Marco Montanaro

Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized, controlled trial

The initial analysis of the oral combination melphalan, prednisone, and thalidomide (MPT) in newly diagnosed patients with myeloma showed significantly higher response rate and longer progression-free survival (PFS) than did the standard melphalan and prednisone (MP) combination and suggested a survival advantage. In this updated analysis, efficacy and safety end points were updated. Patients were randomly assigned to receive oral MPT or MP alone. Updated analysis was by intention to treat and included PFS, overall survival (OS), and survival after progression. After a median follow-up of 38.1 months, the median PFS was 21.8 months for MPT and 14.5 months for MP (P = .004). The median OS was 45.0 months for MPT and 47.6 months for MP (P = .79). In different patient subgroups, MPT improved PFS irrespective of age, serum concentrations of beta(2)-microglobulin, or high International Staging System. Thalidomide or bortezomib administration as salvage regimens significantly improved survival after progression in the MP group (P = .002) but not in the MPT group (P = .34). These data confirm activity of MPT for PFS but failed to show any survival advantage. New agents in the management of relapsed disease could explain this finding. The study is registered at www.clinicaltrials.gov as #NCT00232934.

The coexistence of chronic lymphocytic leukemia and myeloproliperative neoplasms: a retrospective multicentric GIMEMA experience

Although the coexistence of chronic lymphocytic leukemia (CLL) and myeloproliferative neoplasms (MPN) has been sporadically reported in the literature, no systematic studies on this disease association are available. We retrospectively analyzed 46 patients affected by CLL/MPN referred by 15 Italian GIMEMA centers. The aim of this retrospective multicenter study was to define the following: clinico‐biological characteristics, possible familiarity, clinical course of both diseases, and influence of MPN chemotherapy on the course of CLL. Among 46 patients, 30 patients were males, 16 patients were females; median age was 71 years. Only one case had familiar CLL. Myeloproliferative disorders consisted of essential thrombocytemia in 18 cases, polycythemia vera in 10 cases, chronic myeloid leukemia in 9 cases, primary myelofibrosis in 6 cases, and MPN/myelodysplastic syndrome in 3 cases. The lymphoproliferative disorder was diagnosed as monoclonal B‐cell lymphocytosis in 8 patients and as Binet Stage A CLL in 38 patients. After a median follow‐up of 49 months, 9 patients experienced progressive CLL and only 6 patients required treatment after a median of 57.5 months. The biological profile confirmed a subset of low‐risk CLL. Twenty patients received chemotherapy for MPN without influence on the course of CLL: lymphocyte counts remained unchanged after 3, 6, and 12 months of treatment. This series is the largest so far reported in literature. The diagnosis of concomitant CLL/MPN is a rare event and lymphoproliferative disorders present a clinical indolent course with a low‐risk biological profile. MPN therapy does not interfere with the prognosis of patients with CLL. Am. J. Hematol. 2011.

Thrombosis and survival in essential thrombocythemia: a regional study of 1,144 patients.

To identify prognostic factors affecting thrombosis‐free survival (TFS) and overall survival (OS), we report the experience of a Regional cooperative group in a real‐life cohort of 1,144 patients with essential thrombocythemia (ET) diagnosed from January 1979 to December 2010. There were 107 thrombotic events (9.4%) during follow‐up [60 (5.3%) arterial and 47 (4.1%) venous thromboses]. At univariate analysis, risk factors for a shorter TFS were: age >60 years (P < 0.0054, 95% CI 1.18–2.6), previous thrombosis (P < 0.0001, 95% CI 1.58–4.52) and the presence of at least one cardiovascular risk factor (P = 0.036, 95% CI 1.15–3.13). Patients with a previous thrombosis occurred ≥24 months before ET diagnosis had a shorter TFS compared to patients with a previous thrombosis occurred <24 months (P = 0.0029, 95% CI 1.5–6.1); furthermore, patients with previous thrombosis occurred <24 months did not show a shorter TFS compared with patients without previous thrombosis (P = 0.303, 95% CI 0.64–3.21). At multivariate analysis for TFS, only the occurrence of a previous thrombosis maintained its prognostic impact (P = 0.0004, 95% CI 1.48–3.79, RR 2.36). The 10‐year OS was 89.9% (95% CI 87.3–92.5): at multivariate analysis for OS, age >60 years (P < 0.0001), anemia (P < 0.0001), male gender (P = 0.0019), previous thromboses (P = 0.0344), and white blood cell >15 × 109/l (P = 0.0370) were independent risk factors. Previous thrombotic events in ET patients are crucial for TFS but their importance seems related not to the occurrence per se but mainly to the interval between the event and the diagnosis. Am. J. Hematol. 89:542–546, 2014.

