Mariella D'Andrea

Revised International Prognostic Scoring System (IPSS) Predicts Survival and Leukemic Evolution of Myelodysplastic Syndromes Significantly Better Than IPSS and WHO Prognostic Scoring System: Validation by the Gruppo Romano Mielodisplasie Italian Regional Database

PURPOSE The definition of disease-specific prognostic scores plays a fundamental role in the treatment decision-making process in myelodysplastic syndrome (MDS), a group of myeloid disorders characterized by a heterogeneous clinical behavior. PATIENTS AND METHODS We applied the recently published Revised International Prognostic Scoring System (IPSS-R) to 380 patients with MDS, registered in an Italian regional database, recruiting patients from the city of Rome (Gruppo Romano Mielodisplasie). Patients were selected based on the availability of IPSS-R prognostic factors, including complete peripheral-blood and bone marrow counts, informative cytogenetics, and follow-up data. RESULTS We validated the IPSS-R score as a significant predictor of overall survival (OS) and leukemia-free survival (LFS) in MDS (P < .001 for both). When comparing the prognostic value of the International Prognostic Scoring System (IPSS), WHO Prognostic Scoring System (WPSS), and IPSS-R, using the Cox regression model and the likelihood ratio test, a significantly higher predictive power for LFS and OS became evident for the IPSS-R, compared with the IPSS and WPSS (P < .001 for both). The multivariate analysis, including IPSS, WPSS, age, lactate dehydrogenase, ferritin concentration, Eastern Cooperative Oncology Group performance status, transfusion dependency, and type of therapy, confirmed the significant prognostic value of IPSS-R subgroups for LFS and OS. Treatment with lenalidomide and erythropoiesis-stimulating agents was shown to be an independent predictor of survival in the multivariate analysis. CONCLUSION Our data confirm that the IPSS-R is an excellent prognostic tool in MDS in the era of disease-modifying treatments. The early recognition of patients at high risk of progression to aggressive disease may optimize treatment timing in MDS.

Pleural-pericardic effusion as uncommon complication in CML patients treated with Imatinib

To the Editor: Imatinib is usually well tolerated and has significant anti-leukaemic activity in chronic myeloid leukaemia (CML) patients (1). The most frequent adverse events that appear to be related to this drug are nausea, oedema, myalgias and cutaneous rashes (2). We describe a pleural-pericardic effusion as uncommon complication that occurred in three patients during imatinib treatment. The first patient was a 61-yr-old CML female who, after an initial phase of treatment with interferon-a, experienced a lymphoid blast crisis (BC). She started imatinib in October 2001 and returned to a chronic phase (CP) with a complete haematological (CHR) and cytogenetic response (CCR) obtained after 2 months of treatment. At week 40, the patient developed weakness, progressive dyspnoea and weight gain, associated to bilateral pleural effusion and large pericardial effusion detected by echocardiography. Bone marrow analyses confirmed the patient being in CP and in CCR. The patient was treated with diuretics (furosemide at the dose of 40 mg/d) and steroids (prednisone at the dosage of 0.25 mg/kg), while imatinib was discontinued for 3 wk. Two weeks later, symptoms had completely resolved and imatinib was restarted at 400 mg/d. The second patient was a 41-yr-old male with myeloid BC, which after 3 wk of imatinib treatment at the dose of 600 mg/d, developed chest pain with progressive dyspnoea and weight gain. Echocardiography revealed a pericardial effusion and chest X-ray showed a left-pleural effusion. Imatinib was discontinued and steroid therapy (prednisone, 0.25 mg/kg) was started. Bone marrow analysis showed the patients being in persistent CP. After 3 wk the effusions resolved and imatinib was restarted at initial low dosage of 300 mg/d and then restarted at 600 mg/d. The third patient was a 72-yr-old female with a myeloid BC that developed dyspnoea and weakness after 54 wk of imatinib treatment at 600 mg/d, with which had obtained CHR. A chest X-ray showed a bilateral pleural effusion and an echocardiogram revealed a collapse of the right atrium and ventricle, caused by a large pericardial effusion. Imatinib was discontinued and steroid therapy (prednisone at the dosage of 0.25 mg/kg) and diuretics (furosemide, 60 mg/d) were started and continued for 3 wk. Also in this case bone marrow morphology showed the persistence of CP. Imatinib was restarted at 400 mg/d after the effusions had resolved. In all patients, cytospins of pleural fluid samples were analysed, but no evidence of extramedullary leukaemic infiltration was detected. Under imatinib therapy, fluid retention events may occur more frequently in BC patients (up to 16%, as stated by Prod Info Gleevec, 2001, Novartis Pharmaceuticals Inc., Dorval QC, Canada), but are less common in CP patients and are reported among the grade 3–4, only in patients treated with high dosage (600 mg and over) (2, 3). Pleural and pericardial effusions are considered among the grade 3 and 4 of oedema. In literature only one specific case of CML patient was reported, that developed cardiac tamponade under imatinib treatment at the dose of 400 mg/ d (4). In the present cases, we have excluded that the effusions were caused by progression of disease, but probably occurred, in the absence of heart failure and infectious causes, as a result of imatinib treatment at higher doses. The fact that with the discontinuation of imatinib, the weight gain and the effusions rapidly resolved, also suggest that this uncommon events are caused by imatinib. In fact, it is well described that this drug may have an effect on fluid dynamics and may cause a potential retention in visceral spaces. In conclusion, we suggest a close monitoring of patients treated with imatinib at dose of 600 mg/d and over and the preventive use of diuretics during the treatment. Eur J Haematol 2005: 74: 89–90 All rights reserved Copyright Blackwell Munksgaard 2005

