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1.  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.
doi:10.1007/s00277-013-1684-6
PMCID: PMC3648611  PMID: 23370596
Smoothened (SMO) inhibitors; ABT-737; BH3 mimetics; HhAntag; Hedgehog signaling; diffuse large B-cell lymphoma
2.  Diffuse large B cell lymphoma: using pathologic and molecular biomarkers to define subgroups for novel therapy 
Annals of Hematology  2014;93:1263-1277.
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.
doi:10.1007/s00277-014-2116-y
PMCID: PMC4082139  PMID: 24870942
DLBCL; Biomarkers; Prognosis; Diagnosis; Treatment
4.  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;93:1083-1095.
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.
doi:10.1007/s00277-014-2086-0
PMCID: PMC4050292  PMID: 24777705
Guideline; Sepsis; Neutropenia; Management
5.  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;93:1371-1380.
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.
doi:10.1007/s00277-014-2063-7
PMCID: PMC4082140  PMID: 24687382
Cereblon; Immunohistochemistry; Immunomodulatory drugs; Multiple myeloma; Prognosis
6.  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;93:1167-1176.
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. ClinicalTrials.gov 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.
doi:10.1007/s00277-014-2041-0
PMCID: PMC4050299  PMID: 24658964
Chronic myeloid leukemia; Older patients; Different imatinib dose regimens; Early applied higher imatinib dosages
7.  Treatment practice in the elderly patient with chronic lymphocytic leukemia—analysis of the combined SEER and Medicare database 
Annals of Hematology  2014;93:1335-1344.
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.
doi:10.1007/s00277-014-2048-6
PMCID: PMC4082137  PMID: 24638841
Chronic lymphocytic leukemia; Comorbidity; Elderly; Treatment; Survival
8.  Progress in detecting cell-surface protein receptors: the erythropoietin receptor example 
Annals of Hematology  2013;93:181-192.
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.
doi:10.1007/s00277-013-1947-2
PMCID: PMC3890056  PMID: 24337485
Erythropoietin receptor; Erythropoiesis; Cancer; Angiogenesis; Antibody
9.  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.
doi:10.1007/s00277-012-1537-8
PMCID: PMC3750747  PMID: 22893484
AML; 5-azacytidine; ABT-737; BCL-2; MCL-1; p53
10.  The pathogenic relevance of the prognostic markers CD38 and CD49d in chronic lymphocytic leukemia 
Annals of Hematology  2013;93:361-374.
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.
doi:10.1007/s00277-013-1967-y
PMCID: PMC4032465  PMID: 24288111
Chronic lymphocytic leukemia; Microenvironment; CD38; CD49d; VLA-4
11.  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;93:609-616.
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.
doi:10.1007/s00277-013-1920-0
PMCID: PMC3945640  PMID: 24173087
Ph− myeloproliferative neoplasms; JAK2WT level; JAK2V617F level; Housekeeping gene; q-RT-PCR
12.  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;93:71-80.
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.
doi:10.1007/s00277-013-1937-4
PMCID: PMC3889634  PMID: 24162333
Chronic myeloid leukemia; Accelerated phase; Blast crisis; Young adults and adolescents
13.  Protein Z/protein Z-dependent protease inhibitor system in loco in human gastric cancer 
Annals of Hematology  2013;93:779-784.
In gastric cancer, hemostatic system components contribute to cancer progression, as activation of factor X (FX) was observed. The protein Z (PZ)/protein Z-dependent protease inhibitor (ZPI) complex inhibits factor Xa proteolytic activity. The purpose of this study was to determine the distribution of ZPI and PZ in relation to FX, and prothrombin fragment (F1 + 2), a standard marker for blood coagulation activation, in human gastric cancer tissue. ABC procedures and a double staining method employed polyclonal antibodies against PZ, FX, and F1 + 2 and a monoclonal antibody against ZPI. In situ hybridization (ISH) methods employed biotin-labeled 25-nucleotide single-stranded DNA probes directed to either PZ or ZPI mRNAs. FX and components of PZ/ZPI coagulation inhibitory system were observed in cancer cells. F1 + 2 was observed in gastric cancer cells as well. Double staining studies revealed FX/PZ, FX/ZPI, and PZ/ZPI co-localization on gastric cancer cells. ISH studies demonstrated the presence of PZ mRNA and ZPI mRNA in gastric cancer cells indicating induced synthesis of these proteins. The co-localization of PZ/ZPI and FX in gastric cancer cells indicates in loco that these proteins may play a role in anticoagulant events at the tumor tissue.
