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Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is

Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is

Item does not contain fulltext Myelodysplastic syndromes are characterized by ineffective hematopoiesis resulting in peripheral cytopenias. The majority of patients is dependent on regular transfusions of packed red blood cells leading to a secondary iron overload which might result in organ damage. Therefore, sufficient iron chelation therapy in selected patients is mandatory. Deferasirox (DFX) is an orally administered iron chelator which has been highly efficient in the treatment of secondary iron overload. Most frequent side effects of DFX are gastrointestinal disturbances, which leads in some patients to low adherence to the therapy. An expert panel met in Lisbon in July 2010 to develop recommendations on prevention and management of GI disturbances based on existing data and personal experiences.

Suicide stories in newspapers have been identified as an important risk factor for individual suicide because they provide real-life models for vulnerable individuals. The link between suicide ‘stories’ and suicide rates, however, is not clearly understood. One problem is the lack of detailed analysis of how suicide stories are constructed. Yet this is important because it would enable researchers to comprehend more fully how newspaper reports shape and structure ‘reality’. It is argued that the suicide story is a way of mapping out reality and that by de-constructing we can learn how this shapes and constrains our understanding of suicide and the actions adopted in response to it. The aim of this study, therefore, is to explore the social construction of suicide stories in Scottish newspapers. Two broad sheet and two tabloid newspapers were scanned for suicide stories for the year 1999. One hundred and ninety-one articles reporting suicide were identified and analysed using grounded theory. This generated a set of conceptual categories, which formed the basis of a framework. The study found that visualising, locating, social impacting and causal searching were key concepts in the construction of a suicide story, and that these were connected through the core explanatory category of ‘morality’. The study also showed how suicide was rendered explicable through the concepts of deviancy, dysfunction and moral weakness.

Summary Previous studies have found exercise ECG abnormalities in dysvascular amputees who showed normal resting ECGs. The purpose of this pilot study was to investigate whether similar abnormalities would occur in such patients during initial walking using a pneumatic post-amputation mobility (PPAM) aid. Ten patients, seven with below-knee, two with through-knee and one with trans-femoral amputation participated in a standardised exercise session. Data were obtained from continuous ECG and pulse oximeter readings, together with resting and post-exercise blood pressure (BP). Seven of the ten patients had abnormal ECGs prior to the study, and additional irregularities were found during walking in three patients who showed significant (> 1 mm) ST segment depression, although this may have been drug-related rather than due to myocardial ischaemia. Several months after the study, these three patients died from myocardial infarction. Findings of normal BP elevation in nine patients and group mean age-predicted maximum heart rate (HRmax) of less than 70% suggest that exercise levels were generally appropriate. However, five patients reached age-predicted HRmax of over 70%. In view of the multiple pathological profiles of this type of patient, and their diverse medications, it is recommended that therapists should pay closer attention to patients' exercise heart rates and cardiac status during rehabilitation.

AimsAbnormal serum free light chain (FLC) ratios are diagnostically important in almost all plasma cell disorders. However, absolute increases in polyclonal FLC levels are often discarded as inconsequential. Here we report an association between increased combined polyclonal FLC (cFLC: FLCκ plus FLCλ) concentrations and mortality.Methods723 patients sent for 30 routine haematological assessments were enrolled. Patients with a confirmed monoclonal gammopathy were removed. The remaining 527 patients were followed up for up to 4.5 years. Statistical analysis was performed using SPSS (V.19).ResultsDuring follow-up, there were 99 deaths (18.8%). Kaplan-Meier survival analysis revealed 29% of these deaths occurred within the first 100 days (N=29). Multivariate analysis identified only cFLC >65 mg/l, albumin 2 to be independently associated with mortality within 100 days and 4.5 years with, cFLC having the highest HR of 7.1. A simple risk stratification model based only on albumin and cFLC identified 86% mortality within 100 days and 62% over 4.5 years.ConclusionsElevated cFLC is significantly associated with increased mortality and with albumin can be used to identify patients at risk of mortality at 4.5 years with high-risk patients detected within 100 days.

