Clinical significance of occult cerebrospinal fluid involvement assessed by flow cytometry in non‐Hodgkin’s lymphoma patients at high risk of central nervous system disease in the rituximab era

Background and aim: Flow cytometry (FCM) analysis of cerebrospinal fluid (CSF) is more sensitive than conventional cytology (CC) for diagnosis of lymphomatous meningeosis, but the clinical significance of occult central nervous system (CNS) disease (positive FCM with negative CC) remains unknown. Patients and methods: CSF samples from 105 patients with newly diagnosed aggressive lymphomas at high risk of CNS involvement were prospectively studied by both CC and FCM, and results were correlated with cumulative incidence of CNS relapse and overall survival (OS). Patients were divided into three groups: 1) patients without CNS involvement (CC?/FCM?; n = 83); 2) individuals with occult CNS disease (FCM+/CC?; n = 15); and 3) cases with CNS disease (CC+/FCM+; n = 7). Results: Six cases showed CNS relapse or progression: two in Group 1 (2.4%), two in Group 2 (13%) and two in Group 3 (28.5%) (Group 2 vs. 1, P = 0.04; Group 3 vs. 1, P < 0.001). Patients from Groups 2 (P = 0.05) and 3 (P < 0.001) also showed a higher cumulative incidence of CNS relapse than those from Group 1. Significant differences were observed in OS between FCM?/CC? and FCM+/CC+ cases (P = 0.02), while patients with occult CNS disease (FCM+/CC?) displayed intermediate OS rates, although differences did not reach statistical significance. Conclusions: The presence of occult CNS involvement at diagnosis in patients with NHL at high risk of CNS disease is associated with a higher probability of CNS relapse.     

Clinical significance of occult central nervous system disease in adult acute lymphoblastic leukemia: a multicenter report from the Campus ALL Network

In acute lymphoblastic leukemia (ALL), flow cytometry (FCM) detects leukemic cells in patients’ cerebrospinal fluid (CSF) more accurately than conventional cytology (CC). However, the clinical significance of FCM positivity with a negative cytology (i.e., occult central nervous system [CNS] disease) is not clear. In the framework of the national Campus ALL program, we retrospectively evaluated the incidence of occult CNS disease and its impact on outcome in 240 adult patients with newly diagnosed ALL. All CSF samples were investigated by CC and FCM. The presence of ≥10 phenotypically abnormal events, forming a cluster, was considered to be FCM positivity. No CNS involvement was documented in 179 patients, while 18 were positive by modified conventional morphology with CC and 43 were occult CNS disease positive. The relapse rate was significantly lower in CNS disease negative patients and the disease-free and overall survival (OS) were significantly longer in CNS disease negative patients than in those with manifest or occult CNS disease positivity. In multivariate analysis, the status of manifest and occult CNS disease positivity was independently associated with a worse OS. In conclusion, we demonstrate that in adult ALL patients at diagnosis FCM can detect occult CNS disease at high sensitivity and that the status of occult CNS disease positivity is associated with an adverse outcome. (Registered at clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT03803670","term_id":"NCT03803670"}}NCT03803670).     

High sensitivity of flow cytometry improves detection of occult leptomeningeal disease in acute lymphoblastic leukemia and lymphoblastic lymphoma

Conventional cytology (CC) of cerebrospinal fluid (CSF) fails to demonstrate malignant cells in up to 45 % of patients with acute lymphoblastic leukemia or lymphoblastic lymphoma (ALL/LL) in whom occult leptomeningeal disease is present. Flow cytometry (FCM) is considered more sensitive than CC, but clinical implications of CC negativity/CC positivity are not yet established. CSF samples from 38 adult patients with newly diagnosed ALL/LL were examined. Five (13 %) and nine (24 %) specimens were CC positive-FC positive (FCM^pos/CC^pos) and CC negative-FC positive (CC^neg/FCM^pos), respectively. The remaining 24 (63 %) samples were double negative (CC^neg/FCM^neg) (p?=?0.001). CC^neg/FCM^pos patients showed a significantly shorter overall survival (OS) compared to CC^neg/FCM^neg ones. In multivariate analysis, the status of single FCM positivity was demonstrated to affect independently duration of OS (p?=?0.005). In conclusion, FCM significantly improves detection of leptomeningeal occult localization in ALL/LL and appears to anticipate an adverse outcome. Further prospective studies on larger series are needed to confirm this preliminary observation.     

