Search

INTRODUCTION. Hairy cell leukemia (HCL) is a rare indolent B-cell malignancy, mainly characterized by peripheral cytopenias and splenomegaly. The current standard of treatment for HCL are Nucleoside Analogs (NA) cladribine and pentostatin, which produce remarkably high remission rates and durable responses. Aim of this study was to evaluate efficacy, short- and long-term toxicity of NA in HCL pts treated outside clinical trials. PATIENTS AND METHODS. We retrospectively analyzed 86 HCL patients (pts) treated with NA between 1996 and 2015 in two Hematologic Centers in Italy. The study was conducted in accordance to the Helsinki Declaration of 1964, as revised in 2000. Cladribine and pentostatin were administered according to standard schedules. Response criteria published by Jones et al. (Br J Haematol 2012) were retrospectively applied. Molecular assessment of BRAF-V600E mutation before and after NA therapy using quantitative real-time polymerase chain reaction (qRT-PCR)-based allelic discrimination assay (sensitivity 0.1%) was performed in 10 pts. RESULTS. The median follow-up of pts (71 males and 15 females, median age 53 years) was 5.8 years (range 0.5-28). During the disease course, 86 pts were treated with NA (cladribine n=76, 88%; pentostatin n=10, 12%); 59 pts received NA front-line (cladribine in 56/59 pts, 95%). Among the other 27 pts, receiving NA as second or subsequent line of therapy, 25 had been previously treated with interferon. Median time from diagnosis to the first NA was 3.3 months (range 0-315). Hematological toxicity was observed in 53 of 77 evaluable pts (69%), and was not significantly different with cladribine (72%) or with pentostatin (37%) (p=0.1). Grade 3-4 neutropenia, anemia and thrombocytopenia were observed in 50 (65%), 7 (9%) and 7 (9%) pts respectively. Extra-hematological toxicity was reported in 48 of 79 evaluable pts (61%). The incidence of extra-hematological toxicity with cladribine (63%) and pentostatin (37%) was not statistically different (p=0.2). Grade 3-4 febrile neutropenia was observed in 24 pts (30%); 9 pts (11%) had grade 3-4 infections; 4 pts (5%) had grade 3-4 skin toxicity, 1 pt (1%) had grade 3 hepatic toxicity. Four of 86 pts (5%) developed a second malignancy (prostatic adenocarcinoma n=2, colon adenocarcinoma n=1, diffuse large B cell lymphoma n=1). The median time from NA to second malignancy was 58 months (range 49-111). Four of 86 pts (5%) developed a skin cancer (basal-cell carcinoma n=3, squamous cell carcinoma n=1), after a median time of 59 months (range 16-126). Response was assessed at a median time of 3 months after the end of therapy. Overall Response Rate (ORR) and Complete Remission (CR) Rate were respectively 93% and 63% in the entire cohort, and 98% and 72% in pts treated with NA front-line. The allelic burden of BRAF before and after therapy with NA was available in 10 cases; none of the pts in clinical CR after NA achieved a complete molecular response (Table 1). The median Progression-Free Survival (PFS) for pts treated with NA frontline was 6.5 years. There was a trend toward a longer PFS in pts receiving NA as first-line therapy as compared to those treated in second or subsequent lines (p=0.05). PFS curves according to type of NA and line of therapy are shown in Figure 1. The 5- and 10-year Overall Survival (OS) rates were 96% (95% CI: 85% - 99%) and 90% (95% CI 76%-96%) respectively. OS was similar in pts treated with cladribine orpentostatin (p=0.49). CONCLUSIONS. This study shows that: i) NA are associated with an acceptable toxicity, neutropenia and febrile neutropenia being the main complications of therapy; ii) timing of response assessment may account for a CR rate that is slightly lower than reported in the literature, confirming the importance of waiting at least 4 months for response evaluation as recommended by current guidelines; iii) the persistence of molecular disease also in pts achieving a clinical CR supports the implementation of consolidation strategies aimed at eradicating minimal residual disease to prolong disease-free survival. Table 1. BRAF allelic burden before and after therapy Patient Age (years) Sex Line of Therapy Allelic Burden (%) Clinical Response Pre- Post- 1 33 F 1 21,8 0,1 CR 2 36 M 2 5,4 0,4 CR 3 39 M 1 24,2 0,7 CR 4 54 M 1 10,8 0,3 PR 5 42 F 1 44 1,2 CR 6 53 F 1 7,9 0,2 NV 7 56 M 1 6,5 0,3 CR 8 54 M 1 12,2 0,2 CR 9 32 M 1 35,8 9,5 PR 10 38 M 2 54,4 12,2 PR Figure 1. Progression-free survival according to type of NA and line of therapy Figure 1. Progression-free survival according to type of NA and line of therapy Disclosures Arcaini: Gilead: Consultancy, Other: Advisory Board; Celgene: Consultancy, Other: Advisory Board; Roche: Consultancy, Other: Advisory Board.