Chemotherapy in most patients with AML over 80 years of age is not recommended because their median survival is about 1 month. The aim of our study was to identify patients in this age group who might achieve complete remission with standard dose chemotherapy. We report 9 consecutive patients with de novo AML diagnosed and treated in 1992-2008. All bone marrow samples were hypercellular, classified as FAB types M2 in 2 cases, M4 in 6, and M5 in one case. Three patients opted for supportive or palliative therapy and survived 1-4 months. Six patients received standard dose chemotherapy. Two patients with a normal karyotype had resistant AML and survived 1.0 and 2.7 months; one patient with a complex karyotype died of septic shock on the 10th day of therapy. All these three patients exhibited erythroblastic and/or megakaryocytic dysplasia (EMD) at presentation (two in more than 26% erythroblasts, all three in a half or more of megakaryocytes). Three remaining patients with AML M4, a normal karyotype but without EMD, achieved complete remission in spite of co-morbidities and a poor performance status. Two of them survived 18.6 and 28 months on maintenance therapy, the third 16.5 months without it. Very elderly AML patients without EMD appear to represent a favorable prognostic biological category (single-lineage AML) that show a good response to standard dose chemotherapy.

Summary Histone deacetylase inhibitors (HDIs) are emerging as valuable new agents in the treatment of acute myeloid leukaemia (AML). However, since response rates to these agents alone are low, we sought to identify markers associated with responsiveness. In a trial of 20 patients treated with the HDI sodium valproate (VPA) in combination with all trans retinoic acid and theophylline, three patients responded clinically with one complete remission (CR) and two partial remissions. The in vivo response of the CR patient was mirrored by high in vitro sensitivity of their blasts to VPA, indicating that similar factors determine both in vivo and in vitro sensitivity. Microarray analysis of the primary AMLs and a panel of haemato-lymphoid cell lines, with a similar range of VPA sensitivities as the primary leukaemic blasts, identified elevated FOSB-expression as a potential marker of VPA sensitivity. Quantitative polymerase chain reaction confirmed overexpression of FOSB in the CR patient blasts compared to patients failing to achieve CR, and in a subset of a larger panel of AML samples. Overexpression of FOSB in K562 myeloid cells significantly increased in vitro sensitivity to VPA. Thus, we propose that FOSB is a novel, potential marker of VPA sensitivity in AML.

Peripheral blood platelets were examined in 7 patients who underwent bone marrow ablation with high dose chemotherapy and total body irradiation prior to bone marrow transplantation (BMT). Platelets were studied for 9 days, by which time the platelet counts had fallen to levels at which platelet transfusion support was necessary. Values for (111)Indium autologous mean platelet lifespan were similar to those reported in thrombocytopenic patients by other authors. During the period of study, there was no significant change in mean platelet volume or platelet nucleotides. The results indicate that in man, platelet size and platelet nucleotides are not affected when platelets age in the peripheral circulation.

