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This retrospective study is focused on the possible clinical implications of texture analysis-derived PET parameters in patients with smoldering multiple myeloma. Several texture features are significantly associated with progression to symptomatic multiple myeloma and with a shorter time to progression. The results of this study may lead to early identification of patients who could benefit from specific therapies. Background: The aim of the study was to determine whether positron emission tomography parameters derived from texture analysis of axial and peripheral skeleton predict progression to symptomatic multiple myeloma (MM) in patients undergoing 18F-​fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) without evidence of focal sites of 18F-FDG uptake. Patients and Methods: Patients with smoldering MM who underwent 18F-FDG PET/CT from May 2014 to June 2018 were retrospectively reviewed. Volumes of interest (VOIs) were placed on T5-T7 and L2-L4, iliac crests, and femoral diaphyses. Dedicated software (LIFEx) allowed us to obtain PET-derived first-, second-, and higher order texture features. Possible associations between PET parameters and progression to symptomatic MM were determined. Kaplan–Meier curves allowed to assess time to progression (TTP) based on the PET parameters. Results: Forty-five patients were included: 26 patients (58%) did not meet the criteria for symptomatic MM, but 19 patients (42%) progressed to symptomatic MM. Several texture features extracted from VOIs placed on iliac crests and femoral diaphyses were significantly associated with progression to symptomatic MM and with a shorter TTP (P

Background. The overall survival (OS) of multiple myeloma (MM) patients (pts) has improved over the years due to the introduction of several novel drugs, such as proteosome inhibitors (PI), immunomodulatory drugs (IMiDs) and, more recently, anti-CD38 monoclonal antibodies (moAb). Nevertheless, the majority of pts continues to relapse, and MM remains an incurable disease. To date, no standard of care has been established for relapsed/refractory (RR) MM pts who have been exposed to the main anti-myeloma drugs. Currently, these pts have a limited number of available treatment options and represent an unmet medical need. Moreover, the outcome of pts failing standard of care regimens, which is now defined as triple-refractory (including PI, IMiDs and moAb), is poor, with a median progression free survival (PFS) of 3-4 months and OS of 8-9 months. Novel therapeutic strategies with different mechanisms of action are warranted to overcome the natural occurrence of relapse or therapy resistance in RR MM pts. Immunotherapy, especially T-cell based approaches, represents the emerging therapeutic strategy for this subset of pts. Chimeric antigen receptor (CAR)-modified T cells are a promising new therapy approach for triple refractory RRMM. Different constructs and specific CAR-T targets are being studied, but BCMA-directed CAR-T cells have so far provided the most convincing evidence of activity, with one product (idecabtage vicleucel) recently approved by FDA. Aims. The primary endpoint of this observational and retrospective study was to define the clinical characteristics and outcome of a cohort of RR MM pts potentially eligible to CAR-T cell treatment according to the KarMMa trial criteria 1. Secondary endpoints were aimed at defining specific factors influencing CAR-T cell therapy eligibility and at identifying a real-life estimate of RRMM pts truly eligible for CAR-T cells. Methods and Results. This is a cohort analysis that used electronic REDCap, a data capture tool hosted at the Sapienza University, on RRMM pts managed between January 2018 and July 2021 at 4 Italian Centers of the Multiple Myeloma GIMEMA Lazio Group. At the time of data collection, 47 RRMM pts had underwent at least 3 prior therapy regimens; they had received a previous PI, IMiDs and a moAb and were considered refractory to the last regimen. The clinical characteristics are listed in Table 1. Median age was 68 years (43-86), 27 (61%) pts were >65 years; 27 (57%) were male. Of 47 pts, 33 (68%) were ECOG 0-1 and 14 (30%) were ECOG ³2; 21 pts (44%) were ISS III. The majority of pts, 28 (59%), had undergone an autologous stem cell transplantation; 31 pts (65%) had received 3 prior lines of therapy and 16 (34%) >3 prior lines of therapy. Thirty-seven (78%) were triple-refractory and 8 (17%) were penta-refractory. Based on the KarMMa trial criteria, 22/47 pts (47%) would be defined as eligible and 25 (53%) not eligible for CAR-T cell therapy. Specifically, 14 (30%) pts were not eligible because of an ECOG ³2, 24 (62%) had an organ dysfunction such as impaired renal function (eGFR After a median follow-up of 34.7 months (mo) (0-53.8), the median OS for the entire cohort was 21.7 mo (95% CI: 14.2-36.9) (Fig. 1). The median OS was 30.7 mo (95%, CI: 14.21-NA) in eligible pts vs 16.2 mo (95%, CI: 6.28-NA) in non-eligible pts (p=0.002) (Fig.2). The median PFS of the entire cohort was 7.7 mo (95%, CI: 5.39-13.85) (Fig. 3) and the median PFS was 7.8 mo (95%, CI: 5.16-19.1) in eligible pts vs 6.5 mo (95%, CI: 3.36-NA) (p=0.513) in non-eligible pts (Fig.4). Conclusions. Despite the limits of a retrospective study and a limited cohort, our real-life analysis shows that heavily treated pts with RRMM are less likely to be eligible for CAR-T cell therapy. Considering the emergent role of quadruplet combined approaches for first-line therapy and given the therapeutic relevance of CAR-T cells for the management of RRMM pts previously exposed to PI, IMiDs and moAb, our data could help to better define pts who could benefit from CAR-T cells under the current indications, while waiting for an extension of this approach to earlier disease stages. 1. N Engl J Med 2021;384:705-16 Figure 1 Figure 1. Disclosures Fazio: Janseen: Honoraria. Caravita di Toritto: celgene: Other: travel expenses, Research Funding; Janseen: Other: travel expenses, Research Funding; amgen: Other: advisory board; takeda: Research Funding; GSK-SANOFI: Other: advisory board. Martelli: Gilead: Other: advisory board; Novartis: Other: advisory board. Petrucci: Janssen-Cilag: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; GSK: Honoraria, Other: Advisory Board; Karyopharm: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board.

