Leukemic transformation of polycythemia vera after treatment with hydroxyurea and chromosome 17 abnormalities

The authors present two patients with polycythemia vera where they recorded after several years' treatment with hydroxyurea development of acute myeloblastic leukaemia. In both instances they found, associated with leukaemia, abnormalities of chromosome no.17, in one case meeting criteria of the so-called 17p-syndrome. Progression of polycythemia vera into acute leukaemia is explained by the possible association with the long-term use of the drug and loss of chromosomal material (short arm of chromosome 17), the part where genes important in the process of leukaemogenesis are located. The authors draw attention to contemplated long-term administration of hydroxyurea to young patients with polycythemia vera. As cytogenetic analysis is a suitable method for evidence of progressing polycythemia vera into acute leukaemia, dynamic follow up of chromosomal changes is necessary, in particular in patients where long-term treatment with hydroxyurea is assumed.     

Nitric oxide generation from hydroxyurea: significance and implications for leukemogenesis in the management of myeloproliferative disorders

The use of myelosuppressive agents to reduce the risk of thrombosis in patients with polycythemia vera (PV) and essential thrombocythemia (ET) has been associated with an increased risk of transformation to acute myeloid leukemia (AML). Whereas chlorambucil, busulfan, and radiophosphorus (32P) have been demonstrated to increase the risk of transformation, the leukemogenic potential of hydroxyurea (HU) continues to be a matter of debate. Clinical studies have suggested that HU may cause a small increase in the risk of AML, but it has proven difficult to establish whether AML is actually caused by HU or arises during the natural progression of PV and ET. Reports that HU undergoes metabolic activation to species that induce mutation appear to support the notion that it is leukemogenic. Here, we suggest that the ability of HU to induce mutation in cell culture studies results from the generation of nitrogen dioxide via the autoxidation of nitric oxide, a product of HU metabolism. However, we argue that autoxidation would not occur in vivo, leading to the conclusion that generation of the mutagen nitrogen dioxide is peculiar to cell culture systems and has little relevance to the use of HU in the management of PV and ET.     

A clinical update in polycythemia vera and essential thrombocythemia

Polycythemia vera and essential thrombocythemia pose specific management issues that distinguish them from other chronic myeloproliferative disorders. They are associated with a better prognosis, as well as a variable risk of thrombohemorrhagic complications. In addition, essential thrombocythemia occurs comparatively more often in young people and women. Treatment strategies for patients with polycythemia vera and essential thrombocythemia must consider the possibility of long-term survival, morbidity from thrombotic complications, transformation into myelofibrosis with myeloid metaplasia or acute myeloid leukemia, and the effect of specific therapies on the incidence of leukemic transformation and on pregnancy. There is increasing concern about the possible leukemogenic effect of hydroxyurea. Newer therapeutic agents, including interferon alpha and anagrelide, are being used more often. Ongoing studies are reexamining the effects of low-dose aspirin in preventing thrombotic complications.     

Leukemic risk in thrombocythemia

OBJECTIVES: To define pathogenesis, incidence, clinical presentation and prognosis of leukemic transformation (LT) in patients with essential thrombocytemia (ET); to compare the incidence of LT in previously treated versus untreated patients; to search for risk factors of LT, with special reference to the iatrogenic risk of myelosuppressive drugs. DATA SOURCES AND EXTRACTION: Most significant French and English-language papers published between 1981 and 1997 dealing with either ET, LT, clonality, cytogenetics, alkylating agents or hydroxyurea were reviewed. Patient characteristics, clinical presentation, bone marrow and cytogenetic findings, and survival data were extracted from each case report and review, and possible risk factors were analyzed. DATA SYNTHESIS: Despite the existence of clonal hematopoiesis in up to 60-80% of patients with ET, suggesting an intrinsic potential for subsequent leukemia, spontaneous LT is poorly documented and the common presumption that TL occurs in excess in treated patients with ET is still questionable. The incidence of LT, probably underestimated in the past, varies from 0.7% to 5.3% in retrospective series, and from 8% to 12% in prospective studies. Recurrent cytogenetic abnormalities are significantly more frequent and complex in marrow karyotypes performed at the time of blastic crisis, as compared with those performed at diagnosis. A review of 62 reports of LT highlights some important characteristics: a) LT can occur anytime during the chronic phase of ET, especially within the first eight years, b) all subtypes of leukemia are described, notably unclassifiable cases and megakary oblastic acute leukemias, c) bone marrow fibrosis is frequent, as is a progressive onset of a myelodysplastic syndrome preceeding the blastic crisis, d) the prognosis of LT is very poor, two-third of all patients die within 6 months. Apart from the onset of a myelodysplastic syndrome, which carries a poor outcome, there is no well-established risk factor of LT. The leukemogenic risk of myelosuppressive therapies, clearly demonstrated for years in polycythemia vera, cannot be directly ascertained in patients with ET, but is suggested by various indirect observations. This putative risk of inducing secondary leukemia affects not only alkylating agents but also hydroxyurea. CONCLUSION: LT is a highly serious and largely unpredictable complication of ET. The current debate on the specific risk of myelosuppressive treatments deserves large-scale prospective randomized studies. Until this crucial point is elucidated, any cytotoxic therapy should be reserved to elderly and/or symptomatic patients and to those having other vascular risk factors.     

