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Abstract: Objectives: Randomized comparison of two treatment strategies in frontline therapy of acute promyelocytic leukemia (APL): all‐trans retinoic acid (ATRA) and double induction intensified by high‐dose cytosine arabinoside (HD ara‐C) (German AMLCG) and therapy with ATRA and anthracyclines (Spanish PETHEMA, LPA99). Patients and results: Eighty of 87 adult patients with genetically confirmed APL of all risk groups were eligible. The outcome of both arms was similar: AMLCG vs PETHEMA: hematological complete remission 87% vs 83%, early death 13% vs 17% (P = .76), overall survival, event‐free survival, leukemia‐free survival, cumulative incidence of relapse at 6 years 75% vs 78% (P = .92); 75% vs 68% (P = .29); 86% vs 81% (P = .28); and 0% vs 12% (P = .04, no relapse vs four relapses), respectively. The median time to achieve molecular remission (RT‐PCR negativity of PML‐RARA) was 60 days in both arms (P = .12). The AMLCG regimen was associated with a longer duration of neutropenia (P = .02) and a higher rate of WHO grade ≥3 infections. Conclusions: The small number of patients limits the reliability of conclusions. With these restrictions, the outcomes of both approaches were similar and show the limitations of ATRA and chemotherapy. The HD ara‐C–containing regimen was associated with a lower relapse rate in high‐risk APL. [ABSTRACT FROM AUTHOR]

Current guidelines of the European Society of Medical Oncology recommend surgical excision biopsies of lymph nodes for the diagnosis of lymphoma whenever possible. However, core needle biopsies are increasingly used. We aimed to understand the common practice to choose the method of biopsy in Germany. Furthermore, we wanted to understand performance of surgical excision and core needle biopsies of lymph nodes in the diagnosis of lymphoma. The files of 1510 unselected, consecutive lymph node specimens from a consultation center for lymphoma diagnosis were analyzed. Core needle biopsies were obtained frequently from lymph nodes localized in mediastinal, abdominal, retroperitoneal, or thoracic regions. Patients undergoing core needle biopsies were significantly older and suffered significantly more often from lymphoma than patients undergoing surgical excision biopsies. Although more immunohistochemical tests were ordered by the pathologist for core needle biopsies specimens than for surgical excision biopsies specimens, core needle biopsies did not yield a definite diagnosis in 8.3 % of cases, compared to 2.8 % for SEB (p = 0.0003). Restricting the analysis to cases with a final diagnosis of follicular lymphoma or diffuse large B-cell lymphoma, core needle biopsies identified a simultaneous low- and high-grade lymphoma (transformation) in 3.3 % of cases, compared to 7.6 % for surgical excision biopsies (p = 0.2317). In Germany, core needle biopsies are preferentially used in elderly patients with a high likelihood of suffering from lymphoma. Core needle appeared inferior to surgical excision biopsies at providing a definite diagnosis and at identifying multiple lymphoma differentiations and transformation. [ABSTRACT FROM AUTHOR]

Despite substantial progress in the management and outcome of acute promyelocytic leukemia (APL) during the last decades, older age remains a prominent negative prognostic factor. The improvement of long-term stabilization and cure of older APL patients is therefore a particular challenge. Data of unselected population-based studies suggest a high rate of exclusion from clinical trials in older age. The comparison of registry and study data indicates that study patients represent a positive selection. Older APL patients seem as sensitive to therapy as younger patients. With conventional therapy, based on all-trans retinoic acid (ATRA) and chemotherapy, over 50 % of older APL patients can probably be cured. Special problems of advanced age are the high rate of early death before or during induction therapy and the high frequency of death in remission with negative influence on the outcome. Both may be related in part to a higher vulnerability against the common treatment with ATRA and chemotherapy. Alternative less toxic approaches including arsenic trioxide (ATO) with or without ATRA and combinations with gemtuzumab ozogamicin or with reduced chemotherapy can induce long-lasting remission in all stages of APL. Considering the high curative potential and the excellent tolerance of ATO in newly diagnosed and relapsed APL, older patients are probably a particular target group for a chemotherapy-free approach with ATO. [ABSTRACT FROM AUTHOR]