Symptomatic mucocutaneous toxicity of hydroxyurea in Philadelphia chromosome-negative myeloproliferative neoplasms the mister hyde face of a safe drug

The current study was conducted to evaluate severe mucocutaneous toxicity during treatment with hydroxyurea (HU) in a large cohort of patients with Philadelphia chromosome‐negative myeloproliferative neoplasms (MPN).

IgD multiple myeloma a descriptive report of 17 cases: survival and response to therapy

BackgroundImmunoglobulin D multiple myeloma (MM) is rare and has a poorer prognosis than other MM isotypes.Design and methodsSeventeen patients (pts) diagnosed from 1993 to 2009 with IgD MM were selected from six institutions of Multiple Myeloma Latium-Region GIMEMA Working Group.ResultsMedian age was 55 years, 14 patients had bone lesions, eight had renal impairment with estimated glomerular filtration rate (eGFR) < 50 ml/min, one serum calcium ≥ 12 mg/dl, 11 had lambda light chains, five stage III of ISS, six with chromosomal abnormalities. Six pts received conventional chemotherapy (CT): five melphalan + steroids based regimens. Eleven underwent high-doses of chemotherapy with autologous stem cell transplantation (HDT/ASCT), five single and six tandem ASCT: six received bortezomib and/or thalidomide as induction therapy and five VAD. Thalidomide maintenance was used in two pts: one in HDT/ASCT and one in CT group; bortezomib was used in one patient after HDT/ASCT. At a median follow up of 38 (range 19-60) and 50 months (range 17-148) for pts treated with CT and HDT/ASCT, respectively, the overall response rate (ORR) was 83% and 90%. In the group of patients treated with CT, median overall survival (OS) was 34 months (95% CI 15- 54 months), median progression free survival (PFS) was 18 months (95% CI 3-33 months) and median duration of response (DOR) was 7 months (95% CI 5-9 months). Median OS, PFS and DOR were not reached at the time of this analysis in the HDT/ASCT group of patients. Death was observed in 27.3% of pts treated with HDT/ASCT and in 66.7% undergone CT.ConclusionsDespite the retrospective analysis and the small number of pts our study showed that the use of HDT/ASCT seems to improve also the prognosis of IgD MM patients. Treatment options including new drugs, before and after stem cell transplantation, may further improve the outcomes of these patients.

Evolution of bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma and Waldenstrom's macroglobulinemia: a retrospective multicentric study

Bisphosphonates (BPs) are used intravenously to treat cancer-related conditions for the prevention of pathological fractures. Osteonecrosis of the jaw (BRONJ) is a rare complication reported in 4–15% of patients. We studied, retrospectively, 55 patients with multiple myeloma or Waldenstroms macroglobulinemia followed up from different haematological departments who developed BRONJ. All patients were treated with BPs for bone lesions and/or fractures. The most common trigger for BRONJ was dental alveolar surgery. After a median observation of 26 months, no death caused by BRONJ complication was reported. In all, 51 patients were treated with antibiotic therapy, and in 6 patients, this was performed in association with surgical debridement of necrotic bone, in 16 with hyperbaric O2 therapy/ozonotherapy and curettage and in 12 with sequestrectomy and O2/hyperbaric therapy. Complete response was observed in 20 cases, partial response in 21, unchanged in 9 and worsening in 3. The association of surgical treatment with antibiotic therapy seems to be more effective in eradicating the necrotic bone than antibiotic treatment alone. O2 hyperbaric/ozonotherapy is a very effective treatment. The cumulative dosage of BPs is important for the evolution of BRONJ. Because the most common trigger for BRONJ was dental extractions, all patients, before BP treatment, must achieve an optimal periodontal health.