Acute leukemia following treatment of polycythemia vera and essential thrombocythemia with uracil mustard

Transformation to acute leukemia (AL) is known to occur in polycythemia vera (PV) and essential thrombocythemia (ET). Myelosuppressive therapy with agents such as 32P and alkylating agents increase this risk in both disorders. The alkylating agent, uracil mustard (UM), which is an effective agent for controlling thrombocytosis, has not been reported to be leukemogenic. We have treated 29 patients with UM (9 treated continuously and 20 treated intermittently): II with PV, 16 with ET, and 2 with myelofibrosis (MF). Three patients developed AL, two after continuous therapy. These two patients with PV had received the fourth highest and highest total dose of UM, and their duration of treatment was the third and fourth longest among the nine patients treated continuously, respectively. One out of 20 patients treated intermittently with UM developed AL. This patient (3) with ET had received the highest total dose of UM, and her duration of treatment was the longest among the 20 patients treated intermittently.     

Treatment of polycythemia. II.--Comparison of hydroxyurea with pipobroman in 294 patients less than 65 years of age

AIMS: To compare by a prospective study in low risk polycythemia vera (PV) patients alone two drugs: hydroxyurea and pipobroman. Toxicity, efficiency, and leukemogenic potential were studied. PATIENTS: 294 patients with a documented PV, aged less than 65 years, have been included since 1980 in a prospective study comparing hydroxyurea and pipobroman. Blood cell counts were performed every two months and a clinical evaluation by a specialist was obtained every four or six months. RESULTS: Hematologic toxicity of both drugs was higher than expected, requiring strict surveillance. These drugs were tolerated in some (gastric pain and diarrhea on pipobroman, buccal aphtosis and chronic leg ulcers on hydroxyurea), leading to a change of arm in 10% of the cases. Hydroxyurea did not control the megakaryocitic hyperplasia in 40% of the cases, which probably explains a high rate of progression to myelofibrosis with myeloid metaplasia in this arm. Both drugs were leukemogenic with an actuarial risk of about 15% at the 15th year, not significantly lower than that observed in the 32P treated patients. A significant risk of cutaneous malignancy was observed in the hydroxyurea arm. The mean expectancy of life cannot yet be accurately evaluated, but seems significantly lower than that of the reference population. CONCLUSION: The treatment of PV by hydroxyurea or pipobroman has to account for these results less optimistic than those traditionally well-known to hematologists and internists.     

Frequent reduction or absence of detection of the JAK2-mutated clone in JAK2V617F-positive patients within the first years of hydroxyurea therapy

We analyzed the effect of hydroxyurea on the JAK2V617F allelic ratio (%JAK2V617F), measured in purified blood granulocytes, of patients with polycythemia vera and essential thrombocythemia. Thirty-six patients were examined sequentially prior to and after start of hydroxy-urea therapy (8 polycythemia vera, 17 essential thrombocythemia), or while remaining untreated (2 polycythemia vera, 9 essential thrombocythemia). Hydroxyurea therapy (median duration: 15 months) reduced the %JAK2V617F by >30% in 13/25 patients (4 polycythemia vera, 9 essential thrombocythemia). For 3 patients, JAK2V617F remained undetectable for 3-27 months. In addition, a single time point study of two large cohorts of patients, examined either at the time of diagnosis (99 polycythemia vera, 178 essential thrombocythemia) or while receiving hydroxyurea (36 polycythemia vera, 98 essential thrombocythemia; median length of therapy: 32 months), confirmed reduction of %JAK2V617F in the hydroxyurea-treated group (24% vs. 33% JAK2V617F at diagnosis, p<0.01). Prospective studies are needed to determine the prognostic value of reduced JAK2V617F allele burden under cytoreductive therapy.     