Background: Indolent non follicular B-Cell Lymphomas (INFL) are a heterogeneous group of lymphomas and include small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphomas (LPL) and marginal zone lymphomas of splenic (SMZL), nodal (NMZL) and extranodal (ENMZL) subtypes. In 2010 the NF10 study was started by the Fondazione Italiana Linfomi as a prospective registry specifically devised for investigating the prognosis of this group of lymphomas. We provide a preliminary report describing registered cases with an emphasis on initial therapy. Methods: The registration of consecutive adult patients with newly diagnosed INFL and no exclusion criteria is ongoing at a dedicated website via secure HTTP protocols. For the purposes of the study in addition to the conventional INFL subtype, the category of disseminated MZL and CD5- low grade lymphoma were also considered. So far the study has been activated in 65 centers in Europe and South America. Results: Between July 2010 and July 2015, 665 cases have been registered. The current report is based on 395 cases that have been validated. Forty-seven (12%) cases were registered as SLL, 76 (19%) as LPL, 59 (15%) as CD5-low grade and 213 (54%) as MZL, including 73 (18%) SMZL, 18 (5%) NMZL, 81 (21%) ENMZL or 41 (10%) disseminated subtypes. Median age was 67 years (range 29-94), 53% of patients were males; Ann Arbor stage was III-IV in 79%; 14% had B symptoms, 7% had ECOG performance status > 1, lactate dehydrogenase and b2-microglobulin were elevated in 70% and 54% of cases, respectively. Six percent of cases were HCV positive (HCV+ rate was 7.5% among MZL cases). Regarding HBV infection, 21% of patients were HBcAb-positive and 3% of patients were HBsAg-positive. Immediate systemic therapy was planned in 50% of patients. SMZL, SLL and CD5-low grade were the subtypes with the lower rates of immediate therapy (44%, 46% and 24% respectively) whereas ENMZL were addressed to systemic therapy in 67% of cases. When systemic therapy was prescribed rituximab (R) was used in 88%. In 81% of patients R was combined to cytotoxic therapy including alkylating agents in 40%, CHOP-like in 18%, bendamustine in 17% and fludarabine in 6%. ENMZL and CD5-low grade had the highest rates of R-alkylating use (61% and 64%); SMZL and MZL were frequently treated with R-CHOP like regimens (35% and 40%). Young age at diagnosis (less than 60 years) and increased b2-microglobulin were more frequently associated with patients requiring immediate systemic therapy. With 22 months of median follow up, 2-year progression free survival and overall survival (OS) were 88% (95CI: 83-92) and 95% (95CI: 91-97) respectively; the initial choice of deferring immediate therapy did not impact on OS. Conclusions: We provide a complete report on the initial approach to patients with INFL showing that immediate therapy is required in half of the cases with a heterogeneous approach among INFL subtypes. The majority of patients requiring therapy was treated with the combination of R and alkylating agents. The NF10 study confirms that a web-based world-wide cooperation allows the collection of a relevant and complete data set, providing a platform for future prognostic and pathobiological studies in order to identify novel and more efficient therapeutic targets. Disclosures Luminari: Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Ferrero:Mundipharma: Other: Speakers Honoraria; Celgene: Other: Speakers Honoraria. Gaidano:Celgene: Research Funding; Morphosys, Roche, Novartis, GlaxoSmith Kline, Amgen, Janssen, Karyopharm: Honoraria, Other: Advisory boards.