Introduction: Azacitidine (AZA) is approved for the treatment of myelodysplastic syndromes (MDS), including chronic myelomonocytic leukemia (CMML). AZA has improved the overall survival (OS) of patients (pts) with higher-risk MDS, however, to a median OS of 24.5 months (Fenaux P, et al. Lancet Oncol. 2009;10:223-232). Preclinical results showed that panobinostat (PAN), a pan-deacetylase inhibitor, acts synergistically with AZA. This is a phase 1b/2b study in adult pts with higher-risk MDS (International Prognostic Scoring System), CMML, or acute myeloid leukemia (AML) not eligible for stem cell transplant. In the phase 1b portion, the maximum tolerated dose was not reached, and the 30-mg PAN dose was chosen as the recommended phase 2 dose (Ottmann OG, et al. ASH 2011; [abstract 459]). Here we present the results from the randomized, 2-arm phase 2b portion, which was designed to assess efficacy of the combination of PAN + AZA compared with AZA alone. Methods: In phase 2b, pts were randomly assigned to receive PAN 30 mg on days 3, 5, 8, 10, 12, and 15 in combination with AZA 75 mg/m2 on days 1-7 in 4-week cycles, or AZA alone. Pts continued treatment until progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was the composite complete response: complete response (CR) + morphologic CR with incomplete blood count + bone marrow CR (BM-CR). Results: In the phase 2b portion, 82 pts with MDS (n = 47), AML with < 30% bone marrow blasts (n = 22), or CMML (n = 13) were randomized to treatment with PAN + AZA (n = 40) or AZA (n = 42); 80 pts received ≥ 1 dose of treatment. Median pt age was 68 years (range, 44-81 years) in the PAN + AZA arm vs 72 years (range, 42-85 years) in the AZA arm. Among pts with MDS, 80.0% and 72.7% had refractory anemia with excess blasts in the PAN + AZA and AZA arms, respectively. Cytogenetics among pts with AML were also similar between treatment arms, with 33.3% of pts in the PAN + AZA arm and 30.8% of pts in the AZA arm presenting with unfavorable cytogenetics. Most pts in the total study population had not received prior treatment (87.5% in the PAN + AZA arm, 92.9% in the AZA arm). Median duration of PAN treatment was 20.5 weeks; median duration of AZA treatment was 23.4 weeks in the PAN + AZA arm and 16.9 weeks in the AZA arm. A higher proportion of pts achieved composite CR in the PAN + AZA arm than the AZA arm (27.5% vs 14.3%), including a higher proportion of pts in the PAN + AZA arm who achieved CR (15.0% vs 9.5%). However, the overall response rate (ORR; CR + BM-CR + partial response + hematologic improvement) was similar in the 2 treatment arms (37.5% vs 38.1%). The probability of survival at 1 year was also similar between the 2 arms: 60% (95% CI, 50%-80%) in the PAN + AZA arm vs 70% (95% CI, 50%-80%) in the AZA arm. Most pts had ≥ 1 adverse event (AE; PAN + AZA, 100% any grade and 97.4% grade 3/4; AZA, 95.2% any grade and 81.0% grade 3/4). The most common AEs (grade 3/4) with a higher incidence in the PAN + AZA arm, regardless of study drug relationship, were thrombocytopenia (55.3% vs 19.0%), neutropenia (42.1% vs 26.2%), anemia (21.1% vs 11.9%), and pneumonia (15.8% vs 11.9%). QT prolongation-related events were reported in 13.2% of pts in the PAN + AZA arm vs 7.1% in the AZA arm. Treatment discontinuation due to AEs was reported in 36.8% of pts in the PAN + AZA arm and 23.8% of pts in the AZA arm. There were 5 on-treatment deaths (13.2%) in the PAN + AZA arm (progressive disease, sepsis, septic shock, cardiac failure, and bronchopulmonary hemorrhage) and 2 (4.8%) in the AZA arm (septicemia and cardiopulmonary arrest). One death in the PAN + AZA arm was suspected to be treatment related (bronchopulmonary hemorrhage). Conclusions: PAN + AZA doubled the rate of composite CR compared with AZA in pts with higher-risk MDS, CMML, or AML not eligible for stem cell transplant. However, the ORR and 1-year survival rates were similar for the 2 arms, with higher rates of AEs and on-treatment deaths in the PAN + AZA arm. Notably, the dose and schedule of PAN used in this study differ considerably from the dose and schedule approved for use in multiple myeloma. Therefore, in MDS, CMML, and AML, further optimization of the PAN dose and schedule in combination with AZA is needed to improve the efficacy and tolerability of this combination. Disclosures Sekeres: Amgen: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Graux:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavenagh:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Fenaux:Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. DeAngelo:Incyte: Other: Consulting or Advisory Role; Pfizer: Other: Consulting or Advisory Role; Novartis: Other: Consulting or Advisory Role; BMS: Other: Consulting or Advisory Role; ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role; Amgen: Other: Consulting or Advisory Role. Yee:Oncoethix: Research Funding; Astex: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zhu:Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Valcarcel:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Borbenyi:Novartis: Membership on an entity's Board of Directors or advisory committees. Wegener:Novartis: Employment. Gazi:Novartis Pharma AG: Employment. Acharyya:Novartis Pharmaceuticals Corporation: Employment. Binlich:Novartis: Employment. Ottmann:Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