Despite substantial progress in the management and outcome of acute promyelocytic leukemia (APL) during the last decades, older age remains a prominent negative prognostic factor. The improvement of long-term stabilization and cure of older APL patients is therefore a particular challenge. Data of unselected population-based studies suggest a high rate of exclusion from clinical trials in older age. The comparison of registry and study data indicates that study patients represent a positive selection. Older APL patients seem as sensitive to therapy as younger patients. With conventional therapy, based on all- trans retinoic acid (ATRA) and chemotherapy, over 50 % of older APL patients can probably be cured. Special problems of advanced age are the high rate of early death before or during induction therapy and the high frequency of death in remission with negative influence on the outcome. Both may be related in part to a higher vulnerability against the common treatment with ATRA and chemotherapy. Alternative less toxic approaches including arsenic trioxide (ATO) with or without ATRA and combinations with gemtuzumab ozogamicin or with reduced chemotherapy can induce long-lasting remission in all stages of APL. Considering the high curative potential and the excellent tolerance of ATO in newly diagnosed and relapsed APL, older patients are probably a particular target group for a chemotherapy-free approach with ATO. [ABSTRACT FROM AUTHOR]

Despite improvement of prognosis, older age remains a negative prognostic factor in acute promyelocytic leukemia (APL). Reports on disease characteristics and outcome of older patients are conflicting. We therefore analyzed 91 newly diagnosed APL patients aged 60 years or older (30 % of 305 adults with APL) registered by the German AML Cooperative Group (AMLCG) since 1994; 68 patients (75 %) were treated in studies, 23 (25 %) were non-eligible, and 31 % had high-risk APL. Fifty-six patients received induction therapy with all-trans retinoic acid and TAD (6-thioguanine, cytarabine, daunorubicin), and consolidation and maintenance therapy. Treatment intensification with a second induction cycle (high dose cytarabine, mitoxantrone; HAM) was optional ( n = 14). Twelve patients were randomized to another therapy not considered in this report. The early death rate was 48 % in non-eligible and 19 % in study patients. With the AMLCG regimen, 7-year overall, event-free and relapse-free survival (RFS) and cumulative incidence of relapse were 45 %, 40 %, 48 %, and 24 %, respectively. In patients treated with TAD-HAM induction, 7-year RFS was superior (83 %; p = 0.006) compared to TAD only, and no relapse was observed. In our registered elderly patients, we see a high rate of non-eligibility for treatment in studies and of high-risk APL. In patients who can undergo a curative approach, intensified chemotherapy is highly effective, but is restricted to a selection of patients. Therefore, new less toxic treatment approaches with broader applicability are needed. Elderly patients might be a particular target group for concepts with arsenic trioxide. [ABSTRACT FROM AUTHOR]

Abstract: In the past, acute promyelocytic leukemia (APL) was associated with a high risk of early mortality resulting from severe coagulopathy, frequently inducing fatal cerebral hemorrhage. With the introduction of the differentiating agent all-trans retinioc acid (ATRA) APL has changed to the best curable subtype of acute myeloid leukemia (AML). With ATRA and chemotherapy approximately 70–80% of patients with newly diagnosed APL achieve long-term remission and are probably cured. PML/RARα, the molecular fusion transcript of the specific translocation t(15;17) represents not only the target for ATRA but also permits a precise diagnosis and provides a marker for the identification of minimal residual or recurrent disease (MRD). During the last decade, substantial progress has been made with regard to the recognition of prognostic factors and the optimization of the combination of ATRA and chemotherapy. Remaining questions are the role of arsenic and of ara-C in first line therapy of APL as well as the indication of maintenance therapy in the individual patient. Several treatment options exist for patients with APL who have relapsed after ATRA and chemotherapy. Approximately 50% of the patients in first relapse can achieve long-lasting second remission and might be cured with salvage regimens. Currently, arsenic compounds and transplantation procedures seem to be the most promising options in relapsed disease. The role of CD33 antibodies has to be determined in future studies. Refining the molecular monitoring of MRD by quantitative RT-PCR, better elucidation of the biologic mechanisms, and the identification of prognostic factors might be helpful to make further progress in the treatment of APL. [Copyright &y& Elsevier]

