7 years, early course of this disease. Others have not reported such effects in
9.2 years, 9.1 years, and 3.2 years, respectively. In fact, the incorpora- patients with more advanced phases of the disease. In one series, only
tion of these molecular markers into modern risk-adapted treatment four of 11 patients were able to complete 1 year of therapy; the other
stratification has been proposed by some investigators. Additionally, seven patients discontinued the drug because of unacceptable toxic-
MF patients harboring both CALR and ASXL1 mutations have been ity or the development of severe cytopenias. A clinically significant
shown to have a good prognosis compared with patients harboring improvement (degree of BM fibrosis, osteosclerosis, or angiogenesis)
an ASXL1 mutation alone. was not observed in any of these patients. A small phase II pilot study
Most studies have indicated that the OS of patients with in PMF patients demonstrated responses in patients with a prefibrotic
JAK2V617F-positive and -negative PMF are similar; however, patients form of PMF treated with low doses of IFN-α-2b over an extended
with JAK2V617F-positive disease and a low allele burden (<25%) period (median duration: 3 years). Four patients with JAK2V617F-
have been shown to have a shorter survival time. In addition, muta- positive PMF were followed over time, and although each had clinical
tions in MPL or TET2 do not appear to influence overall or responses, only one had a significant reduction in mutant allele
leukemia-free survival. A number of investigators have attempted to burden. The drug was generally well tolerated at doses between 1 and
correlate the presence of a variety of additional mutations with disease 2 million units weekly, and responses in the BM included reduction
outcomes. See Table 70.2 for a list of documented recurrent acquired in the degree of reticulin fibrosis and abnormal cellular morphology.
mutations associated with MF. EZH2 mutations have been identified Eleven patients with PMF were treated with a pegylated form of
in 6% of patients with PMF, 3% of PV patients, 3% of patients with IFN-α-2b (PEG-IFN-α-2b) at starting dose between 2 and 3 µg/
post-PV MF, and 9.4% of patients with post-ET MF. More than 40% kg/week; only a single patient responded. Although the pegylated
of the patients with EZH2 mutations were JAK2V617F-positive, 6% form of this drug allows for weekly injections, the toxicity profile was
have a TET2 mutation, and, 22% harbored an ASXL mutation. found to be similar to the standard formulation and for many patients
Concurrent EZH2 mutations and MPL mutations have not been limited the duration of therapy. The most common grade 3/4 toxicity
observed. EZH2 mutations are usually present at the diagnosis of was fatigue and thrombocytopenia. Because of the recent encouraging
chronic MPN and are maintained universally in the leukemic blasts results reported with PEG-IFN-α-2a (Pegasys) in PV patients, this
at the time of transformation to AML. EZH2-mutated patients are form of IFN-α has also been evaluated in MF patients. The French
characterized by more profound leukocytosis and larger spleens, and Groupe d’Etudes des Myelofibrosis (GEM) and France Intergroupe
have a higher percentage of blasts. The survival of patients with EZH2 des Syndromes Myeloproliferatifs conducted a study of 18 patients
mutations was clearly inferior because they are clustered in patients with PMF and post-ET/PV MF treated with Pegasys. Of the four
with high-risk IPSS scores. In addition, IDH mutations, albeit rare PMF patients included in this study, one had a complete response,
in PMF patients, have been associated with inferior survival in two had a minor response, and one had no response. Responses were
JAK2V617F-positive patients, raising the possibility of the coopera- associated with improvement in the degree of anemia, leukocytosis,
tion between IDH mutations and JAK2V617F in leukemic and thrombocytosis, but not splenomegaly, and appeared to be
transformation. irrespective of JAK2 status. Comprehensive reviews of the literature
suggest that modest benefits may be derived from IFN-α therapy for
PMF after patients have entered the more advanced phases of the
Therapy disease. Further large randomized studies are warranted in patients
with the prefibrotic phase of PMF to determine the effects of this
The treatment of the PMF patient was thought until recently to be modality of treatment on disease-free survival, OS, quality of life,
largely a futile exercise, but with reports of curative nonmyeloablative and progression to more advanced phases of PMF or evolution to
(MA) aSCT for a subpopulation of PMF patients, and the approval acute leukemia. Before such trials are completed, IFN therapy at
of a small-molecule JAK2 inhibitor that is effective in reducing the any phase of PMF should be considered an experimental form of