Transformation from polycythemia vera to acute promyelocytic leukemia: Case report and literature review

Introduction:Transformation from chronic myeloproliferative neoplasm to acute leukemia is a feature of myeloproliferative neoplasm; however, the rate is not high. Transformation to acute promyelocytic leukemia is rare. Here, we report a case of transformation of polycythemia vera to acute promyelocytic leukemia and describe a process of clonal evolution that has not yet been reported.Patient concerns:In this case, a 51-year-old woman was diagnosed with polycythemia vera and concomitant JAK2/V617F mutations in July 2019. She underwent intermittent phlebotomy and oral hydroxyurea irregularly. After 2 years, the patient complained of fatigue and poor sleep quality for 2 months.Diagnosis:Further examination revealed marked hypercellularity and grade 1 bone marrow fibrosis with the PML/RARαV variant (23.85% mutation load), WT1-Exon1 (37.8%), WT1-Exon9 (4.1%), JAK3-Exon7 (49.3%), and RELN-Exon55 (45.8%). According to the World Health Organization classification of tumors of hematopoietic and lymphoid tissues, the patient was ultimately diagnosed with a rare transformation of polycythemia vera to acute promyelocytic leukemia.Interventions:The patient underwent dual induction therapy with all-trans-retinoic acid and arsenic trioxide.Outcomes:After 28 days of induction therapy, the patient achieved complete remission, was compliant and the treatment was well tolerated.Conclusion:Polycythemia vera can transform into acute promyelocytic leukemia; therefore, it is important to review bone aspiration and other tests to perform a comprehensive assessment and monitor the disease status, to detect disease progression and intervene early when it transforms into acute promyelocytic leukemia.     

Myelodysplastic transformation of polycythemia vera: case report and review of the literature

We report a case of refractory anemia with excess blasts (RAEB) developing in a 67-year old man with a history of polycythemia vera; results of cytogenetic and immunophenotyping studies are described. In this report the clinical, cytogenetic and hematologic features of myelodysplasia complicating polycythemia vera are reviewed. Results of immunophenotyping and cytogenetic studies, and the preponderance of cases developing after myelosuppressive therapy suggest that in the majority of cases myelodysplasia is treatment-related.     

Essential thrombocythemia and leukemic transformation

Alkylating agents and 32P have been widely employed in the treatment of patients with essential thrombocythemia (ET). During a four-month period, we observed 3 cases of ET that had transformed into leukemia. Two patients had been treated with uracil mustard: One developed acute myelogenous leukemia 79 months after institution of therapy, and the other patient developed chronic myelomonocytic leukemia 24 months after the start of therapy. The third patient had been treated with busulfan, and ET evolved into myelofibrosis and eventually into acute undifferentiated leukemia with myelofibrosis. The patient who developed acute myelogenous leukemia was asymptomatic at the time of diagnosis of ET but was treated because his platelet count was greater than 1,000,000/mm3. He died 1 month after leukemic transformation, during induction chemotherapy. The other 2 patients presented with symptoms referable to their thrombocythemia. Review of the English literature revealed 12 other definite or probable cases of ET with leukemic transformation, all but 1 having been treated with alkylating agents and/or 32P. We propose that the natural history of ET may be similar to that of polycythemia vera, with evolution into leukemia being an unusual occurrence except in the setting of previous chemotherapy. Therefore, the current practice of treating asymptomatic patients with ET may not be justified, since administration of alkylating agents or 32P may increase the risk of subsequent development of leukemia.     

Analysis of risk factors: the rationale of the guidelines of the Czech Hematological Society for diagnosis and treatment of chronic myeloproliferative disorders with thrombocythemia

