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1.  Efficacy of the Hypomethylating Agents as Frontline, Salvage or Consolidation Therapy in Adults with Acute Myeloid Leukemia (AML) 
Annals of hematology  2013;93(1):10.1007/s00277-013-1940-9.
The hypomethylating agents (HA), azacitidine and decitabine, have emerged as an alternative to initial and salvage therapy in patients with AML. Little is known about how AML responds to hypomethylating agents after standard therapy and the activity of these agents in a real world setting is not well studied.
We retrospectively examined data for 75 consecutive AML patients at Wake Forest from 2002–2011 treated with HAs either as 1st line (n=34), salvage (n=28) or consolidation (n=13). We collected data on age, gender, race, Charlson Comorbidity index (CCI), cytogenetics, type of treatment, Complete Remission (CR), Complete Remission with incomplete count recovery (CRi), and survival. Statistical analysis was performed using Kaplan-Meier estimates and cox proportional hazards models.
Frontline response rate (CR+CRi) was 26.5%, median overall survival (OS) was 3.4 (95% CI 1.3–7.4) months, with 18% alive at one year. In the salvage cohort, the response rate was significantly lower compared to frontline (3.6% versus 26.5%, p=0.017). Despite the reduced response, OS from time of HA treatment was longer than frontline at 8.2 (CI 4.8–10.3) months. In the consolidation cohort OS was 13.8 (CI 8.0 – 21.6) months with one patient in remission more than 30 months from diagnosis.
These data suggest prior cytotoxic therapy decrease marrow response rates to HAs but not survival. Furthermore, use of hypomethylating agents for consolidation resulted in a median overall survival over one year in a cohort of older patients. This suggests that hypomethylating agents have activity in all phases of AML treatment.
PMCID: PMC3879720  PMID: 24149914
Decitabine; azacitidine; acute myeloid leukemia; therapy; unfit patients
2.  The Clinical Importance of Moderate/Severe Bone Marrow Fibrosis in Patients with Therapy-related Myelodysplastic Syndromes 
Annals of hematology  2013;92(10):1335-1343.
The presence of moderate to severe bone marrow (BM) fibrosis has been shown to be an adverse feature in patients with primary myelodysplastic syndromes (MDS). However, the clinical importance of BM fibrosis is not clear in therapy-related MDS.
We retrieved all t-MDS cases (n=266) diagnosed at our hospital over a 10-year period (2003–2012). Reticulin and trichromestains were performed in cases in which BM fibrosis was suspected on initial evaluation of hematoxylin & eosin stained slide. BM fibrosis was graded according to European consensus guidelines, and a score of MF2/MF3 was defined as moderate/severe fibrosis.
Moderate/severe BM fibrosis was found in 47 (17%) patients. Compared to 219 patients with no/mild BM fibrosis, the patients with moderate/severe fibrosis presented with severer thrombocytopenia (p=0.039), higher numbers of circulating blasts (p=0.051) but similar degrees of anemia and neutropenia, transfusion requirements, and similar incidences of hepatosplenomegaly and constitutional symptoms. Histological examination revealed a comparable BM cellularity and BM blast percentage, but markedly increased megakaryocytes (p<0.001) in the fibrotic group. Although the risk distribution of cytogenetic data was similar according to the New Comprehensive Cytogenetic Scoring criteria, −5 and −17 were more frequently observed in t-MDS with moderate/severe BM fibrosis (p=0.031 and p=0.043 respectively). With a median follow-up of 11.5 months, patients with moderate/severe BM fibrosis showed a similar risk of acute myeloid leukemia transformation, and a comparable overall survival in univariate and multivariate analyses.
Moderate/severe BM fibrosis in patients with t-MDS is associated with certain clinicopathological and genetic features. However, unlike the situation in patients with primary MDS, moderate/severe BM fibrosis does not add additional risk to patients with therapy-related MDS.
PMCID: PMC4190057  PMID: 23660629
therapy-related myelodysplastic syndromes; bone marrow fibrosis; cytogenetics; overall survival; AML transformation
3.  Mylotarg has potent anti-leukaemic effect: a systematic review and meta-analysis of anti-CD33 antibody treatment in acute myeloid leukaemia 
Annals of Hematology  2014;94:361-373.
