Abstract 1215
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the expansion of a Leukemic Stem Cell (LSC) clone carrying a Philadelphia translocation, which ...outgrows the non-malignant haematopoietic stem cells. The tyrosine kinase inhibitors (TKIs) imatinib, nilotinib and dasatinib, are the gold standard for CML treatment since each one shows an impressive rates of complete cytogenetic and molecular response in chronic phase (CP) CML. However the major problem concerning the final efficacy of TKIs therapy is that the majority of responding CP CML patients have detectable BCR-ABL transcripts which might arise from a population of quiescent CML LSC not effectively targeted by TKIs. Therefore the molecular monitoring not always provide a sufficiently precise evaluation of patients to allow the appropriate choice of clinical interventions. Accordingly, it is necessary to monitor the appearance and increase of LSCs to identify and to treat quickly the fundamental responsible for relapse. Thus, we focused Hedgehog (Hh) signalling which has been proved essential for maintenance of cancer stem cells in myeloid leukaemia. Notably recent studies reported that the expansion of BCR-ABL positive leukemic stem cell is dependent on Hh pathway activation. Here, we analyzed the mRNA levels of Smoothened (SMO), a seven-transmembrane domain receptor protein, and Ptch1, a surface receptor regulator of SMO, in 20 CP-CML patients (8 High, 4 Intermediate and 8 Low Sokal Risk respectively) at diagnosis and during the follow-up. Using RT-PCR, in diagnosis setting, we proved that 60% of patients (bone marrow samples) showed Hh signalling significantly activated compared to CD34+ cells from healthy donors. In detail 75% (6/8) of High Sokal Risk CML patients showed an up-regulation of Smo and a down-regulation of Ptch1 mRNA levels, suggestive of active Hh signalling at diagnosis. Conversely Low and Intermediate Sokal Risk CML patients did not show features of Hh activation. Finally we monitored, during the follow-up, the mRNA levels of Smo and Ptch1 together with BCR-ABL to assess the kind of relationship between these parameters. Interestingly we noticed a direct correlation between the increase of BCR-ABL mRNA levels and signs of Hh activity (Smo mRNA increase level and Ptch1 mRNA decrease level). Characteristically, molecular monitoring highlighted that all patients developing resistance to TKIs treatment, showed a tendency to Hh activation (high and low mRNA levels of Patch1 and Smo respectively) few months before the development of Abl KD mutation (10/10). Typically this last behaviour was more evident in patients developing the gatekeeper mutation T315I. Finally, in accordance with published data, we noted that the pharmacological inhibition of Hh signalling impairs the growth of TKIs resistant human CML cell line BaF/T315I, suggesting a novel treatment option. All our data provide molecular evidence for a role of the stemness pathway to predict quickly both the relapse and the TKIs resistance during CML treatment. Therefore, we propose to use Ptch1 and Smo mRNA levels together with BCR-ABL for the molecular monitoring of CP CML.
No relevant conflicts of interest to declare.
Abstract 1680
Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 hybrid gene. Different types of BCR-ABL1 fusion transcripts can be found, but the most frequent are the ...e13a2 (b2a2) and the e14a2 (b3a2). In the tyrosine kinase inhibitors (TKIs) era, few data about the prognostic significance of the transcript type in early chronic phase (ECP) CML are available. Three larger studies suggested that the e13a2 transcript may have an adverse prognostic impact in ECP CML patients treated with imatinib (IM): Vega-Ruiz et al. (251 patients, ASH 2007) reported inferior molecular responses; Lucas et al. (71 patients, Haematologica 2009) reported lower cytogenetic response rates and lower event-free survival (EFS); the GIMEMA CML WP (493 patients, EHA 2011) reported a slower time to major molecular response (MMR) with inferior EFS and progression-free survival (PFS). To our knowledge this is the first evaluation of the prognostic influence of the BCR-ABL1 transcript type on the responses and the outcome of ECP CML treated frontline with nilotinib (NIL).