Daratumumab (DARA) is a human IgG-K monoclonal antibody (MoAb) targeting CD38 that is approved alone or in combination with bortezomib and dexamethasone or lenalidomide and dexamethasone for relapsed or refractory MM (RRMM) in patients previously exposed or double refractory to proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs). However, there are limited data on its clinical activity and tolerability in real-world patients. Therefore, in the present study, we aim to determine the efficacy and toxicity profile of daratumumab in a real-life setting. In this study, we report the experience of the multiple myeloma GIMEMA Lazio Group in 62 relapsed/refractory MM patients treated with daratumumab as monotherapy who had previously received at least two treatment lines including a PI and an IMiDs or had been double refractory. Patients received DARA 16 mg/kg intravenously weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks until disease progression or unacceptable toxicity. The overall response rate to daratumumab was 46%. Median progression-free survival (PFS) and overall survival reached 2.7 and 22.4 months, respectively. DARA was generally well tolerated; however, 2 patients interrupted their therapy due to adverse events. Present real-life experience confirms that DARA monotherapy is an effective strategy for heavily pre-treated and refractory patients with multiple myeloma, with a favorable safety profile.

Objective The aim of this study was to evaluate the addition of cyclophosphamide in relapsed-refractory multiple myeloma patients (RRMM) who experienced biochemical relapse or progression without CRAB, during treatment with lenalidomide and dexamethasone (Rd), to slow down the progression in active relapse. Methods This analysis included 31 patients with RRMM treated with Rd who received cyclophosphamide (CRd) at biochemical relapse. The CRd regimen was continued until disease progression. Results The median number of CRd cycles administered was 8 (range: 1-35). A response was observed in 9 (29%) patients. After a median observation time of 11 months, the median overall survival (OS) from the beginning of CRd was 17.7 months. The median progression-free survival (PFS) from the beginning of CRd was 13.1 months. Conclusion The addition of cyclophosphamide delays the progression in patients who present a biochemical relapse during Rd treatment. The response rate and the duration of PFS obtained with minimal toxicities and low costs induced us to setting up a randomized clinical trial.

We performed a retrospective analysis of 88 adult patients with B-ALL diagnosed in our center by a flow-cytometric assessment. Immunophenotypic expression of leukemic cells was explored by simultaneous evaluation of positivity, percentage of expressing cells and median fluorescence intensity (MFI). BCR/ABL1 fusion transcripts were assessed by RT-PCR analysis and were identified in 36 patients (40.9%). CD10 and CD34 were positive in the totality of BCR/ABL1-positive cases. Patients with gene rearrangement had a greater frequency of CD66c, CD13 and CD33 positivity compared with BCR/ABL1-negative cases. Moreover, BCR/ABL1-positive cases exhibited a greater median percentage and MFI values of CD13, CD33, CD66c, CD10, CD34 and CD25 expressions, but a lower median percentage and MFI values of CD38 and CD22 expressions than patients without gene rearrangement. Multivariate logistic regression analysis showed that CD10, CD38 and CD13 expressions were independent predictors for the presence of BCR/ABL1 rearrangement. Predictive probabilities of molecular occurrence based on these markers are proposed. © 2017 International Clinical Cytometry Society.

A new era has started for Chronic lymphocytic leukemia (CLL) thanks to very effective targeted oral therapies which are conducted in a chemo-free regimen (such as Ibrutinib, Idelalisib, and Venetoc...

The purpose of this study was to determine retrospectively, through a single-center evaluation, whether FDG PET-CT normalized semi-quantitative parameters may predict response to induction chemotherapy (iChT) and hematopoietic stem cell transplantation (HSCT), as well as disease progression and progression-free survival in multiple myeloma (MM) patients, thus becoming a tool of personalized medicine. Patients undergoing iChT and HSCT with baseline and post-treatment FDG PET-CTs from January 2008 to July 2015 were included. The following baseline and post-treatment parameters were obtained: SUVmax, SUVmean, SUVpeak, MTVsum, TLGsum, rPET (lesion SUVmax/liver SUVmax) and qPET (lesion SUVpeak/liver SUVmean). Baseline-to-post-treatment changes (Δ) were also calculated. Metabolic and clinical laboratory progression or response at follow-up were noted; time-to-metabolic-progression (TMP) was defined as the interval from post-treatment scan to eventual progression at follow-up FDG PET-CTs. Possible association between each functional parameter and metabolic/clinical-laboratory progression or response was determined. Kaplan-Meier curves allowed to depict the TMP trend according to FDG PET-CT parameters. Twenty-eight patients were included. Significantly higher ΔrPET and ΔqPET values were observed in ten patients with “metabolic response”, with respect to 18 patients having “metabolic progression” (median 0.62 [IQR 0.32 – 1.34] vs median 0.00 [IQR -0.25 – 0.49] for ΔrPET; P = 0.045; median 0.51 [IQR 0.32 – 1.13] vs median 0.00 [IQR -0.31 – 0.67] for ΔqPET; P = 0.035). Neither normalized nor non normalized parameters differed significantly between the 20 patients with “clinical-laboratory response” and the eight patients with “clinical-laboratory progression”. ΔrPET value lower than 0.38 and ΔqPET value lower than 0.27 predicted a significantly shorter TMP (P = 0.003 and P = 0.005, respectively). Normalized semi-quantitative parameters are effective in predicting persistent response to treatment and shorter TMP in patients with MM undergoing iChT and HSCT.

© 2018 The Authors., [Background]: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. [Patients and Methods]: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months., [Results]: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide., [Conclusion]: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits., Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc.

SummaryThe benefit of asparaginase for treating acute lymphoid leukaemia (ALL) has been well established. Native asparaginase derives from Escherichia coli (colaspase) or Erwinia chrysanthemi (crisantaspase); in a third preparation, colaspase is pegylated. Depletion of asparagine leads to decreased synthesis of procoagulant, anticoagulant, and fibrinolytic proteins, with resultant hypercoagulability and greater risk of venous thromboembolism (VTE). Colaspase and crisantaspase are not dose-equivalent, with crisantaspase displaying haemostatic toxicity only at dosages much higher and administered more frequently than those of colaspase. Cerebral venous thrombosis and pulmonary embolism are two life-endangering manifestations that occur during treatment with asparaginase particularly in children and in adults with ALL, respectively. Approximately one-third of VTEs are located in the upper extremities and are central venous line-related. Other risk factors are longer duration of asparaginase treatment and concomitant use of prednisone, anthracyclines, and oral contraceptives. The risk associated with inherited thrombophilia is uncertain but is clearly enhanced by other risk factors or by the use of prednisone. VTE prevention with fresh frozen plasma is not recommended; the efficacy of antithrombin (AT) concentrates has occasionally been reported, but these reports should be confirmed by proper studies, and AT should not be routinely employed. Therapeutic or prophylactic heparin doses are only partially effective, and direct thrombin or factor Xa inhibitors could play significant roles in the near future.

