All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol

We previously reported a benefit for all-trans retinoic acid (ATRA) in both induction and maintenance therapy in patients with acute promyelocytic leukemia (APL). To determine the durability of this benefit and identify important prognostic factors, long-term follow-up of the North American Intergroup APL trial is reported. A total of 350 patients with newly diagnosed APL were randomized to either daunorubicin and cytarabine (DA) or ATRA for induction and then either ATRA maintenance or observation following consolidation chemotherapy. The complete remission (CR) rates were not significantly different between the ATRA and DA groups (70% and 73%, respectively). However, the 5-year disease-free survival (DFS) and overall survival (OS) were longer with ATRA than with DA for induction (69% vs 29% and 69% vs 45%, respectively). Based on both induction and maintenance randomizations, the 5-year DFS was 16% for patients randomized to DA and observation, 47% for DA and ATRA, 55% for ATRA and observation, and 74% for ATRA and ATRA. There was no advantage of either induction regimen among any subgroups when CR alone was considered. However, female sex, classical M3 morphology (vs the microgranular variant [M3v]), and treatment-white blood cell count (WBC) interaction (ATRA/WBC below 2 x 10(9)/L [2000/microL] best, DA/WBC above 2 x 10(9)/L worst) were each significantly associated with improved DFS (P <.05). Treatment with ATRA, WBC below 2 x 10(9)/L, and absence of bleeding disorder were each significantly associated with improved OS. Age more than 15 years, female sex, and treatment-morphology interaction (DA/M3v worst, ATRA best regardless of morphology) were each significantly associated with improved DFS based on maintenance randomization. The improvement in outcome with ATRA in APL was maintained with long-term follow-up.     

Clinical characteristics and outcomes in patients with acute promyelocytic leukaemia and hyperleucocytosis

The clinical characteristics, treatment options and outcomes in patients with acute promyelocytic leukaemia (APL) and hyperleucocytosis remain poorly defined. This study reviewed 242 consecutive patients with APL; 29 patients (12%) had a white blood cell count (WBC) ≥ 50 × 10⁹/l at presentation (median WBC 85·5 × 10⁹/l). Patients with hyperleucocytosis had inferior complete remission (CR) rates (69% vs. 88%; P = 0·004) and higher 4‐week mortality (24% vs. 9%; P = 0·018) compared to patients without hyperleucocytosis. We noted a trend towards inferior 3‐year disease‐free survival (DFS) (69% vs. 80%; P = 0·057) and inferior 3‐year overall survival (OS) (74% vs. 92%; P = 0·2) for patients with hyperleucocytosis. Leukapheresis was performed in 11 (38%) of the 29 patients with hyperleucocytosis. CR rate and 3‐year OS were not significantly improved in patients who received leukapheresis. CR rate and 3‐year OS for the 15 patients with hyperleucocytosis treated with all‐trans retinoic acid (ATRA) plus arsenic trioxide (ATO) plus cytotoxic therapy (idarubicin or gemtuzumab ozogamicin) combinations were 100% and 100% vs. 57% and 35% for the 14 patients treated with non‐ATRA/ATO combinations (P = 0·004 and P = 0·002). Leukapheresis does not improve the outcomes in patients with APL presenting with hyperleucocytosis. ATRA/ATO‐based combinations are superior to other regimens in these patients.     

Predictive factors of all-trans-retinoic acid related complications during induction therapy for acute promyelocytic leukemia

Abstract

Background: The combination of all-trans-retinoic acid (ATRA) and chemotherapy has made acute promyelocytic leukemia (APL) a highly curable leukemia. However, several complications are reported with this treatment the most serious and life threatening being Retinoic Acid Syndrome (RAS). We aimed at identifying factors that could predict complications caused by ATRA during induction treatment of APL.