Conventional chemotherapy is ineffective in the majority of patients with acute myeloid leukaemia (AML), and monoclonal antibodies recognising CD33 expressed on myeloid progenitors (e.g. gemtuzumab ozogamicin (GO)) have been reported to improve outcome in patients with AML. Reports of excess toxicity have resulted in GO’s licence being withdrawn. As a result, the role of these agents remains unclear. A systematic review and meta-analysis included studies of patients with AML who had entered a randomised control trial (RCT), where one arm included anti-CD33 antibody therapy. Fixed effect meta-analysis was used, involving calculation of observed minus expected number of events, and variance for each endpoint in each trial, with the overall treatment effect expressed as Peto’s odds ratio with 95 % confidence interval. Meta-analysis of 11 RCTs with 13 randomisations involving GO was undertaken. Although GO increased induction deaths (p = 0.02), it led to a reduction in resistant disease (p = 0.0009); hence, there was no improvement in complete remission. Whilst GO improved relapse-free survival (hazard ratio (HR) = 0.90, 95 % confidence interval (CI) = 0.84–0.98, p = 0.01), there was no overall benefit of GO in overall survival (OS) (HR = 0.96, 95 % CI = 0.90–1.02, p = 0.2). GO improved OS in patients with favourable cytogenetics, with no evidence of benefit in patients with intermediate or adverse cytogenetics (test for heterogeneity between subtotals p = 0.01). GO has a potent clinically detectable anti-leukaemic effect. Further trials to investigate its optimum delivery and identification of patient populations who may benefit are needed.
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-014-2218-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4317519  PMID: 25284166
Acute myeloid leukaemia; CD33 antigen; Systematic review; Meta-analysis; Randomised clinical trials; Gemtuzumab; Mylotarg; Humanised monoclonal antibodies
4.  Brentuximab vedotin for relapsed or refractory Hodgkin lymphoma: experience in Turkey 
Annals of Hematology  2014;94:415-420.
Current treatment modalities can cure up to 70–80 % of patients with classical Hodgkin lymphoma. Approximately, 20–30 % of patients require further treatment options. Brentuximab vedotin has been approved for the treatment of relapsed and refractory Hodgkin lymphoma. In the present study, we report the experience with brentuximab vedotin as single agent in 58 patients with relapsed or refractory Hodgkin lymphoma. The objective response rate was 63.5 % with 13 complete responders (26.5 %) among 49 patients evaluated at the early phase of treatment (2–5 cycles). Upon treatment prolongation (≥6 cycles), 37 patients achieved a final objective response rate of 32.4 % with 21.6 % of complete and 10.8 % of partial response. Overall survival at 12 months was 70.6 %, and progression-free survival at 12 months was 32.8 %. Median overall survival could not be reached and median progression-free survival was 7 months. While the median duration of response was 9 months in the whole cohort, it was 11.5 months in the complete responders. Complete response rates in patients treated with >3 chemotherapy regimens before brentuximab vedotin were significantly lower (p = 0.016). Fourteen patients were subsequently transplanted. In conclusion, brentuximab vedotin provided a bridge to transplantation in approximately one quarter of the patients. The declining response rates during the course of treatment suggest that transplantation should be implemented early during brentuximab vedotin treatment.
PMCID: PMC4317523  PMID: 25231929
Brentuximab vedotin; Hodgkin Lymphoma; Relapsed; Refractory
5.  Preexisting TP53 mutation in therapy-related acute myeloid leukemia 
Annals of Hematology  2014;94:527-529.
PMCID: PMC4317506  PMID: 25135451
Therapy-related myeloid neoplasms; TP53; Leukemogenesis
6.  Clinical and hematological presentation of children and adolescents with polycythemia vera 
Annals of hematology  2009;88(8):713-719.