Granulocytic sarcoma of the pancreas successfully treated with intensive chemotherapy and stem cell transplantation

Abstract: A case of preleukemic granulocytic sarcoma of pancreas is presented. Pancreas is a well described site of secondary metastasis of solid tumors, but occasionally it has been reported as the primary site of leukemia. Like other cases reported in the literature, the present case was initially misdiagnosed as malignant lymphoma. We highlight the importance of an accurate immunohistochemical diagnosis and of an early and intensive acute myeloid leukemia‐like treatment for these cases representing an uncommon and aggressive form of acute leukemia.

Budd-Chiari syndrome as the first manifestation of polycythemia vera in young women with inherited thrombophilic state: an aggressive form of myeloproliferative disorder requiring multidisciplinary management.

Abstract:  The Budd‐Chiari syndrome (BCS), characterized by the obstruction and occlusion of the suprahepatic veins, is a rare but typical complication occurring in patients with polycythemia vera (PV). We describe three young women who developed BCS as first manifestation of PV, in association with an inherited thrombophilic state and in the absence of concomitant use of oral contraceptives. Our report illustrates the existence of an aggressive form of myeloproliferative disorder, which requires prompt recognition and immediate therapeutic intervention including cytostatic drugs and anticoagulant treatment. Furthermore, we suggest the need of routine screening for thrombophilic state in young women affected by PV.

Cutaneous pleomorphic T‐cell lymphoma coexisting with myelodysplastic syndrome transforming into acute myeloid leukemia: successful treatment with a fludarabine‐containing regimen

Abstract: The coexistence of a primary myelodysplastic syndrome (MDS) and a T‐cell cutaneous non‐Hodgkins lymphoma is an extremely rare event, which has so far only been reported in a single instance in the literature. We describe herein an additional case in which the lymphoid disease was combined with an MDS at the time of its evolution into acute myeloid leukemia (AML). Both diseases were successfully treated with a regimen containing fludarabine. We discuss possible pathogenetic mechanisms and suggest the use of nonalkylating drugs, such as fludarabine, for the treatment of this rare association of malignancies usually characterized by a very poor response to therapy.

The potential role of pre-transplant HBcIgG seroposivity as predictor of clinically relevant cytomegalovirus infection in patients with lymphoma undergoing autologous hematopoietic stem cell transplantation: A study from the Rome Transplant Network

Despite the increased use of intensive immunosuppressive chemo‐immunotherapies in patients with lymphoma observed in the last decade, current data on cytomegalovirus (CMV) infection following autologous stem cell transplantation (Auto‐SCT) are very limited. To address this peculiar aspect, a retrospective study on a cohort of 128 adult patients consecutively transplanted for lymphoma in three Hematology Institutions was performed with the aim to determine the incidence of and the risk factors for CMV symptomatic infection and/or end‐organ disease. Sixteen patients (12.5%) required specific antiviral therapy and 4/16 died (25%); transplant‐related mortality (TRM) was significantly influenced by CMV infection (P = 0.005). In univariate analysis, a pre‐transplant HBcIgG seropositivity, HBV infection according to clinical–virological definitions, a pre‐transplant Rituximab treatment, a diagnosis of B‐cell non‐Hodgkin lymphoma, and age at transplant were significantly associated with the risk of developing a clinically relevant CMV infection. In multivariate analysis, only a pre‐transplant HBcIgG seropositivity (P = 0.008) proved to be an independent predictor of a clinically relevant CMV infection. These results suggest that a pre‐transplant HBcIgG seropositivity could be considered as an independent predictor factor of clinically relevant CMV infection after Auto‐SCT.

Can nifedipine and estrogen interaction with imatinib be responsible for gallbladder stone development

