Farnesyl transferase inhibitor (lonafarnib) in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia: a phase II study

Although an activating mutation of Ras is commonly observed in myelodysplastic syndrome (MDS), the role of Ras in the natural history of MDS remains largely unknown. We prospectively studied efficiency and tolerance of lonafarnib, a compound able to inhibit Ras signalling pathway through an inhibition of farnesyl transferase, in patients with MDS or secondary acute myeloid leukaemia (sAML). Lonafarnib was administered orally at a dose of 200 mg twice daily for three courses of 4 weeks (separated by 1 to 4 weeks without treatment). Sixteen patients were included: FAB/RAEB (n = 10), RAEB-T (n = 2), sAML (n = 2) and chronic myelomonocytic leukaemia (CMML; n = 2); WHO/RAEB-1 (n = 4), RAEB-2 (n = 5), AML (n = 5), CMML (n = 2). Median age was 70 (53–77) years. The karyotype was complex or intermediate in 11 patients, and the International Prognostic Scoring Systems (IPSS) risk groups were low in two patients, INT-1 in one patient, INT-2 in four patients and high in six patients (unknown or not applicable in three patients). Among the 14 patients tested, five had Ras mutations in codons 12, 13 or 61 of N-Ras, K-Ras or H-Ras. One patient was excluded of the analysis for protocol violation, and 15 patients were assessable for tolerance. Gastrointestinal toxicities (diarrhoea, nausea and anorexia) and myelosuppression were the major side effects. Other toxicities included infections, fatigue, increase of liver enzymes, arrhythmia and skin rash. One patient died of infection, and the treatment was stopped in one other who developed atrial fibrillation. Doses were reduced in all but one patient treated with more than one course of farnesyl transferase inhibitor. Responses were assessable in 12 patients. A partial response in one sAML patient and a very transient decrease of blast cell count with normalisation of karyotype in one MDS patient were observed. No relation between improvement of marrow parameters and detected Ras mutations was observed. Lonafarnib alone, administered following our schedule, has shown limited activity in patients with MDS or secondary AML. Gastrointestinal and haematological toxicities appear the limiting toxicity in this population of patients. The experiments comply with laws of Belgium including ethics approval.     

Phase II study of the histone deacetylase inhibitor belinostat (PXD101) for the treatment of myelodysplastic syndrome (MDS)

The inhibition of histone deacetylase (HDAC) can induce differentiation, growth arrest, and apoptosis in cancer cells. This phase II multicenter study was undertaken to estimate the efficacy of belinostat, a potent inhibitor of both class I and class II HDAC enzymes, for the treatment of myelodysplastic syndrome (MDS). Adults with MDS and ≤2 prior therapies were treated with belinostat 1,000 mg/m² IV on days 1–5 of a 21-day cycle. The primary endpoint was a proportion of confirmed responses during the first 12 weeks of treatment. Responding patients could receive additional cycles until disease progression or unacceptable toxicity. Twenty-one patients were enrolled, and all were evaluable. Patients were a median 13.4 months from diagnosis, and 14 patients (67%) had less than 5% bone marrow blasts. Seventeen patients (81%) were transfusion dependent. Prior therapy included azacytidine (n = 7) and chemotherapy (n = 8). The patients were treated with a median of four cycles (range, 1–8) of belinostat. There was one confirmed response—hematologic improvement in neutrophils—for an overall response rate of 5% (95% CI, 0.2–23). Median overall survival was 17.9 months. Grades 3–4 toxicities considered at least to be possibly related to belinostat were: neutropenia (n = 10), thrombocytopenia (n = 9), anemia (n = 5), fatigue (n = 2), febrile neutropenia (n = 1), headache (n = 1), and QTc prolongation (n = 1). Because the study met the stopping rule in the first stage of enrollment, it was closed to further accrual.     