The CML Italian Registry of Nilotinib includes 215 patients treated with NIL-based regimens. The patients were enrolled within 2 multicenter phase II studies conducted by the GIMEMA CML WP (ClinicalTrials.gov. NCT00481052 and NCT00769327) or treated at the “S. Orsola-Malpighi” University Hospital (Bologna, Italy), with NIL 300 mg BID or 400 mg BID as initial treatment. All the registered patients were analyzed. Patients expressing rare transcripts and patients with both b2a2 and b3a2 transcripts were excluded: 201 out of 215 patients were evaluable, 81 (40%) with e13a2 transcript and 120 (60%) with e14a2 transcript. Differences between groups were tested using χ2 test, Fisher exact test or t-test, as appropriate. Response monitoring: conventional cytogenetic examination (bone marrow) and QPCR (peripheral blood). Definitions: MMR: BCR-ABLIS ratio <0.1% (International Scale); failures: according to 2009 ELN recommendations; events: failure or treatment discontinuation for any reason. The time-to-response and the outcome were estimated using the Kaplan-Meier method, and compared by log-rank test.
The baseline characteristics of the 2 groups were comparable (no significant differences in age, Sokal/Hasford/EUTOS score distribution, clonal chromosomal abnormalities in Ph+ cells, NIL dose), except for the percentage of basophils in the peripheral blood, higher in patients with e14a2 transcript (3.4% vs 2.3%, p=0.01). The median observation was 29 months (range 18–47); 92% of the patients had at least 2 year observation. The CCgR and MMR rates at 12 months were comparable in the 2 groups. The time to MMR was longer for patients with e13a2 transcript (6 months vs 3 months, p=0.04), but the overall CCgR rates (93.8 vs 91.7, p=0.79) and the overall MMR rates (85.1 vs 90.0, p=0.38) were not significantly different in patients with e13a2 or e14a2 transcript, respectively. The probability of Overall Survival (OS), Progression-Free Survival (PFS) and Failure-Free Survival (FFS) were comparable: 91.4% vs 95.8% (p=0.61), 90.7% vs 95.0% (p=0.51), and 90.7% vs 88.7% (p=0.40) in patients with e13a2 and e14a2 transcript, respectively.
In our experience, based on 201 early CP CML patients treated frontline with NIL with a minimum follow-up of 18 months, the BCR-ABL transcript type did not show any relevant prognostic impact. The time to MMR was longer in patients with e13a2 transcript, but no response and outcome differences have been observed so far. The number of observed events was low and a longer observation is required.
European LeukemiaNet, COFIN, Bologna University, BolognAIL
Castagnetti:Novartis Pharma: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Gugliotta:Novartis: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria. Breccia:Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Cavazzini:Novartis Pharma: Honoraria; Bristol Myers Squibb: Honoraria. Turri:Novartis: Consultancy, Novartis Other; Bristol Myers Squibb: Bristol Myers Squibb, Bristol Myers Squibb Other, Consultancy. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; ARIAD: Consultancy. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Martinelli:Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Speakers Bureau. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Rosti:Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau.
In essential thrombocythemia (ET) patients, history of thrombosis and age over 60 y are validated risk factors for occurrence of thrombosis during the follow-up. Leukocytosis, JAK2 V617F mutation, ...cardiovascular (CV) general risk factors, and male gender are candidate risk factors for thrombosis. The thrombocytosis, a constitutive abnormality in ET, is associated with both thrombotic and hemorrhagic complications.
To evaluate in a large cohort of ET patients the potential relationship between the thrombosis history and the main clinical and biological characteristics at diagnosis, i.e. before any interference of cytoreductive treatment.
A cohort of ET patients (PVSG or WHO criteria) of the Registro Italiano Trombocitemie (RIT) was retrospectively analyzed through logistic regression models.
A total of 977 patients, 387 males and 590 females, presented at diagnosis: median age 56 y (43% with age >60 y), median PLT count 783 x 109/L (33% with low thrombocytosis, <700 x 109/L), median WBC count 8.8 x 109/L (29% with leukocytosis, >10 x 109/L), median HCT 42.6% (high HCT: >47% in 24% of the males and >44% in 23% of the females), CV general risk factors in 69% of cases (one of smoking, hypercholesterolemia, hypertriglyceridemia, hypertension, diabetes, obesity, CV disease, familiarity for thrombosis), bone marrow fibrosis grade 0 in 67% of cases, JAK2 V617F mutation in 56% of the 399 tested patients.