As for other malignancies, multiple myeloma is associated with an increased risk of venous thromboembolism (VTE). The incidence of VTE is estimated as 8 to 22 per 1,000 person-years; risk factors can be patient related (advanced age, other risk factors shared with the general population), disease related, and treatment related. Disease-related risk factors can derive from the monoclonal component (rarely hyperviscosity or inhibition of natural anticoagulants) or hypercoagulability sustained by inflammatory cytokines (increased von Willebrand factor, factor VIII, fibrinogen levels, decreased protein S levels, acquired activated protein C resistance). The 1 to 2% baseline of incident VTE associated with conventional therapies as melphalan and prednisone is at least doubled by the use of doxorubicin or other chemotherapeutic agents. The VTE rate associated with thalidomide or lenalidomide as monotherapy is similar, whereas combination with high-dose dexamethasone or multiple chemotherapeutic agents induces a multiplicative effect on the VTE rate up to 25%. Low-molecular-weight heparin (LMWH), fixed low-dose warfarin, and aspirin are acceptable strategies for antithrombotic prophylaxis, reducing VTE to 5 to 8% in thalidomide-treated patients and 1 to 3% in lenalidomide-treated patients. LMWH shows an advantage in efficacy not statistically significant. Prophylaxis should be tailored considering individual risk factors for VTE, the stage of disease, the possible occurrence of thrombocytopenia, or renal insufficiency.

Invasive fungal infections (IFIs) are serious, life-threatening complications frequently observed in hematological malignancies, in particular in patients affected by acute myeloid leukemia (AML) or in allogeneic hematopoietic stem cell transplantation (HSCT) recipients.[1][1] Epidemiological data

To evaluate the impact of radiotherapy on pain relief and on recalcification in patients with osteolytic lesions due to plasma cell neoplasm. Pain relief was evaluated according to a 0–10 verbal numerical rating scale (NRS) and recalcification was measured using radiological imaging. From 1996–2007, 52 patients were treated (Table 1). Median total dose was 38 Gy (range, 16–50 Gy). Pain be-fore radiotherapy was reported by 45 of 52 (86.5%) patients (Table 2) as being severe (8 ≤ NRS ≤ 10) in 5 (11%), moderate (5 ≤ NRS ≤ 7) in 27 (60%), and mild in 13 (29%). Pain relief was achieved in 41 of 45 patients (91%): complete relief was ob-tained in 21 (51.2%) and partial relief in 20 patients (48.8%); patients with severe pain experienced resolution and none present-ed an increase of pain. Drugs reduction/suspension was achieved in 7 of the 21 patients with complete response. Of 42 patients evaluable for recalcification (Table 3), 21 (50%) presented a radiological response, which was identified as complete in 16 (38%). Our data confirm the effectiveness of radiotherapy for pain relief, including a reduction in drug intake, and on recalcification, thus, supporting its use in a multidisciplinary approach.

SummaryThe utility of laboratory investigation of relatives of individuals with inherited thrombophilia is uncertain. To assess the risk of venous thromboembolism (VTE) among the carriers, we investigated a family cohort of 1,720 relatives of probands with thrombophilia who were evaluated because of VTE (n=1,088), premature arterial thrombosis (n=113), obstetric complication (n=257), or universal screening before pregnancy or hormonal contraception or therapy (n=262); 968 relatives were carriers of thrombophilia. A first deep venous thrombosis (DVT) occurred in 44 carriers and 10 non-carriers during 37,688 and 29,548 observationyears from birth, respectively. The risk of DVT among the carriers compared with non-carriers was estimated as a hazard ratio (HR). If the proband had VTE and factor V Leiden (FVL) and/or prothrombin (PT)20210A, the HR for DVT was 2.77 (95%CI 1.21–4.82) in the carriers overall, and 5.54 (95%CI 3.20–187.00) in those homozygous or double heterozygous for FVL and PT20210A. If the proband had VTE and a deficiency of antithrombin (AT), protein C or S, the HR for DVT was 5.14 (95%CI 0.88–10.03) in the carriers overall, and 12.86 (95%CI 2.46–59.90) in those with AT deficiency. No increase in risk was found among the carriers who were relatives of the probands who were evaluated for reasons other than VTE. In conclusion, familial investigation for inherited thrombophilia seems justified for probands with previous VTE, but appears of doubtful utility for the relatives of probands without VTE. This should be taken with caution regarding families with deficiency of natural anticoagulants, given the low number of cases analysed.

