Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial.

BACKGROUND: Aponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, is a potential death receptor 4/5-targeted antitumour candidate. Previous phase 1/2 studies have demonstrated the efficacy of aponermin in patients with relapsed or refractory multiple myeloma (RRMM). To confirm the superiority of aponermin plus thalidomide and dexamethasone (aponermin group) over placebo plus thalidomide and dexamethasone (placebo group) in RRMM, a randomized, double-blinded, placebo controlled phase 3 trial was performed. METHODS: Four hundred seventeen patients with RRMM who had previously received at least two regimens were randomly assigned (2:1) to receive aponermin, thalidomide, and dexamethasone or placebo, thalidomide, and dexamethasone. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and overall response rate (ORR). RESULTS: A total of 415 patients received at least one dose of trial treatment (276 vs. 139). The median PFS was 5.5 months in the aponermin group and 3.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.49-0.78; P < 0.001). The median OS was 22.4 months for the aponermin group and 16.4 months for the placebo group (hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Significantly higher rates of ORR (30.4% vs. 13.7%, P < 0.001) and very good partial response or better (14.1% vs. 2.2%, P < 0.0001) were achieved in the aponermin group than in the placebo group. Treatment with aponermin caused hepatotoxicity in some patients, as indicated by the elevated alanine transaminase, aspartate transaminase, or lactate dehydrogenase levels (52.2% vs. 24.5%, 51.1% vs. 19.4% and 44.9% vs. 21.6%, respectively), mostly grade 1/2, transient and reversible. The main grade 3/4 adverse events included neutropenia, pneumonia and hyperglycemia. The incidence of serious adverse events was similar between the two groups (40.6% vs. 37.4%). There was no evidence that aponermin leads to hematological toxicity, nephrotoxicity, cardiotoxicity, or secondary tumors. CONCLUSIONS: Aponermin plus thalidomide and dexamethasone significantly improved PFS, OS and ORR with manageable side effects in RRMM patients who had received at least two prior therapies. These results support the use of aponermin, thalidomide, and dexamethasone as a treatment option for RRMM patients. TRIAL REGISTRATION: The trial was registered at http://www.chictr.org.cn as ChiCTR-IPR-15006024, 17/11/2014.

EphB4/ephrinB2 Contributes to Imatinib Resistance in Chronic Myeloid Leukemia Involved in Cytoskeletal Proteins.

INTRODUCTION: The mechanism of EphB4/ephrinB2 in the resistance of chronic myelogenous leukemia to imatinib keeps unknown. METHODS: The imatinib resistant chronic myelogenous leukemia cell line-K562-R, was established. EphB4 receptor expression was detected in patients and resistant cells. Cell migration and drug sensitivity were tested in the EphB4 knockdown cells and mouse models. RESULTS: The EphB4 receptor was over-expressed in blast crisis patients compared to chronic phase patients. The level of EphB4 receptor expression was associated with a complete cytogenetic response within 12 months. Enhanced expression of the EphB4 receptor was detected in the K562-R cells. EphB4 knockdown inhibited cell migration ability and restored sensitivity to imatinib in vitro and in vivo. Restored sensitivity to imatinib was observed in K562-R cells, along with increased levels of phospho-EphB4 and decreased phosphorylation levels of RhoA, Rac1, and Cdc42. CONCLUSION: Our study illustrates that aberrant activation of EphB4/ephrinB2 may mediate chronic myeloid leukemia resistance involved in cytoskeletal proteins.

miR-29a and miR-142-3p downregulation and diagnostic implication in human acute myeloid leukemia.

Expression profiling of microRNAs (miRNAs) in most diseases might be popular and provide the possibility for diagnostic implication, but few studies have accurately quantified the expression level of dysregulated miRNAs in acute myeloid leukemia (AML). In this study, we analyzed the peripheral blood mononuclear cells (PBMCs) from 10 AML patients (subtypes M1 to M5) and six normal controls by miRNA microarray and identified several differentially expressed miRNAs. Among them miR-29a and miR-142-3p were selectively encountered in Northern blot analysis and their significantly decreased expression in AML was further confirmed. Quantitative real-time PCR in 52 primarily diagnosed AML patients and 100 normal controls not only verified the expression properties of these 2 miRNAs, but also established that the expression level of miR-142-3p and miR-29a in PBMCs could be used as novel diagnostic markers. A better diagnostic outcome was achieved by combining miR-29a and miR-142-3p with about 90% sensitivity, 100% specificity, and an area under the ROC curve (AUC) of 0.97. Our results provide insights into the involvement of miRNAs in leukemogenesis, and offer candidates for AML diagnosis and therapeutic strategy.