Background Despite the prediction of a fairly benign clinical course, a subset of patients with low-risk myelodysplastic syndromes (MDS) have a more aggressive disease and shorter overall survival. The DNA repair and folate pathway genes play an important role in prognosis and progression in both solid and hematological cancers, and their expression has been known to be associated with polymorphism of genes. However, the impact of polymorphisms of these genes on MDS patients outcome has not yet been demonstrated. The aim of this study was to investigate the association between the polymorphisms of genes encoding main proteins of BER system (XRCC1, XRCC3 and APE1) and folate-metabolizing enzymes (TS, MTHFR) and survival in IPSS low-intermediate1 MDS patients. Methods the study was designed according to the Schoenfeld design for biomarkers, assuming the presence of an unfavorable pharmacogenetic profile (one or more adverse genotypes) in at least one-third of the study population. Accordingly, 10 events in 54 patients would allow the detection of an Hazard Ratio (HR) >6 associated with the group having unfavorable genotypes (80% power and 5% type I error for a two-tailed test). We thus prospectively genotyped 54 MDS patients (median age 75 years) with IPSS low (n=23) or intermediate-1 (n=31) treated with best supportive care only. Genomic DNA was isolated from 1ml of peripheral blood by means of commercially available kits. Polymorphisms were determined by PCR-HRM (High Resolution Melting) assay and restriction digests of PCR products. All samples were analyzed for the following polymorphisms: XRCC1 194 (rs1799782 C/T, Arg/Trp) and 399 (rs25487 G/A, Arg/Gln), XRCC3 241 (rs861539 C/T, Thr/Met), TS5'-UTR (2R/3R and rs183205964 G/C) and 3'-UTR Ins/Del (rs11280056 6bp+/6bp-), MTHFR 677 (rs1801133 C/T, Ala/Val) and 1298 (rs801131 A/C, Gln/Ala), APE1 148 (rs1130409 T/G, Asp/Glu). The characteristics and laboratory features of MDS patients with each polymorphisms were compared using Х2-test and Mann-Whitney test. The associations between polymorphisms status and survival were assessed using Kaplan-Meier method and Log-rank test. For the multivariate survival analysis, Cox proportional hazard models, was used to identify the genotypes fitted as indicator variables. Before performing clinical correlations, genotype frequencies were checked for agreement with those expected under the Hardy-Weinberg equilibrium. Results The frequencies of genotypes of studied gene polymorphisms in patients with low/Int-1 risk are listed in Table 1. At univariate analysis, a significantly shorter survival was associated with XRCC1 399 GG, TS3’-UTR -6/-6, TS5’-UTR 2R/3G, 3C/3G, 3G/3G and MTHFR 677 TT variant alleles. In multivariate analysis, using a stepwise logistic regression model, patients with TS3’-UTR -6/-6, XRCC1-399 GG, TS5’-UTR 2R/3G, 3C/3G, 3G/3G and MTHFR- 677 TT unfavorable genotypes presented with an Hazard Ratios of 4.65, 7.07, 11.44 and 67.12, respectively, if compared to the reference group of variant alleles (P=.058, P=.024, P=.026 and P=.000). Accordingly, we performed an exploratory analysis to investigate the effect on survival arising from the combination of the unfavorable genotypes to each other. As a fact, 3-years OS was 33% for those patients with ≥2 variant alleles, as compared to 62.5%, and 100%, respectively, for those with 2 or 0/1 variant alleles, suggesting that patients with a higher number of variant alleles had a shorter survival. Conclusions The mutational status of BER, TS and MTHFR genes predicts the overall survival of patients with low-Int-1 IPSS MDS treated with best supportive care only. If confirmed on larger series, these polymorphisms could help to identify a subset of low-risk MDS patients with shorter survival, who might benefit from an early therapy with hypometilating agents. Acknowledgments The study was supported in part by AIL Pesaro Onlus. Disclosures: No relevant conflicts of interest to declare.

Background We previously demonstrated (Visani et al, Blood 2011) the safety of a new conditioning regimen with bendamustine, etoposide, cytarabine, and melphalan (BeEAM) prior to autologous stem cell transplant (ASCT) in resistant/relapsed lymphoma patients (EUDRACTnumber2008-002736-15). Furthermore, this regimen showed significant anti-lymphoma activity (80% CR). At the time of publication (2011), disease type (NHL versus HL) and disease status at transplant (chemosensitive versus chemoresistant) were the only statistically significant variables influencing PFS (p=0.01; p=0.007). However, median follow-up for surviving patients was short (18 months), therefore, it was not possible to draw final conclusions on the efficacy. Aims We evaluated the efficacy of the BeEAM regimen in terms of disease-free (DFS) and overall survival (OS) after a median follow-up of 41 months. Methods Forty-three patients (median age 47 years, range 18-70) with resistant/relapsed NHL (28) or Hodgkin lymphoma (HL, 15) were consecutively enrolled in the study. Twenty-one patients had primary refractory disease, whereas 22 had relapsed disease, 5 of whom where in second or subsequent relapse, at the time of enrolment. The study was designed according to Fleming’s method. The primary objective of the study was to determine the 36-months event free survival rate. We fixed the lowest acceptable rate as 40% and the successful rate as 60%, with a significance level a=0.05 and a power 1-b =0.80. At the time of publication, the median follow-up was 18 months, and therefore it was not possible to establish if we had met the primary end-point of the study. Results we updated the follow-up at 41 months after transplant. Thirty-one out of 43 patients are still in CR (72%), as documented by both PET and CT scan. Two patients with HL were refractory and rapidly died, whereas 10/43 patients (23%) relapsed after a median time of 7.5 months (range:3-23) from transplant. Five patients died (3 NHL, 2 HL), whereas 5 patients are still alive after relapse. Median PFS and OS were still not reached. Conversely, 3-year PFS was 75%, allowing our study to met its primary end-point. Interestingly, disease type (HL versus NHL) at transplant is no longer influencing PFS (p=0.7), and still does not influence OS (p=0.1). On the other hand, disease status at transplant (chemosensitive vs chemoresistant) is still a strong predictor of both PFS and OS (p=0.03 and p=0.009, respectively). At present, one patient developed myelodisplasia after transplant. No other late effects were observed up to now. Conclusions The new BeEAM regimen met the primary end-point of the study and confirms its safety, after 41 months of follow-up. Interestingly, NHL and HL were not statistically different in terms of both PFS and OS at 41 months of observation. These data confirm the high efficacy of this regimen in heavily pretreated non-Hodgkin, as well as Hodgkin lymphoma. Acknowledgments supported in part by AIL Pesaro Onlus. Disclosures: Ocio: Onyx: Consultancy, Research Funding; Novartis: Consultancy; Array Biopharma: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding.