Introduction .Treatment of multiple myeloma (MM) patients (pts) has radically changed over the last years following the introduction of next generation proteasome inhibitors (PI) and immunomodulatory derivatives (IMiDs). Despite the improvement of pts' outcome due to these drugs, MM remainsan incurable disease given its propensity for clonal heterogeneity and its complex interaction with the surrounding bone marrow microenvironment. Almost all pts eventually relapse despite their responses to PI, IMiDs or both. Recently, one further therapeutic option for MM patients is represented bydaratumumab, an anti-CD38 monoclonal antibody approved alsofor heavily pre-treated pts who have exhausted all other therapeutic options. Patients and Methods. We report the experience of the Multiple Myeloma GIMEMA Lazio Group in 50 relapsed/refractory MM pts treated with daratumumab as monotherapy. Twenty-nine pts (58%) were men and 21 (32%) women. According to the ISS,24 pts (48%) were ISS I, 11 (22%) ISS II, 7 (14%) ISS III and 8(16%)not evaluable. According toDurie& Salmon, 20 pts (40%) were 1 A, 2 (4%) 1 B, 12 (24%) II A, 1 (2%) II B,7 (14%) III A, 3 (6%) III B and 5 (10%) not evaluable. Isotype IgG-k was found in 21 pts (42%), IgG-λ in 13 (26%), IgA-k in 6 (12%), IgA-λ in 3 (6%), micromolecular k in 5 (10%) andmicromolecular λ in 2 (4%). Median age was 62.3 years (range, 43.1 - 85.7); 32 pts (64%) were refractory to the last line of therapy; 26 (52%) had previously received a stem cell transplant (13 single autologous, 12 tandem autologous and one an autologous followed by an allogeneic transplant). After a median follow-up from diagnosis of 54.5 months (range 1.0 - 203.0) and a median of 3 previous lines of therapy (range 2 - 8), pts received a median of 3 cycles (range 1 - 23) of daratumumab. Results.Forty-seven pts (94%) performed at least one cycle and were evaluable for response. The overall response rate was 74%; in particular, 2 pts obtained a CR (4.2%), 3 pts a VGPR (6.3%), 17 pts a PR (36.2%) and 15 pts a SD (32%), while 10 pts (21.3%) presented a PD. After a median follow-up of 5.3 months (range 1 - 31) ,24 pts(65%) were still in response and alive, one pt (5.8%) died in PR due to post-allograft GVHD and 12 (32%) experienced a PD (1 CR, 1 VGPR, 6 PR and 4 SD). Seven (19%) pts died and 30 (81%) are still alive. With regard to the 3 pts not evaluable for response, 2 died early and 1 has not yet completed the first cycle. The median time to response, duration of response, progression-free survival and overall survival were 1.5 months (range 1.0 - 6.0), 6.7 months (95% CI, 4.14 - 14.21), 5.7 months (95% CI, 3.26 - 13.75) and 22.5 months (95% CI, 11.6 - 36.1), respectively. Daratumumab was well tolerated; the most common adverse events, of any grade, were infections in 20 pts (42.0%) and anaemia in 21 pts (44.0%), which did not lead to treatment discontinuation. Infusion-related reactionswere observed in 7pts (14.8%), grade I-II (4 pts), grade III (3 pts). Conclusions.Daratumumab monotherapy is an effective strategy for heavily pre-treated and refractory pts with multiple myeloma, with a favorable safety profile. This treatment option needs to be considered for pts not eligible for combination therapy of daratumumab with bortezomib or lenalidomide, recently approved also in our country. Disclosures Vozella: Takeda Oncology; Amgen: Honoraria. Annibali:Celgene; Takeda; Amgen, Janssen Cilag: Honoraria. Caravita di Toritto:Johnson & Johnson: Other: Advisory Board, Travel and Accomodation EHA; Amgen: Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Travel and Accomodation EMN; Takeda: Other: Advisory Board; Celgene: Other: Advisory Board, Travel and Accomodation ASH, Research Funding. Foà:NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; AMGEN: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau. Petrucci:Takeda Oncology; Amgen; Celgene; BMS; Janssen Cilag: Honoraria, Other: Advisory Board.

Prior thrombosis is a well-established risk factor for re-thrombosis in polycythemia vera and essential thrombocythemia but scarce data are available on the rate of re-thrombosis and the optimal strategy for prevention of recurrence.We retrospectively estimated the rate of recurrence in a multicenter cohort of 494 patients (poly-cythemia vera/essential thrombocythemia 235/259) with previous arterial (67.6%) or venous thrombosis (31%) or both (1.4%). First thrombosis was cerebrovascular disease in 191 cases, acute coronary syndrome in 106, peripheral arterial thrombosis in 44, and venous thromboembolism in 160. Microcirculatory events were not computed.Thrombosis recurred in 166 patients (33.6%), with an incidence of 7.6% patient-years. Sex, diagnosis (polycythemia vera or essential thrombocythemia), and presence of vascular risk factors did not predict recurrence, whereas age60 years did (multivariable hazard ratio [HR], 1.67; 95% confidence interval [CI] 1.19-2.32). Increased leukocyte count at the time of the first thrombosis was a risk factor for recurrence in patients60 years old (HR 3.55; 95% CI 1.02-12.25). Cytoreduction halved the risk in the overall cohort (HR 0.53; 95% CI 0.38-0.73) and the combination with antiplatelet agents or oral anticoagulants was more effective than administration of single drugs. Significant prevention of rethrombosis was independently achieved in patients with venous thromboembolism by both oral anticoagulants (HR 0.32; 95% CI 0.15-0.64) and antiplatelet agents (HR 0.42; 95% CI 0.22-0.77), in those with acute coronary syndrome by cytoreduction (HR 0.30; 95% CI 0.13-0.68), and in those with cerebrovascular disease by antiplatelet agents (HR 0.33; 95% CI 0.16-0.66). The overall incidence of major bleeding was 0.9% patient-years and rose to 2.8% in patients receiving both antiplatelet and anti-vitamin K agents.In patients with polycythemia vera and essential thrombocythemia, cytoreduction protects against recurrent thrombosis, particularly after acute coronary syndrome. The contemporary use of oral anticoagulants (after venous thromboembolism) or antiplatelet agents (after cerebrovascular disease or venous thromboembolism) further improves the protective effect. Such findings call for prospective studies aimed at investigating whether strategies tailored according to the type of first thrombosis could improve prevention of recurrences.

Purpose The risk of recurrent venous thromboembolism (VTE) in patients with polycythemia vera and essential thrombocythemia has been scarcely addressed, and whether long-term oral anticoagulant treatment or acetylsalicylic acid should be recommended after first occurrence of deep venous thrombosis (DVT) is unknown. This multicenter cohort study was aimed to assess the rate of recurrent VTE in patients with polycythemia vera or essential thrombocythemia in comparison with a control group of individuals with previous VTE and without neoplastic diseases. Patients and Methods We retrospectively estimated the rate of recurrence in 79 patients with myeloproliferative disorders (MPDs; polycythemia vera/essential thrombocythemia, 45/34) and with a previous proximal DVT. Patients were divided into 2 groups. The first comprised 41 patients who received acetylsalicylic acid after 6 months of oral anticoagulant treatment. The second group was composed of 38 patients given long-term oral anticoagulant treatment without acetylsalicylic acid. The majority of patients were treated with cytotoxic drugs. The results were compared with the recurrences seen in 176 patients without cancer with previous proximal DVT given short-term oral anticoagulant treatment. Results In the patients with polycythemia vera and essential thrombocythemia, the rate of recurrent DVT was higher in the group receiving acetylsalicylic acid (32%) compared with the group on oral anticoagulant treatment (16%), although not statistically significant. The rate of recurrent DVT in MPD cases receiving acetylsalicylic acid was quite similar to that of patients without cancer (33%). The cumulative probability of recurrent VTE indicated a trend of fewer events in the MPD cases on long-term oral anticoagulant treatment. In the patients with MPDs, the incidence of major bleeding during oral anticoagulant treatment or acetylsalicylic acid was 1% and 0.5% patient-years (years of observation), respectively. Conclusion This retrospective analysis would suggest a long-term oral anticoagulant treatment after a first DVT in patients with polycythemia vera and essential thrombocythemia. However, this indication should be weighed against the risk of major hemorrhagic events that seems lower during long-term prophylaxis with acetylsalicylic acid. Therefore, a prospective clinical trial comparing acetylsalicylic acid in patients with polycythemia vera and essential thrombocythemia with oral anticoagulant treatment in the prevention of recurrent VTE is warranted.