The introduction of recombinant human erythro-poietin (epoetin) transformed the management ofanaemia for the vast majority of dialysis patients.The immediate benefit of transfusion-independencewas a lower risk of contracting blood-borne infectionsand iron overload. The raised haematocrit ledto improvements in quality of life, which in turn hasbeen associated with improved long term survival [1,2].For the first decade or so, various brands orformulations of epoetin were available, includingepoetin alfa (Epogen, Procrit in the US; Eprex,Erypro in Europe). A second-generation erythropoieticagent (darbepoetin alfa) was developed by incorporat-ing an additional two glycosylation chains to theerythropoietin molecule, resulting in a product with alonger half-life and a consequent reduced dosingfrequency [3].Since 1998, there has been a rapid increase in theincidence of epoetin therapy-associated pure red cellaplasia (PRCA), largely associated with the Eprexbrand of epoetin, but described with the Epogen andNeoRecormon brands of epoetin. In 2002, Casadevallet al. [4] described a new complication of epoetintherapy, that of PRCA associated with anti-erythropoietin antibodies.To date, however, no cases of anti-erythropoietinmediated PRCA has been described with darbepoetinalfa, and indeed it has been suggested that theadditional glycosylation may cause this molecule tobe more resistant to antibody generation than epoetin.We describe what we believe to be the first case ofantibody-mediated PRCA associated with the admin-istration of darbepoetin alfa alone.

Paraneoplastic pemphigus is a relatively recently described immunobullous disease with characteristic features. We report three cases of paraneoplastic pemphigus in adult men with chronic lymphocytic leukaemia arising within a week of completion of treatment with fludarabine. In all cases, withdrawal of fludarabine and treatment of the blistering was associated with marked cutaneous improvement. Fludarabine, a synthetic nucleoside analogue, which has only been available in Britain since 1994, is known to be associated with autoimmune phenomena and may have been involved in the development of paraneoplastic pemphigus in these cases.

We others who have long lost the more subtle of the physical senses, have not even proper terms to express an animal's inter-communications with his surroundings, living or otherwise, and have only the word ‘smell’, for instance to include the whole range of delicate thrills which murmur in the nose of the animal night and day, summoning, warning, inciting, repelling.