Abstract 3953 Oral bexarotene, a novel retinoid that selectively activates retinoid × receptors, is approved for the treatment of cutaneous manifestations of refractory or relapsed cutaneous T cell lymphomas (CTCL) as monotherapy. Phase II/III trials have demonstrated a greater than 50% response rate in patients with all stages of CTCL who were refractory or intolerant to the previous therapy but the recommended bexarotene dose of 300 mg/m2/day is associated with significant side-effects. Novel studies are looking for synergistic therapies combining lower bexarotene doses in order to reach the same or even better outcomes while avoiding a negative impact on the quality of life. Early studies with bexarotene and psoralen plus ultraviolet A photochemotherapy (PUVA) show promise. Synergy between bexarotene and PUVA may derive from retinoid-induced reductions in epidermal thickness, which consequently improves UVA penetrations, and/or from retinoid-specific enhancement of immune functions. The aim of this study was to assess the efficacy and safety of a 2 stage-protocol (induction and maintenance) with low dose bexarotene (Targretin) and PUVA in refractory and/or resistant patients with Mycosis Fungoides (MF) and Sézary Syndrome (SS). A prospective, phase 2 clinical study was conducted between February 2007 and May 2010 by two Italian academic hospital centers. We enrolled 15 patients with stages I through IV MF/SS; all patients had failed PUVA or several systemic regimens. Response to treatment was assessed with clinical endpoints such as remission of symptoms (pruritus, pain, sleep disturbance) and signs (erythema, scaling, thickness of plaques, presence of nodules, tumours, peripheral lymphadenopathy). Complete remission (CR) was defined as the disappearance of all clinical evidence of disease for at least 4–6 weeks, partial remission (PR) as 50% or more decrease in extent or severity of disease. Overall response (OR) rate was defined as the combination of CR/PR. Patients with MF/SS were started with bexarotene (150 mg/day) and PUVA (three times weekly). Increments of bexarotene to a maximum of 300 mg/day were scheduled. Patients who achieved CRs and PRs during the induction remained on the same dose in the maintenance period, whereas the frequency of PUVA was gradually reduced. A preventive therapy to lower triglycerides and elevated thyroid hormone levels in the blood, was administered in all cases; therapeutic dietary and lifestyle changes were often recommended. Primary endpoint were OR rate at the end of induction and maintenance; secondary endpoints were safety and event-free survival (EFS). Kaplan-Meyer method and long-rank test was used for statistical analysis. All 15 patients (8 M and 7F) were evaluable for response; ten patients had early-stage (IB) and 5 had advanced stage (2 IIB, 1 IIIA, 1 IIIB, 1 IV). The median age was 68 years (34-81). The OR rate was 93% with 33% CR after induction period and 93% with 47% CR at the end of the protocol. A response was observed even in 1 case with SS and in 2 cases with MF in large cell transformation. Significantly, patients treated previously with PUVA monotherapy achieved better and faster CR compared with those treated with more than one systemic therapy (83% and 22% respectively; χ2 test, P=0.041; median time to maximal response 4 weeks and 8 weeks respectively, P=0.007). Median EFS at 37 months, for the whole group was 27 months. All patients have been closely monitored for adverse events during treatment; 2 of 15 patients (13%) had mild grade I-II asthenia, hypercholesterolemia and central hypothyroidism, 2 patients developed elevations of CPK (grade 3). With regard to hematologic toxicity, leukopenia was mild (grade I) and occurred in 3 patients (20%). In conclusion, our study have demonstrated a greater than 90% response rate in patients with all stages of CTCL refractory or intolerant to the previous therapies; the efficacy is more pronounced in patients previously treated with PUVA monotherapy. Starting treatment at lower dose of bexarotene followed by dose escalation may improve the efficacy and safety of both bexarotene and PUVA. Moreover the additional maintenance phase seems to improve the OR and length of remissions. Disclosures: Leoni: Celgene: Honoraria.