doi:10.1007/s00277-013-1941-8
PMCID: PMC3976510  PMID: 24158387
Gastric cancer; Protein Z; Protein Z-dependent protease inhibitor; Coagulation inhibitor; Factor X
14.  A high sIL-2R/ferritin ratio is a useful marker for the diagnosis of lymphoma-associated hemophagocytic syndrome 
Annals of Hematology  2013;93:821-826.
Lymphoma-associated hemophagocytic syndrome (LAHS), which is the major subtype of adult-onset secondary hemophagocytic lymphohistiocytosis (HLH), has a poor outcome. Although the early diagnosis and treatment of LAHS contributes to a better outcome, the lack of mass formation and the absence of distinct lymph node enlargement often delay the diagnosis of underlying lymphoma. A recent study, which statistically analyzed HLH cases in the literature, showed that the serum soluble interleukin-2 receptor (sIL-2R)/ferritin ratio could be used as a marker to diagnosis of LAHS. To verify this finding, we retrospectively analyzed the laboratory findings of 21 patients with HLH (10 benign disease-associated HLH and 11 LAHS). No significant differences were observed in the levels of LDH or CRP levels. The mean sIL-2R levels (units per milliliter) were significantly higher in the LAHS group (4,176 vs. 13,451, p = 0.0031), and ferritin levels (nanogram per milliliter) were higher in the benign disease-associated HLH group (20,462 vs. 2,561, p = 0.0031). Consequently, the mean serum sIL-2R/ferritin ratio of patients with LAHS was markedly higher than that of patients with benign disease-associated HLH (0.66 vs. 8.56, p = 0.0004). Thus, the results of this study demonstrated that the serum sIL-2R/ferritin ratio is a very useful marker for diagnosing of LAHS, which was further supported by clinical case analysis. Further studies to clarify the pathophysiology of secondary HLH caused by various triggers are needed.
doi:10.1007/s00277-013-1925-8
PMCID: PMC3976506  PMID: 24705932
Lymphoma-associated hemophagocytic syndrome; Malignant lymphoma; Soluble interleukin-2 receptor; Ferritin
15.  BAFF and APRIL as TNF superfamily molecules and angiogenesis parallel progression of human multiple myeloma 
Annals of Hematology  2013;93:635-644.
Tumour necrosis factor alpha (TNF-α) is an inflammatory cytokine with a wide spectrum of biological activity, including angiogenesis. B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are members of the TNF-α family. Vascular endothelial growth factor (VEGF), on the other hand, is one of the most characteristic pro-angiogenic cytokines produced by multiple cell types in multiple myeloma (MM). We have analysed BAFF and APRIL concentrations in parallel with pro-angiogenic cytokines in serum and trephine biopsy, and the bone marrow microvascular density (MVD) in 50 patients with newly diagnosed IgG MM and 24 healthy volunteers. The study showed statistically higher concentrations of BAFF, APRIL and TNF-α, as well as VEGF and its receptor, in MM patients compared to healthy volunteers and patients in advanced stages of the disease. A statistically positive correlation between the concentration of TNF-α and the expression of VEGF was demonstrated, and so was a positive link between BAFF, APRIL, MVD and lactate dehydrogenase (LDH). Furthermore, we observed a significant decrease in all studied cytokines after anti-angiogenic therapy, with meaningful differences between responders (at least partial remission) and patients with stable disease. It was also established that APRIL, but not BAFF, correlated with pro-angiogenic cytokines such as VEGF with its receptor, MVD and syndecan-1. Finally, our results showed that serum BAFF and APRIL levels could be useful biomarkers of MM disease activity and its progression which suggests that APRIL could be a possible novel therapeutic target in MM.
doi:10.1007/s00277-013-1924-9
PMCID: PMC3945232  PMID: 24141333
Multiple myeloma; APRIL; BAFF; VEGF; Angiogenesis
16.  Treatment of invasive fungal infections in cancer patients—updated recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) 
Annals of Hematology  2013;93:13-32.