The clinical course of acute promyelocytic leukaemia (APL) has changed over the last 25 years from one that was fatal for the majority of patients to representing one of the most curable subtypes of acute myeloid leukaemia. Besides improved supportive care this has mainly been achieved through the introduction of novel targeted therapies in the form of all-trans retinoic acid (ATRA) and arsenic trioxide that specifically address the underlying molecular lesion. APL is characterized by chromosomal rearrangements of 17q21 leading to the formation of fusion proteins involving retinoic acid receptor alpha (RARA). To date five different fusion partners of RARA have been identified, but the vast majority of cases are characterized by the presence of the t(15;17)(q22;q12–21), which involves the promyelocytic leukaemia (PML) gene. The identification of different breakpoint microclusters within RARA intron 2 suggests that sequence-associated or structural factors play a role in the formation of the t(15;17). In addition, the comparison of forward and reverse genomic junctions has revealed microhomologies, deletions and/or duplications of either gene consistent with the hypothesis that the t(15;17) occurs by non-homologous recombination of DNA after processing of the double strand breaks by a dysfunctional DNA damage repair mechanism. The detection of the PML-RARA fusion gene by reverse-transcription polymerase chain reaction (RT-PCR) is routinely used for diagnosis and monitoring of minimal residual disease (MRD). In PML-RARA-positive APL about 70% of patients are expected to be cured with a combination of ATRA and anthracycline-based chemotherapy. However, relapse remains a major problem. The identification of patients at high risk of relapse and the development of risk-adapted treatment schedules are therefore clearly the most challenging tasks in the treatment of APL. Recent studies have shown that pre-emptive chemotherapy at the time of molecular relapse improves survival compared to treatment at the point of haematological relapse. Quantitative RT-PCR technology is expected to further improve the predictive value of MRD monitoring and therefore to guide therapy in order to reduce the rate of relapses and to increase rates of cure in high-risk patients. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In order to evaluate the natural history of essential thrombocythaemia (ET), clinical data and prognostic factors of 143 patients with ET were retrospectively analysed (mean observation time 6.1 ± 4.6 years). In 42 patients the early phase of the disease with initial platelet counts between 250 and 600 × 109/l was assessed. In most early cases, ET was suggested by clinical symptoms (79%) and increased megakaryopoiesis (95%) with abnormal megakaryocytes in bone marrow histology (n = 34) and cytology (n = 5). Other myeloproliferative disorders and reactive thrombocytosis were excluded according to the diagnostic criteria of the Polycythemia Vera Study Group. During follow-up of the 38 early cases not treated cytoreductively at diagnosis, the platelet counts increased to >600 × 109/l in 28 patients (74%) and remained between 450 and 600 × 109/l in 10 patients (26%). In primarily asymptomatic patients (n = 46) with initial platelet counts above (n = 37) and below 600 × 109/l (n = 9) the rates of increase of symptomatic patients were similar at about 7% per year. No influence of the initial platelet count on survival was seen in multivariate analysis of prognostic factors which included all 143 cases. Survival was mainly influenced by the rate of ET-related complications during follow-up (P = 0.002). Analysing the influence of cytoreductive therapy on symptom-free survival, platelet reduction benefited patients under 60 years (19 cytoreductively treated v 65 untreated patients, P = 0.075). The results demonstrate the possible clinical relevance of the early stages of ET and suggest that the features of pathologic megakaryopoiesis in the bone marrow are a more reliable diagnostic criterion than a definite platelet limit. Therefore, further therapeutic studies should include all stages of the disease and all age groups. [ABSTRACT FROM AUTHOR]

Although acute promyelocytic leukemia (APL) has evolved to the AML entity with the best prognosis, typical 'early death' (ED) events still account for mortality rates of ∼20% in population-based studies. To investigate this poorly understood issue we performed whole transcriptome analysis of n = 7 APL ED cases compared to n = 7 APL cases with long term remission. We discovered the proteins S100A8/S100A9 and EFEMP1 as the most differentially expressed factors. In an independent cohort of n = 58 APL patients EFEMP1 over-expression was associated with a worse overall survival. Furthermore, a subgroup analysis of ED caused by hemorrhagic complications revealed an association of metallothioneins (MT1G/MT1E) with higher bleeding rates, ED events and negative prognostic effects on overall survival. Finally, we identified a novel TPM4-KLF2 fusion transcripts in 44/64 APL samples. In summary, we report a comprehensive transcriptomic analysis and novel potential biomarkers of ED biology, which highlight novel pathways in ED events in APL. [ABSTRACT FROM AUTHOR]