The history of thrombosis (arterial in 74% of cases) was reported in 194 (19.9%) patients.
The history of thrombosis in univariate analysis was significantly related to: age >60 y (p 0.001), male gender (p 0.009), CV general risk factors (p 0.002), low thrombocytosis (p 0.000), leukocytosis (p 0.003), high HCT (p 0.004), and JAK2 V617F mutation (p 0.008). No relationship was found with bone marrow fibrosis.
In multivariate analysis a relationship was confirmed between thrombosis history and age >60 y (p 0.023), male gender (0.046), CV general risk factors (0.039), low thrombocytosis (p 0.004), leukocytosis (0.019), and JAK2 V617F mutation (p 0.033).
The rate of thrombosis history in the patients without both low thrombocytosis and leukocytosis (11%, 49/428) resulted significantly lower (p 0.0001) than in the patients with leukocytosis (24%, 54/224), the patients with low thrombocytosis (27%, 71/266), and the patients with both low thrombocytosis and leukocytosis (34%, 20/59).
In this cohort of ET patients the rate of thrombosis history in multivariate analysis is significantly related to various clinical and biological characteristics at diagnosis, including low thrombocytosis (PLT <700 x 109/L), leukocytosis (WBC >10 x 109/L), JAK2 V617F mutation, age >60 y, male gender, and CV general risk factors.
this study was partially supported by the GIMEMA Foundation (Promotor of the RIT) and by the AIL Foundation.
Gugliotta:SHIRE Company: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Abstract 453
Imatinib (IM) 400 mg daily is the standard treatment for Ph+ Chronic Myeloid Leukemia (CML) in early Chronic Phase (ECP). Nilotinib (NIL) is a 2nd generation tyrosine kinase inhibitor ...(TKI) with superior efficacy to IM (phase 3 ENESTnd trial). NIL has been approved for the frontline treatment of CML in many countries. The treatment with more than one TKI, according to the principles of cancer polychemotherapy, may improve the response rates and may decrease the frequency of drug-resistance. The combination of different TKIs is potentially toxic, difficult to be explored in the ECP setting. The sequential administration of IM and NIL is worth to be investigated because a significant proportion of CML patients treated with a single TKI as monotherapy develops primary or secondary resistance.
To evaluate the response (either cytogenetic and molecular) and the outcome of ECP Ph+ CML patients treated with the sequential administration of NIL and IM.
A phase 2 study was conducted by the GIMEMA CML WP (ClinicalTrials.gov. NCT00769327). NIL was administered first because it has a more rapid therapeutic effect. Schedule: NIL 400 mg twice daily for 3 months; IM 400 mg daily for the next 3 months; then, NIL and IM turning every 3 months, for a total duration of 24 months (study core). The 3-month rotation schedule was respected, irrespectively of temporary discontinuations. The primary end-point was the Complete Cytogenetic Response (CCgR) rate at 12 months. If the conventional cytogenetic analysis resulted not evaluable, a FISH analysis was performed. If one of the 2 drugs was permanently discontinued for adverse event (AE), the patient remained in study, continuing the treatment with the other drug (except for cardiac AEs). Definitions: Major Molecular Response (MMR): BCR-ABL/ABL ratio < 0,1%IS; failure: according to 2009 ELN recommendations; event: failure, permanent discontinuation of both drug for any reason, patient refusal. All the analysis were performed according to the ITT principle.
