Page 1254 - Hematology_ Basic Principles and Practice ( PDFDrive )

1100 Part VII Hematologic Malignancies

However, it should be avoided in patients with extremely high platelet
Algorithm for Management of Patients With Polycythemia Vera
counts who are at risk for hemorrhage.
Low-Risk Young Patients (Age <60 Years) and No History of Thrombo- After the disappointing results experienced with the alkylating
sis, Platelet Count <1.5 × 10 mm −3 agent chlorambucil, the PVSG began a nonrandomized phase II
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Phlebotomy + low-dose aspirin (81 mg/day) to maintain hematocrit investigation of hydroxyurea, an S-phase–specific ribonucleotide
lower than 45%. Aspirin should not be used in patients with histories reductase inhibitor. The hope was that this agent would be nonleu-
of a hemorrhagic episode or with extreme thrombocytosis (>1.5 × kemogenic. Of 53 patients with PV treated with hydroxyurea who
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−3
10 mm ) or acquired von Willebrand syndrome. had never received other forms of myelosuppression, after follow-up
↓ for a median period of 8.6 years and a maximum follow-up of 795
Thrombosis or hemorrhage weeks, 5.4% developed acute leukemia compared with 1.5% of
Systemic symptoms patients treated with phlebotomy alone on the original PVSG ran-
Severe pruritus refractory to histamine antagonists domized study.
Painful splenomegaly In a comparable trial from Israel, 71 patients were treated with
↓ hydroxyurea for a mean duration of 7.3 years. Remarkably, the
Hydroxyurea 15–20 mg/kg (unless age <40 years, pregnant, intoler-
ant to hydroxyurea; consider pegylated interferon [IFN]) incidence of thrombosis was only 6%, indicating the potential of
↓ hydroxyurea to lower the incidence of thrombosis in patients with
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Pegylated IFN 45–180 µg/week or IFN-α - (3 × 10 units three times PV, confirming an observation previously made by another group.
a week; alter dose depending on response and toxicity) or ruxolitinib The incidence of leukemia in the Israeli trial was 5.6%. In another
10 mg twice daily and titrate dose depending on the response. → retrospective series, the incidence of acute leukemia and myelodys-
In a patient with a prior thrombosis or a history of bleeding due to plasia in patients with PV treated with hydroxyurea alone was 6.9%.
acquired von Willebrand’s syndrome, normalization of platelet numbers In patients treated first with busulphan and then hydroxyurea, the
is necessary. If platelet control is inadequate or the patient cannot rate of acute leukemia and myelodysplasia was 13.8%. Twenty two
tolerate interferon, one option is the use of anagrelide. In this case, patients developed AML and MDS in the ECLAP study that enrolled
supplemental phlebotomy is required to maintain hematocrit lower than
45%, and the use of hydroxyurea should be considered, especially if 1638 patients. AML and MDS were diagnosed after a median of 8.4
the patient continues to have thrombotic episodes. years from the diagnosis of PV; the variable associated with progres-
↓ sion was older age, but overall disease duration (>10 years) failed to
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If the patient has increasing splenomegaly, systemic symptoms, or reach statistical significance. Exposure to P , busulphan, and pipo-
repeated thromboses despite adequate dose of hydroxyurea (2–3 g/ broman but not hydroxyurea alone had an independent role in
day) or if unable to tolerate hydroxyurea, start ruxolitinib 10 mg twice producing an excess risk for progression to AML and MDS compared
daily and titrate up or down based on hematologic parameters with treatment with phlebotomy or IFN. The potential leukemia-
For patients unable to tolerate ruxolitinib or resistant to it, start low promoting potential of hydroxyurea has been readdressed in two
doses of busulphan or melphalan, which should be administered until additional studies. Kiladjian and coworkers reported the results of
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the blood counts are normalized. Therapy should be then discontinued
since patients frequently enjoy drug-free prolonged remissions lasting a randomized trial of hydroxyurea versus piprobroman that was initi-
months. Therapy should only be reinstituted at the time the blood ated in 1980; the overall survival was 20.3 years in the hydroxyurea-
counts begin to be elevated again. Such therapy with alkylating agents treated group compared with 15.4 years for the patients treated with
should be rarely used in young patients. It should be mentioned that piprobroman. The incidence of AML and MDS in the piprobroman
the sequential use of hydroxyurea and alkylating agents may be associ- group was dramatically higher, which is not unexpected because
ated with an increased risk of leukemia. Supplemental phlebotomy pipobroman is an alkylating agent. This trial was designed with a
may be required. cross-over option, but 93 patients only received piprobroman. The
Painful splenomegaly incidence of AML and MDS in the patient group that only received
↓ hydroxyurea was 7.3%, 10.7%, and 16.6% at 10, 15, and 20 years,
Patients should be treated with ruxolitinib
If unable to tolerate or insufficient response respectively. Since there was not a control arm treated with phle-
Splenectomy + continued systemic therapy botomy alone, one cannot determine if this rate of evolution to AML/
↓ MDS represents the natural history of PV or a possible limited leu-
High-risk patients (age >60 years), previous thrombosis, platelet kemogenic effect of hydroxyurea. Interestingly, no difference in the
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count >1.5 × 10 mm −3 incidence of vascular events was seen between the two arms. This
Phlebotomy to hematocrit of 45% same question was again addressed in a nested case–control study
Aspirin (81 mg/day) to be given only in patients with platelet counts performed in Sweden. The most important observation was that
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<1.5 × 10 mm −2 25% of patients with various MPNs (68% had PV) who evolved to
Myelosuppressive therapy with hydroxyurea 30 mg/kg orally for 1 AML and MDS had not been exposed to any chemotherapeutic
week
Then 15–20 mg/kg agent, indicating that the risk of leukemic evolution was higher than
↓ had been previously appreciated. The use of radioactive phosphorous
If patient continues to have thrombotic episodes and has extreme and alkylating agents, but not hydroxyurea, was associated with a
thrombocytosis or cannot tolerate hydroxyurea higher rate of AML and MDS. These reports indicate that
Consider pegylated IFN 45–180 µg/week, anagrelide, or ruxolitinib nontreatment-related factors play a major role in the development of
10 mg twice daily, or add intermittent busulphan or melphalan (in AML and MDS, and the contribution of hydroxyurea based on the
older patients). best available evidence is at best minimal. These data and the ease of
If on busulphan or melphalan, stop when blood counts are normal- administration make hydroxyurea a very useful chemotherapeutic
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ized or platelet count is lower than 300,000 mm . agent in older, high-risk patients with disease that cannot be con-
Occasional supplemental phlebotomy if hematocrit is >45%; when
patient relapses (patient is symptomatic) initiate busulphan therapy trolled with phlebotomy alone. Excessive myelosuppression, macro-
again at same dose. cytosis, hypersegmentation of polymorphonuclear leukocytes,
cutaneous actinic keratosis, squamous cell carcinoma of the skin,
Patient Age >70 Years hyperpigmentation of the skin and nail beds, stomatitis, painful leg
Phlebotomy + low-dose aspirin + hydroxyurea ulcers, creatinine elevations, and jaundice have been attributed to the
↓ use of hydroxyurea. Aphthous and leg ulcers occur in 9% of patients,
No response or poor compliance usually after approximately 10 months of therapy (see Fig. 68.11).
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Ruxolitinib, melphalan, or busulfan.
Rarely, cycling of platelet and leukocyte counts but not RBCs occurs
while patients are being treated with hydroxyurea. In this situation,
the authors have maintained patients on a fixed dose of hydroxyurea
rather than chasing cycling platelet counts. In addition, the use of