Treatment of Philadelphia-negative myeloproliferative neoplasms in accelerated/blastic phase with azacytidine. Clinical results and identification of prognostic factors.

There have been some reports on a possible role of azacytidine (AZA) in the treatment of accelerated/blastic phase evolved from Philadelphia-negative myeloproliferative neoplasms (MPN-AP/BP), but results are conflicting. In this study, we analyzed a cohort of 39 patients with MPN-AP/BP treated frontline with AZA at the standard dosage (75 mg/m2 ). Median time from diagnosis to AP/BP evolution was 92.3 months (IR 29.9-180.1). All patients were evaluable for hematologic response: two patients (5.2%) died early after AZA initiation, 13 patients (33.3%) had a progressive or stable disease, nine (23.1%) had a hematologic improvement (HI), seven (17.9%) achieved a partial response (PR), and eight (20.5%) a complete response (CR). Overall, 24 patients achieved a clinical hematologic response (HI + PR + CR), with an overall response rate of 61.5%. Median overall survival (OS) from AZA start of the whole cohort was 13.5 months (95% CI, 8.2-18.7). There was no difference in median OS among patients with HI, PR, or CR (P = .908). These three subgroups as "responders" having been considered, a significantly better OS was observed in responder compared with nonresponder patients, with a median OS of 17.6 months (95% CI, 10.1-25.0) versus 4.1 months (95% CI, 0.4-10.0) (P = .001) Only female gender was significant for both achievement of response (.010) and OS duration (P = .002). In conclusion, AZA is useful for the management of MPN-AP/BP, with an overall response rate (HI + PR + CR) of 61.5% and a longer OS in responders.

Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.

Disease Overview: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. Diagnosis: Bone marrow morphology remains the cornerstone of diagnosis. In addition, the presence of JAK2 mutation is expected in PV while approximately 90% of patients with ET express mutually exclusive JAK2, CALR, or myeloproliferative leukemia mutations. In ET, it is most important to exclude the possibility of prefibrotic myelofibrosis. Survival: Median survivals are 14 years for PV and 20 years for ET; the corresponding values for younger patients are 24 and 33 years. Certain mutations (mostly spliceosome) and abnormal karyotype might compromise survival in PV and ET. Life-expectancy in ET is inferior to the control population. Driver mutations have not been shown to affect survival in ET. Risk of thrombosis is higher in JAK2-mutated ET. Leukemic transformation rates at 10 years are estimated at <1% for ET and 3% for PV. Thrombosis Risk: In PV, 2 risk categories are considered: high (age > 60 years or thrombosis history present) and low (absence of both risk factors); in ET, 4 risk categories are considered: very low (age ≤ 60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (age > 60 years, no thrombosis history, JAK2 wild-type) and high (thrombosis history present or age > 60 years with JAK2 mutation). Risk-Adapted Therapy: The main goal of therapy in both PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once- or twice-daily aspirin (81 mg), in the absence of contraindications. Very low-risk ET might not require therapy while aspirin therapy is advised for low-risk disease. Cytoreductive therapy is recommended for high-risk ET and PV but it is not mandatory for intermediate-risk ET. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We do not recommend treatment with ruxolutinib in PV, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs.

Polycythemia vera disease burden: contributing factors, impact on quality of life, and emerging treatment options.

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by clonal expansion of a hematopoietic progenitor, erythrocytosis, often leukocytosis and/or thrombocytosis, and nearly always an activating mutation in Janus kinase 2 (JAK2). The PV symptom burden can be considerable, in part driven by small or large vessel thrombotic tendency, splenomegaly, fatigue, pruritus, and a chronic risk of disease transformation to myelofibrosis or acute myeloid leukemia. In addition, patients with PV have an increased risk of mortality compared with the general population that often results from cardiovascular complications or disease transformation. Further, healthcare utilization and costs are higher in patients with PV than noncancer controls. First-line therapy options for high-risk patients may effectively manage PV in some instances; however, some patients do not receive adequate benefit from current treatment options and experience a more severe disease burden as a result. This may be especially true for those patients who are resistant to or intolerant of hydroxyurea or interferon-based therapies. New treatments currently being investigated in phase 3 clinical trials may alleviate disease burden in this patient population.