Chelation efficacy and erythroid response during deferasirox treatment in patients with myeloproliferative neoplasms in fibrotic phase.

At present, very few data are available on deferasirox (DFX) in the treatment of patients with Philadelphia‐negative myeloproliferative neoplasms in fibrotic phase (FP‐MPN) and transfusion dependence. To address this issue, a retrospective analysis of 28 patients (22 male and 6 female) with FP‐MPN and iron overload secondary to transfusion dependence was performed, based on patients enrolled in the database of our regional cooperative group who received treatment with DFX. DFX was started after a median interval from diagnosis of 12.8 months (IR 7.1–43.1) with median ferritin values of 1415 ng/mL (IR 1168–1768). Extra‐hematological toxicity was reported in 16 of 28 patients (57.1%), but only two patients discontinued treatment due to toxicity. Among 26 patients evaluable for response (≥6 months of treatment), after a median treatment period of 15.4 months (IR 8.1–22.3), 11 patients (42.3%) achieved a stable and consistent reduction in ferritin levels <1000 ng/mL. As for hematological improvement, 6 of 26 patients (23%) showed a persistent (>3 months) rise of Hb levels >1.5 g/dL, with disappearance of transfusion dependence in four cases. Treatment with DFX is feasible and effective in FP‐MPN with iron overload. Moreover, in this setting, an erythroid response can occur in a significant proportion of patients.

High-dose epoetin alfa as induction treatment for severe anemia in multiple myeloma patients

Anemia is a common finding in patients with multiple myeloma (MM): it is present in two-thirds of patients (pts) at diagnosis and reflects the course of the disease, since it worsens during resistant or progressive disease and ameliorates when the disease is controlled by treatment [1, 2]. Generally, anemia during myeloma is normochromic and normocytic, characterized by shortened erythrocyte survival with failure of bone marrow to compensate red cell production. The multifactor basis of bone marrow impairment includes: (a) impaired availability of storage iron, (b) inadequate erythropoietin response to the level of anemia, and (c) overproduction of cytokines capable of direct erythropoiesis inhibition. These cytokines (including tumor necrosis factor, interleukin-1 and interleukin-6) may also decrease reutilization of iron stores from reticuloendothelial cells and may interfere with kidney erythropoietin production [3]. Recombinant human erythropoietin (rHuEPO) has been extensively used throughout the course of the disease to increase hemoglobin (Hb) concentration, reduce transfusion requirement and improve the quality of life. Treatment of anemia in lymphoproliferative disorders with erythropoiesis-stimulating agents (ESA) has been shown to be safe, efficacious and effective. Response rate (RR) varied from 31 to 78%, according to the criteria utilized for response [4]. In MM, RR was influenced by the disease duration, ratio between observed and predicted serum erythropoietin concentration and Epo dose. RR at 4 weeks (wk) represents the most powerful predictor of a durable response [5]. Recently, ASCO/ASH guidelines for the use of epoetin and darbepoetin have been revised: FDA-approved starting dose of epoetin is 150 IU/kg 3 times/week or 40,000 IU/week subcutaneously; FDAapproved starting dose of darbepoetin is 2.25 lg/kg/week or 500 lg every 3 week subcutaneously. Alternative starting doses or dosing schedules have shown no consistent differences in transfusion and Hb response, although they may be considered to improve cost/effectiveness. Dose escalation should follow those approved by FDA; no convincing evidences indicate that other schedules may be associated with better results. The threshold for initiating ESA therapy should be a concentration of Hb B 10 g/dL [6]. The aim of this study is to evaluate the safety and efficacy of a regimen based on rHuEPO alfa 40000 IU twice/week as starting dose with weekly IV iron supplementation in MM pts with severe anemia. Between January 2003 and March 2004, 20 pts (10 M/ 10 F) with MM were enrolled in this open-label trial. The starting dose consisted of 40000 IU subcutaneously twice/ week for 5 doses (up to 8 doses if no major response was obtained at week 3), maintained by rHuEPO at the conventional schedule in the responder patients. All pts received iron supplementation (oral or IV). The main pretreatment characteristics were the following: median age 67.5 years (58–81); 9 pts were in first line treatment, 6 pts in second line and 5 received more than 3 lines of T. Caravita A. Siniscalchi P. Niscola S. Amadori P. de Fabritiis Department of Hematology, University ‘‘Tor Vergata’’, St. Eugenio Hospital, Rome, Italy