Therapy-related patterns of cytogenetic abnormalities in acute myeloid leukemia and myelodysplastic syndrome post polycythemia vera

A minor fraction of patients with polycythemia vera (PV) develop a terminal acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Analysis of the cytogenetic abnormalities during AML or MDS may help in understanding if this development is part of the natural course of the disease or induced by myelosuppressive therapy. Thirty-six cases with AML or MDS post PV, collected in a single Swedish institution during a 33-year period, are described with special regard to time to development of AML or MDS, therapy given during active PV, and cytogenetic findings during AML or MDS. A further 118 cases of AML or MDS post PV, in whom type of therapy during active PV and cytogenetic findings during AML or MDS were reported, were collected from the literature. AML or MDS developed in our own series after 1–30 years with a fairly constant rate (two cases per year). The most frequent cytogenetic abnormalities were +1q, −5, 5q−, −7, 7q−, +8, +9, 11q−, 13q−, and 20q−. When patients in the total material (n = 154) were divided with regard to treatment during active PV, marked differences were observed. The highest frequency of abnormalities was found in patients given multiple lines of therapy (n = 61), dominating features being −5/5q− in 28 patients (46%), −7/7q− in 19 patients (31%), numerous translocations in 24 patients (39%), and unidentified markers in 22 patients (36%). Half of the patients treated with hydroxyurea alone showed a −5 or 5q− abnormality. In patients treated with phlebotomy alone, +8 and +9 were the most frequent findings. The type of therapy given during active PV influences the type of chromosome abnormalities present during terminal AML or MDS and can also be instrumental in the development of leukemia.     

Long-term follow-up of clonal evolutions in 802 aplastic anemia patients: a single-center experience

To assess the incidence rates and risk factors for clonal evolutions in aplastic anemia (AA) patients, we studied 802 hospitalization cases from January 1991 through December 2007 by using the cumulative incidence curves and the Cox proportional hazards mode. We found that the case of 19 patients had evolved to myelodysplastic syndrome or acute myeloid leukemia (MDS/AML), while 21 patients (two of them with concurrent MDS) developed paroxysmal nocturnal hemoglobinuria (PNH). The cumulative incidence of clonal evolutions was assessed as 3.7%, whereas the incidences of MDS/AML and PNH were 1.7% and 2.1%, respectively, at 5 years. By multivariate analysis, age, severity of the disease, and the number of days of rhuG-CSF therapy were the risk factors for AA evolution to MDS/AML. The relative risk (RR) for very severe AA was approximately seven times higher than that for severe AA (SAA) and non-SAA (NSAA) (P = 0.001), but the latter two did not differ significantly (P = 0.743). PNH clone was monitored sequentially in 237 patients; positive clones were detected in 41% of the patients, but more than half of them were transient or instable. White blood cell count at initial diagnosis was identified as the only significant risk factor for AA evolution to PNH (P = 0.007). Our results suggest that the transformation to PNH for subpopulations of AA patients may be natural evolution as the clinical manifestation and pathogenesis between AA and PNH were closely related. Furthermore, normalizing hematopoiesis of AA may represent a viable approach to prevent clone evolutions, especially to MDS/AML.     

Impact of primary disease on outcome after allogeneic stem cell transplantation for transformed secondary acute leukaemia

Myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukaemia (CMML) can progress to secondary acute myeloid leukaemia (sAML). We compared the outcome of 4214 sAML patients who received allogeneic haematopoietic stem cell transplantation (allo-HSCT) from an unrelated (62%) or human leucocyte antigen (HLA)-identical sibling donor (38%) according the underlying disease: MDS (n = 3541), CMML (n = 251) or MPN (n = 422). After a median follow up of 46·5 months, the estimated 3-year progression-free (PFS) and overall survival (OS) for the entire group was 36% (34–37%) and 41% (40–43%), respectively. The cumulative incidence of relapse and non-relapse mortality (NRM) was 37% (35–39%) and 27% (26–29%), respectively. In a multivariable analysis for OS, besides age (P < 0·001), unrelated donor (P = 0·011), cytomegalovirus ± constellation (P = 0·007), Karnofsky index ≤ 80 (P < 0·001), remission status (P < 0·001), peripheral blood as stem cell source (P = 0·009), sAML from MPN (P = 0·003) remained a significant factor in comparison to sAML from MDS, while worse outcome of sAML from CMML did not reach statistical significance (P = 0·06). This large registry study demonstrates a major impact of the underlying disease on outcome of sAML after allo-HSCT.     