Venous thromboembolism (VTE) susceptibility genes are widely diffuse in the general population, but clinical penetrance of genotypes is incomplete and has variable expressivity. Therefore, the indiscriminate search for carriers is of doubtful utility and potentially detrimental for screened individuals. A targeted screening in kindreds in which VTE already occurred can be more fruitful in identifying individuals sharing with the proband one or more known susceptibility genes (possibly cosegregating with other ones still unknown). Clinical penetrance is variable, and is higher in the relatively rare deficiencies of antithrombin (AT), protein C (PC), or protein S (PS), and lower in the presence of the common polymorphisms factor V Leiden and prothrombin G20210A. Women with inherited thrombophilia should be warned about the thrombotic risk associated with the use of oral contraceptives or hormonal replacement treatment. Moreover, prophylaxis during puerperium and surgery or after trauma is warranted. The absolute risk associated with such situations is low but not negligible in the presence of deficiencies of AT, PC, or PS, homozygous conditions, and carriership of multiple defects. In such cases primary prophylaxis should be applied also during pregnancy and in general should be more stringent; moreover, in these patients the option for indefinite duration of secondary anticoagulant prophylaxis after VTE should be considered because of the relevant risk of recurrent VTE. In all cases, a careful balance of benefits and risks associated with prophylactic measures should be achieved, and patient preferences should be considered.

Splanchnic vein thrombosis (SVT) and chronic myeloproliferative neoplasms (MPN) are closely related. The JAK2 V617F mutation is a hall-mark of MPN but is present also in a relevant percentage of patients with SVT and without an overt chronic MPN. To investigate in patients with essential thrombocythemia (ET) the impact of this mutation on the risk of thrombosis in unusual sites (splanchnic or cerebral veins), we carried out a retrospective cohort study including 224 patients. One hundred forty-two patients (63%) had the mutation, and 68 had suffered either arterial thromboses (n = 39), venous thromboses in a common site (n = 12), or in the eye (n = 1), SVT (n = 13), or cerebral vein thrombosis (CVT; n = 3). All patients with SVT or CVT were

Report of a novel kindred with antithrombin heparin-binding site variant (47 Arg to His): Demand for an automated progressive antithrombin assay to detect molecular variants with low thrombotic risk

Monoclonal gammopathy of undetermined significance (MGUS) has been associated with an increased risk of thrombosis. We carried out a retrospective multicentre cohort study on 1491 patients with MGUS. In 49 patients (3.3%) MGUS was diagnosed after a thrombotic event. Follow-up details for a period of at least 12 months after diagnosis of MGUS were obtained in 1238 patients who had no recent history of thrombosis (2 years) prior to diagnosis, for a total of 7334 years. During the follow-up, 33 of 1238 patients (2.7%) experienced thrombosis, with an incidence of 2.5 arterial events and 1.9 venous events per 1000 patient-years. Multivariate analysis showed increased risks of arterial thrombosis in patients with cardiovascular risk factors [hazard ratio (HR) 4.92, 95%confidence interval (CI) 1.42-17.04], and of venous thrombosis in patients with a serum monoclonal (M)-protein level16 g/l at diagnosis (HR 3.08, 95%CI 1.01-9.36). No thrombosis was recorded in patients who developed multiple myeloma (n = 50) or other neoplastic diseases (n = 21). The incidence of arterial or venous thrombosis in patients with MGUS did not increase relative to that reported in the general population for similarly aged members. Finally, the risk of venous thrombosis did increase when the M-protein concentration exceeded16 g/l.

Hydroxyurea (Hydroxycarbamide; HU) is commonly used for the long-term treatment of patients with Philadelphia-chromosome negative chronic myeloproliferative neoplasms (MPNs). It is considered a first-choice agent for the treatment of these disorders as underlined by the European Leukemia Net Consensus Conference [1], although it is formally approved for this indication in some countries only. The drug is reportedly well tolerated in the large majority of subjects, although systemic and/or localized toxicities have been reported. Consensus criteria for definition of “intolerance” to HU have been described; patients who develop intolerance are candidate for second-line therapy and, more recently, for investigational drugs. However, no epidemiologic information about the occurrence of the most clinically significant HU-associated adverse events is yet available. In this study, the authors report on a multicenter series of 3,411 patients who were treated with HU among which 184, accounting for 5% of total, developed significant drug-related toxicities. These data provide an estimate of the frequency and a detailed characterization of clinically significant HU-related toxicities; these information have relevance for the management of MPN patients who require second-line therapy after developing HU-related intolerance.