Spleen enlargement is a risk factor for thrombosis in essential thrombocythemia: Evaluation on 1,297 patients

Spleen enlargement, present in 10–20% of Essential Thrombocythemia (ET) patients at diagnosis, is a feature clinically easy to assess, confirmable by echography with a very low chance of misinterpretation. Nonetheless, the clinical and prognostic role of splenomegaly has been seldom evaluated. From 1979 to 2013, 1297 ET patients retrospectively collected in the database of the Lazio Cooperative Group and Bologna University Hospital were evaluable for spleen enlargement at diagnosis and included in the analysis. On the whole, spleen was enlarged in 172/1297 (13.0%) patients; in most cases (94.8%) splenomegaly was mild (≤5 cm). Patients with splenomegaly were younger, predominantly male, presented higher platelet count and JAK2V617F allele burden and had a lower incidence of concomitant cardiovascular risk factors. At least one thrombotic event during follow‐up occurred in 97/1,125 (8.6%) patients without spleen enlargement compared to 27/172 (15.7%) patients with spleen enlargement (P = 0.003). Despite comparable use of cytoreductive/antiplatelet therapies in the two groups, the cumulative risk of thrombosis at 5 years was significantly higher in patients with baseline splenomegaly (9.8% versus 4.4% in patients without splenomegaly, P = 0.012). In multivariate analysis exploring risk factors for thrombosis, splenomegaly retained its negative prognostic role, together with previous thrombosis, leucocyte count and male gender. Baseline splenomegaly seems to be an independent additional risk factor for thrombosis in nonstrictly WHO‐defined ET patients. This data could be useful in the real‐life clinical management of these patients. Am. J. Hematol. 91:318–321, 2016.

Hemoglobin levels and circulating blasts are two easily evaluable diagnostic parameters highly predictive of leukemic transformation in primary myelofibrosis

To predict leukemic transformation (LT), we evaluated easily detectable diagnostic parameters in 338 patients with primary myelofibrosis (PMF) followed in the Latium region (Italy) between 1981 and 2010. Forty patients (11.8%) progressed to leukemia, with a resulting 10-year leukemia-free survival (LFS) rates of 72%. Hb (<10g/dL), and circulating blasts (≥1%) were the only two independent prognostic for LT at the multivariate analysis. Two hundred-fifty patients with both the two parameters available were grouped as follows: low risk (none or one factor)=216 patients; high risk (both factors)=31 patients. The median LFS times were 269 and 45 months for the low and high-risk groups, respectively (P<.0001). The LT predictive power of these two parameters was confirmed in an external series of 270 PMF patients from Tuscany, in whom the median LFS was not reached and 61 months for the low and high risk groups, respectively (P<.0001). These results establish anemia and circulating blasts, two easily and universally available parameters, as strong predictors of LT in PMF and may help to improve prognostic stratification of these patients particularly in countries with low resources where more sophisticated molecular testing is unavailable.