Mean corpuscular volume predicts prognosis in MDS patients with abnormal karyotypes

The prognostic value of karyotype in patients with myelodysplastic syndrome (MDS) is generally appreciated. However, the factors that are predictive of prognosis of patients with abnormal karyotypes are not known. In this study, we evaluated the prognostic value of International Prognostic Scoring System (IPSS) and World Health Organization classification-based prognostic scoring system (WPSS) in 164 adult MDS patients with abnormal karyotypes. We also analyzed the prognostic relevance of mean corpuscular volume (MCV) in these patients. We found that both IPSS and WPSS had strong prognostic value in patients with abnormal karyotypes (P < 0.001, P < 0.001). Furthermore, we observed the significant differences in the survival of patients with abnormal karyotypes based on MCV stratification: The median survival of patients with macrocytosis was 31.0 months, significantly longer than the 16.5-month median survival time of patients with MCVs of less than 100 fl (P = 0.001). Multivariate analysis revealed that lower level of hemoglobin (P = 0.012, HR = 6.83), higher level of marrow blasts (P < 0.001, HR = 1.93), complex karyotype (P = 0.001, HR = 3.32), and MCV of less than 100 fl (P = 0.026, HR = 1.75) were independent risk factors that affected the survival of patients with abnormal karyotypes.     

Results of a randomized double-blind placebo-controlled trial evaluating sequential high-dose cytosine arabinoside/mitoxantrone chemotherapy with or without granulocyte/macrophage-colony-stimulating factor in high-risk myelodysplastic syndromes

A prospective, randomized, double-blind placebo-controlled trial was designed to evaluate the impact of granulocyte/macrophage-colony-stimulating factor (GM-CSF) on the efficacy of sequential high-dose cytosine arabinoside/mitoxantrone chemotherapy (S-HAM) in adult patients with high-risk myelodysplastic syndromes (MDS). GM-CSF or placebo was given subcutaneously once daily at a dose of 250 μg/m², starting 48 h prior to chemotherapy, and continued until neutrophil recovery. Owing to high toxicity and slow patient recruitement the study was closed and unblinded after 31 patients had been enrolled; 15 were randomized to receive placebo and 16 to receive GM-CSF. A total of 29 patients were evaluable for response; their median age was 57 years. Ten patients achieved a complete remission (34.5%), 9 patients had persistent MDS (31%), 10 patients died within 6 weeks after the onset of treatment (early death) (34.5%). The median remission duration was 190 days (range: 2.5–45 months). Among the 29 evaluable patients no significant differences could be found between the two study arms regarding complete remission rate [GM-CSF: 31% (5/16) versus placebo: 38% (5/13) P = 0.45], rate of persistent MDS [GM-CSF: 25% (4/16) versus 38% (5/13) P = 0.35), early death rate [44% (7/16) versus 23% (3/13) P = 0.22] and remission duration (GM-CSF: 87 days versus placebo 221 days). Duration of granulocytopenia (median: 33 days with GM-CSF) versus 35 days with placebo) and frequency of infectious episodes were not significantly influenced by GM-CSF. The small number of patients finally analyzed means that no definite conclusions about the effect of GM-CSF can be reached. Received: 3 June 1998 / Accepted: 5 January 1999     

Importance of early detection and follow-up of FLT3 mutations in patients with acute myeloid leukemia