Impact of detectable measurable residual disease on umbilical cord blood transplantation

The impact of measurable residual disease (MRD) on cord blood transplantation (CBT) outcomes has remained debated. To address this issue, we assessed the impact of measurable MRD at CBT on outcomes in large cohort of patients with acute leukemia. Inclusion criteria included adult patients with acute myeloid (AML) or acute lymphoblastic leukemia (ALL), CBT as first allo-HCT in first or second complete remission (CR) at transplantation, and known MRD status at the time of CBT. Data from 506 patients were included in the analysis. Among them, 317 patients had AML and 189 had ALL. Positive MRD was reported in 169 (33%) patients while the remaining 337 patients were MRD negative at CBT. At 2 years, relapse incidence was 18% in patients with MRD negativity vs 33% in those with MRD positivity at transplantation (P < .001). Two-year leukemia-free survival (LFS) and overall survival (OS) were 57% and 60%, respectively, in MRD negative patients, vs 38% (P < .001) and 48% (P = .004), respectively, in those with MRD positivity. There was no interaction between the impact of MRD on OS and LFS and diagnosis (ie, ALL vs AML), single or double CBT, and reduced-intensity or myeloablative conditioning. On multivariate analysis, MRD positivity was associated with a higher risk of relapse (HR = 1.8, P = .003), comparable non-relapse mortality (P = .44), worse LFS (HR = 1.4, P = .008) and a trend towards worse OS (HR = 1.3, P = .065). In conclusion, these data suggest that novel strategies that are aiming to achieve MRD negativity at CBT are needed for leukemic patients with positive MRD pre-CBT.     

MCM7 polymorphisms associated with the AML relapse and overall survival

The minichromosome maintenance complex component 7 (MCM7) encodes a member of MCM complex, which plays a critical role in the initiation of gene replication. Due to the importance of MCM complex, MCM7 gene has been regarded as a candidate gene for cancer development. In the present study, seven MCM7 polymorphisms were genotyped in 344 subjects composed of 103 acute myeloid leukemia (AML) patients and 241 normal controls to examine the possible associations between MCM7 polymorphisms and the risk of AML. MCM7 polymorphisms were not associated with the risk of AML (P?>?0.05). However, MCM7 polymorphisms were significantly related to the relapse of AML and overall survival. The rs2070215 (N144S) showed a protective effect to the risk of AML relapse (OR?=?0.37; P ^corr?=?0.02). In haplotype analyses, the ht1 and ht2 showed significant associations with the risk of AML relapse (P ^corr?=?0.02–0.03). In addition, rs1534309 showed an association with the overall survival of AML patients. Patients with major homozygote genotype (CC) of rs1534309 showed a higher survival rate than the patients with other genotypes (CG and GG). The results of the present study indicate that MCM7 polymorphisms may be able to predict the prognosis of AML patients.     

Darusentan: An effective endothelinA receptor antagonist for treatment of hypertension