The plasma level of mCRP is linked to cardiovascular disease in antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: C-reactive protein (CRP) has two natural isomers: C-reactive protein pentamer (pCRP) and C-reactive protein monomer (mCRP). The levels of CRP are significantly elevated in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). mCRP not only activates the endothelial cells, platelets, leukocytes, and complements, but also has a proinflammatory structural subtype that can localize and deposit in inflammatory tissues. Thus, it regulates a variety of clinical diseases, such as ischemia/reperfusion (I/R) injury, Alzheimer's disease, age-related macular degeneration, and cardiovascular disease. We hypothesized that plasma mCRP levels are related to cardiovascular disease in AAV. METHODS: In this cross-sectional study, 37 patients with AAV were assessed. Brain natriuretic peptide (BNP) and mCRP in plasma were assessed by enzyme-linked immunosorbent assay (ELISA). The acute ST-segment elevation myocardial infarction (STEMI) was diagnosed by coronary angiography, and the Gensini score calculated. Echocardiography evaluated the ejection fraction (EF%), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and left ventricular mass index (LVMI). Estimated glomerular filtration rate (eGFR) was calculated based on serum creatinine, age, and gender. RESULTS: The plasma level of mCRP in AAV was significantly higher than that in healthy volunteers (P < 0.001). Then, mCRP and CRP levels were compared with and without STEMI complications in AAV. The plasma level of mCRP was higher, but that of CRP was lower in STEMI. The plasma level of mCRP was correlated with Birmingham vasculitis activity score (BVAS), eGFR, BNP, EF%, LVEDV, LVESV, LVMI, and STEMI complications' Gensini score in AAV; however, CRP did not correlate with BNP, EF%, LVEDV, LVESV, LVMI, and Gensini score. CONCLUSIONS: The plasma level of mCRP was related to cardiovascular diseases in AAV patients.

Distinct EphB4-mediated mechanisms of apoptotic and resistance to dasatinib in human chronic myeloid leukemia and K562 cell lines.

OBJECTIVE: To determine the role and mechanism of EphB4 in dasatinib (DAS) resistance in advanced chronic myeloid leukemia (CML), we explored the EphB4-mediated apoptotic and matrix microenvironment pathway in human CML and K562 cell lines. METHOD: Heparinized bone marrow samples were obtained from enrolled five patients (identified as A to E and visits identified by number) at initial diagnosis (A1-E1) and in the DAS-resistance advanced phase (A2-E2). Meanwhile, highly DAS-resistant cells, named K562-R cells, were obtained from K562-W cells with increasing concentrations of DAS. Stable under-expressing EphB4 cells (K562-R-EphB4-sh) were obtained from K562-R cells by RNA interference. K562-W, K562-R and K562-R-EphB4-sh cells (108) were respectively injected subcutaneously on the dorsal surface of BALB/C female nude mice to establish the xenografts models. RESULT: The mRNA/protein of EphB4 was overexpressed in the DAS-resistant A2-E2 in comparison with the A1-E1 human cell lines. Further, compared with K562-R cells, the expressions of EphB4 and p-Rac1/Cdc42 protein/mRNA were significantly downregulated in K562-R-EphB4-sh cells (P<0.01). K562-R cells showed the highest DAS resistance (IC50 10.54±0.67µg/ml), but K562-R-EphB4-sh cells became sensitive to DAS (IC50 1.02±0.1µg/ml, P<0.01). The expression of EphB4/p-RhoA/MCL-1 protein was gradually increased in the stimulating of EphrinB2-Fc, which partly made K562-R-EphB4-sh cells restore sensitivity to DAS (4.18±0.30µg/ml). Meanwhile, the K562-R-EphB4-sh xenografts group had relatively good efficacy compared to K562-R xenografts nude mice receiving the same dose of DAS. The analysis of xenografts tissue also suggested parallel results with the overexpression of EphB4/RhoA/ROCK1/PTEN/MCL-1 in K562-R xenografts, which decreased in the A2-R-EphB4-sh xenografts (P<0.01). CONCLUSIONS: The present study found that a new DAS resistance pathway of EphB4 overexpression was triggered by EphrinB2-Fc, which induced the resistance to DAS by activating RhoA/ROCK1/PTEN/MCL-1 signaling.