Polycythemia vera (PV) in children and adolescents is very rare. Data on clinical and laboratory evaluations as well as on treatment modalities are sparse. Here, we report the long-term clinical course of a PV patient first diagnosed more than 40 years ago at age 12. In addition, after a systematic review of the scientific medical literature, clinical and hematological data of 35 patients (19 female and 17 male) from 25 previous reports are summarized. Three patients developed PV following antecedent hematological malignancies. Budd–Chiari syndrome was diagnosed in seven patients indicating a particular risk of young patients of developing this disorder. One patient presented with ischemic stroke, one patient with gangrene, and three patients with severe hemorrhage. Three patients died from disease-related complications. Hematocrit levels and platelet counts were not correlated with disease severity. Leukocytosis >15×109/L was present in 9/35 patients and associated with a thromboembolic or hemorrhagic complication in seven patients. The few available data on molecular genetics and endogenous erythroid colony growth indicate changes comparable to those detectable in adult patients. Treatment varied enormously. It included aspirin, phlebotomy, hydroxycarbamide, busulfan, melphalan, pyrimethamine, and interferon-alpha. Two patients successfully underwent stem cell transplantation. Currently, it is impossible to treat an individual pediatric PV patient with an evidence-based regimen.
PMCID: PMC4135082  PMID: 19468728
Polycythemia vera; Childhood; Adolescence; Erythrocytosis; Budd–Chiari syndrome
7.  The impact of TNF superfamily molecules on overall survival in acute myeloid leukaemia: correlation with biological and clinical features 
Annals of Hematology  2014;94:35-43.
B cell-activating factor (BAFF), a proliferation-inducing ligand (APRIL) and apoptosis-inducing ligand (TRAIL) were demonstrated in several haematological diseases including acute myeloid leukemia (AML). Those cytokines are capable of activating a broad spectrum of intracellular signalling cascades that can either induce apoptosis or protect from programmed cell death. We have analysed BAFF, APRIL and TRAIL serum concentrations in 76 patients with newly diagnosed AML and 40 healthy volunteers. The values were significantly higher for APRIL and BAFF but lower for TRAIL compared to healthy volunteers. Induction therapy significantly reduced the values for BAFF and increased them for TRAIL. Moreover, the concentration of BAFF and APRIL was significantly lower and the concentration of TRAIL higher in a group of patients with complete remission compared to non-respondent AML patients. In addition, higher concentrations of BAFF and lower of TRAIL predicted a shorter overall survival, suggesting thereby an important prognostic marker and possible therapeutic target in AML.
PMCID: PMC4281378  PMID: 25085377
Acute myeloid leukaemia; APRIL; BAFF; TRAIL
8.  Pulmonary Manifestations of the Pre-Engraftment Syndrome after Umbilical Cord Blood Transplantation 
Annals of hematology  2013;93(5):847-854.
Pre-engraftment syndrome (PES) is a condition occurring after umbilical cord blood transplantation (UCBT) characterized by fever and erythematous skin rash prior to neutrophil engraftment. We sought to determine the incidence and characterize the pulmonary manifestations of PES.
A retrospective review of patients who underwent UCBT at the University of Kansas Medical Center over a 5 year period was performed. Data collected included patient baseline characteristics, presence of PES, pulmonary findings, treatments and survival.
Forty-four patients underwent UCBT with 22 of those patients developing PES. Full-intensity myeloablative conditioning regimen was found to be a risk factor for development of PES. Of those 22 patients, 13 had resting hypoxemia. The most common radiographic findings included diffuse ground glass opacities with pleural effusions. Fifteen patients with PES received corticosteroids, of which twelve had improvement in fevers and rash. These patients had a trend towards worse mortality than those not receiving corticosteroids. There was a non-significant trend towards worse survival in patients with PES and hypoxemia compared to those without hypoxemia.
PES is a common complication following cord blood transplantation, with hypoxemia being present in over half of patients with PES. Hypoxemia with PES and treatment with corticosteroids may portend a worse prognosis.
PMCID: PMC4109706  PMID: 24346710
Immunocompromised; pre-engraftment syndrome; respiratory failure; umbilical cord blood transplantation
10.  Recommendations of the SFH (French Society of Haematology) for the diagnosis, treatment and follow-up of hairy cell leukaemia 
Annals of Hematology  2014;93(12):1977-1983.