BackgroundThe antihypertensive efficacy and safety of darusentan, a new selective endothelin_A antagonist was investigated.MethodsIn a multicenter randomized, double-blind, parallel-group, dose-response study, a 2-week placebo run-in period was followed by a 6-week treatment period and then a 2-week placebo withdrawal period. At baseline before darusentan therapy, the average blood pressure (BP) of the patient population studied was diastolic 103.49 (SD 3.55) and systolic 168.27 (SD 16.63) mm Hg. In total, 392 patients were randomized (darusentan 10 mg: 94 patients, 30 mg: 103 patients, 100 mg: 96 patients, placebo: 99 patients).ResultsDarusentan significantly reduced diastolic (mean difference to placebo: 10 mg: −3.7 mm Hg, 95% confidence interval (CI): −6.6, −0.9, P = .009; 30 mg: −4.9 mm Hg, 95% CI: −7.7, −2.2, P = .0005; 100 mg: −8.3 mm Hg, 95% CI: −11.1, −5.5, P = .0001) and systolic BP (mean difference to placebo: 10 mg: −6.0 mm Hg, 95% CI: −11.0, −0.9, P = .02; 30 mg: −7.3 mm Hg, 95% CI: −12.3, −2.4, P = .004; 100 mg: −11.3 mm Hg, 95% CI: −16.3, −6.2, P = .0001). Pulse rate remained unchanged in all groups. There was a trend toward more adverse events in the active treatment groups (placebo: 30.3%, 10 mg: 44.7%, 30 mg: 40.8%, 100 mg: 49.0%). Héadache was the most commonly reported adverse event, with no relevant difference among treatments. Flushing and peripheral edema were seen in a dose-dependent fashion in the active treatment groups only.ConclusionThese data, the first, suggest the therapeutic benefit of selective endothelin_A receptor antagonism in human hypertension.     

Prognostic factors for clinical outcomes of patients with central nervous system leukemia

Prognostic factors associated with clinical outcomes of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients with central nervous system (CNS) involvement are unknown. We retrospectively studied the characteristics and outcomes of 66 (18 pediatric and 48 adult) patients with CNS leukemia with ALL (n = 41) or AML (n = 25). The median age of patients at diagnosis of CNS leukemia was 30 (range, 1–69) years. Nearly two-third patients had CNS involvement at the initial diagnosis of leukemia. Complete remission of CNS leukemia was attained in 58 (88%) patients, and probability of overall survival at 36 months after the diagnosis of CNS leukemia was 43% for the entire cohort. We identified that achieving remission of systemic leukemia and having CNS leukemia diagnosed and treated before allogeneic transplantation were the factors associated with CNS leukemia remission. Prognostic factors associated with better overall survival in patients with CNS leukemia included pediatric age, diagnosis of CNS leukemia before receiving allogenic transplantation, achieving clearance of systemic or CNS leukemia, receiving no cranial radiation in conjunction with intrathecal chemotherapy (IT), and receiving IT consolidation after achieving remission of CNS leukemia. Our findings show that patients with CNS leukemia are at considerable risk of mortality. Awareness of modifiable prognostic factors such as avoidance of cranial radiation whenever possible and use of IT consolidation can result in improved outcomes in subset of patients with CNS leukemia.     

Factors associated with risk of central nervous system relapse in patients with non‐core binding factor acute myeloid leukemia

Central nervous system (CNS) relapse is uncommon in patients with acute myeloid leukemia (AML) with the use of high‐dose cytarabine containing chemotherapy regimens. The clinical and molecular features associated with a higher risk of CNS relapse are not well defined. We assessed the incidence and outcome of CNS relapses among 1245 patients with relapsed/refractory AML referred to our institution between 2000 and 2014. CNS leukemia relapse was observed in 51 patients (4.1%). Using a multivariate regression model and after adjusting for age, FLT3‐ITD mutation (OR = 2.33; P = .02) and elevated LDH (>1000 IU/L, OR = 1.99; P = .04) were independent predictive factors for CNS relapse. Patients under 64 years of age with 0, 1, or 2 baseline adverse features had a probability of 3.8%, 7.0%‐8.0%, and 13.9% for developing CNS disease, respectively. Our study identifies patients with AML at higher risk for CNS relapse in whom prophylactic CNS therapy may be warranted.     