The rationale of the Czech Hematological Society guidelines for diagnosis and treatment of Philadelphia chromosome-negative myeloproliferative disorders with thrombocythemia (MPD-T) is reviewed. For diagnosis of MPD-T, the classification according to the World Health Organization or to the Rotterdam criteria is preferred because they distinguish true essential thrombocythemia from prefibrotic or early fibrotic idiopathic myelofibrosis and prepolycythemic polycythemia vera. The histopathology-based nosological distinction provided by these classifications yields valuable information on prognosis (including the risks of transition into secondary acute myeloid leukemia and myelofibrosis). Another serious complication in MPD-T is thrombosis (arterial or venous), the main risk factors of which are age, previous thrombosis, platelet counts 350 to 2,200 x 10 (9)/L (peak at approximately 900 x 10 (9)/L) and the presence of additional thrombophilic risk factors (hereditary thrombophilia, any hypercoagulable state, cardiovascular disease). The hemorrhagic risk starts increasing progressively at platelet counts > 1,000 x 10 (9)/L. Treatment should be stratified with respect to the thrombotic and hemorrhagic risks. In high-risk patients, thromboreductive therapy is warranted. All of the cytostatic drugs, including hydroxyurea, may be leukemogenic and should be given only to patients > 60 years old, whereas anagrelide or interferon alpha are preferred in younger individuals. In low-risk patients, antiaggregation therapy is sufficient, unless the platelet count exceeds 1,000 x 10 (9)/L, which is another indication for thromboreduction. Thrombopheresis is indicated in thrombocythemia > 2,000 x 10 (9)/L.     

Therapy for polycythemia vera and essential thrombocythemia is driven by the cardiovascular risk

The clinical course of polycythemia vera (PV) and essential thrombocythemia (ET) is characterized by an increased incidence of thrombotic and hemorrhagic complications and an inherent tendency to progress into myelofibrosis or acute myeloid leukemia. Major predictors of vascular events are increasing age and previous thrombosis. Myelosuppressive drugs can reduce the rate of thromboses and hemorrhages, but there is concern that their use accelerates the rate of leukemic transformation. Thus, a risk-oriented management strategy is recommended. Low-risk patients with PV should be treated with phlebotomy and low-dose aspirin, whereas those with ET can be left untreated. Cytotoxic agents are recommended in high-risk cases and hydroxyurea is the drug of choice in most patients. Interferon alpha or anagrelide could be considered in selected young patients or as second-line therapy in those refractory or intolerant of hydroxyurea. The recent identification of JAK2V617F mutation in a substantial proportion of patients with PV and ET raises new questions regarding both risk classification and management, but additional studies on these issues are required.     

Phase II open label trial of imatinib in polycythemia rubra vera

Polycythemia rubra vera is a chronic myeloproliferative disorder characterized by panmyelosis with the resultant potential for thrombosis, myelofibrosis, and acute leukemia. Treatment has rested on phlebotomy and hydroxyurea. In 2002, we reported two patients who were unable to tolerate hydroxyurea but responded to imatinib mesylate (Gleevec). These patients have remained in complete hematologic remission on imatinib since 1999. As a result we began a phase II, open label trial of imatinib in patients with polycythemia vera. Patients meeting the Polycythemia Vera Study group criteria for the diagnosis of polycythemia vera, either naïve or intolerant to prior treatment were allowed to enroll. Initial therapy was begun with imatinib mesylate at 400 mg a day and two dose escalations, one to 600 and second to 800 mg a day, were allowed for patients not achieving a target hematocrit of 44 or less; or a platelet count of less than 600,000/mm³. Twenty patients were enrolled, 15 achieved complete hematologic remission within 12 weeks and ten remain on study. Six patients remain in remission on 400 mg a day and four on 500 mg a day. Gastrointestinal or cutaneous toxicities were primarily grade I or II. All patients were negative for bcr/abl. Imatinib mesylate is capable of producing hematologic remission in the majority of patients with polycythemia vera and provides another option for patient management, particularly in those intolerant to hydroxyurea.     

Evidence-based management of polycythemia vera

The clinical course of polycythemia vera is marked by significant thrombotic complications and a variable risk of the disease turning either into myeloid metaplasia with myelofibrosis or into acute myeloid leukemia. Cytoreductive treatment of blood hyperviscosity by phlebotomy or chemotherapy and antiplatelet therapy with low-dose aspirin have dramatically reduced the number of thrombotic complications and substantially improved survival. However, there is concern that certain myelosuppressive drugs accelerate the disease progression to acute leukemia. Thus, the objective of management is two-fold: first, to minimize the risk of thrombotic complications; second, to prevent progression to myelofibrotic or leukemic transformation. This chapter provides updated estimates of the risk of thrombosis and disease progression and evaluates the various randomized and observational studies in polycythemia vera, according to an evidence-based approach.     