Hairy cell leukaemia (HCL) is a rare haematological malignancy, with approximately 175 new incident cases in France. Diagnosis is based on a careful examination of the blood smear and immunophenotyping of the tumour cells, with a panel of four markers being used specifically to screen for hairy cells (CD11c, CD25, CD103 and CD123). In 2011, the V600E mutation of the BRAF gene in exon 15 was identified in HCL; being present in HCL, it is absent in the variant form of HCL (HCL-v) and in splenic red pulp lymphoma (SRPL), two entities related to HCL. The management of patients with HCL has changed in recent years. A poorer response to purine nucleoside analogues (PNAs) is observed in patients with more marked leukocytosis, bulky splenomegaly, an unmutated immunoglobulin variable heavy chain (IgVH) gene profile, use of VH4–34 or with TP53 mutations. We present the recommendations of a group of 11 experts belonging to a number of French hospitals. This group met in November 2013 to examine the criteria for managing patients with HCL. The ideas and proposals of the group are based on a critical analysis of the recommendations already published in the literature and on an analysis of the practices of clinical haematology departments with experience in managing these patients. The first-line treatment uses purine analogues: cladribine or pentostatin. The role of BRAF inhibitors, whether or not combined with MEK inhibitors, is discussed. The panel of French experts proposed recommendations to manage patients with HCL, which can be used in a daily practice.
PMCID: PMC4221655  PMID: 24994538
Hairy cell leukaemia; Recommendations; Diagnosis; Treatment
11.  Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group 
Annals of Hematology  2014;93(11):1825-1838.
Data on efficacy and safety of azacitidine in acute myeloid leukemia (AML) with >30 % bone marrow (BM) blasts are limited, and the drug can only be used off-label in these patients. We previously reported on the efficacy and safety of azacitidine in 155 AML patients treated within the Austrian Azacitidine Registry ( identifier NCT01595295). We herein update this report with a population almost twice as large (n = 302). This cohort included 172 patients with >30 % BM blasts; 93 % would have been excluded from the pivotal AZA-001 trial (which led to European Medicines Agency (EMA) approval of azacitidine for high-risk myelodysplastic syndromes (MDS) and AML with 20–30 % BM blasts). Despite this much more unfavorable profile, results are encouraging: overall response rate was 48 % in the total cohort and 72 % in patients evaluable according to MDS-IWG-2006 response criteria, respectively. Median OS was 9.6 (95 % CI 8.53–10.7) months. A clinically relevant OS benefit was observed with any form of disease stabilization (marrow stable disease (8.1 months), hematologic improvement (HI) (9.7 months), or the combination thereof (18.9 months)), as compared to patients without response and/or without disease stabilization (3.2 months). Age, white blood cell count, and BM blast count at start of therapy did not influence OS. The baseline factors LDH >225 U/l, ECOG ≥2, comorbidities ≥3, monosomal karyotype, and prior disease-modifying drugs, as well as the response-related factors hematologic improvement and further deepening of response after first response, were significant independent predictors of OS in multivariate analysis. Azacitidine seems effective in WHO-AML, including patients with >30 % BM blasts (currently off-label use). Although currently not regarded as standard form of response assessment in AML, disease stabilization and/or HI should be considered sufficient response to continue treatment with azacitidine.
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-014-2126-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4176957  PMID: 24951123
Austrian Azacitidine Registry; Azacitidine; AML; Overall survival; Prognostic factors; Bone marrow blasts
12.  Functional Inhibition of BCL2 is Needed to Increase the Susceptibility to Apoptosis to SMO Inhibitors in Diffuse Large B-Cell Lymphoma of Germinal Center Subtype 
Annals of hematology  2013;92(6):777-787.