Mutations in the fms-like tyrosine kinase 3 (FLT3) gene, such as internal tandem duplication (FLT3/ITD) in the juxtamembrane domain and point mutations in the tyrosine kinase domain, are the most common abnormalities in acute myeloid leukemia (AML). FLT3/ITD and FLT3/D835 mutations were analyzed in 113 Serbian adult AML patients using polymerase chain reaction. Twenty patients were found to be FLT3/ITD positive (17.7%). The mutations occurred most frequently in M5 and M0 subtypes of AML. They were mainly associated with the normal karyotype. All patients harboring FLT3/ITD had a higher number of white blood cells than patients without it (p = 0.027). FLT3/ITD mutations were associated with lower complete remission (CR) rate (χ ²= 5.706; p = 0.017) and shorter overall survival (OS; Log rank = 8.76; p = 0.0031). As for disease-free survival, the difference between FLT3/ITD-positive and FLT3/ITD-negative patients was not statistically significant (Log rank = 0.78; p = 0.3764). In multivariate analysis, the presence of FLT3/ITD mutations was the most significant prognostic factor for both OS and CR rate (p = 0.0287; relative risk = 1.73; 95% CI = 1.06–2.82). However, in the group of patients with the intermediate-risk karyotype, the mere presence of FLT3/ITD was not associated with inferior clinical outcome. FLT3/D835 point mutation was found in four patients (3.5%) only. Follow-up of the FLT3/ITD-positive patients revealed stability of this mutation during the course of the disease. However, changes in the pattern of FLT3/D835 mutations in initial and relapsed AML were observed. Our results indicate an association of FLT3/ITD with the adverse outcome in AML patients treated with standard induction chemotherapy. Because FLT3/ITD mutation is a target for specific therapeutic inhibition, its early detection could be helpful in clinical practice. Ms. Colovic and Ms. Tosic contributed equally to this work.     

Presenting features and outcome of chronic lymphocytic leukemia patients diagnosed at age 80 years or more. An ICLLSG study

Although the incidence of chronic lymphocytic leukemia (CLL) increases exponentially with age, data on patients 80 years or older at diagnosis are sparse. The records of patients diagnosed with CLL at age ≥80 years at seven medical centers in Israel during 1979–2009 were reviewed. Patients included 118 men and 96 women with a mean age of 84 years (range 80–94). Diagnosis was established in 56.5% due to routine blood count; 56% had Rai stage 0 disease and 25% of the patients received treatment. By June 2010, 72% had died. Mean survival was 67.7 months (median 56 ± 5.4 months) and 5-year survival rate 47.2 ± 3.6%. On univariate analysis, factors associated with better survival were age <84 years (p = 0.002), early Rai and Binet stages (p = 0.023, 0.003), low white blood cell count at time of diagnosis (p = 0.015), low β2 microglobulin level (p = 0.006), diagnosis by routine blood test (p < 0.001), and low CD38 level (p = 0.036). Multivariate analysis using Cox regression revealed that younger age, low white cell count, and diagnosis by routine blood test were independent predictors of good prognosis (hazards ratios 1.8, 1.6, and 1.9, respectively). Patients diagnosed with CLL at age ≥80 years may expect to live a long life. This study identifies several factors predicting good prognosis which are easy to obtain.     

Oral fludarabine and cyclophosphamide as front-line chemotherapy in patients with chronic lymphocytic leukemia. The impact of biological parameters in the response duration