Patients: Forty-two patients with confirmed APL (by t(15;17) and/or PML/RARA) treated at our institution (University hospital of Tunis) between January 1998 and June 2006 using two consecutive protocols: European APL93 trial (24 patients) until February 2004 and Spanish PETHEMA LPA99 trial (18 patients) more recently. Induction regimen consisted of ATRA 45 mg/m²/d until CR combined to DNR 60 mg/m²/d×3+Cytarabine 200 mg/m²/d×7 (APL93) and Idarubicin 12 mg/m² d2, 4, 6, 8 (LPA99). Prednisone (0·5 mg/kg d1–d15) was added if WBC >10×10⁹/L to prevent RAS in LPA 99.

Results: Median age was 36 yr (7–64 yr), M/F=16/26 (0·61), median WBC was 2·4×10⁹/L (range 0·6–100×10⁹/L). WBC >10×10⁹/L was noted in 14 patients (33%). Additional cytogenetic abnormalities were seen in 12/42 (28%). Median body mass index (BMI=weight/height²:N 20–25) was 24 kg/m² (range 16–40 kg/m²), BMI >30 was noted in nine patients (8F and 1M). Thirty-three patients achieved CR (78·57%):18/24 (75%) in APL93 versus 15/18 (83%) in LPA99. Nine patients (21·42%) had early death. Causes of early death were: RAS (6) and CNS hemorrhage (3). Complications due to ATRA were: RAS (10), Scrotal ulcerations (3), Sweet syndrome (2), Perineal ulcerations (1), and Pseudotumor cerebri (1). Prognostic factors for complications of ATRA (Fisher exact test) were: BMI >35 (p=0·055), induction treatment without cytarabine (LPA99 trial) (p=0·047), whereas age (p=0·74), gender (p=0·51), initial WBC (p=0·47), and additional cytogenetic abnormalities (p=0·83) were not predictive. Retinoic Acid Syndrome was more reported in patients with initial WBC >10×10⁹/L (p=0·08).

Conclusion: We found high BMI (>35) in female and treatment without Cytarabine to increase the risk of developing complications with ATRA.     

Mechanisms of action and resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) in acute promyelocytic leukemia

Since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (As₂O₃) for the treatment of acute promyelocytic leukemia (APL), the overall survival rate has improved dramatically. However, relapse/refractory patients showing resistance to ATRA and/or As₂O₃ are recognized as a clinically significant problem. Genetic mutations resulting in amino acid substitution in the retinoic acid receptor alpha (RARα) ligand binding domain (LBD) and the PML-B2 domain of PML-RARα, respectively, have been reported as molecular mechanisms underlying resistance to ATRA and As₂O₃. In the LBD mutation, ATRA binding with LBD is generally impaired, and ligand-dependent co-repressor dissociation and degradation of PML-RARα by the proteasome pathway, leading to cell differentiation, are inhibited. The PML-B2 mutation interferes with the direct binding of As₂O₃ with PML-B2, and PML-RARα SUMOylation with As₂O₃ followed by multimerization and degradation is impaired. To overcome ATRA resistance, utilization of As₂O₃ provides a preferable outcome, and recently, a synthetic retinoid Am80, which has a higher binding affinity with PML-RARα than ATRA, has been tested in the clinical setting. However, no strategy attempted to date has been successful in overcoming As₂O₃ resistance. Detailed genomic analyses using patient samples harvested repeatedly may help in predicting the prognosis, selecting the effective targeting drugs, and designing new sophisticated strategies for the treatment of APL.     

Treatment of acute promyelocytic leukemia with PETHEMA LPA 99 protocol: a Tunisian single center experience

