bl-4162a and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Myeloproliferative disorders (MPDs) are chronic conditions that require long-term treatment. MPDs have been considered neoplastic disorders that have a propensity to transform to acute leukemia or myelodysplastic syndrome. One of the MPDs, chronic myeloid leukemia (CML), has the distinct cytogenetic abnormality of the Philadelphia chromosome. In CML, transformation to acute leukemia is a common occurrence, with the timeline measured in years rather than decades. With the other three disorders from this group, polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (IMF), transformation to acute leukemia is less frequently seen and, although variable, can take a longer period of time. The choice of therapy used for MPDs may contribute to leukemic transformation; chlorambucil, busulfan, and radiophosphorus are all examples of therapy that have been shown to be leukemogenic. Several studies have suggested the potential leukemogenicity of hydroxyurea (HU), but this remains controversial because no randomized studies have been conducted. The two newest agents used for MPDs, interferon-alpha and anagrelide, have both been studied for efficacy, but their influence on the potential for leukemic transformation has not been well studied to date.

Topics: Antineoplastic Agents, Alkylating; Busulfan; Chlorambucil; Hydroxyurea; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myelodysplastic Syndromes; Myeloproliferative Disorders; Philadelphia Chromosome; Platelet Aggregation Inhibitors; Quinazolines; Radiopharmaceuticals

We report phase II trial results of the use of oral anagrelide hydrochloride for treating 38 patients with hydroxyurea (HU)-resistant thrombocytosis accompanying chronic myeloid leukemia (CML). Anagrelide's efficacy was well established during a phase II study of more than 400 patients with one of the four myeloproliferative disorders: essential thrombocythemia, polycythemia, idiopathic myelofibrosis, and CML. In the last subgroup, there were 114 CML patients with significant thrombocytosis treated with anagrelide. Out of these patients, 38 had symptoms of thrombosis or hemorrhage and had thrombocytosis resistant to HU. They were then treated with anagrelide at an initial dose of 2.0 mg/day, followed by modifications based upon response and toxicity. In all, 71% of these patients responded with platelet reductions of more than 50% in a median time of approximately 4 weeks. The response rate was not influenced by age, gender, or prior thrombosis or hemorrhage. Importantly, the response rate to anagrelide in patients refractory to prior HU was essentially the same as that of the other 76 CML patients. Treatment with anagrelide was well tolerated and without undue toxicity. Reduction of excessive platelet counts by anagrelide sometimes occurring in CML may lead to the prevention of thrombohemorrhagic complications occurring in this clinical setting and is relevant even in those patients in whom imatinib mesylate is primary therapy.

Topics: Adult; Drug Resistance; Female; Humans; Hydroxyurea; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Quinazolines; Thrombocytosis

Chronic myelogenous leukemia (CML) is usually treated with hydroxyurea or interferon-alpha. In some patients high platelet counts develop although leukocyte counts are well controlled with these drugs. If in such a situation cytoreductive therapy has to be intensified by a increase of the dosage, anemia and leukocytopenia as well as adverse effects of the drugs are likely to occur. In twelve CML patients we have therefore combined the basic CML treatment with anagrelide. This drug which selectively reduces platelet counts has been shown to be efficacious in the control of thrombocytosis in essential thrombocythemia. The diagnosis had been confirmed in all CML patients by cytogenetic and/or molecular biological analysis. The median age of our group was 58 years. Five were women and seven men. All patients were on treatment with hydroxyurea, some of them had previously received treatment with interferon-alpha (alone or in combination with hydroxyurea), busulfan or melphalan. Prior to the initiation of anagrelide treatment the platelet count was between 970,000 and 3,600, 000/microl (median about 2,000,000/microl). Seven patients had thrombohemorrhagic complications. All twelve patients, experienced hematologic responses, since their platelet counts decreased to less than 600,000/microl. The median platelet count after reduction was 343,000/microl. The median dosage required to achieve these responses and to maintain them for a period of at least four weeks was 1.9 mg/day. Thrombohemorrhagic complications disappeared or did not recur in all symptomatic patients. Adverse effects were seen in 3/12 patients: headache (1), tachycardia (1), palpitation (1) and fluid retention (1). Whereas these symptoms were mild and transitory they caused one patient to request discontinuation of treatment. Currently five patients are still on treatment with anagrelide (median duration of treatment 11 months) while therapy had to be discontinued in the seven others because of bone marrow transplantation, development of osteomyelofibrosis, blast crisis or on patient request. In our experience anagrelide is a useful therapeutic adjunct when thrombocytosis in patients with CML cannot properly controlled alone with traditional drugs.