Decitabine plus thalidomide yields more sustained survival rates than decitabine monotherapy for risk-tailored elderly patients with myelodysplastic syndrome.

OBJECTIVE: The open-label, prospective, observational study aimed to evaluate whether decitabine (DAC) plus thalidomide versus DAC monotherapy improved progression-free (PFS), overall survival (OS) and acute myeloid leukemia-free survival (AML-FS) for risk-tailored elderly patients with myelodysplastic syndromes (MDS). METHOD: Enrolled 107 patients (age: 65-82 years) received DAC (52/107) or DAC plus thalidomide (55/107) therapy for MDS. RESULTS: 35/52 patients (67.3%) with DAC therapy reached overall response (OR), compared with 36/55 patients (65.5%) in DAC+thalidomide regimen (P>0.05). DAC+thalidomide administered did not gain more profits of PFS and OS than DAC monotherapy. Risk-tailored analysis showed that DAC+thalidomide therapy did not enhance PFS (48.9% versus 42.8%, P>0.05) and OS (78.6% versus 71.2%, P>0.05) when compared with simple DAC regimen. Nevertheless, DAC+thalidomide markedly improved OS over DAC monotherapy (50.6% versus 40.2%, P<0.05) in high risk profile. Meanwhile, low risk group was superior to high risk group in AML-FS (57.2% versus 21.3%, P<0.01), but DAC+thalidomide still did not prolong 2-year AML-FS when compared with DAC (32.4% versus 27.8%, P<0.05). Moreover, thalidomide had a favorable toxicity profile as a single agent. In comparison with DAC monotherapy, the DAC+thalidomide regimen was relatively well tolerated. There was no severe non-hematological toxicity appearing in elderly patients with MDS. CONCLUSIONS: The study demonstrated that DAC+thalidomide improved 2-year OS for high risk patients. Thalidomide's proven activity and low toxicity profile made it an alternative treatment option for risk-tailored elderly patients with MDS.

Homoharringtonine contributes to imatinib sensitivity by blocking the EphB4/RhoA pathway in chronic myeloid leukemia cell lines.

The purpose was to investigate the role of EphB4 in imatinib (IM) resistance and the mechanism responsible for homoharringtonine (HHT) contributing to imatinib sensitivity for a chronic myeloid leukemia (CML) cell lines. We established cell lines from a patient with CML at the time of first diagnosis and relapsed phase and designated them as NPhA1 and NPhA2, respectively. Stable underexpressing EphB4 cells (NPhA2-sh) were obtained. The activated signal proteins in cells were tested by Western blot. The EphB4 was overexpressed in IM-resistant NPhA2 in comparison with the NPhA1 cell line, but the expression of EphB4 mRNA and protein significantly decreased in knockdown NPhA2-EphB4-sh cells compared with NPhA2 and NPhA1 (P < 0.001) cell lines. NPhA2-EphB4-sh cells were sensitive to IM (IC50 0.93 mg/L), and NPhA2 showed IM resistance (IC50 5.45 mg/L) (P < 0.001). Meanwhile, phospho-Rac1/cdc42 was significantly increased in NPhA2 cells compared to NPhA2-EphB4-sh (P < 0.001). The apoptosis rate reached 58.71 ± 2.39 % with NPhA2 cells incubated with HHT + IM, which was higher than NPhA2 cells incubated with IM alone (P = 0.002). IC50 of NPhA2 cells incubated with IM was 5.45 mg/L. However, co-stimulation with HHT + IM decreased the IC50 of NPhA2 cells from 5.45 to 1.17 mg/L (P < 0.001). Furthermore, HHT blocked the expressions of EphB4/RhoA, but did not down-regulate the phospho-MEK/ERK in NPhA2 cells. The overexpression of EphB4 contributed to IM resistance in CML line cells. EphB4/RhoA may be a new marker of IM resistance. HHT + IM gained more treatment advantages than IM alone by blocking EphB4/RhoA pathways in CML cell lines.