Abstract

Acute promyelocytic leukemia (APL) has now become the most curable of all subtypes of acute myeloid leukemia. A cure rate of 75–80% can be anticipated with a combination of all-trans retinoic acid (ATRA) and anthracyclines. In Tunisia, the ATRA era began in 1998 with the use, consecutively, of two regimens of a combination of ATRA with anthracycline and cytarabine (APL93), and without cytarabine (LPA99). From 2004, 39 patients with confirmed APL either by t(15;17) or PML/RARA were treated by the PETHEMA LPA 99 trial. The rationale of this protocol by avoiding cytarabine is to reduce death in complete remission (CR) without increasing the incidence of relapse. Thirty-three patients achieved CR (84·6%). The remaining six patients were considered as failure due to early death: three caused by differentiation syndrome (DS) and three died from central nervous system hemorrhage. Baseline blood cell count (WBC) >10 × 10⁹/l (P=0·26) and creatinine >1·4 mg/dl (P=0·42) were not predictive of mortality. DS was observed in 11 patients (30·5%) with a median onset time of 12 days (range: 3–23 days) and median WBC of 29 × 10⁹/L (range: 1·2 × 10⁹–82·7 × 10⁹/l). DS was severe in seven cases, moderate in four, and fatal in three cases. Body mass index ≥30 (P=0·044) and baseline WBC ≥20 × 10⁹/l (P=0·025) are independent predictors of DS. The median follow-up of this study is 36 months. Thirty patients are alive in continuous complete remission; two patients died in CR from septic shock and secondary myelodysplastic syndrome respectively; one patient died 47 months after achieving two relapses. Event free survival from diagnosis was 80% and overall survival was 82%. Our results are quite acceptable and can be improved by reducing mortality rate.     

Difference in causes and prognostic factors of early death between cohorts with de novo and relapsed acute promyelocytic leukemia

Early death (ED) remains the most critical issue in the current care of patients with acute promyelocytic leukemia (APL). Very limited data are available regarding ED in patients with relapsed APL. In this retrospective study, 285 de novo and 79 relapsed patients were included. All patients received single-agent arsenic trioxide as induction therapy. The differences in baseline clinical features, incidence, causes, and prognostic factors of ED were compared between the two patient cohorts. The relapse cohort exhibited a better overall condition than the de novo cohort upon hospital admission. The ED rate in the relapsed patients (24.1%) was somewhat higher than that in the de novo patients (17.9%), although the difference was not significant (P?=?0.219). For both cohorts, hemorrhage was the main cause of ED, followed by differentiation syndrome, infection, and other causes. Increased serum creatinine level, older age, male sex, white blood cell (WBC) count?>?10?×?10⁹/L, and fibrinogen?<?1 g/L were independently risk factors for ED in the de novo patients, whereas WBC count?>?10?×?10⁹/L, elevated serum uric acid level, and D-dimer?>?4 mg/L were independent risk factors for ED in the relapsed patients. These data furnish clinically relevant information that might be useful for designing more appropriate risk-adapted treatment protocols aimed at reducing ED rate in patients with relapsed APL.     

Gangrenous cheilitis associated with all-trans retinoic acid therapy for acute promyelocytic leukemia

A 67-year-old Japanese woman who presented with erythema on the abdomen and pancytopenia was found to have acute promyelocytic leukemia (APL). A skin biopsy revealed invasion of APL cells. She was started on induction treatment with all-trans retinoic acid (ATRA) at 45 mg/m². On day 4, the leukemic cell number had increased to over 1.0 × 10⁹/L. Consequently, chemotherapy with idarubicin and cytarabine was initiated. On day 10, dryness of the lips appeared. The lower lip swelled and developed painful black eschars. A high fever was also present. Despite discontinuing ATRA on day 20 and administering antibiotics, an anti-fungal agent and valaciclovir, these signs did not improve. Histopathologically, the biopsied lip revealed infiltration of neutrophils and vasculitis. The patient was given ATRA on days 29 and 30 due to an increase in APL cell numbers, after which the gangrenous cheilitis extended over the whole lip. On day 49, the patient was started on re-induction treatment with arsenic trioxide. She achieved complete remission and the gangrenous cheilitis slowly healed over the following 8 weeks. Since the clinical features of the gangrenous cheilitis in this case were similar to those of ATRA-associated scrotal ulcers, it appears that activated neutrophils derived from differentiated APL cells may have caused the gangrenous cheilitis. Physicians should be alert to the development of gangrenous cheilitis during treatment with ATRA.     