The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient’s risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information.
doi:10.1007/s00277-013-1867-1
PMCID: PMC3889633  PMID: 24026426
Mycoses; Antifungal agents; Aspergillosis; Invasive candidiasis; Hematologic malignancies
18.  Lenalidomide as a disease-modifying agent in patients with del(5q) myelodysplastic syndromes: linking mechanism of action to clinical outcomes 
Annals of Hematology  2013;93:1-11.
Deletion of the long arm of chromosome 5, del(5q), is the most prevalent cytogenetic abnormality in patients with myelodysplastic syndromes (MDS). In isolation, it is traditionally associated with favorable prognosis compared with other subtypes of MDS. However, owing to the inherent heterogeneity of the disease, prognosis for patients with del(5q) MDS is highly variable depending on the presence of factors such as additional chromosomal abnormalities, >5 % blasts in the bone marrow (BM), or transfusion dependence. Over recent years, the immunomodulatory drug lenalidomide has demonstrated remarkable efficacy in patients with del(5q) MDS. Advances in the understanding of the pathogenesis of the disease have suggested that lenalidomide targets aberrant signaling pathways caused by haplosufficiency of specific genes in a commonly deleted region on chromosome 5 (e.g., SPARC, RPS14, Cdc25C, and PP2A). As a result, the agent specifically targets del(5q) clones while also promoting erythropoiesis and repopulation of the bone marrow in normal cells. This review discusses recent developments in the understanding of the mechanism of action of lenalidomide, and how this underlies favorable outcomes in patients with del(5q) MDS. In addition, we discuss how improved understanding of the mechanism of disease will facilitate clinicians’ ability to predict/monitor response and identify patients at risk of relapse.
doi:10.1007/s00277-013-1863-5
PMCID: PMC3889654  PMID: 24018623
Erythropoiesis; Immunomodulatory; Lenalidomide; Myelodysplastic syndromes
19.  IP-10/CXCL10 and MIG/CXCL9 as novel markers for the diagnosis of lymphoma-associated hemophagocytic syndrome 
Annals of Hematology  2013;93:393-401.
Lymphoma-associated hemophagocytic syndrome (LAHS) is a serious disorder, and its early diagnosis and treatment with appropriate chemotherapy are very important. However, reliable markers for early diagnosis of LAHS have not been identified. We screened serum cytokines using a newly introduced assay system, cytometric bead array (CBA), and identified interferon-inducible protein 10 (IP-10)/CXCL10 and monokine induced by interferon gamma (MIG)/CXCL9 as useful markers. Serum concentrations of IP-10 and MIG at the time of LAHS diagnosis were greater than 500 and 5,000 pg/ml, respectively. The sensitivity and specificity for LAHS diagnosis were 100 and 95 %, respectively, when we set the above values as the cut-off levels. Serum levels of these two chemokines were already elevated at the time of admission and significantly decreased after successful treatment, indicating their usefulness for both the diagnosis and therapeutic outcomes for LAHS. IP-10 and MIG were also useful in distinguishing severe from moderate/mild LAHS, and B-cell-type LAHS from T-cell/natural killer cell-type LAHS. Furthermore, IP-10 and MIG were of use to distinguish LAHS from sepsis in patients with hematologic malignancies. Rapid measurement of IP-10 and MIG by CBA appeared to be important for early diagnosis and treatment of LAHS.
doi:10.1007/s00277-013-1878-y
PMCID: PMC3918116  PMID: 23975214
Lymphoma-associated hemophagocytic syndrome; IP-10; MIG; Cytometric bead array
20.  CHO(E)P-14 followed by alemtuzumab consolidation in untreated peripheral T cell lymphomas: final analysis of a prospective phase II trial 
Annals of Hematology  2013;92:1521-1528.