Therapeutic options for patients with polycythemia vera and essential thrombocythemia refractory/resistant to hydroxyurea.

Hydroxyurea (HU) has traditionally been the first-line treatment for patients with polycythemia vera (PV) or essential thrombocythemia (ET) at high risk for vascular complications. However, approximately 20-25% of patients develop resistance or intolerance to HU and must be treated with second-line therapies. Resistance is associated with disease transformation and reduced survival. However, given the dearth of large-scale controlled clinical trials in this patient population, there is no clear consensus on how to best treat patients who develop resistance or intolerance to HU. Herein, we review current literature on treatment options for patients with HU-refractory/resistant PV or ET and provide recommendations for treating these patients.

Treatment of polycythemia vera with hydroxyurea and pipobroman: final results of a randomized trial initiated in 1980.

PURPOSE: The overall impact of hydroxyurea (HU) or pipobroman treatments on the long-term outcome of patients with polycythemia vera (PV) has not been assessed in randomized studies. We report final analyses from the French Polycythemia Study Group (FPSG) study, which randomly assigned HU versus pipobroman as first-line therapy in 285 patients younger than age 65 years. PATIENTS AND METHODS: The full methodology has been described previously. FPSG results were updated with a median follow-up of 16.3 years. Statistical analysis was performed by using competing risks on the intention-to-treat population and according to main treatment received. RESULTS: Median survival was 17 years for the whole cohort, 20.3 years for the HU arm, and 15.4 years for the pipobroman arm (P = .008) and differed significantly from that in the general population. At 10, 15, and 20 years, cumulative incidence of acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) was 6.6%, 16.5%, and 24% in the HU arm and 13%, 34%, and 52% in the pipobroman arm (P = .004). Cumulative myelofibrosis incidence at 10, 15, and 20 years according to main treatment received was 15%, 24%, and 32% with HU versus 5%, 10%, and 21% with pipobroman (P = .02). CONCLUSION: Data from this unique randomized trial comparing HU with another cytoreductive drug in PV showed that (1) survival of patients with PV treated with conventional agents differed from survival in the general population, (2) evolution to AML/MDS is the first cause of death, (3) pipobroman is leukemogenic and is unsuitable for first-line therapy, and (4) incidence of evolution to AML/MDS with HU is higher than previously reported, although consideration should be given to the natural evolution of PV.

A review of the therapeutic agents used in the management of polycythaemia vera.

The acquired clonal disorder Polycythaemia Vera leads to increased erythropoiesis, myelopoiesis and megakaryopoeisis. These anomalies result in an increased incidence of thromboembolic events, transformation to acute leukaemia and myelofibrosis. Treatments which aim to reduce the event rate may increase anaemia but may also affect the rate of complications. This paper reviews the evidence for the treatments which have been used in the management of the disorders over a 50 plus year period. Assessment of this evidence and its limitations form the basis for the current suggested management plans.

Long-term incidence of hematological evolution in three French prospective studies of hydroxyurea and pipobroman in polycythemia vera and essential thrombocythemia.

Despite recent discoveries made in myeloproliferative disorders other than chronic myelogenous leukemia, which it is hoped will result in earlier diagnosis, and better evaluation and management of patients, hematological evolution to myelofibrosis, acute leukemia, and myelodysplastic syndromes (AL/MDS) remain major causes of long-term mortality in polycythemia vera (PV) and essential thrombocythemia (ET) patients. Evaluation of long-term leukemogenic risk of currently available drugs, therefore, is crucial. We report updated results of three French prospective trials of hydroxyurea and pipobroman in PV and ET patients with a median follow-up longer than 10 years. The results show that the incidence of AL/MDS is higher than previously reported with no evidence of a plateau (with approximately 40% of AL/MDS cases occurring after the 12th year of follow-up). Although hydroxyurea currently remains the first choice in the treatment of high-risk PV and ET patients, the use of nonleukemogenic drugs, such as interferon alpha (IFN-alpha) or anagrelide, should be assessed more widely in randomized trials using accurate diagnostic criteria and taking into account the presence of the JAK2 mutation, given that they may have an impact on disease evolution.