We tested the efficacy and safety of oral fludarabine and cyclophosphamide as front-line therapy in chronic lymphocytic leukemia (CLL) and assessed the influence of immunoglobulin variable region heavy chain (IgVH) gene mutation status, interphase cytogenetic abnormalities, and expression of ZAP-70 and CD38 on clinical outcome. Thirty-seven patients with previously untreated CLL received oral fludarabine (30 mg m²) and oral cyclophosphamide (250 mg m²) for three consecutive days every 4 weeks for six cycles. Eighteen patients had unmutated and 15 had mutated IgVH genes. Nine patients had the ‘high risk’ cytogenetic abnormality del(11q22.3) or del(17p13.1). Fifteen patients were ZAP-70-positive and eight patients were CD38-positive. Among the 35 valuable patients, 14 patients (40%) obtained a complete response and 13 (37%) a partial response. The median progression-free survival (PFS) was 23 months and median time to re-treatment (TTR) was 38 months. A significantly lower overall response rate (43% vs. 85%, p = 0.011), a shorter PFS (22 vs. 27 months, p = 0.015), and a shorter TTR (22 vs. 40 months, p = 0.031) were noticed in the ‘high risk’ cytogenetic abnormalities group; TTR was also shorter in IgVH-unmutated than in IgVH-mutated patients (26 vs. 41 months, p = 0.035). Hematologic toxicity included grade IV neutropenia (ten patients) and grade III/IV anemia (three patients). Gastrointestinal toxicity was mild and no patient required hospitalization. The oral combination of fludarabine and cyclophosphamide is an effective, safe, and well-tolerated regimen that, if confirmed with larger series, will be appropriate especially in patients with low risk biological parameters.     

Primary localized stages I and II non-Hodgkin’s lymphoma of the nasopharynx: a retrospective 17-year single institutional experience

The aim of this retrospective study was to define the natural history, clinicopathological findings, prognostic factors, and treatment outcome of 43 patients with localized stages I and II primary non-Hodgkin’s lymphoma (NHL) of the nasopharynx, followed up in a single institution over a 17-year period. Forty-three (13 women and 30 men) consecutive patients with localized stages I (N = 12) and II (N = 31) primary nasopharyngeal NHL were treated in our institution between 1990 and 2007. The pathologic reports were classified according to the International Working Formulation (N = 22) or Revised European-American Lymphoma classification (N = 21). The vast majority of patients (88%) were managed with a sequential combination of chemotherapy and radiation therapy. Chemotherapy mainly consisted of 4–8 (median 6) cycles of CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone). Involved-field radiation therapy with a median dose of 44 Gy was delivered to the primary site and entire cervical lymph nodes. The median age of the patients was 53 years (range, 6 to 86 years). The majority of the patients (70%) had high-grade histology. B-cell types represented 67% of the cases, among which diffuse large B cell was the most common histological subtype. After a median follow-up of 70 months, the 5-year disease-free survival and overall survival were 58.8% and 70.6%, respectively. In multivariate analysis, age less than or equal to 30 years (hazard ratio (HR) = 5.32, 95% confidence interval (CI) = 1.69–16.76), elevated serum lactate dehydrogenase level (HR = 3.69, 95% CI = 1.43–9.51), and modified International Prognostic Index with more than or equal to two risk factors (HR = 17.99, 95% CI = 2.32–139.30) retained statistical significance. Our limited data suggest that primary nasopharyngeal NHL tends to have aggressive histology and unfavorable clinical course with poor outcome, despite a considerably localized disease at the time of presentation and high frequency of complete initial response rates. Combined modality therapy should be considered for the majority of patients with primary localized nasopharyngeal NHL.     

Intensive chemotherapy with idarubicin, ara-C, etoposide, and m-AMSA followed by immunotherapy with interleukin-2 for myelodysplastic syndromes and high-risk Acute Myeloid Leukemia (AML)