Increased post‐induction intensification improves outcome in children and adolescents with a markedly elevated white blood cell count (≥200 × 109/l) with T cell acute lymphoblastic leukaemia but not B cell disease: a report from the Children's Oncology Group

Children and adolescents presenting with a markedly elevated white blood cell (ME WBC) count (WBC ≥200 × 10⁹/l) comprise a unique subset of high‐risk patients with acute lymphoblastic leukaemia (ALL). We evaluated the outcomes of the 251 patients (12% of the study population) with ME WBC treated on the Children's Cancer Group‐1961 protocol. Patients were evaluated for early response to treatment by bone marrow morphology; those with a rapid early response were randomized to treatment regimens testing longer and stronger post‐induction therapy. We found that ME WBC patients have a poorer outcome compared to those patients presenting with a WBC <200 × 10⁹/l (5‐year event‐free survival 62% vs. 73%, P = 0·0005). Longer duration of therapy worsened outcome for T cell ME WBC with a trend to poorer outcome in B‐ALL ME WBC patients. Augmented therapy benefits T cell ME WBC patients, similar to the entire study cohort, however, there appeared to be no impact on survival for B‐ALL ME WBC patients. ME WBC was not a prognostic factor for T cell patients. In patients with high risk features, B lineage disease in association with ME WBC has a negative impact on survival.     

A retrospective observational study of leucoreductive strategies to manage patients with acute myeloid leukaemia presenting with hyperleucocytosis

Acute myeloid leukaemia (AML) patients with hyperleucocytosis have higher early mortality, lower complete remission (CR) and overall survival (OS). Whether different pre‐induction leucoreduction strategies can improve outcome is unknown. A single centre retrospective cohort study was conducted on AML patients with a white blood cell count (WBC) >100 × 10⁹/l between 1987 and 1997, and on all AML patients between 1998 and 2006, to determine (a) the effect of four different leucoreductive strategies (leukapheresis, hydroxycarbamide, leukapheresis and hydroxycarbamide or no pre‐induction leucoreduction) on early (day 28) mortality, CR, and OS; and (b) whether a high presenting WBC remains a negative predictor of OS in patients surviving induction (first 28 d). In the 1998‐2006 cohort (n = 702), higher WBC was associated with higher early mortality and lower OS but its effects were greatly diminished in patients who survived the first 28 d (Hazard Ratio 1·094 vs. 1·002). A WBC of 34·1 × 10⁹/l had the highest sensitivity (75·6%) and specificity (67·4%) for early mortality. None of the four leucoreduction strategies differed significantly in early mortality, CR, or OS in patients with WBC>100 × 10⁹/l (n = 166). The number of leucostatic signs was a significant predictor of early mortality (P < 0·0001) and OS (P = 0·0007). The results suggest that AML patients with hyperleucocytosis should be induced, if eligible, without pre‐induction leucoreduction.     

急性早幼粒细胞白血病分化综合征临床特征及对预后的影响研究

目的探讨急性早幼粒细胞白血病(APL)分化综合征(DS)的临床特征和影响预后的因素。方法收集中山大学附属第一医院2003—2010年收治的97例APL患者,采用维甲酸或维甲酸联合三氧化二砷(ATO)双诱导治疗,初诊者诱导分化治疗后WBC≥5×109/L联合化疗,完全缓解后采用ATO联合常规化疗巩固治疗方案。结果27例(27.83%)并发DS,出现DS中位时间为诱导分化治疗第6(2～24)天,其中24例(88.89%)发生在第1、2周。27例DS均给予地塞米松治疗,其中12例暂时停用诱导分化剂患者DS症状均缓解,15例继续使用者2例(7.41%)病情恶化死亡。中位随访37个月,DS组与未并发DS组患者无病生存(LFS)差异无统计学意义(P=0.269)。分析与DS发生的相关因素表明DS更多见于初诊WBC>10×109/L患者(χ2=4.994)。结论初诊WBC>10×109/L患者易并发DS,DS主要发生在诱导分化治疗前2周,DS对长期预后无影响。     

A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group.