In the multicentre prospective randomized HD2002 trial, rituximab maintenance therapy (375 mg/m² every 3 months for 2 years) versus observation was evaluated for CD20+ B-cell lymphoma. Out of 321 patients [161 randomized to the treatment group (TG), 160 to the observation group (OG)], 295 data sets were evaluable for statistical analysis. Estimated 5-year relapse-free survival (RFS) was 81% in the TG and 70% in the OG (logrank test, P = 0.047). In the diffuse large B-cell lymphoma (DLBCL) subgroup (n = 152), 5-year RFS was excellent, at 87% in the TG and 84% in the OG (logrank test, P = 0.35). Of note, only in male patients of the DLBCL subgroup was RFS significantly superior in the TG in comparison to the OG (5-year RFS: 88% vs. 74%; logrank test, P = 0.05). Cox regression analysis showed a significant interaction between treatment and gender regarding overall survival (OS) (P = 0.006) and RFS (P = 0.02), with a lower hazard in females than males in the OG [OS: hazard ratio (HR) (female:male) = 0.11; 95% confidence interval (CI) = 0.00-1.03; RFS: HR (female:male) = 0.27; 95% CI = 0.05-0.97], and no significant differences between males and females in the TG. We conclude that Rituximab maintenance therapy improves survival in male patients with DLBCL. [ABSTRACT FROM AUTHOR]

To date risk stratification in acute promyelocytic leukemia (APL) is based on highly dynamic leukocyte and platelet counts only. To identify a more robust risk stratification model, a molecular risk score was developed based on expression levels of the genes BAALC , ERG and WT1 . Hereby, the main focus was on prediction of relapse. The integrative risk score divided patients into two groups with highly significant differences in outcome. It discriminated a high risk group with a high incidence of relapse successfully from a low risk group with no APL-related events after achievement of first remission. Especially the concurrent presence of molecular risk factors showed to be a negative prognostic factor in APL. The molecular risk score might be a promising approach to guide monitoring of APL patients and therapeutic decisions in the future. [ABSTRACT FROM AUTHOR]

Wilms’ tumor 1 gene (WT1) is known to be highly expressed in acute promyelocytic leukemia (APL) but information on its impact on prognosis is lacking.WT1expression was analyzed in bone marrow samples of 79 patients with APL at initial diagnosis. Patients had a differing outcome according to their level ofWT1expression. In patients who achieved a complete remission (CR), low or highWT1expression was significantly associated with inferior overall survival (OS) compared to intermediateWT1expression (49% forWT1highvs. 63% forWT1lowvs. 93% forWT1int;p= 0.008). Moreover, there were significant differences in relapse-free survival (RFS) between the three expression groups (42% forWT1highvs. 63% forWT1lowvs. 83% forWT1int;p= 0.047). In multivariable analysisWT1expression showed an independent prognostic impact on OS of responders to induction therapy. In conclusion, the level ofWT1expression can add prognostic information in APL risk stratification. [ABSTRACT FROM PUBLISHER]

The antiproliferative effects of the tyrosine kinase inhibitor imatinib mesylate were reported in single cases with polycythemia vera (PV). We, therefore, conducted a clinical phase II study to assess the rate and quality of response in patients with PV. Thirty-one patients, with a median age of 64 years (range, 45-84 years), were included. All but one patient were on phlebotomy; 14 (45 %) had previously received cytoreductive therapy. Imatinib was started with 400 mg/day. In 26 % of patients, dose escalation up to 800 mg was performed. After a median treatment duration of 8.3 months (range, 0.1-62.1 months), the overall response rate was 55 %. No complete remission (normalization of all parameters: hematocrit, white blood cell (WBC) count, platelet count, and spleen size determined by ultrasound examination) was reached because the spleen remained enlarged in all patients. Thirteen patients (42 %) achieved partial remission (≥25 % reduction of at least one of the previously mentioned parameters); in 10 of these, the respective reduction was ≥50 %. In four patients (13 %) with minor response, the reduction was <25 %. No change or progressive disease was seen in 14 patients (45 %). The nonresponders had a longer previous disease duration and had received more antecedent cytoreductive therapy ( p = 0.009). Compared to baseline characteristics, imatinib induced the reduction of phlebotomies ( p = 0.003), of WBC count ( p = 0.002), and of platelet count ( p = 0.04). Three patients became free from phlebotomies. In six investigated patients, no significant reduction of the JAK2V617F burden was observed despite clinical improvement. The results show that imatinib has moderate cytoreductive effects in PV. [ABSTRACT FROM AUTHOR]