123 patients have been enrolled in 38 italian hematologic Centers; median age 56 years (range 18–84); 33% low, 45% intermediate and 22% high Sokal score; median follow-up 21 months (at least 12 months observation, 24 months by November 2011). The cumulative CCgR rate by 12 months was 87%; CCgR at each milestone: 68% at 3 months, 73% at 6 months, 67% at 12 months (primary efficacy variable). The cumulative MMR rate by 12 months was 82%, while the rates of MMR at 3, 6 and 12 months were 59%, 62% and 60%, respectively. The discrepancies between cumulative response rates and response at each timepoint were mainly due to the number of patients not evaluable at each timepoint (10% of cytogenetic analysis not evaluable at 12 months) and to protocol discontinuation in stable CCgR and/or MMR. The incidence of hematologic AEs was low. Non-hematologic AEs or lab abnormalities grade > 2 observed in >5 % of patients were as follows: NIL - skin rash, pruritus, bilirubin increase, transaminase increase, lipase increase; IM - fluid retention, periorbital edema. AEs were manageable with appropriate dose adaptations. Four patients (3%) showed a prolongation of the QTcF above 450 msec (none above 500 msec). At the end of the first 12 months, 95 patients (77%) remained on study: 6 and 3 on NIL and IM monotherapy, respectively, 86 on sequential treatment with both drugs; 15% of patients permanently reduced the NIL dose to 400 mg daily and 9% of patients permanently reduced the IM dose to 300 mg daily. During the first year, 28 patients (23%) experienced an event: 10 treatment failure (8%); 2 death in CP (2%); 16 refusal, protocol violation or AE (13%). Six out of the 10 patients who failed the treatment progressed to advanced phase (3 patients: detection of a T315I mutation).
The cumulative response rates achieved with a sequential administration of NIL and IM seem to be superior to the historical data of IM alone. The response rates at each timepoint, lower than expected, were probably due to the high number of not evaluable patients and to the number of patients not continuing the study despite a stable CCgR/MMR. However, if compared to the excellent results of 2nd generation TKI as monotherapy in ECP CML (single and randomized trials), the present analysis do not support an alternating schedule of NIL and IM as frontline treatment of ECP CML.
European LeukemiaNet, COFIN, Bologna University, BolognAIL
Castagnetti:Novartis Pharma: Honoraria; Bristol-Myers Squibb: Honoraria. Rosti:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Soverini:Novartis: Consultancy; ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy. Martinelli:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding.
Tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec, Novartis, formerly known as STI571) are confirmed to be the first line treatment of Chronic Myelogenous Leukemia (CML) and of a rare ...form of gastroenteric stromal cancer. It has been reported that in the latter case, the response to the drug in vivo is mainly due to immunocompetent cells, able to produce cytokines with antineoplastic activity. In this study, peripheral blood and bone marrow of 20 CML patients were studied, prior and during treatment with imatinib, to assess morphologic, phenotypic, cytogenetic and biomolecular patterns. Plasma from BM and PB was also tested to evaluate (by ELISPOT and real time polymerase chain reaction) cytokines able to induce B lymphocytes differentiation, and/or proliferation, such as interleukin (IL)-4, IL-6 (ligand for CD126), IL-3, IL-10 or IL-21 together with chemokines MCP-1, SDF-1, IP-10 and IL-8. In 14 out of 20 CML patients a significant increase in the percentage of BM lymphoplasmocytoid cells was observed on imatinib treatment with >10% (range 8–12%) of CD20+CD126+cells. Among this population, two third of cells coexpressed IgM and one third was IgD+, moreover a lower fraction of IgM+CD126+CD20− (3–4%) or IgD+CD126+CD20− (2–3%) cells was found too. In all these patients SDF1 increased in the BM plasma after imatinib (from 10–80pg/ml to 150–450pg/ml) and its receptor CXCR4 was up-regulated on CD20+CD126+cells. In 4 patients the amount of IP-10 in BM plasma and the expression of its receptor CXCR3 were also increased. No significant modification in transcription and secretion of IL-3, IL-4, IL-6, IL-10, IL-21, IL-8 or MCP1 were observed. The lasting 6 patients had<5% of CD20 +CD126+ lymphocytes (range2–4%), 2/3 coexpressing IgM and 1/3 coexpressing IgD. Every patients with increased number of CD126+ B lymphocytes achieved hemathologic remission, 7 of them complete cytogenetic and biomolecular remission. On the other hand, among the patients with low or undetectable CD20+CD126+cells, 2 obtained only hemathological remission. In the 2 relapsed patients, BM CD20+CD126+ lymphocytes decreased from 11% and 8% to 7 and 5%, respectively, with undetectable IgM+ CD126+CD20− or IgD+ CD126+CD20− cells. The increased production of SDF-1, following imatinib administration, might increase BM lymphoplasmocitoid cells, thanks to the double proliferative/chemotactic effect of the cytokine on B cells, with redistribution and in situ differentiation of CD20+ CD126+ lymphocytes. These findings shed some light on the possibility that, even in CML, immunological events may play a role in disease control;moreover they could be useful in monitoring disease outcome.