Topics: Aged; Female; Hematologic Tests; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Count; Quinazolines

Topics: Algorithms; Aniline Compounds; Antineoplastic Agents; Aspirin; Blood Transfusion; Dasatinib; Hematopoietic Stem Cell Transplantation; Humans; Hydroxyurea; Imidazoles; Japan; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myeloproliferative Disorders; Nitriles; Phlebotomy; Prognosis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyridazines; Pyrimidines; Quinazolines; Quinolines; Risk

Topics: Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Megakaryocyte Progenitor Cells; Platelet Aggregation Inhibitors; Quinazolines; Thrombocythemia, Essential

Topics: Adult; Blood Cell Count; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 9; Fibrinolytic Agents; Fusion Proteins, bcr-abl; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocytosis; Male; Megakaryocytes; Primary Myelofibrosis; Quinazolines; Splenomegaly; Thrombocytopenia; Translocation, Genetic

A 65-year-old woman presented with clinical features of primary thrombocythemia (PT), and absence of the BCR/ABL fusion gene. She responded to hydroxyurea treatment, although after 1 year she required progressive increases in the dose. Six years later, she maintained a high platelet count despite hydroxyurea at 2 g/day and treatment was changed to anagrelide. After 3 weeks, both platelet and leukocyte counts increased. A karyotype study detected the Philadelphia chromosome in all of the 24 metaphases studied. Fluorescent in situ hybridization (FISH) analysis revealed the BCR/ABL rearrangement. The patient was treated with imatinib mesylate and achieved a normal platelet and leukocyte count in 3 weeks. Patients presenting clinical features of PT expressing the Ph chromosome or the BCR/ABL fusion gene have been well documented but, to our knowledge, this is the first report of evolution from typical PT to chronic myeloid leukemia.

Topics: Aged; Antineoplastic Agents; Benzamides; Blood Platelets; Bone Marrow Cells; Cells, Cultured; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 9; Chronic Disease; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Fusion Proteins, bcr-abl; Humans; Hydroxyurea; Imatinib Mesylate; In Situ Hybridization, Fluorescence; Karyotyping; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocytes; Piperazines; Pyrimidines; Quinazolines; Thrombocythemia, Essential; Time Factors; Translocation, Genetic; Treatment Outcome

Chronic myeloid leukemia in blast phase (BP) is resistant to chemotherapy and majority of patients die within 6 months. Inhibitor Bcr-Abl tyrosine kinase imatinib mesylate dramatically improved outcome of patients in chronic phase (CP) and is also effective in BP of CML. The prognosis of patients treated with imatinib in BP is worse than in CP. High platelet counts are often observed at diagnosis or in the subsequent course of the CML in about 25% of patients. Thrombohemorrhagic complications associated with the thrombocythemia may be serious. Anagrelide selectively reduces circulating platelets and is used in treatment of thrombocythemia in chronic myeloproliferative disorders. Efficacy and safety of combination imatinib mesylate with anagrelide was demonstrated in chronic and accelerated phase of CML. No study about the use of imatinib with anagrelide in BP has been found. 51-year-old white man with CML presented in blast phase was followed for 4 years. Imatinib mesylate in dose of 600 mg p.o. qd. was administered after the failure of initial chemotherapy. The patient was treated with imatinib for 45 months, 14.5 months in combination with anagrelide. Partial hematologic response in duration of 33 months was induced by imatinib, cytogenetic response was not reached. Imatinib-resistant thrombocythemia was controlled with anagrelide in dose of 0.5-1 mg p.o. qd. No thrombohemorrhagic complications were observed. The patient tolerated the combination of imatinib and anagrelide well and long-term survival gave him the chance of treatment with the new tyrosin kinase inhibitor (dasatinib).

Topics: Antineoplastic Agents; Benzamides; Blast Crisis; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Piperazines; Platelet Aggregation Inhibitors; Protein Kinase Inhibitors; Pyrimidines; Quinazolines; Thrombocytosis

To report a case of severe life-threatening hypersensitivity pneumonitis temporally associated with the use of anagrelide in a patient with myeloproliferative disorder.. A 60-year-old white woman with chronic myeloid leukemia who had been treated with hydroxyurea for 7 years was offered anagrelide to control thrombocytosis. She developed severe hypersensitivity pneumonitis soon after the drug was initiated and required intubation and mechanical ventilation. A high-resolution computed tomography scan of the chest demonstrated extensive multifocal ground glass attenuation and patchy alveolar consolidation involving both lungs. Bronchoalveolar lavage revealed a preponderance of lymphocytes, suggesting hypersensitivity phenomenon, but was otherwise negative for malignancy and other causes of interstitial pneumonitis. An objective causality assessment revealed that an adverse drug event was probable. Discontinuation of anagrelide and hydroxyurea, and institution of corticosteroid therapy resulted in dramatic improvement.. To our knowledge, this is the first case report of severe hypersensitivity pneumonitis closely related to anagrelide therapy. Pulmonary infiltrates have rarely been noted in patients treated with anagrelide. Anagrelide does not depress white blood cell production, causes mild anemia, and is devoid of the leukemogenic potential characteristic of radioactive phosphorus and other alkylating agents. Common adverse effects to anagrelide include headache, nausea, diarrhea, peripheral edema, and palpitations. Frank congestive heart failure and cardiomyopathy have occurred in a small number of patients, but severe pulmonary adverse effects have not emerged as a frequent problem.. Vigilance is advised in patients who develop dyspnea while taking anagrelide and hydroxyurea. Healthcare providers need to be aware of the possibility of the development of serious life-threatening hypersensitivity pneumonitis. These patients may benefit from serial chest X-rays, pulmonary function testing, and echocardiography.