All transretinoic acid (ATRA) followed by daunorubicin (DNR)-AraC chemotherapy (CT) has improved the outcome of acute promyelocytic leukemia (APL) by comparison to CT alone. In a randomized trial, (1) we compared 2 induction schedules (ATRA followed by CT [ATRA-->CT] and ATRA plus CT [ATRA+CT, with CT added on day 3 of ATRA treatment]) and (2) we assessed the role of maintenance treatment. Four hundred thirteen patients CT and ATRA+CT (initially randomized patients); patients with a WBC count greater than (high WBC count group, n = 163) and patients 66 to 75 years of age with a WBC count greater than 5,000/microL (elderly group, n = 42) were not initially randomized and received ATRA+CT from day 1 and ATRA -->CT, respectively. All patients achieving CR received 2 additional DNR-AraC courses (only 1 in patients 66 to 75 years of age) and were then randomized for maintenance between no treatment, intermittent ATRA (15 days every 3 months) for 2 years, continuous low-dose CT (6 mercaptopurine + methotrexate) for 2 years, or both, using a 2-by-2 factorial design. Overall, 381 (92%) of the patients achieved complete remission (CR), 31 (7%) suffered an early death, and only 1 patient had leukemic resistance. ATRA syndrome occurred in 64 patients (15%) and was fatal in 5 cases. The CR rate was similar in all induction treatment groups. Event-free survival (EFS) was significantly lower in the high WBC group (P =.0002) and close to significance in the elderly group (P =.086) as compared with initially randomized patients. Relapse at 2 years was estimated at 6% in the ATRA+CT group, versus 16% in the ATRA-->CT group (P =.04, relative risk [RR] =.41). EFS at 2 years was estimated at 84% in the ATRA+CT group, versus 77% in the ATRA-->CT group (P =.1, RR =.62). Two hundred eighty-nine patients were randomized for maintenance. The 2-year relapse rate was 11% in patients randomized to continuous maintenance CT and 27% in patients randomized to no CT (P =.0002) and 13% in patients randomized to intermittent ATRA and 25% in patients randomized to no ATRA (P =.02). An additive effect of continuous maintenance CT and intermittent ATRA was seen, and only 6 of the 74 patients who received both maintenance treatments had relapsed. Overall survival was improved in patients who received maintenance CT (P =.01), and there was a trend for better survival in patients who received maintenance ATRA (P =.22). Our findings strongly suggest that early addition of chemotherapy to ATRA and maintenance therapy combining continuous CT and intermittent ATRA can reduce the incidence of relapse in APL. This effect already translates into significantly better survival for maintenance treatment with continuous CT.     

ALL R-87 protocol in the treatment of children with acute lymphoblastic leukaemia in early bone marrow relapse

Seventy-three children with acute lymphoblastic leukaemia (ALL) in first bone marrow (BM) relapse, occurring within 30 months from complete remission (CR), were enrolled in an Italian cooperative study (ALL R-87 protocol). This treatment programme consisted of an induction phase with intermediate-dose cytarabine (IDARA-C) plus idarubicin (IDA) and prednisone (PDN), followed by a multidrug consolidation therapy and bone marrow transplant (BMT). 55/73 children achieved CR (75.3%); 15 (20.5%) failed to respond and three (4.2%) died during induction. The response rate was significantly higher for children with a first CR duration 12 months (P = 0.0005) and for those with a white blood cell (WBC) count at relapse <20 × 10⁹/l (P=0.004). The estimated disease-free survival (DFS ± SE) at 82 months was 0.18 ± 0.05 for all responders, and 0.70 ± 0.14 for allotransplanted patients versus 0.05 ± 0.05 for those autografted (P = 0.001). The estimated probabilities of survival ± SE and event-free survival (EFS ± SE) at 83 months were 0.16 ± 0.07 and 0.13 ± 0.04, respectively, for all enrolled children. Univariate analysis showed that age <10 years at initial diagnosis and B-lineage immunophenotype favourably influenced both DFS (P = 0.001) and EFS probabilities (P = 0.0014 and P = 0.012, respectively), whereas a first CR duration 12 months and a WBC count at relapse <20 × 10⁹/l were associated only with a better EFS rate (P = 0.026 and P = 0.004, respectively). Our results show the efficacy of the IDA plus IDARA-C schedule used in the ALL R-87 protocol in high-risk relapsed ALL children. Allogeneic BMT proved effective for patients with an HLA sibling donor. In a multivariate analysis, age 10 years at initial diagnosis (P = 0.016) and WBC count at relapse 20 × 10⁹/l (P = 0.048) were independently associated with a worse disease outcome.     