Myelofibrosis with myeloid metaplasia (MMM) is a clonal disorder involving disregulation of angiogenesis and immunomodulatory mechanisms. Thalidomide (Thal) retains antiangiogenic, immunomodulatory ...and cytokine regulatory properties and recently it has been used successfully in multiple myeloma. Here, we report our experience in 10 MMM patients treated with Thal. Patients with agnogenic MMM treated in an early phase of the disease obtained significant benefits from the therapy and remain transfusion‐free. In contrast, all secondary MMM failed to respond. These preliminary findings confirm that Thal plays a role in MMM therapy, although the efficacy in the different phases of the disease must be further evaluated.
Objectives: Infections are the major cause of morbidity and mortality in patients with acute myeloid leukaemia (AML). They primarily occur during the first course of induction chemotherapy and may ...increase the risk of leukaemia relapse, due to a significant delay in consolidation therapy. The intensification of induction chemotherapy and the use of non‐conventional drugs such as fludarabine are considered responsible for the increased risk of infections.
Methods: In this study, we retrospectively analysed the infections occurred in 224 newly diagnosed AML patients ≤65 yr, consecutively treated between 1997 and 2002 with an induction regimen including fludarabine, arabinosyl cytosine and idarubicin, with or without etoposide (FLAI/FLAIE), in the context of three multicentric prospective trials (AML97, AML99, AML02).
Results: During the induction phase, 146 (65%) patients experienced fever of undetermined origin (FUO), 30 (13%) and 47 (21%) patients had Gram‐negative and positive bacteremias, respectively, and 10 (4%) patients developed a probable/proven invasive fungal infection (IFI). The fatality rate for Gram‐negative, Gram‐positive bacteremias and probable/proven IFI was 10%, 8% and 60% respectively. During consolidation, 75 (35%) patients had FUO, 43 (20%) and 40 (19%) patients had Gram‐negative and positive bacteremias, respectively, and 5 (2%) patients developed a probable/proven IFI. The fatality rate for Gram‐negative, Gram‐positive bacteremias and probable/proven IFI was 14%, 5% and 80% respectively. Interestingly, the overall incidence of microbiologically documented infections during induction was 38% and the incidence of probable/proven IFIs during the induction/consolidation programme was 7%. No infections caused by viruses or opportunistic pathogens were observed neither during induction, nor during consolidation.
Conclusions: These data, although retrospectively collected, suggest that fludarabine‐based chemotherapy is not associated with an increased incidence of infections, in particular IFIs, compared to conventional regimens commonly used for AML induction.
Abstract 701
Hairy cell leukemia (HCL) is generally responsive to intravenous Cladribine (iv2CdA). Subcutaneous Cladribine (sc2CdA) is an alternative route with 100% bioavailability. In indolent ...non-Hodgkin lymphomas other than HCL, at the dose of 0.7 mg/kg/cycle, efficacy of sc2CdA is similar to iv2CdA and reduction to 0.5 mg/kg/cycle determines equivalent efficacy and lower toxicity.
In a national multicentre clinical trial (protocol EudraCT code: ICGHCL 2004), we prospectively evaluated toxicity and efficacy of sc2CdA given 0.1mg/kg/die for 5 (total dose 0.5 mg/kg, arm A) or for 7 consecutive days (total dose 0.7 mg/kg, arm B) as a single course in classic HCL requiring first treatment.