A prospective, observational study of added medium-dose cytosine arabinoside versus As2O3 for elderly patients with acute promyelocytic leukemia.

This open-label, prospective, observational study aimed to evaluate disease-free survival (DFS), overall survival (OS), PML-RARα polymerase chain reaction (PCR) monitoring and safety in elderly patients with de novo acute promyelocytic leukemia (APL) who were treated with either arsenic trioxide (As2O3) or medium-dose cytosine arabinoside (MiDAC) as frontline consolidation regimens. A total of 167 patients (age≥65 years old) received all-trans retinoic acid + daunorubicin as induction therapy. Of these patients, 22 died before attaining complete remission; the remaining 145 subjects received MiDAC- or As2O3-based consolidation therapy. As2O3 was superior to MiDAC for improving DFS and OS. This benefit appeared to result from the longer 5-year DFS (92.0 vs. 69.1%, P<0.01) and OS (94.5 vs. 79.7%, P<0.05) of As2O3 compared to MiDAC. PCR monitoring demonstrated that As2O3 promoted a lower positive rate than MiDAC (21.7 vs. 4.5%, P<0.05), but this treatment had no advantage for maintaining a low positive rate in the high-risk group. The most common life-threatening adverse drug effects in patients with MiDAC were platelet counts<25×10(9)/L (85.7%), leukocyte counts<1.0×10(9)/L (81.4%) and severe infection (84.3%). In contrast, the As2O3 regimen rarely caused leukocyte counts<1.0×10(9)/L (22.7%, P<0.01), platelet counts<25×10(9)/L (37.3%, P<0.01) or severe infection (21.3%, P<0.01). These data confirm that MiDAC should not be added during the initial consolidation of patients with APL because this treatment is far less effective, particularly in patients with a low-risk profile, and far more toxic than As2O3.

Interferon α-2b gains high sustained response therapy for advanced essential thrombocythemia and polycythemia vera with JAK2V617F positive mutation.

OBJECTIVE: This open-label, prospective, observational study aimed to evaluate treatment response, efficacy therapy and safety to IFN α-2b for the essential thrombocythemia (ET) and polycythemia vera (PV) with JAK2V617F positive mutation. METHOD: A total of 123 ET patients received IFNα-2b therapy with JAK2V617F positive or negative mutation; and 136 PV patients with JAK2V617F(+) received IFNα-2b or hydroxyurea (HU) therapy according to random number assignment (ages 18-65 years old). RESULT: ET patients receiving IFN α-2b with JAK2V617F(+) had a greater advantage in overall hematologic response (OHR) than JAK2V617F(-) (83.3% versus 61.4%, P<0.01). For PV patients with JAK2V617F(+), IFN had no OHR superiority to HU (70.3% versus 70.8%, P>0.05), but which gained a greater satisfactory molecular response than HU (54.7% versus 19.4%, P<0.01). IFN significantly decreased the phlebotomy rate, which was better than HU for MPDs patients with OHR than HU (3.6% versus 65.7%, P<0.01). Furthermore, ET patients with JAK2V617F(+) demonstrated a definite advantage over JAK2V617F(-) in five-year PFS (75.9% versus 47.6%, P<0.05). For PV patients with JAK2V617F(+), IFN α-2b was superior to HU in five-year PFS (66.3% versus 46.7%, P<0.01). Moreover, IFN α-2b also contributed to improved vasomotor symptoms in MPDs, and especially significantly decreased the incidence of distal paresthesias (14.1% versus 37.5%) and erythromelalgia (9.4% versus 29.2%) better than HU (P<0.01). Meanwhile, IFN did not observe the severe hematological adverse events in patients with PV or ET. CONCLUSION: The data confirmed that IFN α-2b benefited the patients with ET or PV, particularly for JAK2V617F(+) mutation.

How to determine post-FCR therapy for cytogenetic risk-tailored elderly patients with chronic lymphocytic leukemia, maintenance rituximab or observation.