Abstract 4604 Currently standard first line therapy for fit patients with B-CLL/SLL are fludarabine-based regimens. Elderly patients or patients with comorbidities poorly tolerate purine analogue-based chemotherapy and they are often treated with Chlorambucil (Chl). However, complete response (CR) and overall response (OR) rates with Chl are relatively low. We now investigated whether the addition of Rituximab to Chl will improve the efficacy without impairing the tolerability in elderly and unfit patients. We included in our study 23 elderly or unfit patients that had not received prior therapy. All patients were treated with Chl (1mg/Kg monthly for 8 cycles) plus Rituximab (375 mg/m2 for the first course and 500 mg/m2 for subsequent cycles until the 6th cycle). Fifteen patients were male and 8 were female, with a median age at the time of treatment of 70 years (range 58 to 81 years). Eight patients (35%) were unfit with a median age of 68 years (range 58 to 79 years). Five patients were in stage A/I, 10 were in stage B/II and 8 in stage C/IV. FISH analysis was done in all patients: 78% showed karyotype abnormalities. Low-risk FISH karyotype was detected in 20/23 pts: 12 of them had del(13q14), 1 had trisomy 12, 1 trisomy 12 and del(13q14) and 6 had a normal karyotype. Three patients showed a high risk karyotype: all of them had del(11q). None of the patients had a 17p deletion. Nineteen pts were studied for IGHV mutational status (83%), 12 had unmutated while 7 had mutated IGHV genes. Twenty-one patients were evaluable for response to treatment. The median number of Chl and RTX cycles administered in the 21 patients who completed the treatment protocol was 8 (range 6 to 8 cycles) and 6 (range 4 to 6 cycles) respectively. The median total dose of Chl administered during the treatment was 600 mg per patient (median dose 85 mg each cycle). The median dose of RTX administered was 4000 mg per patient (median dose 710 mg each cycle). Among 21 pts evaluable for response, the Overall Response Rate (ORR) was 76%. Six pts (28%) obtained a complete response, 10 pts (48%) obtained a partial response. No significant statistical differences were noticed in terms of ORR for age more or less than 70 years, fitness status, bulky disease, cytogenetic risk abnormalities or IgVH, ZAP-70 and CD38 categories. On an intention to treat basis the median PFS was not reached at a median time of 21 months (range 2–45). Eleven pts experienced progression after treatment at a median time of 20 months (range 2–36). No significant statistical differences were found among the analyzed risk groups. After a median time of 25 months (range, 2–45 months), TTR was not reached. No significant statistical differences were noticed between the Unmutated and Mutated IgVH groups and for ZAP-70 and CD38 categories with respect to TTR. At present the median follow-up is 29 months, with an OS rate of 80% (19/23). None of the risk factors analyzed were found to influence significantly the OS. In conclusion, this study suggests that the combination Chl-R is a safe and effective therapeutic option for untreated B-CLL pts that are not eligible for fludarabine treatment because of age and/or comorbidities. A multicentre trial to confirm these data is planned. Disclosures: No relevant conflicts of interest to declare.

The term splanchnic vein thrombosis encompasses Budd-Chiari syndrome (BCS), extrahepatic portal vein obstruction (EHPVO), and mesenteric vein thrombosis. Risk factors can be local or systemic. A local precipitating factor is rare in BCS, while it is common in patients with portal vein thrombosis. Chronic myeloproliferative neoplasms (MPN) are the leading systemic cause of splanchnic vein thrombosis, and are diagnosed in half BCS patients and one-third of EHPVO patients; the molecular marker JAK2 V617F is detectable in a large majority of patients with overt MPN and up to 40% of patients without overt MPN. Inherited thrombophilia is present in at least one-third of patients, and the factor V Leiden or the prothrombin G20210A mutations are the most common mutations found in BCS or EHPVO patients, respectively. Multiple factors are present in approximately one-third of patients with BCS and two- thirds of patients with portal vein thrombosis. In a few patient series from the Southern Mediterranean area the high prevalence of MPN and thrombophilia as underlying cause of BCS is confirmed, although the data should be considered preliminary. Peculiar risk factors present in the area are Behcet’s disease and hydatidosis; moreover, the presence of membraneous webs, typically found in Asian patients, can be found in a significant portion of cases.

There is evidence that leukocytosis is associated with an increased risk of first thrombosis in patients with polycythemia vera (PV) and essential thrombocythemia (ET). Whether it is a risk factor for recurrent thrombosis too is currently unknown. In the frame of a multicenter retrospective cohort study, we recruited 253 patients with PV (n = 133) or ET (n = 120), who were selected on the basis of a first arterial (70%) or venous major thrombosis (27.6%) or both (2.4%), and who were not receiving cytoreduction at the time of thrombosis. The probability of recurrent thrombosis associated with the leukocyte count recorded at the time of the first thrombosis was estimated by a receiver operating characteristic analysis and a multivariable Cox proportional hazards regression model. Thrombosis recurred in 78 patients (30.7%); multivariable analysis showed an independent risk of arterial recurrence (hazard ratio [HR] 2.16, 95% CI 1.12-4.18) in patients with a leukocyte count that was >12.4 x 109/L at the time of the first thrombotic episode. The prognostic role for leukocytosis was age-related, as it was only significant in patients that were aged

Evidence suggests that the JAK2 V617F mutation is associated with an increased risk of first thrombosis in patients with essential thrombocythemia (ET). Whether this mutation is also a risk factor for recurrent thrombosis is currently unknown. To investigate the impact of the JAK2 V617F mutation on the risk of recurrent thrombosis in patients with ET, we carried out a multicentre retrospective cohort study. We recruited 143 patients with previous arterial (64.4%) or venous major thrombosis (34.8%) or both (0.8%); 98 of them (68.5%) carried the mutation. Thrombosis recurred in 43 of the patients (30%); overall, after adjustment for sex, age, presence of vascular risk factors, and treatment after the first thrombosis, the presence of the JAK2 mutation did not predict recurrence (multivariable hazard ratio, HR, 0.88, 95% CI 0.46-1.68). Indeed, the individuals homozygous for the JAK2 V617F (allele burden >50%) mutation had an increased risk of recurrence in comparison with wild-type patients (HR 6.15, 95% CI 1.51-24.92). In conclusion, a homozygous JAK2 V617F mutation is an independent risk factor for recurrent thrombosis in patients with ET. © Springer-Verlag 2009.

It is uncertain whether the JAK2 V617F mutation increases the thrombotic risk in patients with essential thrombocythemia, and it is unknown whether inherited thrombophilia is an additive risk factor in mutated subjects. We studied 132 patients with essential thrombocythemia, 38 of them (29%) with a history of thrombosis. The JAK2 mutation was present in 83 (63%), and inherited thrombophilia in 7. The mutated patients60 years had a relative risk (RR) for thrombosis at any time of 3.83 (95%CI 1.27-11.49) in comparison with wild-type patients; in those with both the mutation and thrombophilia the RR was 2.23 (95%CI 1.57-3.18) and 7.66 (95%CI 2.66-22.03) in comparison with mutated or wild-type patients without thrombophilia, respectively. During the follow-up, only the homozygotes for JAK2 V617F were more prone to thrombosis (RR 17.25, 95%CI 2.33-127.4). Among the patients60 years, no increase in RR was associated with the JAK2 mutation. In conclusion, in the younger patients with ET the thrombotic risk is higher in the JAK2 V617F-mutated and is further increased by the presence of inherited thrombophilia.