Abstract 3072 Thromboembolic disease (TE) is a major cause of morbidity and mortality in Essential Thrombocythemia (ET). Recently JAK2V617 mutational status and allele burden seem to add prognostic significance to standard risk factors; furthermore it was reported an interesting but not confirmed association between baseline leukocytosis and thrombosis. The aim of the study was to evaluate such factors in a series of patients with ET. Study subjects were recruited from the Ancona Hematology Clinic database of ET patients; clinical and laboratory data were collected at time of diagnosis and correlated with the occurrence of TE. In addition, qualitative and quantitative PCR for JAK2V617F was performed on stored samples of peripheral blood or bone marrow in a subset of study patients. Qualitative JAK2V617F analysis was done according to standard PCR-based methods and quantitative JAK2V617F was determined with a commercially available Taqman assay. Standard statistical methods were applied to test significance of associations between thrombosis and other variables. A total of 218 ET patients were included in the study (median age 59, range 18–90; 71 males and 147 females). At diagnosis the median of platelets, hemoglobin and leukocytes were 776×109/L, 13.9g/dL, and 8.4 ×109/L respectively. At diagnosis a history of remote thrombosis was recorded in 27 patients (12,4%). Of the 122 patients analysed for JAK2 mutational status, 70 (57.4%) were JAK2 wild-type and 52 (42.6%) were JAK2V617F positive. Quantitative analysis was carried out in 48 cases: 6 patients (11.5%) were homozygotic and 42 (80.8%) were heterozygotic. At diagnosis, a total of 17 patients (7.8%) had TE: 8 (3.7%) arterial thrombosis (AT) and 9 (4.1%) venous thrombosis (VT). the AT included acute coronary syndromes (ACS; n=4), transient ischemic attack/cerebrovascular accidents (TIA/CVA; n=3), and peripheral arterial thrombosis (PAT; n=1). The VT included deep vein thrombosis/pulmonary embolism (DVT/PE; n= 4), abdominal vein thrombosis (AVT; n=4) and dural sinus thrombosis (n=1). During follow-up 25 patients experienced TE: 13 VT (6%) and 12 AT (5.5%). Post diagnosis VT included.: DVT/PE (n= 4), AVT (n=4), superficial vein thrombosis (TVS; n=3), retinal vein thrombosis (n=1) and dural sinus thrombosis (n=1). Post diagnosis AT included TIA/CVA (n=6), ACS (n=3) and PAT (n=3). Gender, age, hemoglobin, platelets, leucocyte count, splenomegaly, increased cellularity of bone marrow, bone marrow fibrosis and common vascular risk factors did not affect the probability of thrombotic events at diagnosis and during follow-up. On univariate analysis a significant increase of thrombosis as presenting manifestations, was registered in patients with a history of remote thrombosis (OR= 10.0, 95% CI 4,1-24,5; p Subjects with both JAK2 mutation and a history of remote thrombosis have a OR of 24.44 (95% CI 3.07–194.66; p=0.01) in comparison with wild-type patients without a history of thrombosis. During follow-up, the probability of vascular events was predicted only by a history of remote thrombosis (OR=2.3, 95% CI 1.01–5.35; p=0.05), and neither by JAK2V617F mutational status (OR=1.24, 95% CI 0.43–3.62; p=0.76). The present analysis suggests that the thrombotic risk is higher in JAK2V617F positive patients and is further increased by a past history of thrombosis. The opportunity of combine such criteria must be defined in prospective trials. Disclosures: Leoni: Celgene: Honoraria.

Combination therapy is commonly used in the treatment of advanced and aggressive cutaneous T-cell lymphomas (CTCL), like Mycosis Fungoides (MF) and Sézary Syndrome (SS). Alemtuzumab, the humanized anti-CD52 antibody primarily developed for the treatment of B-CLL, has been also administered effectively in patients with CTCL as monotherapy, but it might be an ideal candidate for combination therapy either with a biological immune response modifier like interferon (IFN)-α, or with a drug known to be particularly active in CTCL like gemcitabine. No data on the activity of combination schemes including alemtuzumab in CTCL seem to be available. The aim of this study was to explore the clinical activity of alemtuzumab in two combination modalities, including either IFN-α or gemcitabine. We enrolled 5 patients, 4 males and 1 female, affected by SS/erythrodermic MF, with a median age of 57 yrs (43–74) and a median disease history of 21 mo.s (9–95). Two patients were treated with both combination schemes. Before starting therapy, all patients except one had a rapidly progressive disease, relapsed or refractory to previous treatments, and had previously received three or more systemic chemotherapy regimens. Most patients had reduced performance status and all had severe itching. Four patients received alemtuzumab in combination with IFN-α: subcutaneous alemtuzumab was administered at 3 mg on day 1, 10 mg on day 3, followed by 15 mg on alternating days for 7 total doses; after a further 3 months of treatment with IFN-α (3 MU