The rate of long-term remissions after treatment of peripheral T cell lymphomas (PTCL) with standard CHOP-like protocols is unsatisfactory. A prospective multicenter phase II trial was initiated in untreated patients with PTCL of all International Prognostic Index-risk groups, evaluating alemtuzumab consolidation in patients with complete or good partial remission after CHO(E)P-14 induction. Twenty-nine (70.7 %) of the 41 enrolled patients received alemtuzumab consolidation (133 mg in total). The main grades 3–4 toxicities during alemtuzumab therapy were infections and neutropenia with one potentially treatment-related death. Complete responses were seen in 58.5 %, partial responses in 2.4 % and 29.3 % had progressive disease. After a median observation time of 46 months, 19 patients have died, 16 of them due to lymphoma and/or salvage therapy complications. Event-free and overall survival at 3 years in the whole intent to treat population are 32.3 and 62.5 %, respectively, and 42.4 and 75.1 % in the patients who received alemtuzumab. In conclusion, application of a short course of alemtuzumab after CHO(E)P-14 induction is feasible although complicated by severe infections. A current phase III trial, applying alemtuzumab as part of the initial chemotherapy protocol to avoid early progression, will further clarify its significance for the therapeutic outcome.
doi:10.1007/s00277-013-1880-4
PMCID: PMC3790248  PMID: 23978945
Alemtuzumab; Phase II trial; T cell lymphoma
21.  Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma 
Annals of Hematology  2013;93:403-409.
Patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) are treated with salvage regimens and may be considered for high-dose chemotherapy and autologous stem cell transplantation if disease is chemosensitive. Bendamustine is active in indolent B cell lymphomas and chronic lymphocytic leukemia but has not been extensively studied in aggressive lymphomas. This trial examines the combination of bendamustine and rituximab in patients with relapsed and refractory DLBCL. Patients received bendamustine at 90 mg/m2 (n = 2) or 120 mg/m2 (n = 57) on days 1 and 2 and rituximab at 375 mg/m2 on day 1 every 28 days for up to 6 cycles. The study evaluated objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and treatment safety. Fifty-nine patients were treated, and 48 were evaluable for response. Median age was 74; 89 % had stage III or IV disease, and 63 % had high revised International Prognostic Index scores; the median number of prior therapies was 1. Based on analysis using the intent-to-treat population, the ORR was 45.8 % (complete response, 15.3 %; partial response, 30.5 %). The median DOR was 17.3 months, and the median PFS was 3.6 months. Grade 3 or 4 hematological toxicities included neutropenia (36 %), leukopenia (29 %), thrombocytopenia (22 %), and anemia (12 %). The combination of bendamustine and rituximab showed modest activity in patients with relapsed and refractory DLBCL and has an acceptable toxicity profile.
doi:10.1007/s00277-013-1879-x
PMCID: PMC3918114  PMID: 23955074
Diffuse large B cell lymphoma; Bendamustine; Alkylating agents; Rituximab; CD20; Chemotherapy; Aggressive lymphoma
22.  Deferasirox effectively reduces iron overload in non-transfusion-dependent thalassemia (NTDT) patients: 1-year extension results from the THALASSA study 
Annals of Hematology  2013;92:1485-1493.
Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload that requires chelation to levels below the threshold associated with complications. This can take several years in patients with high iron burden, highlighting the value of long-term chelation data. Here, we report the 1-year extension of the THALASSA trial assessing deferasirox in NTDT; patients continued with deferasirox or crossed from placebo to deferasirox. Of 133 patients entering extension, 130 completed. Liver iron concentration (LIC) continued to decrease with deferasirox over 2 years; mean change was −7.14 mg Fe/g dry weight (dw) (mean dose 9.8 ± 3.6 mg/kg/day). In patients originally randomized to placebo, whose LIC had increased by the end of the core study, LIC decreased in the extension with deferasirox with a mean change of −6.66 mg Fe/g dw (baseline to month 24; mean dose in extension 13.7 ± 4.6 mg/kg/day). Of 166 patients enrolled, 64 (38.6 %) and 24 (14.5 %) patients achieved LIC <5 and <3 mg Fe/g dw by the end of the study, respectively. Mean LIC reduction was greatest in patients with the highest pretreatment LIC. Deferasirox progressively decreases iron overload over 2 years in NTDT patients with both low and high LIC. Safety profile of deferasirox over 2 years was consistent with that in the core study.
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-013-1808-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s00277-013-1808-z
PMCID: PMC3790249  PMID: 23775581
Iron overload; Iron chelation; Non-transfusion-dependent thalassemia; Deferasirox
23.  Inhibition of p38 MAPK activity promotes ex vivo expansion of human cord blood hematopoietic stem cells 
Annals of Hematology  2012;91(6):813-823.