Previously, we have demonstrated that inhibition of Hedgehog pathway induces predominantly apoptosis in diffuse large B-cell lymphoma (DLBCL) cell lines of activated B-cell (ABC) type but predominantly cell cycle arrest in those of germinal center (GC). Here, we explored the possibility of overcoming the resistance to apoptosis to SMO inhibitors in 5 DLBCL cells of GC type using the combination of the SMO inhibitor HhAntag (Genentech Inc) with the BH3 mimetic ABT-737 (Abbott Laboratories). As controls we have used 2 DLBCL of ABC type (OCI-LY10 and OCI-LY3). Combinatorial treatments were performed with increasing concentrations of the HhAntag with low-doses (equal or less than the IC20) of ABT-737. MTT assays were used to detect changes in cell viability and Annexin-V and PARP1 cleavage assays were used to detect apoptosis. Combining low-doses of ABT-737 with increasing concentrations of HhAntag in GC DLBCL cell lines resulted in significantly increase of apoptosis in comparison to treatments with the SMO inhibitor alone. We concluded that in GC DLBCL cell lines, in contrast to those of ABC type, functional inhibition of BCL2 family members is usually needed to overcome the resistance to apoptosis to SMO inhibitors. These findings provide a rationale to explore the use of SMO and BCL2 inhibitors as adjuvant therapy for treatment of DLBCL of GC type.
PMCID: PMC3648611  PMID: 23370596
Smoothened (SMO) inhibitors; ABT-737; BH3 mimetics; HhAntag; Hedgehog signaling; diffuse large B-cell lymphoma
13.  Diffuse large B cell lymphoma: using pathologic and molecular biomarkers to define subgroups for novel therapy 
Annals of Hematology  2014;93(8):1263-1277.
Diffuse large B cell lymphoma (DLBCL) comprises specific subtypes, disease entities, and other not otherwise specified (NOS) lymphomas. This review will focus on DLBCL NOS because of their prevalence and their heterogeneity with respect to morphology, clinical presentation, biology, and response to treatment. Gene expression profiling of DLBCL NOS has identified molecular subgroups that correlate with prognosis and may have relevance for treatment based on signaling pathways. New technologies have revealed that the “activated B cell” subgroup is linked to activation of the nuclear factor kB (NF-kB) pathway, with mutations found in CD79A/B, CARD11, and MYD88, and loss of function mutations in TNFAIP3. The “germinal center B cell-like” subgroup is linked to mutational changes in EZH2 and CREBBP. Biomarkers that are related to pathways promoting tumor cell growth and survival in DLBCL have been recognized, although their predictive role requires clinical validation. Immunohistochemistry for detecting the expression of these biomarkers is a practical technique that could provide a rational for clinical trial design.
PMCID: PMC4082139  PMID: 24870942
DLBCL; Biomarkers; Prognosis; Diagnosis; Treatment
15.  Identification of acquired mutations by whole-genome sequencing in GATA-2 deficiency evolving into myelodysplasia and acute leukemia 
Annals of Hematology  2014;93(9):1515-1522.
Heterozygous GATA-2 germline mutations are associated with overlapping clinical manifestations termed GATA-2 deficiency, characterized by immunodeficiency and predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, there is considerable clinical heterogeneity among patients, and the molecular basis for the evolution of immunodeficiency into MDS/AML remains unknown. Thus, we conducted whole-genome sequencing on a patient with a germline GATA-2 heterozygous mutation (c. 988 C > T; p. R330X), who had a history suggestive of immunodeficiency and evolved into MDS/AML. Analysis was conducted with DNA samples from leukocytes for immunodeficiency, bone marrow mononuclear cells for MDS and bone marrow-derived mesenchymal stem cells. Whereas we did not identify a candidate genomic deletion that may contribute to the evolution into MDS, a total of 280 MDS-specific nonsynonymous single nucleotide variants were identified. By narrowing down with the single nucleotide polymorphism database, the functional missense database, and NCBI information, we finally identified three candidate mutations for EZH2, HECW2 and GATA-1, which may contribute to the evolution of the disease.
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-014-2090-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4119934  PMID: 24782121
GATA-2; GATA-2 deficiency; MonoMAC; Myelodysplastic syndrome; Whole-genome sequencing; EZH2; GATA-1
16.  Management of sepsis in neutropenic patients: 2014 updated guidelines from the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology (AGIHO) 
Annals of Hematology  2014;93(7):1083-1095.