Abstract 4001 Introduction Serum free light chain (FLC) measurements are used routinely to identify monoclonal immunoglobulin (M-Ig) production in patients. In addition, summated kappa + lambda concentrations have recently been shown to have prognostic value in chronic lymphocytic leukaemia (CLL), Hodgkins lymphoma and HIV patients; presumably reflecting immune stimulation. A recently developed companion assay to FLC testing measures intact immunoglobulin heavy chain/light chain (HLC) pairs in serum calculating Ig'κ/Ig'λ ratios as a reflection of clonality. Here we report on a computational approach combining FLC and HLC measurements to identify clonal disease, hyper- and hypo-gammaglobulinemia, and as markers of immune dysfunction. Furthermore, we comment on the potential of such an algorithm to risk stratify haematological and non-haematological malignancies. Patients, Materials and Methods 1468 patients referred to the Royal Wolverhampton Hospital for haematological evaluation were enrolled on to the study. Median patient age was 64 years, with a slight female preponderance (60%). Patient sera were analysed at presentation using routine electrophoresis tests (serum protein electrophoresis, SPEP and immunofixation, IFE). FLC and HLC (IgG, IgA and IgM) were measured by nephelometric immunoassay. Each immunoassay result was assessed with respect to individual normal ranges (FLCκ = 3.3–19.4mg/L, FLCλ = 5.71–26.30mg/L, IgGκ = 4.03–9.78g/L, IgGλ = 1.97–5.71g/L, IgAκ = 0.48–2.82g/L, IgAλ = 0.36–1.98, IgMκ = 0.29–1.82g/L, IgMλ = 0.17–0.94g/L) and ratios (FLCκ/FLCλ = 0.26–1.65, Gκ/Gλ = 0.98–2.75, Aκ/Aλ = 0.8–2.04, Mκ/Mλ = 0.96–2.3). The results were used to create an algorithm which assessed the degree of abnormality individually and with respect to the other results generated. Diagnosis was recorded ∼3 months after the analysis and patients were followed for up to 3 years. Results 293/1468 (19%) samples had an abnormal SPEP of which 95/293 were confirmed by IFE including: 10 intact immunoglobulin Multiple Myeloma (MM, 6 IgGκ, 1 IgGλ, 2 IgAκ, 1 IgAλ), 6 light chain MM (LCMM, 4 FLCκ, 2 FLCλ), 2 Waldenstrom macroglobulinemia (2 IgMκ), 1 IgMκ cryoglobulinemia, 3 CLL, 1 mantle cell lymphoma, 3 other lymphoma, 1 IgGκ plasmacytoma, and 68 MGUS patients, 26/68 were confirmed MGUS (1 FLCκ, 13 IgGκ, 4 IgGλ, 4 IgAκ, 2 IgMκ, 2 IgMλ), 42 were laboratory findings requiring follow up (1FLCκ, 3 FLCλ, 19 IgGκ, 5 IgGλ, 4 IgAκ, 1 IgAλ, 8 IgMκ, 1 IgMλ). FLC/HLC algorithm identified 85/95 IFE positive patients; of the 10 patients reported not identified by the algorithm, 3 had oligoclonal banding indicative of infection and 7 had monoclonal bands secondary to other diagnoses (including 2 colon cancer patients and 2 rheumatoid arthritis patients). In addition the algorithm identified 15 IFE negative patients with M-Ig production including: 2 AL amyloid patients, 1 asymptomatic LCMM, 1 patient with ∼1g/L FLCκ (lost to follow up), 1 follicular lymphoma patient and 1 CLL; diagnosis was not available for 9/15 patients. Furthermore, the algorithm identified 205/1468 patients as having elevated polyclonal FLC (cFLC) >50mg/L without evidence of clonal production. In a subset analysis comparing matched numbers of patients with elevated or normal cFLC concentrations, cFLC >50mg/L predicted all cause mortality (logistic regression odds ratio 9.96, 95% CI 4.72–21.0, p Discussion MM presents with disparate and vague symptoms pervasive in an elderly population. Current guidelines recommend SPEP and FLC analysis reflexing to IFE for confirmation in the event of abnormality. However, SPEP and IFE require interpretation making the assessment variable. Standardised immunoassays (FLC+HLC) may obviate the need for interpretation and in this study identified additional haematological malignancies. Furthermore, standard assessments can be used to identify M-Ig, but in the absence of this finding may offer little information pertaining to the symptoms that prompted referral. By contrast this algorithm identified patients with elevated cFLC which in agreement with other reports was associated with increased risk of mortality. Further work is required to assess the algorithm, and determine if cFLC measurements should be used as a prompt for additional diagnostic investigations. Disclosures: Faint: The Binding Site Group, Ltd.: Employment. Harding:The Binding Site Group Ltd.: Membership on an entity's Board of Directors or advisory committees. Mirbahai:The Binding Site Group, Ltd: Employment.