Ex vivo expansion of hematopoietic stem cells (HSCs) depends on HSC self-renewing proliferation and functional maintenance, which can be negatively affected by HSC differentiation, apoptosis, and senescence. Therefore, inhibition of HSC senescence may promote HSC expansion. To test this hypothesis, we examined the effect of inhibition of p38 mitogen-activated protein kinase (p38) on the expansion of human umbilical cord blood (hUCB) CD133+ cells because activation of p38 has been implicated in the induction of HSC senescence under various physiological and pathological conditions. Our results showed that ex vivo expansion of hUCB CD133+ cells activated p38, which was abrogated by the p38 specific inhibitor SB203580 (SB). Inhibition of p38 activity with SB promoted the expansion of CD133+ cells and CD133+CD38− cells. In addition, hUCB CD133+ cells expanded in the presence of SB for 7 days showed about threefold increase in the clonogenic function of HSCs and engraftment in non-obese diabetic/severe combined immunodeficient mice after transplantation compared to the input cells. In contrast, the cells expanded without SB exhibited a significant reduction in these HSC functions. The enhancement of ex vivo expansion of hUCB HSCs is primarily attributable to SB-mediated inhibition of HSC senescence. In addition, inhibition of HSC apoptosis and upregulation of CXCR4 may also contribute to the enhancement. However, p38 inhibition had no significant effect on HSC differentiation and proliferation. These findings suggest that inhibition of p38 activation may represent a novel strategy to promote ex vivo expansion of hUCB HSCs.
doi:10.1007/s00277-011-1397-7
PMCID: PMC3390192  PMID: 22258328
Human umbilical cord blood; Hematopoietic stem cells; Ex vivo expansion; p38; Senescence
24.  Management of elderly patients with acute promyelocytic leukemia: progress and problems 
Annals of Hematology  2013;92:1181-1188.
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.
doi:10.1007/s00277-013-1788-z
PMCID: PMC3734597  PMID: 23694997
Acute promyelocytic leukemia; Elderly patients; Incidence; Early death; Treatment; Prognosis
25.  Monitoring dendritic cell and cytokine biomarkers during remission prior to relapse in patients with FLT3-ITD acute myeloid leukemia 
Annals of Hematology  2013;92(8):1079-1090.
Relapse occurs frequently after treatment of acute myeloid leukemia (AML) patients with the FMS-like tyrosine kinase 3-internal tandem duplication (ITD) mutation. The availability of immunologic biomarkers to predict patients at high risk could allow clinicians to accelerate alternative treatments such as stem cell transplantation, immunotherapy, or novel drugs. We have previously reported that first diagnostic (FD) ITD+ AML showed immunophenotypic and functional characteristics of arrested dendritic cell (DC) precursors. In this study, we show that the high frequency of precursor DCs in 16 FD ITD+ AML samples (Lin−/HLA-DR+/CD11c+/CD123+) was associated with a lack of terminal DCs (myeloid DCs: BDCA-1+ or BDCA-3+; plasmacytoid DC: BDCA-2+). We further evaluated prospectively the peripheral blood complete remission (CR) samples obtained from 11 ITD+ AML patients after chemotherapy regarding the frequency of DCs and their pattern of cytokine production. Whereas the aberrant frequencies of precursor and terminal plasmacytoid DCs resolved during remission, the myeloid DC compartment did not fully recover. For an available cohort of patients (n = 4) who could be monitored over a period of >15 months after FD, we identified IL-10, TNF-α, IL-6, and IL-1β as cytokines produced by the CR samples at high levels a few months prior to relapse. Cell-free supernatant of an FD ITD+ AML sample stimulated monocytes obtained from two healthy donors to secrete IL-10, TNF-α, IL-6, and IL-1β. Thus, we hypothesize that ITD+ AML minimal residual disease can act directly as dysfunctional antigen-presenting cells or indirectly by production of factors that convert monocytes into myeloid-derived suppressor cells secreting cytokines that promote immune evasion. Monitoring these immunologic biomarkers could improve prediction of relapse.
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-013-1744-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s00277-013-1744-y
PMCID: PMC3701796  PMID: 23616009
Leukemia; Dendritic cell; Immune monitoring; Myeloid-derived suppressor cells; Risk of relapse; Inflammatory cytokines

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