Standardized response criteria to interpret and compare clinical trials are needed for approval of new therapeutic agents by regulatory agencies. The European LeukemiaNet (ELN) response criteria for essential thrombocythemia (ET) and polycythemia vera (PV) issued in 2009 have been widely adopted as end points in a number of recent clinical trials. However, evidence exists that they do not predict response or provide clinically relevant measures of benefit for the patients. This article presents revised recommendations for assessing response in ET and PV provided by a working group established by ELN and International Working Group-Myeloproliferative Neoplasms Research and Treatment. New definitions of complete and partial remission incorporate clinical, hematological, and histological response assessments that include a standardized symptom assessment form and consider absence of disease progression and vascular events. We anticipate that these criteria will be adopted widely to facilitate the development of new and more effective therapies for ET and PV. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated the prognostic value of BAALC expression in 86 patients with acute promyelocytic leukemia (APL). At 10 years, the overall survival (OS) was 66% in all patients and 75% in patients who achieved a complete remission (CR). Patients in the BAALClow group showed an OS of 87% as compared to 60% in the BAALChigh group (p =0.019). This difference was more pronounced in treatment responders (92% vs. 70%; p =0.035). In multivariate analyses low BAALC expression retained its prognostic relevance. In conclusion, BAALC expression analysis might be useful in further risk stratification in APL patients. [Copyright &y& Elsevier]

In acute promyelocytic leukemia (APL), relapse occurs in about 15 % of cases and is a major cause for death. Molecular markers identifying patients at high risk for relapse are not well established. High expression of the transcription factor Ets-related gene (ERG) is associated with inferior overall survival (OS) and disease-free survival in different types of hematologic malignancies. There are no data available about the impact of ERG expression in APL. ERG expression levels were analyzed in bone marrow samples of 86 APL patients at initial diagnosis. High ERG expression was significantly associated with an inferior OS in patients who had reached first complete remission. It was also significantly correlated with inferior relapse-free survival (RFS) and time to relapse (i.e., relapse-free interval, RFI). In multivariate analysis, high ERG expression had an independent negative impact on RFS and RFI. High ERG expression was significantly associated with inferior OS, RFS, and RFI. Moreover, in multivariate analysis, it maintained its value as an independent negative prognostic factor with regard to RFS and RFI. Therefore, ERG expression might serve as a molecular marker for risk stratification in APL and might identify patients who could benefit from intensified treatment regimens. [ABSTRACT FROM AUTHOR]

In acute promyelocytic leukemia (APL), relapse occurs in about 15 % of cases and is a major cause for death. Molecular markers identifying patients at high risk for relapse are not well established. High expression of the transcription factor Ets-related gene (ERG) is associated with inferior overall survival (OS) and disease-free survival in different types of hematologic malignancies. There are no data available about the impact of ERG expression in APL. ERG expression levels were analyzed in bone marrow samples of 86 APL patients at initial diagnosis. High ERG expression was significantly associated with an inferior OS in patients who had reached first complete remission. It was also significantly correlated with inferior relapse-free survival (RFS) and time to relapse (i.e., relapse-free interval, RFI). In multivariate analysis, high ERG expression had an independent negative impact on RFS and RFI. High ERG expression was significantly associated with inferior OS, RFS, and RFI. Moreover, in multivariate analysis, it maintained its value as an independent negative prognostic factor with regard to RFS and RFI. Therefore, ERG expression might serve as a molecular marker for risk stratification in APL and might identify patients who could benefit from intensified treatment regimens. [ABSTRACT FROM AUTHOR]