The open-label, prospective, observational study aimed to evaluate whether the addition of maintenance rituximab (MR) improved progression-free survival (PFS) and overall survival (OS), after fludarabine, cyclophosphamide, and rituximab (FCR) for cytogenetic risk-tailored elderly patients with chronic lymphocytic leukemia (CLL). Enrolled 201 patients (ages 65-84 years) who received FCR and gained an overall response. One hundred and four of 201 patients were in the observation (OBS) arm while 97/201 patients continued to receive MR therapy. After FCR, no more benefits were provided by MR versus OBS in cytogenetic better intermediate-risk cohort. PFS at 10 years reached 68.6 versus 58.1 % (P > 0.05). Ten-year OS was 81.8 versus 74.6 % (P > 0.05). However, the improvement of PFS and OS were as dramatic as the improvements of being MR treating versus OBS mainly in the poor-risk cohort. PFS at 10 years reached 57.1 versus 22.7 % (P < 0.01), and 10-year OS was 71.2 versus 41.7 % (P < 0.01). Compared with OBS, no severe hematologic adverse events (AEs) (Grades 3-4) appeared in patients with MR; only some mild non-hematologic AEs incurred (nausea-vomiting 0.96 %, allergy 1.9 % and infection 1.9 %) during the maintenance treatment. The study showed that MR improved 10-year RFS and OS for cytogenetic poor-risk patients with CLL.

Standard intensive chemotherapy is less effective and far more toxic than attenuated induction and post-induction regimen in elderly patients with acute myeloid leukemia.

The open-label, prospective study aimed to evaluate the efficacy and safety for standard intensive chemotherapy compared with attenuated therapy in elderly patients with acute myeloid leukemia (AML). A total of 297 patients between 65 and 82 years were enrolled in the study. The 141 patients received standard-dose therapy (daunorubicin 45 mg/m(2) × 3 days with cytarabine 100 mg/m(2) × 7 days for induction therapy, while post-induction therapy consisted of high-dose cytarabine 1.5 g/m(2) × 4 days), and the attenuated treatment (daunorubicin 30 mg/m(2) × 3 days with cytarabine 75 mg/m(2) × 7 days for induction therapy, while post-induction therapy consisted of attenuated high-dose Ara-C 1.0 g/m(2) × 3 days) was administered to the remaining 156 patients, based on a random number assigned. Total 168 patients (56.6%) achieved complete remission with an incomplete blood recovery (CR)/CRi. No significant differences were observed between the two treatments (P = 0.60). Attenuated chemotherapy improved overall survival (OS) and progression-free survival (PFS) compared to standard-dose therapy; 5-year OS values for these two groups were 39 and 24 months, respectively (P < 0.001), and the PFS values for these two groups were 35 versus 23 months (P < 0.001). In addition, the attenuated treatment with a poor risk profile overcame the negative impact and yielded OS and PFS values similar to those of the standard-dose chemotherapy with a better-to-intermediate risk profile. Five-year OS values for these two groups were 28 versus 28 months (P = 0.89), and the 5-year PFS values were 27 and 28 months, respectively (P = 0.89). The most common adverse drug effect for chemotherapy was agranulocytosis (98.3%). There was a significant difference in early mortality between the attenuated and standard-dose treatment groups (0.64% vs. 7.1%, respectively, P < 0.01). Standard intensive chemotherapy is less effective and far more toxic than attenuated induction and post-induction regimen in elderly patients with AML.

How to determine bortezomib-based regimen for elderly patients with multiple myeloma: PAD versus CBd, an observational study.

