The long-term and extensive efficacy of low dose thalidomide in a case of an untransfusable patient with Non-Transfusion-Dependent Thalassemia.

Patients with Non-Transfusion-Dependent Thalassemia may require regular transfusion therapy. However, these patients are at risk of developing irregular antibodies, making them untransfusable. Second line treatment usually includes hydroxyurea, which however is not effective in all patients. Other treatment options include thalidomide, which has been reported to be safe and effective in selected patients. We report the case of a patient who experienced improvement of hemoglobin levels and of a part of NTDT related complications, following 36months of continuous therapy with low doses of thalidomide.

Cytoreductive therapy in younger adults with polycythemia vera: a meta-analysis of safety and outcomes.

ABSTRACT: Cytoreductive therapy is not routinely recommended for younger patients with polycythemia vera (PV) due to concern that treatment toxicity may outweigh therapeutic benefits. However, no systematic data support this approach. To support objective risk/benefit assessment of cytoreductive drugs in patients with PV aged <60 years (PV<60), this systematic review and meta-analysis was conducted to evaluate toxicity and disease-related complications in PV<60 treated with interferon alfa (rIFN-α) or hydroxyurea (HU). A search of PubMed, Scopus, Web of Science and Embase identified 693 unique studies with relevant keywords, of which 14 met inclusion criteria and were selected for analysis. The weighted average age of patients treated with rIFN-α was 48 years (n = 744 patients; 12 studies) and for HU was 56 years (n = 1397; 8 studies). The weighted average duration of treatment for either drug was 4.5 years. Using a Bayesian hierarchical model, the pooled annual rate of discontinuation due to toxicity was 5.2% for patients receiving rIFN-α (n = 587; 95% confidence interval [CI], 2.2-8.2) and 3.6% for HU (n = 1097; CI, 1-6.2). The average complete hematologic response for rIFN-α and HU was 62% and 52%, respectively. Patients experienced thrombotic events at a pooled annual rate of 0.79% and 1.26%; secondary myelofibrosis at 1.06% and 1.62%; acute myeloid leukemia at 0.14% and 0.26%; and death at 0.87% and 2.65%, respectively. No treatment-related deaths were reported. With acceptable rates of nonfatal toxicity, cytoreductive treatment, particularly with disease-modifying rIFN-α, may benefit PV<60. Future randomized trials prioritizing inclusion of PV<60 are needed to establish a long-term benefit of early cytoreductive treatment in these patients.

Long-term clinical efficacy and safety of thalidomide in patients with transfusion-dependent ß-thalassemia: results from Thal-Thalido study.

Regular blood transfusion is the mainstay of treatment in transfusion-dependent ß-thalassemia (TDT); however, transfusions culminate in an array of serious complications. Therefore, a single-arm, non-randomized clinical trial was conducted in hydroxyurea refractory TDT patients to explore the long-term safety and efficacy of thalidomide. The primary outcomes for efficacy were rise in hemoglobin (Hb) level and changes in transfusion frequency. Whereas, several clinical and laboratory parameters were assessed for safety of thalidomide. Secondary outcomes included changes in serum ferritin, serum lactate dehydrogenase (LDH), serum uric acid, red blood cell indices, and size of liver and spleen. A total of 532 patients were followed for a period of 30 months. Significant increase in mean Hb level was identified at 6 months (1.4 g/dL, p ≤ 0.001) and 30 months (2 g/dL, p ≤ 0.001) in comparison with baseline. A total of 408 (76.7%) patients responded to thalidomide therapy (excellent responders 25.8%, good responders 31%, and partial responders 19.9%) and attained transfusion independence within 6 months of therapy. A significant decline in mean ferritin, LDH level, liver size, and spleen size was observed. No unfavorable effects were observed on kidney and liver functions. Mild adverse events were reported in 48 (9%) patients and serious adverse events, including cerebral vascular accident and portal vein thrombosis were reported in two patients each. This study concludes that thalidomide is an effective and well-tolerated drug that can improve Hb levels and reduce transfusion burden in hydroxyurea refractory TDT patients.Trial registration: This trial is registered at http://www.clinicaltrial.gov as # NCT03651102.

Scleroderma-like syndrome due to hydroxyurea.