White blood cell count and endothelin-1 vasoconstrictor tone in middle-aged and older adults

BackgroundHigher white blood cell (WBC) count is associated with impaired endothelium-dependent vasodilation. However, the influence of higher WBC count on endothelin (ET)-1 vasoconstrictor activity is currently unknown. We tested the hypothesis that adults with elevated WBC count demonstrate enhanced ET-1 system activity.MethodsThirty-four healthy adults were studied: 17 with WBC count < 5.0 × 10⁹ cells/L (lower WBC; 9M/8F; age: 53 ± 2 yr) and 17 with WBC count > 5.0 × 10⁹ cells/L (higher WBC; 10M/7F; 54 ± 3 yr). Forearm blood flow (FBF) responses to intra-brachial infusion of ET-1 (5 pmol/min for 20 min) and selective ET_A receptor blockade (BQ-123; 100 nmol/min for 60 min) were measured by venous occlusion plethysmography.ResultsThe vasoconstrictor response to ET-1 was significantly blunted (～60%) in the higher WBC group versus the lower WBC group. The FBF responses to selective ET_A receptor blockade were also significantly different (P < 0.05) between the groups. In the lower WBC group, resting FBF increased marginally (～5%) to BQ-123, whereas the increase in FBF to BQ-123 was significantly greater (～15%) in higher WBC group. Furthermore, there was a significant relation between WBC count and FBF response to ET-1 (r = ?0.43) and BQ-123 (r = 0.41).ConclusionsRelative elevations in WBC count in middle-aged and older adults, independent of adiposity and other cardiometabolic risk factors, are associated with enhanced ET-1-mediated vasoconstrictor tone. Elevated ET-1 system activity may be a mechanism linking higher WBC count with increased cardiovascular risk.     

Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results

All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 x 10(9)/L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.2% versus 14.3% (P = .03), although 3-year survival was similar in both trials. This suggested that AraC is not required in APL with WBC count less than 10 x 10(9)/L, at least in trials with high-dose anthracycline and maintenance treatment. In patients with WBC of 10 x 10(9)/L or more, however, the CR rate (95.1% vs 83.6% P = .018) and 3-year survival (91.5% vs 80.8%, P = .026) were significantly higher in APL 2000 trial, and there was a trend for lower 3-year CIR (9.9% vs 18.5%, P = .12), suggesting a beneficial role for AraC in those patients.     