To the Editor: Drug interactions with imatinib mesylate are well established, but possible clinical effects are not yet well known (1). We describe here two patients with Ph+ CML, who during imatinib treatment developed calculi of the gallbladder: both patients were also receiving other drugs. We suggest a possible role of drug interaction, which might have been responsible for incremented cholesterol synthesis predisposing the development of gallstones. Case 1. A 76-year-old man was admitted to our Institution in March 2004 for leukocytosis (100 · 10/L) and Ph+ CML was diagnosed, intermediate Sokal risk. Since January 2002, the patient was affected by hypertension and was on treatment with nifedipine. Before the start of imatinib, at a standard dose of 400 mg, an ultrasound scan revealed no organomegaly and a normal gallbladder without evidence of stones; liver enzymatic tests were in the normal range. After 8 wk of therapy the patient experienced nausea, vomiting and abdominal pain; his serum bilirubin level was normal (0.42 mg/dL) and only alkaline phosphatase level was increased to 140 U/L (n.v. 30–80 U/ L). Abdominal ultrasound showed a thickened gallbladder wall with a gallstone of 35 mm, and dilatation of the principal bile ducts. Imatinib was discontinued until the abdominal pain was resolved and was then resumed at a lower dosage (200 mg). Appropriate dietetic habits were recommended to the patient, who presently is in good clinical conditions and in complete cytogenetic remission (CCR) under imatinib. Case 2. A 31-year-old woman was diagnosed as having Ph+ CML in September 1999; she was started on IFN and a CCR was achieved in June 2000. After 54 months of IFN therapy the patient, while in stable CCR but with persistent molecular disease, experienced severe anorexia, weight gain and severe hypothyroidism. Due to IFN intolerance, she was started on imatinib at 400 mg/d. Before the start of this therapy, a screening including abdominal ultrasound scan and liver enzymatic tests, resulted as normal. Owing to recurring severe menorragic episodes, the patient was on therapy with low dosage oral estrogen contraceptives. After 4 months of imatinib, she experienced acute abdominal pain and nausea. Liver enzymatic tests showed only increased alkaline phosphatase level (145 U/L); an ultrasound scan displayed multiple stones with a diameter of 40 mm, and increased thickness of gallbladder wall with no evidence of enlarged cystic duct. Imatinib was temporarily stopped, and oral contraceptives were definitively discontinued. At the time of this writing we have not encountered other patients in treatments with imatinib (with or without other drugs) that developed gallbladder stones. Both patients described are in good clinical and haematological conditions and are periodically monitored for gallbladder stones, which are stable in size. Imatinib is a specific tyrosine kinase inhibitor of BCR/ABL transcript originating from the Ph chromosome. It is metabolized by via cytocrome p450 CYP3A4, with a consequent inhibition of CYP2D6, CYP4A isoenzymes, which may lead to clearance reduction for co-administered drugs, with the same metabolic pathways (2). Many pharmacological interactions have been described and for a number of drugs plasma levels may be increased by imatinib. Among these drugs is nifedipine, a dihydropyridine calcium channel blocker, which belongs to a family of agents with different beneficial properties on the development of atherosclerosis, through a direct protective effect on lipoproteins from oxidative modification (3). Generally this effect is only seen at high drug dosage, but it is possible to hypothesize that an interference by imatinib on its metabolism (through the cytocrome p450 utilization), may enhance its effect and lead to accumulation of lipidic particles, with consequent increased biliary Eur J Haematol 2005: 75: 89–90 doi: 10.1111/j.0902-4441.2005.t01-1-EJH2073.x All rights reserved Copyright Blackwell Munksgaard 2005

FCR (Fludarabine, Cyclophosphamide, Rituximab) regimen followed by 90yttrium ibritumomab tiuxetan consolidation for the treatment of relapsed grades 1 and 2 follicular lymphoma: a report of 9 cases

BackgroundThis retrospective analysis is focused on the efficacy and safety of radioimmunotherapy (RIT) with Zevalin® in nine patients with recurrent follicular lymphoma (FL) who were treated in a consolidation setting after having achieved complete remission or partial remission with FCR.MethodsThe median age was 63 yrs (range 46-77), all patients were relapsed with histologically confirmed CD20-positive (grade 1 or 2) FL, at relapse they received FCR every 28 days: F (25 mg/m2x 3 days), C (1 gr/m2 day 1) and R (375 mg/m2 day 4) for 4 cycles. Who achieved at least a partial remission, with < 25% bone marrow involvement, was treated with 90Yttrium Ibritumomab Tiuxetan 11.1 or 14.8 MBq/Kg up to a maximum dose 1184 MBq, at 3 months after the completion of FCR. The patients underwent a further restaging at 12 weeks after 90Y-RIT with total body CT scan, FDG-PET/CT and bilateral bone marrow biopsy.ResultsNine patients have completed the treatment: FCR followed by 90Y-RIT (6 patients at 14.8 MBq/Kg, 3 patients at 11.1 MBq/Kg). After FCR 7 patients obtained CR and 2 PR; after 90Y-RIT two patients in PR converted to CR 12 weeks later. With median follow up of 34 months (range 13-50) the current analysis has shown that overall survival (OS) is 89% at 2 years, 76% at 3 years and 61% at 4 years. The most common grade 3 or 4 adverse events were hematologic, one patient developed herpes zoster infection after 8 months following valacyclovir discontinuation; another patient developed fungal infection.ConclusionsOur experience indicate feasibility, tolerability and efficacy of FCR regimen followed by 90Y-RIT in patients relapsed with grades 1 and 2 FL with no unexpected toxicities. A longer follow up and a larger number of patients with relapsed grades 1 and 2 FL are required to determine the impact of this regimen on long-term duration of response and PFS.