Sepsis is a major cause of mortality during the neutropenic phase after intensive cytotoxic therapies for malignancies. Improved management of sepsis during neutropenia may reduce the mortality of cancer therapies. Clinical guidelines on sepsis treatment have been published by others. However, optimal management may differ between neutropenic and non-neutropenic patients. Our aim is to give evidence-based recommendations for haematologist, oncologists and intensive care physicians on how to manage adult patients with neutropenia and sepsis.
PMCID: PMC4050292  PMID: 24777705
Guideline; Sepsis; Neutropenia; Management
17.  Expression of cereblon protein assessed by immunohistochemicalstaining in myeloma cells is associated with superior response of thalidomide- and lenalidomide-based treatment, but not bortezomib-based treatment, in patients with multiple myeloma 
Annals of Hematology  2014;93(8):1371-1380.
Cereblon (CRBN) is essential for the anti-myeloma (MM) activity of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide. However, the clinical implications of CRBN in MM patients are unclear. Using immunohistochemical (IHC) staining on paraffin-embedded bone marrow sections, the expression of CRBN protein in myeloma cells (MCs) was assessed in 40 relapsed/refractory MM (RRMM) patients who received lenalidomide/dexamethasone (LD) and 45 and 22 newly diagnosed MM (NDMM) patients who received thalidomide/dexamethasone (TD) and melphalan/bortezomib/prednisolone (MVP), respectively. IHC staining were scored on a scale representing the diffuseness and intensity of positive-staining MCs (range, 0–8) and a score ≥4.5 was used for CRBN positivity (CRBN+) on a cut-point analysis of all possible scores and response of TD and LD. Compared to CRBN+ NDMM patients, CRBN− NDMM patients had more international staging system (ISS) III (26 vs. 61 %, respectively; P = 0.006). In the LD and TD cohorts, the response rate (RR) was higher in CRBN+ patients than CRBN− patients (LD 79 vs. 33 %, respectively; P = 0.005) (TD 75 vs. 29 %, respectively; P = 0.005); however, this trend was not observed in the MVP cohort. In the LD and TD cohorts, the positive and negative prediction value of CRBN+ for treatment response was 79 and 67 % and 75 and 71 %, respectively. Multivariate analysis showed that CRBN+ was a significant factor associated with superior RR for LD and TD. The data suggest that expression of CRBN protein in MCs assessed using the IHC is a feasible approach to predict the response of IMiDs in MM patients.
PMCID: PMC4082140  PMID: 24687382
Cereblon; Immunohistochemistry; Immunomodulatory drugs; Multiple myeloma; Prognosis
18.  Older patients with chronic myeloid leukemia (≥65 years) profit more from higher imatinib doses than younger patients: a subanalysis of the randomized CML-Study IV 
Annals of Hematology  2014;93(7):1167-1176.
The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 %) on IM400 and 83 (21 %) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. identifier: NCT00055874
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-014-2041-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4050299  PMID: 24658964
Chronic myeloid leukemia; Older patients; Different imatinib dose regimens; Early applied higher imatinib dosages
19.  Treatment practice in the elderly patient with chronic lymphocytic leukemia—analysis of the combined SEER and Medicare database 
Annals of Hematology  2014;93(8):1335-1344.
The median age at diagnosis of chronic lymphocytic leukemia (CLL) is 72, but patients enrolled in randomized trials are often a decade younger. Therapy selection and outcomes in the older, comorbid population are less understood. We evaluated treatment patterns and outcomes among 2,985 first primary CLL patients from the linked Surveillance, Epidemiology, and End Results–Medicare database. There were 151 chlorambucil (CLB), 594 rituximab monotherapy (R-mono), 696 rituximab + intravenous chemotherapy (R + IV Chemo), and 1,544 IV chemo-only patients. Patients administered CLB and R-mono were the oldest and had the highest comorbidity burden while patients receiving R + IV Chemo were the youngest and had the lowest comorbidity burden (p < 0.0001). In the multivariate survival analysis, receipt of R + IV Chemo was associated with significantly lower mortality risk vs. IV Chemo-only (hazard ratio (HR) = 0.73; 95 % confidence interval (CI) 0.62–0.87) and a non-significant mortality risk reduction with R-mono vs. CLB (HR = 0.47; 95 % CI: 0.21-1.05). Older age and increasing comorbidity score were significantly associated with higher mortality. These findings suggest that chemoimmunotherapy is more effective than chemotherapy in an elderly population with a high prevalence of comorbidity, and this extends the conclusions from clinical trials in younger, medically fit patients.