BACKGROUND: This was an open-label, observational, prospective assessment. We conducted an analysis of the impact of bortezomib-based therapy (PAD: bortezomib, doxorubicin, high-dose dexamethasone vs. CBd: cyclophosphamide bortezomib, low-dose dexamethasone) on the survival rates and adverse events in elderly patients with newly diagnosed multiple myeloma (MM). METHODS: Out of 303 patients, 128 received the PAD regimen and the other 175 patients received the CBd induction therapy (age 65-89 years). Baseline patient characteristics between the two cohorts were balanced in age (P = 0.69), international staging system (ISS) prognostic stages (P = 0.90), serum calcium (P = 0.70), and serum creatinine (P = 0.52). RESULTS: Overall response (OS) after the induction chemotherapy was achieved in 214 of 303 patients (70.6 %), with no significant differences observed between the two treatment groups (71.9 vs. 69.7 %, P = 0.68). Patients with ISS stage 2 reached the same 5-year OS advantages compared to patients with ISS stage 1, because they received bortezomib-based PAD or CBd treatments. Patients receiving CBd protocol gained similar satisfactory progression-free survival (PFS) results when compared to the PAD regimen group: PFS at 5 years reached 58.2 versus 58.9 % (P = 0.85). Five-year OS in the CBd arm had significant advantages compared to the PAD group, 79.9 versus 49.9 % (P < 0.05). The overall safety profiles showed that 26 of 128 (20.3 %) patients died in the PAD arm, while 13 of 175 patients died (7.4 %) in the CBd group (P < 0.01). Similarly, the PAD arm had a higher serious infection rate than that of the CBd arm (39.2 vs. 13.1 %, P < 0.01). CONCLUSIONS: Bortezomib benefits elderly patients with newly diagnosed MM; they achieve satisfactory treatment responses and survival advantages. Further, patients treated with CBd have superior treatment advantages, with a predictable safety profile, when compared to the PAD regimen.

High-dose homoharringtonine versus standard-dose daunorubicin is effective and safe as induction and post-induction chemotherapy for elderly patients with acute myeloid leukemia: a multicenter experience from China.

The purpose of the study was to compare the antitumor efficacy and safety profile of high-dose homoharringtonine as induction and post-induction therapy compared to either standard-dose homoharringtonine or daunorubicin in elderly patients with newly diagnosed acute myeloid leukemia. A total of 254 patients, age range 60-77 years received induction and post-induction therapy containing daunorubicin, standard-dose homoharringtonine, or high-dose homoharringtonine. After one course of induction therapy, the overall complete remission rate was similar between treatment arms (58.7%, P = .92). Among 161 patients with acute myeloid leukemia (non-M5 subtype), estimated median overall survival was 39, 29, and 37 months, respectively, in the daunorubicin, standard-dose homoharringtonine, and high-dose homoharringtonine treatment groups (P = .53). In the 93 patients with acute myeloid leukemia-M5 subtype, there was a significant difference in estimated median overall survival: 24, 24, and 52 months, respectively, in the daunorubicin, standard-dose homoharringtonine, and high-dose homoharringtonine treatment groups (P = .003). There was no significant difference in drug-related adverse events between treatment arms. High-dose homoharringtonine does not clearly increase the complete remission rate of elderly patients with acute myeloid leukemia. However, in the subset of elderly patients with acute monocytic leukemia, high-dose homoharringtonine as a first-line regimen prolonged overall survival with minimal toxicity.

How to determine post-RCHOP therapy for risk-tailored adult patients with diffuse large B-cell lymphoma, addition of maintenance rituximab or observation: multicenter experience.

BACKGROUND: In international prognostic index (IPI) risk-tailored adult patients with diffuse large B-cell lymphoma (DLBCL), it is still unclear whether the addition of maintenance rituximab (MR) improves progression-free (PFS) and overall survival (OS), after RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy. METHODS: In our study, 207 patients (age: 21-59 years) received six 14-day cycles of RCHOP and gained overall response. After RCHOP, 98 patients were enrolled in the observation (OBS) arm. 109 patients continued to receive MR therapy. RESULTS: In IPI risk <2 profile, PFS at 5 years reached 72.9% (MR arm) versus 56% (OBS arm) (P = 0.033). In IPI risk ≥2 profile, PFS estimation at 5 years was 44.9% (MR arm) versus 33.5% (OBS arm) (P = 0.006). It is noteworthy that patients with IPI ≥2 who received MR achieved PFS similar to that for patients in the OBS arm with the IPI <2, 44.9% versus 56% (P = 0.97). In patients with an IPI <2, OS at 5 years was 83.2% (MR arm) versus 81.2% (OBS arm) (P = 0.708). In patients with an IPI ≥2, 5-year OS estimation was 44.6% (MR arm) versus 40.5% (OBS arm) (P = 0.067). Subgroup analysis of patients with an IPI ≥3 risk profile shows a survival benefit for patients receiving MR. OS at 5 years was 62% (MR arm) versus 49% (OBS arm), (P = 0.033). CONCLUSIONS: In conclusion, maintenance rituximab after RCHOP improves progression-free survival. In addition, overall survival is improved for patients with an IPI ≥3 risk profile receiving MR.