Scleroderma-like cutaneous changes have been reported in association with several drugs, but not with hydroxyurea (HU), to our knowledge. We report the case of a 67-year-old man who was treated with HU (hydroxycarbamide) for 12 years for a myeloproliferative disorder, and presented a progressive pruritic woody induration, symmetrically affecting both legs. He also had Gottron-like papules on the back of the metacarpophalangeal joints, and a retroauricular undifferentiated squamous cell carcinoma. On histological examination of a skin biopsy taken from the leg, massive dermal fibrosis was seen, with thickening of collagen bundles throughout the entire dermis. Six months after HU withdrawal, the skin induration resolved without scarring. Scleroderma-like syndrome has not been previously considered one of the secondary effects of HU. The evolution of our patient's condition supports a causal relationship between the HU treatment and the sclerodermiform changes of the skin.

[Ulcers following therapy with hydroxyurea. Three case reports and review of the literature]. / Ulzerationen unter Therapie mit Hydroxyharnstoff. Drei Fallberichte mit Literaturüberblick.

Hydroxyurea is frequently used for therapy of myeloproliferative disorders. One cutaneous side-effect is painful, therapy-resistant ulcers which have bizarre configurations and occur at atypical sites for venous ulcers. Improvement or healing often first occurs when hydroxyurea is discontinued. We report on one patient with essential thrombocythemia and two with polycythemia vera, who developed such ulcers during hydroxyurea therapy. In one case, the ulcers developed shortly after hydroxyurea was started. In addition we give a short overview of the current literature.

[Leg ulcers in patient affected by polycythemia vera in treatment with hydroxycarbamide. Case report]. / Ulcere cutanee in paziente con policitemia vera in trattamento con idrossicarbamide. Case report.

Leg ulcers are a frequent and serious complication of polycythemia vera (PV). They are caused by a synergic action of vascular, neurological and infectious physiopathologic mechanisms. Furthermore, cytostatic therapies commonly employed to control the myeloproliferative disease negatively interfere on the development of granulation tissue, slowing down the recovery of the ulcer. We describe the case of a 70 years old woman with PV, who had calcaneous and perimalleolar ulcers. They were so painful that they made it almost impossible for her to sleep and walk normally. These ulcers were particularly resistant to common topical therapy. Further and accurate investigations showed that these ulcers were a complication of hydroxycarbamide therapy employed and they were not a complication of the ematologic disease. Leg ulcers during hydroxycarbamide therapy are a relatively frequent but underestimated condition. Pathogenesis is bound to numerous factors, i.o. cellular damage and tissutal hypoxia, consequent of drug induced macroerythrosis. In our patient drug substitution and prosecution of topic therapies allowed the recovery of the leg ulcers, particularly serious for both, extensiveness and symptoms.

Hydroxyurea in the management of thalassemia intermedia.

Hydroxyurea (HU) is an antineoplastic agent that enhances fetal hemoglobin. The clinical significance induced by this compound is well known in sickle cell disease. This clinical significance could also be expected in beta-thalassemia patients. Although studies on beta-thalassemia major patients showed significant results, but these clinical responses are expected to be more in thalassemia intermedia (TI) patients because of lesser alpha/beta globin imbalance. Studies showed that HU therapy in TI patients has significant effects on increasing Hb levels that can cause reducing blood transfusion dependency and transfusion free in some patients, decreasing skeletal deformities and splenomegaly and increasing energy state. So HU therapy could be a useful alternative to blood transfusion in some TI patients.

[Multiple skin cancers in a patient treated with hydroxyurea]. / Multiple kutane Neoplasien nach Therapie mit Hydroxyurea.

A 62-year-old patient treated for 9 years with hydroxyurea for chronic myeloproliferative disease developed multiple cutaneous neoplasms. Hydroxyurea minimizes DNA synthesis via inhibition of the enzyme ribonucleotide reductase and is used to treat hematological malignancies. The most important and severe side-effect is a dose-dependent myelodepression. An association with multiple skin tumors has been reported. The presented case emphasizes this potential risk of hydroxyurea therapy. Continuous dermatologic monitoring of patients treated with hydroxyurea is recommended.

Hydroxyurea-induced leg ulcers treated with a protease-modulating matrix.

BACKGROUND: The development of painful leg ulcers in the ankle area is a rare and only partially described complication in patients receiving high-dose, long-term hydroxyurea treatment for myeloproliferative diseases. Several reports have described treatments for chronic wound management with this type of lesion. OBSERVATIONS: We describe 2 patients who were diagnosed as having hydroxyurea-induced leg ulcers that were successfully treated with a freeze-dried sponge containing oxidized regenerated cellulose and bovine purified collagen. This dressing is able to modulate the activity of proteases such as plasmin, neutrophil-derived elastase, and matrix metalloproteinase by physically entrapping them and thus inhibiting their activity. CONCLUSION: This case demonstrates that topical application of a matrix metalloproteinase modulator can be a successful and safe treatment option for patients with hydroxyurea-induced recalcitrant leg ulcers.