Del(5q) and MLL amplification in homogeneously staining region in acute myeloblastic leukemia: a recurrent cytogenetic association.

We report here a 71 year-old female presenting with acute myeloblastic leukemia (FAB-M1) after treatment of essential thrombocythemia with Vercyte. Conventional cytogenetic techniques showed a complex karyotype, 44,XX,-5,-7,-11,add(11)(q23),-14,+mar,+r. The use of several fluorescent in situ hybridizations (FISH) lead to the identification of these complex rearrangements. The marker was found to be tricentric, with pericentromeric material of chromosome 7 inserted in the short arm of chromosome 5, resulting in monosomy 5q and 7q. The derivative chromosome 11 was dicentric and had subtelomeric sequences of 11p on both ends; several copies of the MLL gene were located in two different regions separated by a centromere of chromosome 11. Twenty-one cases, including ours, of myelodysplastic syndromes and acute myelogenous leukemia with MLL amplification present in hsr or dmin were found in the literature. Most of these patients shared some characteristics: they were old, they had de novo acute myeloid leukemia (AML) with a complex karyotype and a short survival, 90% of them having also a del(5q). Therefore, the simultaneous presence of MLL amplification and del(5q) appears to be a nonrandom association that could be the signature of AML in elderly patients with a poor prognosis.

Long-term evaluation of 164 patients with essential thrombocythaemia treated with pipobroman: occurrence of leukaemic evolution.

Essential thrombocythaemia (ET) is usually considered an indolent disease, but it may progress during its natural course into acute leukaemia (AL); however, an influence of myelosuppressive agents in the blastic transformation of ET cannot be excluded. We performed a retrospective study to assess the incidence of AL in ET patients treated with pipobroman (PB) as first-line therapy. One hundred and sixty-four patients with ET were managed with PB at a dose of 1 mg/kg/d until a stable platelet count below 400 x 10(9)/l was achieved. Maintenance therapy was given at a planned dose ranging between 0.2 and 1 mg/kg/d according to platelet count, in all cases, with a median daily dose of 25 mg (range 7-75 mg/d). The median treatment time was 100 months (range 25-243 months). The patients were evaluated for the occurrence of AL and/or secondary malignancies and survival end-points. AL was observed in nine patients (5.5%) after a median treatment time of 153 months (range 79-227 months). The overall survival (OS) and the event-free survival (EFS) at 120 months were 95% and 97%, whereas at 180 months, they were 84% and 76% respectively. In conclusion, this retrospective analysis shows a low incidence of AL in a large group of patients consecutively treated with PB as first-line chemotherapy. Therefore, an investigation of the role of myelosuppressive agents in the blastic transformation of ET would be of interest.

Treatment of polycythemia vera and essential thrombocythemia: the role of pipobroman.

Pipobroman (PB) is a neutral amide of piperazine with a chemical structure close to that of alkylating agents, although the exact mechanism of action of PB has not been demonstrated. PB has well documented clinical activity in polycythemia vera (PV) and essential thrombocythemia (ET). Recent long-term follow-up studies on PV and ET patients receiving PB have facilitated the definition of the risk of late transformation into myelofibrosis with myeloid metaplasia (MMM) or acute leukemia (AL). This report gives an overview of the treatment with PB in patients with PV and ET focusing on clinical activity, administration dose and schedule, toxicity, impact on short- and long-term complications. From our experience and from the data reported in the literature the high clinical activity of PB in both PVand ET becomes evident. This drug allows, within 3 months, to attain a response in more than 90% of patients, without clinically relevant toxicities. The 10-years risk of thrombosis of patients treated with PB is about 15%, similar to that registered with hydroxyurea, the most widely used agent in PVand ET. The antiproliferative activity of PB on bone marrow megakaryocytes seems of particular value in lowering the occurrence of post-PV and post-ET MMM, whose risk (< 4% at 10 years) is the lowest registered with available treatments. The 10-year risk of acute leukemia with PB is 5% in PVand 3% in ET, which is only slightly higher than that expected as a natural evolution of the disease. In conclusion, the use of PB is a definite alternative to hydroxyurea in patients with PV and ET at high risk of thrombosis.