The early addition of arsenic trioxide versus high-dose arabinoside is more effective and safe as consolidation chemotherapy for risk-tailored patients with acute promyelocytic leukemia: multicenter experience.

The purpose of the study was to evaluate event-free survival (EFS), overall survival (OS) and safety for early addition of arsenic trioxide (As(2)O(3)) as frontline consolidation therapy compared to high-dose arabinoside (HiDAC) in adult patients with de novo acute promyelocytic leukemia (APL). 271 patients (aged 17-65 years) received consolidation therapy containing As(2)O(3) (two 21-day courses) or HiDAC regimen. EFS at 5 years was 75% versus 54% (P < 0.001), and OS at 5 years was 83% versus 71% (P = 0.002) in As(2)O(3) and HiDAC treatment arms. 139 patients treated with As(2)O(3), EFS at 5 years reached 79% versus 56% (P = 0.014), but OS at 5 years was 77% versus 84% (P = 0.32) in low-risk (WBC ≤ 10 × 10(9)/L) and high-risk (WBC > 10 × 10(9)/L) cohorts. Further, patients treated with As(2)O(3) rarely incurred agranulocytosis (1.4%, P < 0.001), or severe infection (0.7%, P < 0.001). It is still very well tolerated compared to HiDAC. We confirmed that As(2)O(3) as a first-line consolidation regimen provided significant benefits of OS to patients with APL. The As(2)O(3) regimen made low-risk patients gain more EFS benefits than high-risk group. The high-risk cohort receiving As(2)O(3) overcame the negative impact, yielding OS similar to that for with the low-risk patients treated with As(2)O(3).

[Identification of differentially expressed genes related to blastic crisis in chronic myeloid leukemia].

OBJECTIVE: To identify differentially expressed genes between chronic phase and blast crisis in chronic myeloid leukemia, explore the mechanism and screen potential biomarkers of disease progression. METHODS: The differences in the gene expression profiles of bone marrow mononuclear cells between chronic phase and blastic crisis were examined using DNA microarray. PANTHER database, Genomatix database and Bibliosphere software were used to analyze and predict the critical genes or transcription factors during disease progression. Some of the genes or transcription factors were selected for verification by semi-quantitative RT-PCR. RESULTS: In blastic crisis, 68 of the 1176 tested genes were obviously up-regulated. Sixteen of these differential genes were selectively expressed in leukocyte membranes. CD40, CCR3, LGALS3, RGS3, CEACAM3 and the related transcription factors RAC1, CTNNB1, TP53, and NF-κB, all as the nodes of the entire regulatory network, were presumed to play key roles in disease progression. The results of RT-PCR were consistent with the microarray data and showed high expression of CEACAM3, RGS3, CTNNB1 and RAC1 in blastic crisis. CONCLUSION: A group of genes have been identified to very likely play key roles or serve as biomarkers in the transition from the chronic phase to blastic crisis in chronic myeloid leukemia.

[Cytogenetic differences between adults and children with acute lymphoblastic leukemia: eight-probe fluorescence in situ hybridization and karyotype analyses].

OBJECTIVE: To investigate the cytogenetic differences between children and adults with acute lymphoblastic leukemia (ALL) using eight-probe fluorescence in situ hybridization and karyotype analysis. METHODS: Eight-probe (MYC, P16, E2A, TEL/AML1, BCR/ABL , MLL , IGH, and hyperdiploidy) fluorescence in situ hybridization and karyotype analysis were performed for 86 adults and 39 children with acute lymphoblastic leukemia. RESULTS: Eight-probe fluorescence in situ hybridization showed significant differences in the positivity rate of TEL/AML1, BCR/ABL, and hyperdiploidy between adult patients and children with ALL. By karyotype analysis, the positivity rate of t(9;22) and hyperdiploidy differed significantly between the children and adult patients (P<0.05). CONCLUSION: Adults and children with ALL have different expression profiles of the fusion genes. Eight-probe fluorescence in situ hybridization is time-saving, accurate and efficient in detecting common genetic abnormalities in ALL patients, and can be well complementary to karyotype analysis in clinical diagnosis of ALL.