Clinical data and diagnostic samples were collected from all patients for central revision of classical HCL diagnosis (WHO criteria) and for molecular analyses at the University of Siena, prior to study entry. Early grade 3–4 toxicity was assessed on days 7 to 30 after treatment, according to the 2003 NCI/CTCAE v3 criteria and occurrence of second tumors was assessed at every subsequent follow-up. Enpoints of sc2CdA efficacy were response to treatment, treatment free interval (TFI), relapse free survival (RFS), time to second tumor (TTST) and overall survival (OS). Responses to treatment were assessed on days 60 and 180 after treatment and defined according to the 1987 Consensus criteria. Complete Remissions (CR) and Partial Remissions (PR) were rated as beneficial responses (CR/PR), while minor Responses (mR) and No Responses (NR) were rated as treatment failures (mR/NR). TFI was measured as the time elapsed from sc2CdA initiation to second treatment because of new progression or failure to sc2CdA. RFS was measured in patients with a CR/PR from treatment inititation to relapse. OS was measured from sc2CdA initiation to death for any cause.
of 156 patients screened centrally, 148 scored as classical HCL and entered the study. Gender (male total 116/148, 78,4%; arm A: 62/77, 80,5% vs arm B: 54/71, 76,1%), age (total: median age 52 years, range 30–83; arm A: median 56, range 30–83; arm B: median 51, range 33–82), clinical and laboratory parameters prior to treatment (including spleen, hemoglobin, platelet, leucocyte and hairy cell counts) were equally balanced in the two arms. Dose reduction was required in no patients from arm A and in 2 patients from arm B due to concurrent infection. Overall hematological toxicity was no different among the two treatment arms. Requirement of platelet transfusions (total 7/148, 4,7%; arm A: 2/77, 2,6% vs arm B: 5/71, 7%), red blood cell transfusion (total 32/148; 21,6%, arm A: 15/77, 19,5% vs arm B: 17/71, 23,9%), or G-CSF (total 102/148; 68,9%, arm A: 55/77, 71,4% vs arm B: 47/71, 66,2%) was no different among the two arms. However, a significantly higher non hematological toxicity (total 28/148; 18,9%, arm A: 9/77, 11,7% vs arm B: 19/71, 26,8%) was observed in arm B (p=.019). Non haematological toxicity was mainly represented by infections or FUO (total 25/148; 16,9%) that were significantly more frequent in arm B (arm A: 8/77, 10,4% vs arm B: 17/71, 23,9%, p=.028). Higher prevalence of toxicity resulted in a higher hospitalization rate in arm B than in arm A (total 29/148; 19,6%, arm A: 9/77, 11,7% vs arm B: 20/71, 28,2%, p=.012) and one early death was experienced because of lung aspergillosis in arm B. Onehundred-forty patients (94,6%) had a beneficial response (101 CR, 68,2%; 39 PR, 26,4%) and 8 (5,4%) failed treatment (5 mR, 3,4%; 3 NR, 2%). Responses were equivalent in the two arms, with 72/77 (93,5%) beneficial responses (49/77 CR, 63,6%; 23/77 PR, 29,9%; 4/77 mR, 5,2% and 1/77 NR, 1,3%) in arm A versus 68/71 (95,8%) beneficial responses in arm B (52/71 CR, 73,2%; 16/71 PR, 22,5%; 1/71 mR, 1,4%; 2/71 NR, 2,8%). After a median follow-up of 36 months (range 12–66), 5 year TFI, RFS, TTST and OS were 67%, 71% 87% and 94%, respectively. Causes of late death were 2 cardiac events and 3 second tumors. No differences of TFI, RFS, TTST and OS were observed in the 2 arms of treatment.
The present data indicate that overall activity of sc2CdA is similar to iv2CdA (Cheson, 1998). Furthermore, this study indicates that sc2CdA given at 25% reduced doses (0.5 mg/kg) has equivalent activity and significantly lower toxicity than sc2CdA at standard doses (0.7 mg/kg). The reduced infection rates and hospitalization rates of sc2CdA have important pharmaco-economic implications.
No relevant conflicts of interest to declare.
Abstract 1973
Hematological and extra-hematological adverse events associated to Hydroxyurea (HU) treatment in patients with chronic myeloproliferative neoplasms (MPN) are object of particular ...interest in the Ph-negative MPN since they can significantly limit the HU use.
To evaluate the extra-hematological adverse events associated to HU treayment in a large cohort of Essential Thrombocythemia (ET) patients.