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-014-2048-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4082137  PMID: 24638841
Chronic lymphocytic leukemia; Comorbidity; Elderly; Treatment; Survival
21.  Progress in detecting cell-surface protein receptors: the erythropoietin receptor example 
Annals of Hematology  2013;93(2):181-192.
Testing for the presence of specific cell-surface receptors (such as EGFR or HER2) on tumor cells is an integral part of cancer care in terms of treatment decisions and prognosis. Understanding the strengths and limitations of these tests is important because inaccurate results may occur if procedures designed to prevent false-negative or false-positive outcomes are not employed. This review discusses tests commonly used to identify and characterize cell-surface receptors, such as the erythropoietin receptor (EpoR). First, a summary is provided on the biology of the Epo/EpoR system, describing how EpoR is expressed on erythrocytic progenitors and precursors in the bone marrow where it mediates red blood cell production in response to Epo. Second, studies are described that investigated whether erythropoiesis-stimulating agents could stimulate tumor progression in cancer patients and whether EpoR is expressed and functional on tumor cells or on endothelial cells. The methods used in these studies included immunohistochemistry, Northern blotting, Western blotting, and binding assays. This review summarizes the strengths and limitations of these methods. Critically analyzing data from tests for cell-surface receptors such as EpoR requires understanding the techniques utilized and demonstrating that results are consistent with current knowledge about receptor biology.
PMCID: PMC3890056  PMID: 24337485
Erythropoietin receptor; Erythropoiesis; Cancer; Angiogenesis; Antibody
22.  Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells 
Annals of hematology  2012;91(12):1861-1870.
DNA methylation and BLC-2 are potential therapeutic targets in acute myeloid leukemia (AML). We investigated pharmacologic interaction between the DNA methyltransferase inhibitor 5-azacytidine (5-AZA) and the BCL-2 inhibitor ABT-737. Increased BCL-2 expression determined by reverse phase protein analysis was associated with poor survival in AML patients with unfavorable cytogenetics (n=195). We found that 5-AZA, which itself has modest apoptotic activity, acts synergistically with ABT-737 to induce apoptosis. The 5-AZA/ABT-737 combination enhanced mitochondrial outer membrane permeabilization, as evidenced by effective conformational activation of BAX and Δψm loss. Although absence of p53 limited apoptotic activities of 5-AZA and ABT-737 as single agents, the combination synergistically induced apoptosis independent of p53 expression. 5-AZA down-regulated MCL-1, known to mediate resistance to ABT-737, in a p53-independent manner. The 5-AZA/ABT-737 combination synergistically induced apoptosis in AML cells from 7 of 8 patients. 5-AZA significantly reduced MCL-1 levels in 2 of 3 samples examined. Our data provide a molecular rationale for this combination strategy in AML therapy.
PMCID: PMC3750747  PMID: 22893484
AML; 5-azacytidine; ABT-737; BCL-2; MCL-1; p53
23.  The pathogenic relevance of the prognostic markers CD38 and CD49d in chronic lymphocytic leukemia 
Annals of Hematology  2013;93(3):361-374.
The interactions of chronic lymphocytic leukemia cells with the microenvironment in secondary lymphoid tissues and the bone marrow are known to promote CLL cell survival and proliferation. CD38 and CD49d are both independent prognostic risk parameters in CLL with important roles in shaping these interactions. Both are reported to influence CLL cell trafficking between blood and lymphoid organs as well as their survival and proliferation within the lymphoid organs, thereby impacting the pathophysiology of the disease. The expression of CD38 and CD49d is associated in the majority of cases, and they exist as part of macromolecular complexes. Here, we review the current evidence for the individual and associated contributions of these molecules to CLL pathophysiology.