three times weekly) the patients received reinduction with alemtuzumab (10 mg weekly for another month). Three patients received alemtuzumab in combination with gemcitabine: subcutaneous alemtuzumab was given at 10 mg on days 1, 8 and 15 of a 28-day schedule in combination with gemcitabine at a dose of 1200 mg/m2 intravenously (median number of cycles=4). Trimethoprim/sulphamethoxazole (twice daily 2 times per week) and valacyclovir (500 mg twice daily) were administered from day 2 until at least 2 months after alemtuzumab discontinuation. The response (complete/CR, partial/PR, stable disease/SD) was assessed in skin, lymph nodes and peripheral blood, by using the SWAT criteria and by comparing the absolute number of circulating Sezary cells (SC) detected by flow-cytometry before and after treatment. The overall response (OR) was determined as the worse result obtained in the different sites. The OR rate was 57.1% (4 PR vs 3 SD), higher in the group treated with alemtuzumab and gemcitabine (66.7%: 2 PR vs 1 SD) than in the group treated with alemtuzumab and IFN-α(50%, 2 PR and 2 SD). The better response rate obtained in the group treated with gemcitabine was due to the higher activity in the skin (2 CR, 1 SD vs 2 PR, 2 SD) and in the lymph nodes (3 PR vs 3 PR, 1 SD). The circulating SC count was low at the end of therapy (median, 164, range, 24–530), with a lower median value in the group treated with gemcitabine (131), than in the group treated with IFN-α (303). Itching, self-assessed on a 0 to 10 visual analog scale, was significantly reduced from a median score of 9 before treatment, to 1 at the end of therapy. Both combination treatments were well tolerated. Infusion-related adverse events were not reported. Grade 3–4 hematologic toxicity was observed only in one case treated by alemtuzumab and gemcitabine (grade 3 leukopenia). One patient from the group treated with alemtuzumab and IFN-α had infectious complications (CMV pneumonitis and pulmonary aspergillosis). Two patients treated with gemcitabine showed CMV detectable viral load in peripheral blood without any occurrence of complications. All patients treated with alemtuzumab and IFN-α experienced a progressive disease, respectively at 5, 9, 11, 12 months, whereas the 3 patients treated with alemtuzumab and gemcitabine are still in PR at 4, 10, 12 months (median overall PFS: 9 mo.s). At last follow-up, 3 patients are still alive with disease, while two had died, one for unrelated causes and the other for progressive disease. Although the present series is small, our observations point towards a potential role of alemtuzumab in combination schemes in heavily pretreated CTCL patients, as the response rate (57%) appears better than that reported in the literature for alemtuzumab alone (OR 33%), and the toxicity profile of both combination seems to be fairly acceptable. Moreover, gemcitabine might be a better candidate than IFN-α for combination therapy with alemtuzumab, since the progression-free survival seems to be prolonged.

The oral anticoagulant therapy (OAT) in oncologic patient is often problematic because both the haemorragic risk and the thrombotic risk, i.e. the recurrence of venous thromboembolism, are increased. Many studies have been conducted in patient with solid neoplasms; it remains still unclear whether these results could be entirely extrapolated to patients with haematological malignancies. Our aim was to analyse the clinical outcomes and the control of anticoagulation, measured as % time in target INR range, in the patients with cancer compared to patients without cancer; moreover we focused on patients with haematological neoplasms. A total of 500 patients were recruited in 6 years, regardless of the indication for OAT; 146 (29%) of them were affected by cancer (47 haematological and 99 solid neoplasms); those being treated with warfarin for less than 1 month were excluded from this analysis. It resulted that patients affected with cancer had a worse anticoagulation control, compared to those without cancer (55% vs 60%; p

Pegylated liposomal doxorubicin (PLD) is approved in breast cancer, ovarian cancer, Kaposi’s sarcoma. Its skin-tropism suggests a role in the therapy of primary cutaneous lymphomas (PCLs). Among the cutaneous toxicities of PLD, the palmar-plantar erythrodysesthesia (PPE) is characterized by tingling, dysesthesia, erythema, swelling and, in severe cases desquamation, crusting, ulceration and necrosis. PPE is dose- and schedule-dependent and is usually reversible. Different pathophysiologic mechanisms are suggested: PLD, excreted from sweat glands, penetrates into the corneum stratum with local oxidative and inflammatory reactions; direct cytotoxic effect; extravasation of PLD from the deep microvessels through the local pressure. At our knowledge no specific reports on PPE in patients (pts) with PCLs treated with PLD were presented. We report 31 PCL pts treated with PLD: 26 affected by primary cutaneous T-cell lymphomas (PCTCL) and 5 by