Conversion of polycythemia vera to refractory anemia with hyperplastic bone marrow

Summary Clinical and morphologic findings in the conversion of treated polycythemia vera to pancytopenia with hyperplastic bone marrow (refractory anemia or pancytopenia with hyperplastic bone marrow) are described in light of our own observation. The nomenclature associated with this condition (pancytopenia, chronic erythroleukemia, preleukemia) is not uniform, whereas the morphologic findings are virtually identical. Some patients subsequently develop acute leukemia. The prognosis in cases of refractory anemia with hyperplastic bone marrow following polycythemia vera is, independent of the subsequent acute leukemia, invariably terminal.     

Risk stratification, staging, and treatment of patients with polycythemia vera: Italian and European collaboration on low-dose aspirin in polycythemia data

The clinical course of polycythemia vera (PV) is marked by a high incidence of thrombotic complications, which represent the main cause of morbidity and mortality. Major predictors of vascular events are increasing age and previous thrombosis. Myelosuppressive drugs can reduce the rate of thrombosis, but there is concern that their use increases the risk of transformation into acute leukemia. To tackle this dilemma, a risk-oriented management strategy is recommended. Low-risk patients should be treated with phlebotomy and low-dose aspirin based on the results of the European Collaboration on Low-Dose Aspirin in Polycythemia study. Cytotoxic therapy is indicated in high-risk patients, and the drug of choice is hydroxyurea because its leukemogenicity is low. New therapeutic options, that theoretically are devoid of leukemic risk (such as interferon alpha and imatinib), should be reserved for selected patients and require additional clinical experience.     

The effect of hydroxyurea on hemoglobin F in patients with myeloproliferative syndromes

Fetal hemoglobin (Hb F) may increase in patients receiving chemotherapeutic drugs, a result of potential use in patients with symptomatic hemoglobinopathies. We examined Hb F in 13 patients with myeloproliferative disease (six polycythemia vera, five polycythemia vera with myeloid metaplasia, one agnogenic myeloid metaplasia, and one chronic myelogenous leukemia) who were treated with hydroxyurea. Four patients showed an increase in Hb F from less than 1% to between 5% and greater than 8% while on hydroxyurea, and a decline to less than 1% when the drug was discontinued. This group of "responders" received a higher average daily dose of hydroxyurea, which was administered continuously rather than intermittently, when compared to the "nonresponders." Mean corpuscular volumes (MCVs) rose in most patients, and i antigen remained elevated or decreased; neither parameter correlated with Hb F levels. Both responders and nonresponders had therapeutically desirable suppression of WBCs and platelets, and almost all had no depression of reticulocytes or Hb.     

Treatment of polycythemia vera with hydroxyurea

Conventional treatment of polycythemia vera (PV) with radioactive phosphorus or alkylating agents is associated with a significant excess of acute leukemia and cancer of the gastrointestinal tract and skin. There is thus a need for a nonmutagenic agent in the treatment of this disorder. Hydroxyurea (HU) was administered to 118 patients with a loading dose of 30 mg/kg/day for 1 week, which was then reduced to 15 mg/kg/day. Initial control of the elevated hematocrit and platelet count was achieved within 12 weeks in over 80% of patients. Long-term disease control was defined and the accumulative 1-year failure-free survival was 73% in the previously untreated patients and 59% in those patients previously treated with other myelosuppressive modalities. The HU was well tolerated and cytopenia, which generally occurred within the first 8 weeks of therapy, was transient and of little clinical significance. However, it is recommended because of this toxicity that HU be administered initially at a dose of 15-20 mg/kg/day. Three patients developed acute leukemia; two were untreated and one had had myelosuppressive therapy. Hydroxyurea is an effective agent in the treatment of PV, but continued assessment of its mutagenic potential is necessary.     

Familial polycythemia vera with Budd-Chiari syndrome in childhood

Polycythemia vera is a myeloproliferative disorder that, in most cases, occurs sporadically with a median age at presentation of 60 years. Familial cases are very rare and usually manifest in elderly family members. The Budd-Chiari syndrome, characterized by the obstruction and occlusion of the suprahepatic veins, is a rare typical complication in polycythemia vera patients. To date, only two children or adolescents with polycythemia vera and Budd-Chiari syndrome have been described. Here, we report an 11-year-old girl with Budd-Chiari syndrome as the initial symptom of familial polycythemia vera, which was also found in the girl's grandmother. Details of the diagnostic procedures used and the clinical course are reported. The patient underwent orthotopic liver transplantation and is being treated with hydroxyurea. The available literature on familial polycythemia vera and polycythemia vera in childhood with and without Budd-Chiari syndrome is reviewed.