[Application of multiprobe fluorescence in situ hybridization panel in the diagnosis of acute myeloid leukemia].

OBJECTIVE: To assess the value of multiprobe fluorescence in situ hybridization (FISH) panel in the diagnosis of acute myeloid leukemia (AML). METHODS: The multiprobe AML/MDS panel comprising 8 different FISH probes for AML1/ETO transfusion gene, PML-RARα transfusion gene, CBFß/MYH11 transfusion gene, MLL breakapart, P53 deletion, Del(5q), -7/Del(7q), and Del(20q) was tested in 40 cases of AML, and the results were compared with those by conventional cytogenetic G-banding (CCG) test. RESULTS: With multiprobe FISH panel, 22 of the 40 AML cases were found to carry 7 types of cytogenetic abnormalities, namely AML1/ETO transfusion gene, PML-RARα transfusion gene, MLL breakapart, P53 deletion, Del(5q), -7/Del(7q) and trisomy 8. The positive ratio of the multiprobe FISH was 57.5%. CCG only identified 8 cases with the corresponding cytogenetic abnormalities and 3 cases with other cytogenetic abnormalities, and the positive ratio was only 27.50%. CONCLUSION: Mutiprobe FISH panel is more rapid, accurate and effective than CCG in the diagnosis of AML.

Analysis of efficacy and cost-effectiveness of high-dose arabinoside versus daunorubicin chemotherapy in older adult patients with acute myeloid leukemia by cytogenetic risk profile: retrospective review from China.

High-dose arabinoside (HiDAC) and daunorubicin (DNR)-based chemotherapy are the primary consolidation treatment options for older adults (50-60 years old) with acute myeloid leukemia in China. We analyzed the event-free survival (EFS) and hospital treatment charges of older adult patients with different cytogenetic risk profiles. In patients with a better/intermediate risk profile, the average total treatment cost of HiDAC was similar to that of DNR (P = 0.11). A 5-year follow-up of patients with better/intermediate cytogenetic risk profiles revealed that the median EFS of patients who received HiDAC was significantly longer than for patients who received the DNR-based regimen (27 vs. 20 months, P = 0.03). Average cost per year of life saved was 18,746.84 USD for HiDAC, compared to 32,733.37 USD for DNR. In contrast, for patients with a poor cytogenetic risk profile, the average total treatment cost for HiDAC was higher than for DNR (P < 0.005). In addition, the median EFS in the HiDAC protocol group was significantly lower than in the DNR group (11 vs. 20 months, P = 0.003). Meanwhile, in this risk group, the average cost per year of life saved was 103,237.70 USD compared to 32,277.93 USD, respectively, in the HiDAC and DNR regimens. We conclude that HiDAC is a more efficacious and cost-effective consolidation treatment regimen in the better/intermediate risk group, while the DNR-based regimen is more cost-effective in the poor risk group.

[Expressions of LRP, GST-pi and MRP1 in acute leukemia patients and its clinical significance].

This study was purposed to investigate the relationship of expressions of gluthatione-S-transferase-pi (GST-pi), multidrug resistance protein-1 (MRP-1), lung resistance protein (LRP) with multidrug resistance of acute leukemia (AL), the correlation between 3 kinds protein expressions and the correlation of their protein expression with clinical features of AL patients. The S-P immunohistochemical staining method was used to determine the expressions of GST-pi, MRP1 and LRP proteins in 80 AL patients and 30 normal subjects. The results showed that there was the correlation between GST-pi, MRP1, LRP protein expression and chemotherapy resistance, meanwhile CR rates of patients with positive expression of those proteins were lower than that of patients with negative expression (P<0.05), so those protein expressions may be accounted for poor prognosis. There was the positive relationship between expression of GST-pi and MRP1 in refractory group (r=0.851, P<0.01). It is concluded that co-examination of GST-pi and MRP1 has greater significance than examination of one kind of protein in evaluating poor prognosis of leukemia patients. LRP protein expression increase obviously when WBC counts >or= 10 x 10(9)/L (63.6%, P<0.05), therefore LRP protein has great judging value for evaluating drug resistance and prognosis of acute leukemia patients whose peripheral blood WBC counts were high.