Phase II clinical trial of parenteral hydroxyurea in combination with fluorouracil, interferon and filgrastim in the treatment of advanced pancreatic, gastric and neuroendocrine tumors.

PURPOSE: Combined inhibition of ribonucleotide reductase (RR) and thymidylate synthase (TS), the enzymes responsible for a balanced supply of nucleotides for DNA synthesis, has been shown to induce synergistic antiproliferative effects in vitro. In the clinic, prolonged infusion of the RR inhibitor, hydroxyurea (HU), may be more effective than bolus or oral administration of drug. The purpose of the current study was to determine whether dose intensification of parenteral hydroxyurea in combination with fluorouracil could enhance the response rates of the combination against refractory upper gastrointestinal malignancies. METHODS: A clinical trial of parenteral, weekly, high-dose HU in combination with weekly, high-dose infusional fluorouracil (5FU) was initiated in patients with advanced pancreatic and gastric cancer. Patients received 5FU 1.3 g/m(2) by continuous intravenous infusion (CIVI) daily over 48 h weekly in combination with HU 4.3 g/m(2) CIVI per day over 48 h weekly. Patients also received the biologic agent interferon alfa-2a 9 MU subcutaneously (s.c.) three times per week and filgrastim 480 microg s.c. on days 3 (starting after midday), 4, 5, and 6 each week. Each cycle required treatment on days 1 and 8 every 22 days. RESULTS: Enrolled in the study were 32 patients, of whom 30 were evaluable. The median age was 56 years. Primary sites included pancreas (18), gastric (13) and islet cell (1). Despite filgrastim, the major toxicities were hematologic with 15 of 30 patients developing grade 3/4 granulocytopenia. Of the 30 patients, 4 developed grade 3/4 diarrhea. Interferon-mediated fatigue was mild. Of 12 evaluable patients with gastric cancer, 1 had a partial response, and there were no responders among patients with pancreatic cancer. CONCLUSIONS: Combined inhibition of RR and TS using this high-dose, weekly, 48-h infusional regimen is not an improvement over single-agent therapy in these tumor types.

Melanonychia and mucocutaneous hyperpigmentation from hydroxyurea use for the treatment of essential thrombocytosis.

Hydroxyurea is an antineoplastic agent commonly used to treat essential thrombocytosis. We report the case of a 50-year-old woman who was incidentally detected to have essential thrombocytosis after suffering an episode of cerebrovascular accident with faciobrachial monoparesis. She was subsequently initiated on hydroxyurea. Within seven weeks of therapy, the patient noticed irregular hyperpigmented patches over her feet, hands and perioral region, with bluish-grey longitudinal bands on all 20 nails. Hydroxyurea-induced hyperpigmentation and melanonychia are not commonly reported. To the best of our knowledge, this is only the third published report of hydroxyurea-induced hyperpigmentation and melanonychia involving all 20 nails. Physicians need to be aware of such mucocutaneous side effects to avoid misdiagnosis and unwarranted fear in patients. The decision to discontinue the intake of the drug depends heavily on the future risk of thrombotic events.

Gangrene of the toes in a patient with chronic myelogenous leukemia after long-term hydroxyurea therapy.

Gangrene of the toes and digits appears to be a rare but very severe complication of long-term hydroxyurea therapy. Nothing is known regarding the pathophysiology and the type of vascular damage leading to this syndrome. Here we report a case of a 49-year-old male presenting with gangrene of the toes of both feet 4.5 years after initiation of hydroxyurea therapy for chronic myelogenous leukemia. Blisters on the toes occurred for the first time 9 months prior to hospitalization. Successively, all ten toes showed signs of beginning gangrene with one toe removed surgically 8 months before admission. Presence of diabetes mellitus or peripheral angiopathy was ruled out and platelet counts were within the physiologic range during the last years, excluding thrombocythemia as another rare cause for gangrene in patients with myeloproliferative diseases. Whereas perimalleolar ulcerations of the legs are a more common complication of hydroxyurea, gangrene of the toes as a consequence of hydroxyurea treatment has been described previously only once in the literature. At this point in time cessation of hydroxyurea treatment appears to be the only therapeutic option, thereby avoiding further progress of gangrene in patients with chronic myelogenous leukemia treated with hydroxyurea.