primary cutaneous B-cell lymphomas (PCBLC). Among PCTLC, 21 pts (16 M, 5 W, median age 67 yrs) received PLD in monotherapy at the dosage of 20 mg/m2 every 3–4 weeks. They were affected by relapsed or refractory PCTCLs: Mycosis Fungoides (MF) (52%), transformed MF in large cell lymphoma (20%), Sèzary Syndrome (SS) (14%), peripheral T-cell lymphoma unspecified (PTCL–U) (14%). After 6 courses, 47% achieved a CR, with ORR of 81%. The median time to the max response was 3 mo.s. After a median follow-up of 36 months 5 pts had progression of disease (PD) and 5 relapsed. To date 9 pts are alive and 12 dead, 4 for PD and 8 for non-related causes. Median OS, EFS and PFS are 36, 17 and 19 mo.s respectively; OS, EFS and PFS rates at 66 mo.s are 33%, 16% and 37%, respectively. Among the remaining 5 PCTLC pts one with transformed MF in large cell lymphoma was treated with PLD in monotherapy and then intensified with bortezomib and dexamethasone obtaining a VGPR. Another pt with PTCL-U received PLD plus rituximab with a CR and the last 3 pts (MF, MF transformed and SS) underwent CBVD scheme obtaining a PR. Among the 5 PCBCLs a woman was affected by marginal zone lymphoma (PCMZL) and 4 men by large B-cell lymphoma (PCLBCL) (all in stage: T3,N0,M0). All pts showed a CR with PLD monotherapy, in a short period (median 2,5 mo.s), even when heavily pretreated. One of them experienced a relapse. One died for PD; to date the others are still in CR after 5, 52, 63 and 69 mo.s. PLD was well tolerated. In PCTLC adverse effects were observed in 6 pts (23%) and grade III–IV toxicity occurred in 2 (8%): capillary leakage syndrome and neutropenia. Nobody required dose modifications or delays. Grade II gastrointestinal toxicity was present in 2 pts. Only two showed a grade I PPE. In these cases we delayed the dose up to 1 week, obtaining a complete resolution, thus returning to the original interval. Even in the five pts affected by PCBCL, PLD was well tolerated and no one decreased or delayed the dose. A pt showed a reversibile grade I neurotoxicity; the hematological toxicity was mild with one case of grade III neutropenia treated with G-CSF. Nobody experienced PPE. PPE is frequently reported in pts with cancer treated with PLD: about 50% off all pts who received the currently approved dose of 50 mg/m2 every 4 weeks experienced PPE and about 20% grade III PPE. When PPE develops, PLD dose reduction, schedule modification, ultimately drug withdrawal are considered. In our pts affected by PCLs, PPE occurred rarely, with mild grade (2 case of grade I). It is probably due to low dosages of Peg-Doxo, compared to the commonly used in other solid neoplasms. Besides oral prophylaxis with pyridoxine 300 mg daily was administered from the beginning of the treatment until 1 month after its discontinuation in all pts, as suggested by some authors. This is the first report of PLD in PCBCL; as regarding the other few studies (Wollina, Cantonetti, Di Lorenzo, Lybaek, Quereux) concerning PLD in PCTLC the incidence of PPE resulted always low. In conclusion, it emerges that PLD shows a significantly high clinical activity and a good safety profile in PCLs. Our data seem to confirm the dose dependent toxicity effect of PLD, since three-four weekly schedule of PLD at the dose of 20 mg/m2 has less PPE compared to the classical schedule of 50 mg/m2 every 4 weeks. Some studies in ovarian and breast cancer demonstrated that PLD dose intensity reduction can prevent PPE. The administration of prophylactic pyridoxine seems to be useful in the reduction of the incidence and severity of PPE.

Background: Recruitment of neoplastic T-cells in skin is a critical step in the pathogenesis of Mycosis Fungoides (MF) lesions. The chemokine CCL27 attracts memory CCR10-positive T cells to the skin. Increased CCL27 serum levels and skin epidermal expression have been observed in MF patients compared to normal controls, but the interactions between neoplastic cells and the skin immune system needs to be further elucidated. Aims: We investigated whether CCL27 expression in MF is related to the density of dendritic cells (DC), CD8+ lymphocytes and CD4+ neoplastic lymphocytes; moreover, whether it influences the clinical response to therapy, it is modifiable by therapy itself and if the changes eventually observed can predict the frequency of recurrences and event-free survival. Material and methods: CCL27 epidermal immunohistochemical staining was performed in 52 early stage-MF patients, 34 M/18 F, treated by PUVA plus interferon a for 14 months, with a complete follow-up data. Specimens were obtained at diagnosis and at the end of treatment. Formalin-fixed/paraffin-embedded tissue sections were immunostained with anti-CCL27, CD1a, CD8, CD4 antibodies. CCL27 immunoreactivity was graded as + (faint/moderate staining, limited to epidermal basal layer, as in normal skin); ++ (faint/moderate staining in the suprabasal layers; strong staining up to the lower two-thirds of epidermis); +++ (strong staining of