White blood cell count and mortality in patients with acute pulmonary embolism

Although associated with adverse outcomes in other cardiovascular diseases, the prognostic value of an elevated white blood cell (WBC) count, a marker of inflammation and hypercoagulability, is uncertain in patients with pulmonary embolism (PE). We therefore sought to assess the prognostic impact of the WBC in a large, state‐wide retrospective cohort of patients with PE. We evaluated 14,228 patient discharges with a primary diagnosis of PE from 186 hospitals in Pennsylvania. We used random‐intercept logistic regression to assess the independent association between WBC count levels at the time of presentation and mortality and hospital readmission within 30 days, adjusting for patient and hospital characteristics. Patients with an admission WBC count <5.0, 5.0–7.8, 7.9–9.8, 9.9–12.6, and >12.6 × 10⁹/L had a cumulative 30‐day mortality of 10.9%, 6.2%, 5.4%, 8.3%, and 16.3% (P < 0.001), and a readmission rate of 17.6%, 11.9%, 10.9%, 11.5%, and 15.0%, respectively (P < 0.001). Compared with patients with a WBC count 7.9–9.8 × 10⁹/L, adjusted odds of 30‐day mortality were significantly greater for patients with a WBC count <5.0 × 10⁹/L (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.14–2.03), 9.9–12.6 × 10⁹/L (OR 1.55, 95% CI 1.26–1.91), or >12.6 × 10⁹/L (OR 2.22, 95% CI 1.83–2.69), respectively. The adjusted odds of readmission were also significantly increased for patients with a WBC count <5.0 × 10⁹/L (OR 1.34, 95% CI 1.07–1.68) or >12.6 × 10⁹/L (OR 1.29, 95% CI 1.10–1.51). In patients presenting with PE, WBC count is an independent predictor of short‐term mortality and hospital readmission. Am. J. Hematol. 88:677–681, 2013. © 2013 Wiley Periodicals, Inc.     

Minimal residual disease assessed by multi‐parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia

The prognostic value of minimal residual disease (MRD) assessed by multi‐parameter flow cytometry (MFC) was investigated among 340 adult patients with B‐cell acute lymphoblastic leukaemia (B‐ALL) treated between 2004 and 2014 using regimens including the hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) backbone. Among them, 323 (95%) achieved complete remission (CR) and were included in this study. Median age was 52 years (range, 15–84). Median white blood cell count (WBC) was 9·35 × 10⁹/l (range, 0·4–658·1 ×1 0⁹/l). MRD by MFC was initially assessed with a sensitivity of 0·01%, using a 15‐marker, 4‐colour panel and subsequently a 6‐colour panel on bone marrow specimens obtained at CR achievement and at approximately 3 month intervals thereafter. MRD negative status at CR was associated with improved disease‐free survival (DFS) and overall survival (OS) (P = 0·004 and P = 0·03, respectively). Similarly, achieving MRD negative status at approximately 3 and 6 months was associated with improved DFS (P = 0·004 and P < 0·0001, respectively) and OS (P = 0·004 and P < 0·0001, respectively). Multivariate analysis including age, WBC at presentation, cytogenetics (standard versus high risk) and MRD status at CR, 3 and 6 months, indicated that MRD negative status at CR was an independent predictor of DFS (P < 0·05). Achievement of an MRD negative state assessed by MFC is an important predictor of DFS and OS in adult patients with ALL.     

Synchronization in the Heart Rate and the Vasomotion in Rat Aorta: Effect of Arsenic Trioxide

Arsenic trioxide (As₂O₃) is used clinically in the management of acute promyelocytic leukemia, and the use of electrocardiogram (ECG) in this management is important as arsenic use may cause distortion of the electrical properties with its attendant sequel. We studied the effect of As₂O₃ on vasomotion in rat aortic rings using isometric tension recordings and ECG in anesthetized rats. The results showed that As₂O₃ (10^?5 M) significantly (p < 0.01) reduced the frequency of acetylcholine (10^?5 M ACh)- and KCl (10 mM)-induced vasomotion, and it also increased the relaxation time (R _t) of vasomotion. This effect was restored by 10^?8 M sodium nitroprusside (nitric oxide donor). ACh-induced NO release in the aorta was blunted in the presence of As₂O₃. The corrected QT interval (QTc) of the ECG, and time dilation (T _d) of the pulse wave in the tail artery of the anesthetized rat were significantly (p < 0.05) increased in the arsenic-treated group (50 ppb As) versus control. In conclusion, data suggest that arsenic-induced reduction in vasomotion frequency of the isolated aortic rings is associated with a decreased bioavailability of NO, an increase in QTc and a decrease in the frequency of the pulse wave generated by the cardiac cycle in anesthetized rats.