The origin of aberrant DNA methylation in cancer remains largely unknown. In the present study, we elucidated the DNA methylome in primary acute promyelocytic leukemia (APL) and the role of promyelocytic leukemia-retinoic acid receptor a (PML-RARα) in establishing these patterns. Cells from APL patients showed increased genome-wide DNA methylation with higher variability than healthy CD34+ cells, promyelocytes, and remission BM cells. A core set of differentially methylated regions in APL was identified. Age at diagnosis, Sanz score, and Flt3-mutation status characterized methylation subtypes. Transcription factor-binding sites (eg, the c-myc-binding sites) were associated with low methylation. However, SUZ12- and REST-binding sites identified in embryonic stem cells were preferentially DNA hypermethylated in APL cells. Unexpectedly, PML-RARα-binding sites were also protected from aberrant DNA methylation in APL cells. Consistent with this, myeloid cells from preleukemic PML-RARα knock-in mice did not show altered DNA methylation and the expression of PML-RARα in hematopoietic progenitor cells prevented differentiation without affecting DNA methylation. Treatment of APL blasts with all-trans retinoic acid also did not result in immediate DNA methylation changes. The results of the present study suggest that aberrant DNA methylation is associated with leukemia phenotype but is not required for PML-RARα-mediated initiation of leukemogenesis. [ABSTRACT FROM AUTHOR]

Pharmacokinetics of 8 doses of rituximab (375 mg/m2) given in combination with 2-week cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone/ prednisolone (CHOP-14) was determined by ELISA in 20 elderly patients with diffuse large B-cell lymphoma (DLBCL) 10 minutes before and after each infusion and 1 week and 1, 2, 3, 6, and 9 months after the last infusion. Population pharmacokinetic modeling was performed with nonlinear mixed-effect modeling software (NONMEM VI). Concentration-time data were fitted into an open 2-compartment model and total clearance, central compartment volume, intercompartment clearance, and volume of distribution at steady-state (Vdss) were investigated. Total clearance was 9.43 mL/h and Vd5S was 9.61 I. Rituximab clearance was reduced (8.21 mL/h vs 12.68 mL/h; P= .003) and elimination half-life was prolonged in women compared with men (t1/2&bgr; = 30.7 vs 24.7 days; p; = .003). Body weight also affected Vdss (0.1 I increase of Vdss per kilogram above median of 75 kg). A sexdependent effect and the higher weight of males contribute to their faster rituximab clearance, which might explain why elderly males benefit less from the addition of rituximab to CHOP than females. This trial was registered on www.clinicaltrials. gov as numbers NCT00052936, EU-20243 (RICOVER-60 Trial), EU-20534, and NCT00726700 (Pegf ilgrastim Trial) [ABSTRACT FROM AUTHOR]