Pharmacotherapy of essential thrombocythaemia: economic considerations.

The clinical course of essential thrombocythaemia (ET) is mainly outlined by a predisposition to both thromboembolic, and more rarely, haemorrhagic complications. The individual clinical course is, however, variable, ranging from an event-free course to life-threatening thromboembolic episodes. In order to treat ET patients economically, it is necessary, above all, to consider if cytoreductive therapy is really indicated. Risk stratification according to clinical criteria such as age, previous ET-related events and platelet count may help to define patients at risk. In low-risk ET patients, a watch-and-wait strategy seems to be feasible. There is a clear indication for cytoreductive therapy in high risk ET patients as demonstrated in a Phase III clinical trial. Because of the lack of Phase III trials, it is not clear which of the cytoreductive drugs - hydroxyurea, pipobroman, IFN-alpha, pegylated-IFNs or anagrelide - is the best therapeutic option. Factors that influence the choice out of the available drugs are efficacy, safety and cost. The efficacy and safety data of the available drugs for ET are derived from Phase II studies or observational studies. IFN-alpha is the most expensive drug. Newer drugs like anagrelide or pegylated-IFNs are still expensive, but may have a better cost-benefit effect in patients < 60 years of age. Two cost-effectiveness analyses revealed a result in favour of anagrelide, however, in these cost-effectiveness models, assumptions were based on non-randomised trials. For patients > 60 years of age, hydroxyurea may be the best therapeutic option with regard to both the efficacy and cost-effectiveness.

Long-term outcomes of polycythemia vera patients treated with pipobroman as initial therapy.

From 1968 to 1993, 179 newly diagnosed patients with polycythemia vera (PV) were enrolled in a prospective study using pipobroman as first chemotherapy. Among them, 140 fulfilled the Polycythemia Vera Study Group criteria for PV, and 39 patients (22%) can be considered as idiopathic erythrocytosis (IE). Vascular events occurred in 10% of IE and 20% of PV patients and solid tumors in 7.7% of IE and 12.8% of PV patients. There were no differences between PV and IE patients with regard to progression to myelofibrosis (MF), leukemic events and overall survival. Overall, 98.3% of patients initially responded to pipobroman, with very mild toxicity. A total of 164 PV patients who received more than 1 year of pipobroman were analyzed for long-term evolution. The actuarial risk of thrombosis was 15.6 and 23.8% at 10 and 18 years, respectively. In all, 21 patients developed a solid tumor during follow-up, added and/or switched drugs being a risk factor. Actuarial risk of MF was as low as 4.9 and 9.4% at 10 and 15 years, respectively. Actuarial risk of leukemia was 14.4 and 18.7% at 10 and 15 years, respectively. Hyperleukocytosis at diagnosis was the only variable significantly associated with higher risk of leukemia. The median survival was 15.5 years, with two initial adverse prognostic factors: age above 60 years and hyperleukocytosis. Despite an increasing risk of leukemia with time, survival was not lower when compared to the French matched population. Only age and hyperleukocytosis at diagnosis were found to have a prognostic value in PV.

Acute myeloid leukemia (AML) having evolved from essential thrombocythemia (ET): distinctive chromosome abnormalities in patients treated with pipobroman or hydroxyurea.