SummaryIt is uncertain whether the presence of inherited thrombophilia influences the risk of developing symptomatic pulmonary embolism (PE) and whether different thrombophilic alterations are associated with different risks of symptomatic PE. To investigate such issue, we retrospectively studied 920 patients with proximal deep vein thrombosis (DVT) of the legs with or without symptomatic PE referred for thrombophilia screening; patients with overt cancer or antiphospholipid antibodies had been excluded. Three hundred fifty-four patients (38.5%) had deficiency of antithrombin (AT, n=16), protein C (PC, n=26), protein S (PS, n=22), factor V Leiden (FVL, n=168), prothrombin G20210A (PT-GA, n=87), or multiple abnormalities (n=35), and 566 had none of the studied thrombophilic abnormalities. Symptomatic PE complicated the first DVT in 242 patients (26%); the risk of PE was increased in patients with AT deficiency (relative risk [RR] 2.4, 95% confidence interval [CI] 1.6–3.6) or with PT-GA (RR 1.5, 95%CI 1.1–2.0) and decreased in those with FVL (RR 0.7, 95%CI 0.5–1.0) in comparison with those with unknown inherited defect. These data suggest that patients with proximal DVT have different risks of symptomatic PE according to the type of inherited thrombophilia.

The acronym POEMS refers to polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes. This disease is progressive and weakening for patients and lead to death generally for neurological problem without therapy. We treated four patients affected by POEMS syndrome with front-line chemotherapy and autologous peripheral blood stem cell transplantation (aPBSCT). After a median follow-up of 40.5 months (range 12-52), all patients are alive with slow but progressive improvement in neurological disease, skin changes, performance status and without evidence of clonal plasmacytosis and organomegaly. In conclusion early diagnosis is crucial to obtain best response and improve clinical outcome.

Summary. Background: The relationship between the G20210A prothrombin variant (PT-G20210A) and adverse pregnancy outcome has been studied by several groups in the last few years. However, because of the different design and sample sizes of these studies the estimated risks have varied. Objective: In this retrospective, multi-center, cohort study we assessed the risk of thromboembolic or obstetric complications in women belonging to families of probands with isolated PT-G20210A and that were symptomatic for venous thromboembolism (VTE). Methods: Two hundred and eighty-three female family members that had been pregnant at least once were enrolled. The occurrence of VTE and obstetric complications during pregnancy and postpartum were assessed in carriers of PT-G20210A and compared with non- carriers. Results: One thromboembolic event occurred during the postpartum period in the carriers group. In the same group, 48 out of 359 pregnancies resulted in unexplained fetal loss as compared with 50 out of 357 pregnancies in the non-carriers (RR 0.9; 95% CI: 0.7–1.4). After adjustment, carriers of PT-G20210A showed a trend towards a higher risk of late fetal loss as compared with non-carriers (RR 2.2; 95% CI: 0.8–6.2). Furthermore, in pregnancies subsequent to those with previous fetal loss there was not a different risk of adverse outcome regardless of the carrier status. Conclusions: Female family members who are heterozygous carriers of isolated PT-G20210A do not seem to be at significant increased risk for fetal loss as compared with non-carriers. Screening for PT-G20210A of fertile age women belonging to these families is not warranted in this situation.

Whether or not pregnant women with a previous episode of venous thromboembolism (VTE) should receive antithrombotic prophylaxis is a matter of debate. In order to estimate the rate of recurrent deep venous thrombosis (DVT) or pulmonary embolism (PE) during pregnancy and puerperium we retrospectively investigated a cohort of 1104 women with previous VTE; after a single DVT or isolated PE, 88 of them became pregnant at least once without receiving antithrombotic prophylaxis. Overall, 155 pregnancies and 120 puerperium periods without prophylaxis were recorded. There were nine recurrences during pregnancy and 10 during puerperium, with a rate of 5.8% [95% confidence interval (CI) 3.0-10.6] and 8.3% (95%CI 4.5-14.6) respectively. In pregnancy, the rate of recurrence was 7.5% (95%CI 4.0-13.7) if the first VTE was unprovoked, related to pregnancy or to oral contraceptive use, whereas no recurrence occurred if the first VTE was related to other transient risk factors. In puerperium, the rate of recurrence was 15.5% (95%CI 7.7-28.7) in women with a pregnancy-related first VTE, with a risk 3.9-times higher than in the remaining women. Inherited thrombophilia was not associated with a statistically significant increase in risk of recurrence in pregnancy or in puerperium, yet the rate of recurrence in puerperium was 14.2% (95%CI 5.7-31.4) in overall carriers of factor V Leiden and 30% (95%CI 10.7-60.3) in carriers with a pregnancy-related first VTE, with a risk 6.8 times higher than in women without thrombophilia and with a non pregnancy-related first VTE.

Essential Thrombocythemia (ET) and Polycythemia Vera (PV) are chronic myeloproliferative diseases characterized by frequent episodes of deep venous thrombosis (DVT), arterial thromboembolism (AT) and by hemorrhagic complications. Surgical procedures could represent a risk factor for thrombosis and bleeding, but no data on the real frequency of these complications are available. To estimate the frequency of thrombosis and haemorrhages after surgical procedures and their outcomes, a multicenters retrospective analysis was performed. Data from 105 PV and 150 ET patients (128 males, 127 females, median age at diagnosis 60, were analyzed, for a total of 311 surgical interventions. At least one risk factor for arterial thrombosis (diabetes mellitus, hypercholesterolemia, arterial hypertension, previous AT, smoke) was present in 128/255 (50.1%), more frequently in PV than in ET patients (58.5 vs. 46.8%, p=0.02). An excess of male and older patients in PV than in ET explained this finding (multivariate analysis). Previous DVT was present in 9/255 patients (3.5%). After diagnosis, antiplatelet drugs were given to 211/255 patients (82.7%); cytoreductive treatments to 188/255 (74%), warfarin to 16/255 (6.2%); all PV patients were phlebotomized. In 25/311 surgeries (8.0%), an emergency procedure was performed; 195 surgeries were done under general anaesthesia; 21/91 abdominal interventions (23%) were performed under laparoscopy. Major surgeries were 160/311 (51.4%). Data about antithrombotic prophylaxis were available for 292/311 surgeries: in 126 (43.2%) low molecular heparin, in 38 (13%) unfractioned heparin, in 5 (1.7%) warfarin and in 123 no anticoagulant therapy was administered. In 45/123 (36.6%) patients without antithrombotic prophylaxis, antiplatelet therapy was administered before surgery. 189/255 (74%) were on cytoreductive therapy before surgery; for 9 surgical procedures, a short cycle of chemotherapy was administered before surgery. Clinical outcomes after surgery were recorded with a 3 months follow-up. No event was observed in 259/311 procedures (83.2%); there were 12 arterial and 12 venous thrombotic events, 23 major and 7 minor hemorrhages and 5 deaths. AT were more frequent in ET patients (5.3 vs. 1.5%, p=0.08) while venous events were more frequent in PV patients (7.7 vs. 1.1%, p=0.002). There was a strong risk gradient for AT associated with the presence of one or more arterial risk factors (OR for 4 or more risk factors: 40.9, p=0.003). Platelet count and hematocrit at surgery (median 477 x 109 /l and 42.6%, respectively) were not associated with either venous or arterial thrombosis. There was no correlation between bleeding episodes and type of diagnosis, use of antithrombotic prophylaxis and type of surgery. In conclusion, despite an active approach (cytoreduction and antithrombotic prophylaxis in the majority of the cases) a high proportion of PV and ET surgeries was complicated by DVT and AT (7.7%) but also by major hemorrhages (7.3%), requiring more investigation on the optimal prophylaxis in these patients.