 Intensive chemotherapy followed by treatment with interleukin-2 (IL-2) was evaluated in a prospective, randomized, multicenter trial including 18 patients with refractory anemia with excess of blasts in transformation (RAEB-T), 86 patients with acute myeloid leukemia (AML) evolving from myelodysplastic syndromes, and six patients with secondary AML after previous chemotherapy. Median age was 58 years (range: 18–76 years). Forty-nine patients (45%) achieved a complete remission (CR) after two induction cycles with idarubicin, ara-C, and etoposide, 52% of them aged ≤60 years and 35% aged >60 years (p=0.06). After two consolidation courses, patients were randomized to four cycles of either high- or low-dose IL-2. Patients aged up to 55 years with an HLA-identical sibling donor were eligible for allogeneic bone marrow transplantation. The median relapse-free survival was 12.5 months, with a probability of ongoing CR at 6.5 years of 19%. Overall survival of all patients was 8 months, and 21 months for the CR patients. Median survival was significantly longer among patients aged ≤60 years than among the older patients (16 vs 6 months, p<0.001). Median duration of survival and relapse-free survival were not statistically different in the two IL-2 treatment arms. Received: March 23, 1999 / Accepted: June 23, 1999     

Improved survival in an Asian cohort of young colorectal cancer patients: an analysis of 523 patients from a single institution

Background  Colorectal cancer (CRC) in the young is rare. Outcomes remain varied compared to older populations. The study reviews characteristics and overall survival (OS) of CRC in patients ≤50 years old. Materials and methods  Five hundred and twenty-three (14%) of 3,796 sporadic CRCs were identified. Patients were compared for demographics, tumour characteristics, treatment, and 5-year overall specific survival. Independent prognostic factors were evaluated. Results  The majority were males (54%) with a median age of 45 years (range 19–50 years). Sixty-three percent of the patients presented with advanced stage disease (stage III and IV), and tumours were predominantly left-sided (83%). A higher frequency of mucinous or signet ring cell histological subtypes (16% vs 9%, p = 0.028) as well as poorly differentiated tumours (30% vs 12%, p = 0.0001) were present in younger patients ≤40 years. With a median follow-up of 41 months, the 5-year OS is 58% (95% confidence interval 53–64%). Younger patients ≤40 years had significantly superior 5-year OS of 62% vs 58% in the age group 41–50 years old (p = 0.004). Multivariate analysis identified five independent prognostic features: age group of 41–50 years, poorly differentiated tumour grade, presence of perineural infiltration, high tumour stage, and carcinoembryonic antigen values ≥5 ng/ml. Conclusion  This study has revealed significantly improved 5-year survival in young CRC compared to those reported in the literature.     

The prognostic factors of stage IV colorectal cancer and assessment of proper treatment according to the patient’s status

Background and aims Approximately 20% of patients with colorectal cancer are initially diagnosed with stage IV. The majority has non-curative metastases, and their chances of survival are pitiful. This study evaluated the prognostic factors of survival and the access to the effective treatment in accordance with patients. Materials and methods We retrospectively analyzed 503 patients for demographics, tumor characteristics, the treatment modality, and the survival outcome. Curative operation was performed in 127 patients and palliative operation in 376 patients. Results For the curative operation group, the 5-year survival rate was 34.5%, and the prognostic factors of survival and recurrence were male gender (p = 0.003, 0.009), pathologic N stage (p < 0.001, p = 0.002), and perineural invasion (p = 0.003, p = 0.026), respectively. For the non-curative operation group, the 5-year survival rate was 0%, and the median survival duration was 16.5 months. The potential predictors of survival for the palliative operation group were carcinoembryonic antigen level (p = 0.013), differentiation of tumor (p = 0.011), resection of primary tumor (p < 0.001), and chemotherapy (p < 0.001). But for the 131 patients with asymptomatic incurable disease, only chemotherapy was related to survival (p < 0.001). Conclusions The potential predictors of survival for curative stage IV colorectal cancer were male gender, pathologic N stage, and perineural invasion. Resection of the primary tumor and chemotherapy showed benefit for the incurable patients. But for the asymptomatic incurable patients, only chemotherapy prolonged the survival. This study was presented at the 21st Biennial Congress of International Society of the University of Colon and Rectal Surgeons held in Istanbul, Turkey in June 2006.     