Summary: Background: Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) is used to treat patients with non-Hodgkin lymphoma. Interval decrease from 3 weeks of treatment (CHOP-21) to 2 weeks (CHOP-14), and addition of rituximab to CHOP-21 (R-CHOP-21) has been shown to improve outcome in elderly patients with diffuse large B-cell lymphoma (DLBCL). This randomised trial assessed whether six or eight cycles of R-CHOP-14 can improve outcome of these patients compared with six or eight cycles of CHOP-14. Methods: 1222 elderly patients (aged 61–80 years) were randomly assigned to six or eight cycles of CHOP-14 with or without rituximab. Radiotherapy was planned to sites of initial bulky disease with or without extranodal involvement. The primary endpoint was event-free survival; secondary endpoints were response, progression during treatment, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat. The trial is registered on National Cancer Institute website, number NCT00052936 and as EU-20243. Findings: 3-year event-free survival was 47·2% after six cycles of CHOP-14 (95% CI 41·2–53·3), 53·0% (47·0–59·1) after eight cycles of CHOP-14, 66·5% (60·9–72·0) after six cycles of R-CHOP-14, and 63·1% (57·4–68·8) after eight cycles of R-CHOP-14. Compared with six cycles of CHOP-14, the improvement in 3-year event-free survival was 5·8% (−2·8–14·4) for eight cycles of CHOP-14, 19·3% (11·1–27·5) for six cycles of R-CHOP-14, and 15·9% (7·6–24·2) for eight cycles of R-CHOP-14. 3-year overall survival was 67·7% (62·0–73·5) for six cycles of CHOP-14, 66·0% (60·1–71·9) for eight cycles of CHOP-14, 78·1% (73·2–83·0) for six cycles of R-CHOP-14, and 72·5% (67·1–77·9) for eight cycles of R-CHOP-14. Compared with treatment with six cycles of CHOP-14, overall survival improved by −1·7% (−10·0–6·6) after eight cycles of CHOP-14, 10·4% (2·8–18·0) after six cycles of R-CHOP-14, and 4·8% (−3·1–12·7) after eight cycles of R-CHOP-14. In a multivariate analysis that used six cycles of CHOP-14 without rituximab as the reference, and adjusting for known prognostic factors, all three intensified regimens improved 3-year event-free survival (eight cycles of CHOP-14: RR [relative risk] 0·76 [0·60–0·95], p=0·0172; six cycles of R-CHOP-14: RR 0·51 [0·40–0·65], p<0·0001; eight cycles of R-CHOP-14: RR 0·54 [0·43–0·69], p<0·0001). Progression-free survival improved after six cycles of R-CHOP-14 (RR 0·50 [0·38–0·67], p<0·0001), and eight cycles of R-CHOP-14 (RR 0·59 [0·45–0·77], p=0·0001). Overall survival improved only after six cycles of R-CHOP-14 (RR 0·63 [0·46–0·85], p=0·0031). In patients with a partial response after four cycles of chemotherapy, eight cycles were not better than six cycles. Interpretation: Six cycles of R-CHOP-14 significantly improved event-free, progression-free, and overall survival over six cycles of CHOP-14 treatment. Response-adapted addition of chemotherapy beyond six cycles, though widely practiced, is not justified. Of the four regimens assessed in this study, six cycles of R-CHOP-14 is the preferred treatment for elderly patients, with which other approaches should be compared. [Copyright &y& Elsevier]

Abstract: Undertreatment of the older patients with AML can explain, in part, their inferior outcome when compared with that in younger patients. In analogy to the benefit of patients under the age of 60 years from high-dose AraC there are dosage related therapeutic effects in the patients over 60 years in particular for daunorubicin in the induction treatment, and for maintenance versus no maintenance in the post-remission treatment. Utilizing these effects can partly overcome the mostly unfavorable disease biology in older age AML, whereas the role of risk factors involved is not completely understood and the concept of dose–response needs to be requestioned. We recommend an adequate dosage of 60mg/(m2 day) daunorubicin for 3 days in a combination with standard dose AraC and 6-thioguanine given for induction and consolidation and followed by a prolonged monthly maintenance chemotherapy. Further improvements in supportive care may help delivering additional anti-leukemic cytotoxicity. As a novel approach, reduced toxicity preparative regimens may open up allogeneic transplantation for older patients with AML. Other new options like MDR modulators, antibody targeted therapies and tyrosine kinase inhibitors are under clinical investigation. A questionnaire study in patients with AML showed that according to patients’ self-assessment intensive and prolonged treatment did not result in decreasing quality of life. This finding did not vary by age under or above 60 years. Given the actual median age in this disease being more than 60 years the adequate management of older age AML remains as the major challenge. [Copyright &y& Elsevier]

Introduction: Acute promyelocytic leukemia (APL) is a distinct entity characterized by a specific bone marrow morphology and a rearrangement of the PML- and the RARα-gene mostly due to a balanced translocation between the long arm of chromosome 15 with a breakpoint in 15q22 and the long arm of chromosome 17 with a breakpoint in 17q12-21. The introduction of all trans retinoic acid (ATRA) into treatment protocols has improved the outcome of APL dramatically. Therefore, it is essential to establish the diagnosis of APL as quickly and as reliably as possible. Materials and methods: We investigated 1714 newly diagnosed AML. In 92 cases an AML M3 (n=67) or M3v (n=25) was diagnosed using cytomorphology. In all these cases chromosome banding analysis and molecular studies were performed. Results: In 3/92 APL cases (3.2%) normal chromosomes 15 and 17 in chromosome banding analysis were observed. In these cases either an insertion of parts of the PML-gene into the RARα-locus or an insertion of parts of the RARα-gene into the PML-locus was detected by FISH analysis. In all three patients a PML-RARα-rearrangement was also observed by RT-PCR. Conclusion: A small subgroup of APL shows cryptic rearrangements of the PML- and RARα-gene that are undetectable by cytogenetics. This is analogous to Ph-negative, BCR-ABL-positive CML cases. FISH and RT-PCR have to be performed in all cases that show the typical characteristics of AML M3 or M3v in cytomorphology in addition to chromosome banding analysis. [ABSTRACT FROM AUTHOR]