Abstract 5018 Introduction Historically, serum protein electrophoresis (SPE), urine protein electrophoresis (UPE) and immunofixation (IFE) have been used to identify and quantify monoclonal proteins (M-proteins). Whilst this approach is adequate for the identification of intact immunoglobulin multiple myeloma (MM), it is not sensitive enough to detect free light chain MM (LCMM). Therefore, an algorithm which utilises SPE, serum free light chain (FLC) immunoassays and IFE for the identification of M-proteins has been suggested. Assays have now been developed which utilise polyclonal antisera raised against the kappa and lambda light chain types of IgG, IgA and IgM immunoglobulins (HLC). Here we report the use of these assays as an alternative to IFE and propose a screening algorithm which utilises SPE, FLC and HLC Materials and Methods Serum FLC measurement was added to 1063 requests for SPE, from primary care or from a hospital source. Samples from patients with previously diagnosed MM, Waldenstrom's Macroglobulinemia and lymphoma were, where possible, removed. Sera showing monoclonal proteins or hypogammaglobulinemia (by SPE) or an abnormal FLC ratio were tested further by IFE and IgG, IgA, IgM HLC assays. SPE and IFE were performed on a SEBIA Hydrasys system, and gels were interpreted by experienced clinical chemists. FLC and HLC measurements were performed on a Siemens BN™II nephelometer. HLC results were compared with IFE results and clinical diagnoses. The study was approved by the Wolverhampton, New Cross, NHS Trust Review Board Results 80/1063 patients were identified as having abnormal SPE or abnormal FLC results. 42/80 patients had positive IFE results. 24/42 of these patients were positive by HLC (Table 1), 11/42 had light chain only myeloma/MGUS, the remaining 7/42 were MGUS patients. The 7 MGUS patients (6 IgG and 1 IgM) with normal HLC ratios and positive IFE all had less than 2g/L monoclonal protein measured by SPE densitometry and a normal FLC ratio. Of the 38/80 with normal IFE's all had been investigated further because of abnormal FLC results. 9/38 had abnormal HLC ratios of which 3/9 had confirmed hematological malignancies (1× chronic lymphocytic leukemia (CLL), 1× small lymphocytic lymphoma (SLL) and 1× asymptomatic MM (ASMM)). The use of FLC immunoassays alongside SPE as part of the primary screening protocol identified 10 additional hematological malignancies (1× ASMM, 6×CLL, 2× non-Hodgkin lymphoma, 1× SLL). Discussion HLC ratio analysis matched IFE for the identification of all symptomatic haematological malignancies. Abnormal FLC ratios identified 10 additional haematological malignancies of which 3 also had abnormal HLC ratios, which would have been missed using SPE/ IFE. In 7/19 MGUS (6×IgG, 1×IgM) patients there were normal HLC ratios. In all cases the monoclonal protein load was below 2g/L and the FLC ratio was normal; identifying the IgG patients as having a low risk and the IgM patient as having a low/intermediate risk of progression. It may be beneficial not to identify these patients, who do not require therapeutic intervention or justify close monitoring. Another advantage of using HLC analysis instead of IFE is that the HLC ratio has been found to be a prognostic indicator in myeloma and MGUS. It would also form a useful “baseline” comparison if HLC assays were used in monitoring or for the detection of residual disease. Conclusions HLC analysis identified all symptomatic patients who were IFE positive and in an additional 3 hematological malignancies. Low risk MGUS patients may not be identified using these tests but this might be beneficial to patients and physicians alike Disclosures: Harding: Binding Site Group Ltd: Employment.