full-thickness epidermis). Density of CD1a-positive DC and CD8+ lymphocytes was graded as + (few/isolated cells), ++ (small, ≤5 cell clusters), +++ (larger, >5 cell clusters). Density of CD4+ lymphocytes was graded as + (perivascular infiltrate), ++ (discontinuous subepidermal band), +++ (continuous band). Statistical analysis was also performed (c2 test for tables of contingency; event-free survival curves (EFS) by Kaplan-Meier method). Results: At diagnosis, CCL27 expression was similar to normal skin in 16 cases and abnormal/suprabasal in 36, with 12 +++ cases. A normal/basal CCL27 expression tended to be correlated with a high DC density and with a low neoplastic infiltrate density (although P=NS). CCL27 at diagnosis was not correlated with clinical response (50 complete remission/CR, 2 partial remission). Treatment induced a significant CCL27 increase (suprabasal in 42 cases with 24 +++ cases; c2 test: P=0.004). Skin CCL27 expression at the end of treatment, but not at diagnosis, was related to recurrence and influenced EFS. During follow-up (median, 92.5 mo.s; range, 43–165), 33 patients relapsed (median EFS, 46 mo.s). A normal/basal CCL27 expression at the end of treatment, was correlated with a lower incidence of disease recurrence (3/9 compared to 30/41 with suprabasal expression; c2 test: P=0.022) and a longer median EFS (111 mo.s vs 39 mo.s with suprabasal expression; log rank test: P=0.031). Conclusions: Increased CCL27 expression in early-stage MF lesions might be related to a balance between neoplastic cells and immunomodulant dendritic cells. CR induction in almost all patients by treatment is not correlated with a CCL27 reduction, but a normal CCL27 expression after treatment designates a subset of patients (about 20%) with a favourable behaviour. The mechanisms involved in the increased CCL27 expression after therapy in the remaining 80% patients, which have a higher probability to recur, need to be further investigated.

Patients with primary cutaneous lymphomas (PCLs) are treated with multiple therapeutic regimens, which may increase the risk of subsequent solid and haematological neoplasms. The aim of our study was to assess the incidence of other malignancies in our series of PCLs. From March 1994 to January 2007, 272 patients with PCLs (179 M, 93 F, median age 65 yr, range 14–88) were referred to our center for staging, treatment and follow-up. The clinical charts were reviewed to detect the incidence of malignancies occurred before or after the diagnosis of PCL or concomitantly. The series was composed by 228 patients (150 M, 78 F, median age 66 yrs) with T-cell lymphomas (202 Mycosis Fungoides/MF, 10 Sézary Syndrome/SS, 9 CD30+ PCL, 7 non MF/non CD30+ T cell PCL); 43 patients (28 M, 15 F, median age 60 yrs) with B-cell lymphomas (25 Follicular/FL, 14 marginal/MZL, 3 Leg-type, 1 Lymphoblastic) and one patient with CD4+/CD56+ hematodermic neoplasm. Chemotherapy was administered to 48 patients. During follow-up 12 patients died for the disease and 24 for other causes. A second tumor was observed in 41 patients (15%): 6 of them experienced more than one neoplasms: overall we observed 48 malignancies, 38 solid and 10 haematological. The other neoplasms appeared similarly before (20) and after (21) the diagnosis of PCL; in 7 cases they were diagnosed simultaneously. Solid tumours (17 preceding, 4 concurrent, 17 subsequent) were diagnosed in: skin (11), colon (5), lung (4), breast (3), CNS (3), bladder (2), liver (2), kidney (2), uterus (2), testis (1), prostate (1), stomach (1), thyroid (1). The haematological malignancies (3 preceding, 3 concurrent, 4 subsequent) were: B-cell lymphomas (4), acute myeloid leukemias (3), plasmocytoma (1), T-cell lymphoma (1), Hodgkin’s lymphoma (1). Among the six patients with more than one adjunctive neoplasms one patient had lung and kidney carcinoma preceding PCL; two patients a preceding carcinoma (skin and bladder, respectively) and subsequently a lung carcinoma; other two patients showed both a preceding and a concurrent neoplasm (skin and colon carcinoma, B-cell lymphoma and skin carcinoma, respectively). Finally a patient had a preceding skin carcinoma, a concurrent nodal Hodgkin’s lymphoma and a subsequent nodal B-cell lymphoma. So we have reported 48 other neoplasms in 41 patients within 272 PCLs (15%). The occurrence of the other malignancy was not related to the B/T phenotype of PCLs, as it was observed in 35/228 (15.4%) T-cell lymphomas (32 MF, 2 SS, 1 non MF/non CD30+ T cell lymphoma) and in 6/43 (14%) B-cell lymphomas (3 FL, 3 MZL; χ2 test: P=0.88). The interval of occurrence was longer for tumors preceding (median 60 mo.s, range 8–180) than for tumors following PCL (median 45, range 6–122). The administration of chemotherapy for PCL was not associated with an increased incidence of second neoplasm(χ2 test, P=0.77). Multicentric studies might help in elucidating the role of genetic and immunitary factors in the pathogenesis of multiple neoplasms in patients with PCLs.