Phase II study of tosedostat with cytarabine or decitabine in newly diagnosed older patients with acute myeloid leukaemia or high‐risk MDS

Tosedostat, an oral aminopeptidase inhibitor, has synergy with cytarabine and hypomethylating agents. We performed a Phase II trial to determine rates of complete remission (CR) and survival using tosedostat with cytarabine or decitabine in older patients with untreated acute myeloid leukaemia (AML) or high‐risk myelodysplastic syndrome (MDS). Thirty‐four patients ≥60 years old (median age 70 years; range, 60–83) were randomized to receive tosedostat (120 mg on days 1–21 or 180 mg continuously) with 5 d of either cytarabine (1 g/m²/d) or decitabine (20 mg/m²/d) every 35 d. Twenty‐nine patients (85%) had AML, including 15 (44%) with secondary AML/MDS, and 5 (15%) had MDS‐refractory anaemia with excess blasts type 2. The CR/CR with incomplete count recovery (CRi) rate was 53% [9 in each arm; 14 CR (41%) and 4 CRi (12%)], attained in 6 of 14 patients with adverse cytogenetics and 4 of 7 with FLT3‐internal tandem duplication mutations. Median follow‐up was 11·2 months (range, 0·5–22·3), and median survival was 11·5 months (95% confidence interval, 5·2–16·7). Twenty‐three patients (67·6%) were treated as outpatients and 10 of these patients required hospitalization for febrile neutropenia. No Grade 3–4 non‐haematological toxicities required withdrawal from study. Tosedostat with cytarabine or decitabine is tolerated in older patients with untreated AML/MDS, results in a CR/CRi rate of >50%, and warrants further study in larger trials.     

Ten‐Eleven‐Translocation 2 (TET2) is downregulated in myelodysplastic syndromes

TET2, a member of the ten‐eleven‐translocation (TET) family genes that modify DNA by converting 5‐methylcytosine (5‐mC) to 5‐hydroxymethylcytosine (5‐hmC), is located in chromosome 4q24 and is frequently mutated in myeloid malignancies. The impact of TET2 mutation on survival outcomes is still controversial; however, functional studies have proved that it is a loss‐of‐function mutation that impairs myeloid cell differentiation and contributes to the phenotype of myeloid neoplasia. We, herein, aimed to investigate TET2 expression in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). A significantly decreased TET2 expression was observed in bone marrow cells from AML (n = 53) and patients with MDS (n = 64), compared to normal donors (n = 22). In MDS, TET2 expression was significantly reduced in RAEB‐1/RAEB‐2 compared to other WHO 2008 classifications, and a lower TET2 expression was observed at the time of MDS disease progression in four of five patients. In multivariate analysis, low TET2 expression (P = 0.03), male gender (P = 0.02), and WHO 2008 classification (P < 0.0001) were independent predictors of poorer overall survival. These results suggest that defective TET2 expression plays a role in the MDS pathophysiology and predicts survival outcomes in this disease.     

Elevated fetal haemoglobin is a predictor of better outcome in MDS/AML patients receiving 5‐aza‐2′‐deoxycytidine (Decitabine)

Although azanucleoside DNA‐hypomethylating agents (HMAs) are routinely used for the treatment of myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), very few outcome predictors have been established. Expression of the β‐like globin gene locus is tightly regulated by DNA methylation, is HMA‐sensitive in vitro, and fetal haemoglobin (HbF) expression is under study as a potential biomarker for response of MDS patients to azacitidine. We determined HbF expression in 16 MDS and 36 AML patients receiving decitabine (DAC). Pre‐treatment HbF was already elevated (>1·0% of total haemoglobin) in 7/16 and 12/36 patients, and HbF was induced by DAC in 81%/54% of MDS/AML patients, respectively. Elevated pre‐treatment HbF was associated with longer median overall survival (OS): 26·6 vs. 8·6 months for MDS (hazard ratio [HR] 8·56, 95% confidence interval [CI] 1·74–42·49, P = 0·008, with similarly longer progression‐free and AML‐free survival), and 10·0 vs. 2·9 months OS for AML (HR 3·01, 95% CI 1·26–7·22, P = 0·014). In a multivariate analysis, the prognostic value of HbF was retained. Time‐dependent Cox models revealed that the prognostic value of treatment‐induced HbF induction was inferior to that of pre‐treatment HbF. In conclusion, we provide first evidence for in vivo HbF induction by DAC in MDS/AML, and demonstrate prognostic value of elevated pre‐treatment HbF, warranting prospective, randomized studies.     