One thousand and seventy-five out of the 2005 ET patients registered in the RIT were treated with HU and are the object of this report. The patients, 641 females (59.6%) and 434 males (40.4%), diagnosed according to the PVSG or WHO criteria in 54 hematological centers of the RIT, started treatment with HU as first (92%) or second (8%) line, at median age of 65 years.The mean duration of HU treatment was 3.3 years. The HU treatment was withdrawn in 221 (20.5%) patients after a mean of 3.0 years.The administered dose of HU was 0.25–3.0 g/day (median 1), and a mean cumulative dose was 1113 g. The extra-hematological adverse events (EHAEs) observed during the HU treatment were distinguished in HU related AEs (HU-EHAEs), ET related AEs (ET-EHAEs) and HU or ET unrelated AEs (U-EHAEs).Results. During the HU treatment (3587 pt-y) 378 EHAEs were reported in 207 (19.3%) patients, being the HU-EHAEs 244 (6.8/100 pt-y) in 170 (15.8%) patients. In detail, the HU-EHAEs were: dermatological in 108 (48.3%) cases (38 hyperpigmentation, 26 leg ulcers, 22 maculo-papular rash, 10 lichenoid eruptions, 5 skin cancer, 4 alopecia); gastro-intestinal in 80 (32.8%) cases (37 nausea/vomiting, 30 diarrhea, 13 gastro-intestinal intolerance); systemic in 35 (14.3%) cases (28 fever, 7 fatigue); neurological in 19 (7.8%) cases (headache); miscellanea in 2 (0.8%) cases.
This preliminary analysis in 1075 ET patients of the Registro Italiano Trombocitemia (RIT) treated with HU shows that the extra-hematological adverse events referred to the HU (HU-EHAEs) occurred with not negligible rate (6.8/100 pt-y) and need to be object of attention in the management of ET patients.
No relevant conflicts of interest to declare.
Abstract 4404
Cancer cells almost invariably exhibit aberrant histone deacetylase (HDAC) activity leading to changes in chromatine structure, altered gene expression, poor differentiation, impaired ...apoptosis and increased proliferation. Accordingly, virtually all the HDAC inhibitors currently available show some degree of antitumor activity in preclinical cancer models and several of these compounds are currently under investigation or already approved for the treatment of human malignancies. Such is the case of the hydroxamic acid derivative suberoylanilide hydroxamic acid (Vorinostat, Zolinza), approved for the treatment of cutaneous T cell lymphomas. Sirtuins are a large family of deacetylases characterized by a unique, NAD+-dependent enzymatic mechanism. In addition to their established role in metabolism and longevity, recent evidence points to an emerging role for sirtuins in carcinogenesis. In the attempt to identify drug combinations that would increase the activity of traditional HDAC inhibitors we have explored the combination of valproic acid (VA) and butyrate (BU) with the sirtuin inhibitors cambinol and sirtinol in primary B-cell chronic lymphocytic leukemia (B-CLL) cells (n=35), acute myelogenous leukemia (AML) cells (n=10) and leukemia cell lines. Cell viability was assessed by propidium iodide staining and flow cytometry. Combination indices were determined using the median-effect method. In leukemia cells, exposure to sirtuin inhibitors synergistically increased VA and BU mediated cytotoxicity. Conversely, these drugs were poorly active and failed to show any cooperation in healthy cells, including peripheral blood mononuclear cells and fibroblasts, suggesting a cancer-specific mode of action. Similar results were obtained by combining VA or BU with the Nampt inhibitor APO866, which reduces intracellular NAD+ levels and thereby prevents sirtuin activity. Remarkably, SIRT1 and SIRT6 inhibition per se did not seem to account for cell demise upon HDAC inhibition since expression of a dominant negative SIRT1 isoform or RNA interference-mediated SIRT6 silencing failed to increase VA and BU activity. Our data indicate a specific requirement by leukemia cells for sustained sirtuin activity when classical HDACs are inhibited. This feature is suitable to be therapeutically exploited by combining sirtuin inhibitors or APO866 with classical HDAC inhibitors especially for the treatment of hematological malignancies.
No relevant conflicts of interest to declare.
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