PMCID: PMC4032465  PMID: 24288111
Chronic lymphocytic leukemia; Microenvironment; CD38; CD49d; VLA-4
24.  A highly specific q-RT-PCR assay to address the relevance of the JAK2WT and JAK2V617F expression levels and control genes in Ph-negative myeloproliferative neoplasms 
Annals of Hematology  2013;93(4):609-616.
In Ph− myeloproliferative neoplasms, the quantification of the JAK2V617F transcripts may provide some advantages over the DNA allele burden determination. We developed a q-RT-PCR to assess the JAK2WT and JAK2V617F mRNA expression in 105 cases (23 donors, 13 secondary polycythemia, 22 polycythemia vera (PV), 38 essential thrombocythemia (ET), and 9 primary myelofibrosis (PMF)). Compared with the standard allele-specific oligonucleotide (ASO)-PCR technique, our assay showed a 100 % concordance rate detecting the JAK2V617F mutation in 22/22 PV (100 %), 29/38 (76.3 %) ET, and 5/9 (55.5 %) PMF cases, respectively. The sensitivity of the assay was 0.01 %. Comparing DNA and RNA samples, we found that the JAK2V617F mutational ratios were significantly higher at the RNA level both in PV (p = 0.005) and ET (p = 0.001) samples. In PV patients, JAK2WT expression levels positively correlated with the platelets (PLTs) (p = 0.003) whereas a trend to negative correlation was observed with the Hb levels (p = 0.051). JAK2V617F-positive cases showed the lowest JAK2WT and ABL1 mRNA expression levels. In all the samples, the expression pattern of beta-glucoronidase (GUSB) was more homogeneous than that of ABL1 or β2 microglobulin (B2M). Using GUSB as normalizator gene, a significant increase of the JAK2V617F mRNA levels was seen in two ET patients at time of progression to PV. In conclusion, the proposed q-RT-PCR is a sensitive and accurate method to quantify the JAK2 mutational status that can also show clinical correlations suggesting the impact of the residual amount of the JAK2WT allele on the Ph− MPN disease phenotype. Our observations also preclude the use of ABL1 as a housekeeping gene for these neoplasms.
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-013-1920-0) contains supplementary material, which is available to authorized users.
PMCID: PMC3945640  PMID: 24173087
Ph− myeloproliferative neoplasms; JAK2WT level; JAK2V617F level; Housekeeping gene; q-RT-PCR
25.  Younger patients with chronic myeloid leukemia do well in spite of poor prognostic indicators: results from the randomized CML study IV 
Annals of Hematology  2013;93(1):71-80.
Since the advent of tyrosine kinase inhibitors, the impact of age on outcome of chronic myeloid leukemia (CML) patients has changed. We therefore analyzed patients from the randomized CML study IV to investigate disease manifestations and outcome in different age groups. One thousand five hundred twenty-four patients with BCR-ABL-positive chronic phase CML were divided into four age groups: (1) 16–29 years, n = 120; (2) 30–44 years, n = 383; (3) 45–59 years, n = 495; and (4) ≥60 years, n = 526. Group 1 (adolescents and young adults (AYAs)) presented with more aggressive disease features (larger spleen size, more frequent symptoms of organomegaly, higher white blood count, higher percentage of peripheral blasts and lower hemoglobin levels) than the other age groups. In addition, a higher rate of patients with BCR-ABL transcript levels >10 % on the international scale (IS) at 3 months was observed. After a median observation time of 67.5 months, no inferior survival and no differences in cytogenetic and molecular remissions or progression rates were observed. We conclude that AYAs show more aggressive features and poor prognostic indicators possibly indicating differences in disease biology. This, however, does not affect outcome.
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-013-1937-4) contains supplementary material, which is available to authorized users.
PMCID: PMC3889634  PMID: 24162333
Chronic myeloid leukemia; Accelerated phase; Blast crisis; Young adults and adolescents

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