Topics: Adrenal Cortex Hormones; Alveolitis, Extrinsic Allergic; Antineoplastic Agents; Drug Interactions; Female; Humans; Hydroxyurea; Injections, Intravenous; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Middle Aged; Platelet Aggregation Inhibitors; Quinazolines; Thrombocytosis

The co-existence of thalassaemia major and chronic myeloid leukaemia (CML) is a very rare event. We report a 32-year-old man with thalassaemia major whose progressively increasing leukocytosis and thrombocytosis led to the diagnosis of CML confirmed by the characteristic t(9;22)(q34;q11) chromosomal translocation and the bcr-abl (b3a2) DNA fusion. The patient was treated with hydroxyurea and anagrelide. This combination resulted in the satisfactory control of both the white blood cell and platelet counts, which has continued over the past 14 months with no major side-effects, albeit with no molecular response. The administration of hydroxyurea was also associated with a significant HbF increase.

Topics: Adult; Antisickling Agents; beta-Thalassemia; Drug Therapy, Combination; Humans; Hydroxyurea; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocyte Count; Male; Platelet Aggregation Inhibitors; Platelet Count; Quinazolines; Remission Induction; Thrombocytosis

Three patients, one with polycythaemia vera (PV) and two with chronic myeloid leukaemia (CML), are described who had cycling of blood counts which became apparent whilst receiving hydroxyurea therapy. Significant periodicity was confirmed with the use of the Lomb periodogram. This is Fourier power spectral analysis tailored for unevenly sampled data. The patient with PV had marked oscillations of platelet counts with a periodicity of 29 d and an amplitude of (202-588)x10(9)/L. Smaller oscillations of neutrophil, monocyte and lymphocyte numbers and Hb levels occurred with a similar periodicity. Anticipatory changes in hydroxyurea dosage or the maintenance of a constant dose did not abolish periodicity, but a change in therapy to the non-cycle-specific drug anagrelide dampened and abolished the cycling. One of the patients with CML had tremendous and clear oscillations in white cell, platelet and Hb levels, with a mean periodicity of 74 d. The other had erratic counts which were confirmed to be significantly periodic (64 d), on spectral analysis. A change in therapy to busulphan in both these patients again dampened and abolished the cycling. Hydroxyurea, which is a cell-cycle-specific agent, probably exacerbates the periodicity which may be present in some patients with myeloproliferative disease. A change in therapy to non-cycle-acting compounds such as busulphan or anagrelide results in much more stable counts in such patients.

Topics: Adult; Aged; Antineoplastic Agents; Blood Cell Count; Busulfan; Female; Hemoglobins; Humans; Hydroxyurea; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocyte Count; Lymphocytes; Male; Monocytes; Neutrophils; Periodicity; Platelet Count; Polycythemia Vera; Quinazolines

Thrombocytosis is a common clinical condition. Drugs used for thrombocytosis are hydroxy urea, alkylating agents and interferon alpha. We are reporting a case of chronic myeloid leukemia with thrombocytosis who did not respond to hydroxy urea but was controlled with the addition of a new drug anagrelide. Anagrelide is a platelet reducing agent with no serious side effects. It may be the main weapon against thrombocytosis associated with chronic myeloid leukaemia (CML) and essential thrombocytosis in the coming years.

Topics: Aged; Antineoplastic Agents; Female; Humans; Hydroxyurea; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Platelet Aggregation Inhibitors; Platelet Count; Quinazolines; Thrombocytosis

Thrombocytosis is the cause of various complications in myeloproliferative disorders. We present the case of a 54-year-old woman with chronic myelogenous leukaemia who developed large ulcers on both lower legs that were refractory to standard treatment. As concomitant thrombocytosis persisted despite treatment with hydroxyurea, the new megakaryocyte inhibitor anagrelide (Agrelin) was administered and led to normalization of the platelet count within 11 days. The leg ulcers started to heal after 2 weeks and disappeared over a period of 5 months. Our findings argue for a pathogenic role of platelets in the development of leg ulcers in patients with thrombocytosis due to a myeloproliferative disorder.

Topics: Female; Humans; Leg Ulcer; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Middle Aged; Paraneoplastic Syndromes; Platelet Aggregation Inhibitors; Quinazolines; Thrombocytosis