Survival of elderly patients with de novo acute myeloid leukemia (AML) is poor. A single published study on patients with AML aged 80 years and above (DeLima et al., Br. J. Haematol.1996; 93: 89) concluded that chemotherapy was not indicated since median overall survival (OS) of 29 treated patients was 1 month, 9 patients reached complete remission (CR) of 3 months median duration, and only two survived over 1 year: for 15.5 and >18 months. The aim of our study was to identify the characteristics of elderly AML patients who may reach CR by standard chemotherapy. We analyzed 9 consecutive patients with de novo AML aged 80–90 (median 83) years treated by us in 1992–2007. All bone marrow films were hypercelullar with 48–92 (median 80) % leukemic cells, classified as FAB types: 2 M2, 6 M4, and 1 M5. Six patients, all with hypertension and five with ischaemic heart disease (IHD), received chemotherapy, while 3 patients (82–87 years old) opted for supportive or palliative therapy and survived 1–4 months. Cytosine arabinoside (Ara-C) 100 mg/sqm/12 h in 3-h infusion for 7 days and 3 doses of daunorubicin (DNR) 45 mg/sqm/d i.v. (D+A, 1 case) or mitozantrone (MTZ) 10 mg/sqm/d i.v. (M+A, 3 cases) was given to 4 patients. The remaining two patients received D+A with thioguanine (TG) 100 mg/sqm/12 h p.o. for 7 days (TAD). Their WHO performance status (PS) was 4x PS3, 1x PS2, 1x PS1, and median WBC 58 (17.9–97.8) × 10^9/L. Three patients with AML M4 and normal karyotype reached CR. Maintenance therapy consisted of 4-day courses administered in intervals of 5–12 (median 8) weeks according to the patient’s clinical status and tolerance until relapse. Courses containing Ara-C 60 mg/sqm/12h s.c. with TG 70 mg/sqm/12h p.o. were repeated 3x. The fourth course was 1+4 containing a single dose DNR or MTZ as described and Ara-C. The outcomes: An 85 year-old female with IHD and LVEF 25 % reached CR with TAD. She was on maintenance in CR for 17 months when severe heart arrhythmia developed. She refused a pacemaker implantation and died 3 days later. Her OS was 18.6 months. An 80 year-old male reached CR with M+A and was on maintenance therapy when relapsed after 19.7 months. He refused further chemotherapy and his OS was 28 months. An 80 year-old female (PS1, Flt3-ITD neg.) reached CR after D+A 3+7 and got one cycle D+A 2+5 without further maintenance. Her CR lasted 10.1 months. She was further treated with 2 cycles of low-dose Ara-C and her OS was 16.5 months. Three other patients, two with normal karyotype, did not reach CR after chemotherapy. A 90 year-old male with AML M4 died of mycotic pneumonia on the 24th day of TAD induction. An 83 year-old male with AML M5, PS2, experienced nonQ myocardial infarction after M+A induction and did not reach CR. He was further treated with hydroxyurea with OS of 2.7 months. An 80 year-old female with AML M2, complex karyotype, renal insufficiency and sepsis died after 7th hemodialysis in septic shock on 10th day of M+A induction. All three patients who reached CR did not exhibit dysplasia in erythroblastic or megakaryocytic lineage showing that only granulocyte-macrophage lineage was involved in the leukemic clone (single–lineage AMLs). In contrast, all 3 patients who did not reach CR exhibited megakaryocytic dysplasia in a half or more of megakaryocytes and two had erythroblastic dysplasia in more than 26% erythroblasts. They represent a different biological category of AMLs with multi-lineage involvement. In summary, we defined a biological category of single-lineage AML patients over 80 years of age who may benefit from standard dose chemotherapy in spite of their poor performance status.

There is increasing evidence that perturbations in chromatin structure contribute to the pathogenesis of AML raising the possibility that modulators of chromatin structure may be of therapeutic benefit. Sodium valproate (VPA) is a potent histone deacetylase inhibitor (HDI) and in conjunction with ATRA induces apoptosis of primary AML blasts in vitro. It has been postulated that induction of pro-apoptotic genes including p21 and TRAIL play a critical role in determining the tumor selectivity of HDIs. We have therefore conducted a Phase I/II study of combined VPA/ATRA therapy in patients with high risk AML ineligible for chemotherapy and correlated clinical response with alterations in chromatin structure, induction of pro-apoptotic genes and in vitro sensitivity to VPA. In light of evidence that modulating cAMP levels may increase rexinoid responsiveness theophylline was added in patients who had failed to respond to 28 days combined VPA/ATRA therapy. A total of 20 patients (median age 72 yrs) have been treated to date including 12 patients with relapsed AML, 6 with previously untreated disease and 2 with primary refractory disease. Nine patients completed treatment for at least 8 weeks. Four patients (all with relapsed AML) demonstrated a haematological response. One patient achieved a complete remission and two a partial remission. Myeloblasts isolated from trial patients prior to the commencement of therapy demonstrated varying sensitivity to VPA and ATRA in vitro which correlated with clinical response. Combined treatment with VPA and ATRA resulted in increased levels of histone acetylation and methylation and induced expression of p15, p16 and p21 in myeloblasts from treated patients. Induction of TRAIL was documented in three patients-two of whom demonstrated a clinical response. p21 induction was documented in all responding patients. Induction of p21 and TRAIL was most marked in the patient who achieved a CR. There was no apparent correlation between induction of p15 or p16 and response. We have previously documented that exposure of AML cell lines to HDIs results in specific changes in HDAC expression patterns with selective up-regulation of HDAC11 and to a lesser extent HDAC9 and SIRT4. Similar changes in HDAC expression were documented in myeloblasts from patients after 28 days treatment with VPA/ATRA. This study demonstrates that VPA, in combination with ATRA and theophylline, has significant clinical and biological activity and identifies possible mechanisms underlying the tumor-specific activity of VPA in AML in vivo.