Undertreatment of older patients with acute myeloid leukemia (AML) can explain, in part, their inferior outcome when compared to that of younger patients. In agreement with the benefit seen by patients under age 60 from high-dose cytosine arabinoside (Ara-C), there are dose effects in the over 60s, in particular for daunorubicin, in induction treatment and for the duration of postremission treatment. The use of these effects can partly overcome the mostly unfavorable disease biology in older age AML, as expressed by the absence of favorable and the over-representation of adverse chromosomal abnormalities as well as the expression of drug resistance. We recommend an adequate dosage of 60 mg/m2 daunorubicin on 3 days in combination with standard dose Ara-C and 6-thioguanine given for induction and consolidation, and followed by a prolonged monthly maintenance chemotherapy for at least 1 year's duration. Further improvements in supportive care may help to deliver additional antileukemic cytotoxicity. As a novel approach, nonmyeloablative preparative regimens may open up the possibility of allogeneic transplantation for older patients with AML. Other new options like multidrug resistance modulators, antibody targeted therapies and molecular targeting are under clinical investigation. A questionnaire study in patients with AML showed that, according to patients’ self-assessment, intensive and prolonged treatment did not result in a diminished quality of life. This finding did not vary by age, under or over 60 years. As the median age in this disease is more than 60 years, the adequate management of AML in older patients remains the major challenge. [ABSTRACT FROM AUTHOR]

Abnormalities of the short arm of chromosome 12 (12p) are found in about 5% of acute nonlymphocytic leukaemias (ANLL) and myelodysplastic syndromes (MDS). They are described to be characteristic of secondary leukaemias, especially after prior mutagenic exposure, and to be associated with a poor prognosis. In our series of 59 patients with 12p abnormalities and ANLL or MDS, exposure to genotoxic agents was proven only in five patients, but in 13/44 patients ANLL evolved from an MDS. Patients with a small deletion del(12)(p11.2p13) having a mild clinical course were distinguished from those with a large del(12)(p11.2), additional chromosomal anomalies, and a poor clinical course. Among the 31 patients with translocations or dicentric chromosomes involving 12p, a group of eight with t/dic(12;13) was the most frequent and was associated with a poor prognosis. The clinical outcome was adverse in the majority of patients with complex karyotype abnormalities, but in some patients a milder clinical course seems likely. A new, hitherto undescribed, abnormality in an MDS case with a duplication dup(12)(p11.2p13) was the amplification of the signal of the yeast artificial chromosome (YAC) clone 964c10 (D12S736). In 38 cases with deletions or unbalanced translocations/dicentrics one YAC signal was lost. Five patients with balanced translocations demonstrated breakpoints within the YAC, containing the ETV6 (TEL) gene. The breakpoints were telomeric to the YAC 964c10 in seven cases and centromeric in one patient. [ABSTRACT FROM AUTHOR]

The article focuses on the formation of the international working group (WG), to produce a definition of resistance or intolerance to hydroxyurea drug in polycythaemia vera (PV) and primary myelofibrosis (PMF) patients. WG was formed in December 2008 and composed of 14 experts in myeloproliferative neoplasms (MPNs) and was chaired by a clinician with expertise in clinical epidemiology. WG proposed six conceptual criteria for the definition of resistance/ intolerance.

A correction to the article "High expression of the Ets-related gene (ERG) is an independent prognostic marker for relapse-free survival in patients with acute promyelocytic leukemia" that was published in a 2013 issue is presented.