s / Thrombosis Research 131, Suppl. 1 (2013) S71–S103 S77 is a loop region which is in contact with the longest helix of PZI. Other regions have been identified, which hold anomalous flexibility associated with potentially protective gene variants. A possible explanation of the effect of the observed gene variants is given, based on the interaction between PZ and PZI. P-002 Underlying bleeding disorders in patients are equally important in menorrhagia with and without gynaecological abnormalities H.M. Knol 1,2, A.B. Mulder 3, D.H. Bogchelman2, H.C. Kluin-Nelemans1, A.G.J. van der Zee2, K. Meijer 1 1Division of Haemostasis and Thrombosis, Department of Haematology, University Medical Centre Groningen; 2Department of Obstetrics and Gynaecology, University Medical Centre Groningen, Groningen; 3Department of Laboratory Medicine, University Medical Centre Groningen, Groningen, the

Donor erythrocytosis induced by sorafenib treatment after allogeneic hematopoietic SCT in a patient with acute myeloid leukemia

Reply to ‘Absence of JAK-2 (Val617Phe) point mutations in multiple myeloma’ by Dr Qin Huang et al. referred to ‘Screening of JAK2 V617F mutation in multiple myeloma’ from Fiorini A et al. published in Leukemia 2006, October 20

The current standard first line therapy for fit patients with B-CLL/SLL is based on combination of fludarabine-cyclophosphamide and rituximab. However, elderly patients or patients with comorbidities poorly tolerate purine analogue-based chemotherapy and they are often treated with Chlorambucil (Chl) only. However, complete response (CR) and overall response (OR) rates with Chl are relatively low. We now investigated whether the addition of Rituximab to Chl will improve the efficacy without impairing the tolerability in elderly and unfit patients. We included in our study 27 elderly or unfit patients that had not received prior therapy. All patients were treated with Chl (1mg/Kg per 28-day cycle for 8 cycles) plus Rituximab (375 mg/m(2) for the first course and 500 mg/m(2) for subsequent cycles until the 6(th) cycle). We obtained an OR rate of 74%. The most frequent adverse effect was grade 3-4 neutropenia, which occurred in 18.5% of the patients. Infections or grade 3-4 extra-hematological side effects were not recorded. None of the patients required reduction of dose, delay of therapy or hospitalization. Overall, these data suggest that Chl-R is an effective and well tolerated regimen in elderly/unfit patients with CLL.

We have previously demonstrated that clonal hemopoiesis in female ET patients was significantly associated to the risk of thrombosis. When data on JAK2 V617P mutation became available we aimed to evaluate the incidence of this mutation according to clonality status. Ninety-two female patients, median age 32 (19–65) with a diagnosis of ET according to PVSG criteria were studied for clonality with X-CIP, 83 patients were evaluable for endogenous erythroid colonies (EECs) growth and 44 patients were evaluable for JAK2 V617P mutation. Twenty episodes of thromboses (21.7%) were detected and they include splanchnic (11), CNS (5), limb (3) thromboses and pulmonary embolism (1). Thromboses were mainly detected at diagnosis. Thirthy-seven patients showed clonal hemopoiesis (40%), 27 had polyclonal hemopoiesis (29.5%) and 28 were considered uninterpretable due to constitutional skewing (30.5%). Thromboses were overrepresented in the monoclonal group in respect to the polyclonal one (15/37 vs 2/27, p=0.003). DNA for analysis of JAK2 V617P by allele-specific PCR was available for 44 of these patients. Thirty-two patients of 44 (73%) showed JAK2 V617P mutation; JAK2 V617P was found in 16/21 patients with monoclonal hemopoiesis (76%), in 9/13 in the polyclonal group (69%) and in 7/10 (70%) in patients with constitutional skewing. Thirteen of the 32 patients with JAK2 V617P mutation (41%) had thromboses while no thrombotic event was recorded in wild type patients (p=0.008); among the 13 patients with thrombosis and JAK2 V617P mutation, 9 (69%) had monoclonal hemopoiesis, 2 (15%) had polyclonal hemopoiesis, and 2 had constitutive skewing. Thus there was a significant increase in thrombotic events in patients with JAK2 V617P mutation and monoclonal hemopoiesis (p=0.04). JAK2 V617P mutation was also significantly associated to the presence of EECs (p=0.02); in fact 22/26 patients with EECs growth showed JAK2 mutation (85%). Finally when patients with splanchnic thromboses were analyzed 9/11 had a monoclonal X-CIP (81.8%) and 7 of them who were evaluable for JAK2 V617P mutation were invariably carriers of the mutation. Thus we confirm that X-CIP in young female ET is correlated to the risk of thrombosis. JAK2 V617P mutation is significantly associated to the development of thrombosis and is present in the vast majority of patients with monoclonal hemopoiesis. The mechanisms underlying monoclonal hemopoiesis in the absence of JAK2 V617P mutation are unclear, notwithstanding these patients are clinically characterized by both absence of EECs and thrombosis.

Background Immunoglobulin D multiple myeloma (MM) is rare and has a poorer prognosis than other MM isotypes. Design and methods Seventeen patients (pts) diagnosed from 1993 to 2009 with IgD MM were selected from six institutions of Multiple Myeloma Latium-Region GIMEMA Working Group. Results Median 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. Conclusions Despite 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.