ET is a chronic myeloproliferative disorder rarely evolving into AML, sometimes preceded by a myelodysplastic syndrome (MDS). Such transformations mostly occur in patients treated with radiophosphorous ((32)P) or alkylating agents, especially busulfan. Recently, concern has also arisen about the long-term safety of hydroxyurea (HU). Pipobroman (PI), a well tolerated and simple to use drug, constitutes a valid alternative to those cytoreductive treatments. The present study reports on 155 ET patients treated at our institution from 1985 to 1995, and monitored until December 2000. A good control of thrombocytosis was achieved with PI as the only treatment in 106 patients and with HU in 23 patients. Twenty-six patients received no treatment. After a median follow-up of 104 months, seven patients (four treated with HU, and three with PI) developed AML whereas one patient treated with PI developed MDS. A significant difference in progression-free survival was observed between HU- and PI-treated patients (P = 0.004). A short-arm deletion of chromosome 17 was most frequently detected in HU-treated patients, while a long-arm trisomy of chromosome 1 and a monosomy 7q were seen in PI-treated patients. No TP53 mutation was discovered in the six patients studied (two HU-treated and four PI-treated). We conclude that these cytogenetic abnormalities are not linked to the natural history of the disease, but rather that they might be induced by the cytoreductive treatment.

Pipobroman is safe and effective treatment for patients with essential thrombocythaemia at high risk of thrombosis.

Essential thrombocythaemia (ET) is a disease associated with an elevated risk of thrombosis. This study evaluated the efficacy and safety of pipobroman (PB) in the long-term control of ET patients who had, at diagnosis, one or more of the following currently known risk factors for thrombosis or haemorrhage (high-risk patients): age > 60 years, history of thrombosis or haemorrhage, platelets >1000 x 10(9)/l. From 1978 to 2000, with a median follow-up of 10 years, 118 previously untreated high-risk ET patients (median age 62 years, range 25-82), were treated with PB at the starting dose of 0.8-1 mg/kg/d. All patients reached a platelet count <600 x 10(9)/l and 91% achieved a platelet count <400 x 10(9)/l. During follow-up, 13 patients had thrombosis, with a 10-year cumulative risk of 14%. Acute myeloid leukaemia, myelofibrosis and solid tumours occurred in three, two and seven patients with a 10-year cumulative risk of 3%, 2% and 7% respectively. Actuarial survival at 20 years was 64% and the standardized mortality ratio was 1.1 (95% CI: 0.7-1.7), not statistically different from the general population (P = 0.54). Age was associated with a higher risk of death (P = 0.00009) and thrombosis (P = 0.003). The duration of PB treatment did not correlate with the occurrence of second malignancies. This study, with a median follow-up of 10 years, demonstrates that pipobroman is effective and well tolerated. The low cumulative 10-year risk of thrombosis, leukaemia and solid tumours indicates that pipobroman is an adequate treatment for patients with high risk ET.

Current treatment practice for essential thrombocythaemia in adults.

Essential thrombocythaemia (ET) is a relatively benign chronic myeloproliferative disorder that occurs primarily in middle-aged patients. Its clinical course is characterised by thomboembolic and, less frequently, by haemorrhagic complications. Life expectancy of ET is generally of normal length and progression to acute leukaemia is a rare event. About one third of all patients are asymptomatic at diagnosis and many of them remain without complications for years. Therefore, the main challenge for treating patients with ET is to select patients who will benefit from a cytoreductive or antiplatelet therapy, because it is doubtful whether the beneficial effects of therapy outweigh the potential hazards in all cases. For this reason a risk stratification in high and low risk ET patients is essential. The treatment of ET has evolved from alkylating agents to hydroxyurea (HU) or pipobroman and more recently to agents such as IFN-alpha and anagrelide. Aspirin as an antiplatelet therapy is also expected to play a part in the treatment of ET. HU is first-line therapy for elderly patients with high risk ET. In young ET patients without ET related complications and a platelet count << 1000 - 1500 x 10(9)/l abstention from cytoreductive therapy or therapy with low-dose aspirin alone seems to be appropriate. The aim of this review is to address the current treatment practice for ET in adults.