Autoimmune diseases,infections, use of antibiotics and the risk of acute myeloid leukaemia: a national population‐based case‐control study

Previous studies reported increased risk of acute myeloid leukaemia (AML) in individuals with inflammatory conditions. However, it is unclear whether this association is explained by preceding cytotoxic therapy or haematological diseases. We conducted a nationwide case‐control study that included 3053 AML patients, diagnosed in Denmark between 2000 and 2013, and 30 530 sex‐ and age‐matched population controls. We retrieved information on autoimmune disease, infections, and use of antibiotics and computed odds ratios for AML (conditional logistic regression). Results were stratified by AML type, sex, and age. Autoimmune diseases were associated with an overall increased risk of AML {odds ratio [OR] 1·3 [95% confidence interval (CI) = 1·1–1·5]}. However, the risk was confined to patients with previous haematological disease or cytotoxic therapy exposure [secondary/therapy‐related AML (sAML/tAML0) OR 2·0 (95% CI = 1·6–2·6)] and not de novo AML [OR 1·1 (95% CI = 0·9–1·3)]. Similarly, any prior infection requiring hospitalization was associated with a higher risk of AML [OR 1·3 (95% CI = 1·1–1·4)]. Again, this association was evident for sAML/tAML [OR 1·8 (95% CI = 1·5–2·2)], and not de novo AML [OR 1·1 (95% CI = 1·0–1·2)]. In conclusion, autoimmune diseases and infections were associated with an increased AML risk only in subjects with prior haematological disease and/or cytotoxic treatment. These observations suggest, that inflammation plays – if any – a minor role for the development of de novo AML.     

Autologous hematopoietic stem cell transplantation—what determines the outcome: an experience from North India

Limited information is available from developing countries about complications, pattern of infections, and long-term outcome of patients following high-dose chemotherapy (HDCT) and autologous blood stem cell transplantation (ASCT). Between April, 1990 and December 2009, 228 patients underwent ASCT. Patients’ median age was 48 years, ranging from 11 to 68 years. There were 158 males and 70 females. Indications for transplant included multiple myeloma, n = 143; lymphoma, n = 44 (Hodgkin’s, n = 25 and non-Hodgkin’s, n = 19); leukemia, n = 22; and solid tumors, n = 18. Patients received HDCT as per standard protocols. Following ASCT, 175 (76.7%) patients responded; complete, 98 (43%); very good partial response, 37 (16.2%); and partial response, 40 (17.5%). Response rate was higher for patients with good Eastern Cooperative Oncology Group (ECOG) performance status (0–2 vs. 3–4, p < 0.001), pretransplant chemo-sensitive disease (p < 0.001) and those with diagnosis of hematological malignancies (p < 0.003). Mucositis, gastrointestinal, renal, and liver dysfunctions were major nonhematologic toxicities, 3.1% of patients died of regimen-related toxicities. Infections accounted for 5.3% of deaths seen before day 30. At a median follow-up of 66 months (range, 9–234 months), median overall (OS) and event-free survival (EFS) were 72 months (95% CI 52.4–91.6) and 24 months (95% CI 17.15–30.9), respectively. For myeloma, OS and EFS were 79 months (95% CI 52.3–105.7) and 30 months (95% CI 22.6–37.4), respectively. Pretransplant good performance status and achievement of significant response following transplant were major predictors of survival. Our analysis demonstrates that such procedure can be successfully performed in a developing country with results comparable to developed countries.