Clinical significance of RAS pathway alterations in pediatric acute myeloid leukemia

RAS pathway alterations have been implicated in the pathogenesis of various hematological malignancies. However, their clinical relevance in pediatric acute myeloid leukemia (AML) is not well characterized. We analyzed the frequency, clinical significance, and prognostic relevance of RAS pathway alterations in 328 pediatric patients with de novo AML. RAS pathway alterations were detected in 80 (24.4%) of 328 patients: NF1 (n=7, 2.1%), PTPN11 (n=15, 4.6%), CBL (n=6, 1.8%), NRAS (n=44, 13.4%), KRAS (n=12, 3.7%). Most of these alterations in the RAS pathway were mutually exclusive also together with other aberrations of signal transduction pathways such as FLT3-ITD (P=0.001) and KIT mutation (P=0.004). NF1 alterations were frequently detected in patients with complex karyotype (P=0.031) and were found to be independent predictors of poor overall survival (OS) in multivariate analysis (P=0.007). At least four of seven patients with NF1 alterations had biallelic inactivation. NRAS mutations were frequently observed in patients with CBFB-MYH11 and were independent predictors of favorable outcomes in multivariate analysis (OS, P=0.023; event-free survival [EFS], P=0.037). Patients with PTPN11 mutations more frequently received stem cell transplantation (P=0.035) and showed poor EFS than patients without PTPN11 mutations (P=0.013). Detailed analysis of RAS pathway alterations may enable a more accurate prognostic stratification of pediatric AML and may provide novel therapeutic molecular targets related to this signal transduction pathway.     

Inferior outcome after allogeneic transplant in first remission in high‐risk AML patients who required more than two cycles of induction therapy

While some patients with high‐risk acute myeloid leukemia (AML) require one or two cycles of induction chemotherapy to achieve a complete remission (CR), others require more than two cycles. We examined the outcomes of patients with high‐risk AML who received allogeneic HPC transplant in CR1. Forty five consecutive high‐risk AML patients in CR1 were included. All 45 patients had adverse cytogenetics, FLT 3 mutations, or secondary AML. Group A patients (n = 33) received one or two cycles, and Group B (n = 12) three or more cycles of induction chemotherapy. The patients were comparable in age, sex, white cell count at presentation, and time from diagnosis and from last chemotherapy to transplant. The 100‐day mortality rate was higher in Group B patients (50% vs. 9%, P = 0.006). They had a higher non‐relapse mortality (33% vs. 6%, P = 0.035) and a longer length of hospital stay from the day of stem cell infusion (median 21 vs. 20, P = 0.02; third quartile 22 vs. 28, P = 0.02). There was also a trend toward inferior event‐free survival and overall survival. High‐risk AML patients undergoing allogeneic transplant in CR1 after three or more cycles of induction chemotherapy have an inferior outcome and higher mortality when compared to those who only needed one or two cycles of induction chemotherapy. Novel strategies are needed to reduce the transplant‐related mortality in high‐risk AML patients needing more than two cycles of induction chemotherapy prior to allogeneic transplant in CR1. Am. J. Hematol. 90:715–718, 2015. © 2015 Wiley Periodicals, Inc.     

BAALC overexpression retains its negative prognostic role across all cytogenetic risk groups in acute myeloid leukemia patients

Overexpression of brain and acute leukemia cytoplasmic (BAALC) gene confers poor prognosis in cytogenetically normal acute myeloid leukemia (AML) patients, while less defined is its role in AML with abnormal karyotype. We evaluated the effect of BAALC overexpression on outcome of 175 adult AML patients with different cytogenetic risks. Karyotype was favorable in 13, intermediate in 117 and unfavorable in 45 patients, respectively. Quantitative BAALC expression was determined by real‐time PCR, with cut off value set at 50th percentile. BAALC was overexpressed in 87/175 (50%) patients, without association with cytogenetic status. High BAALC was associated with unmutated NPM (P = 0.006) and CD34 positivity (P < 0.0001). Complete remission (CR) was attained in 111 patients (63%), and was maintained at 5 years in 52 ± 7%. BAALC overexpression had a negative impact on CR achievement (P = 0.04), while did not influence relapse probability. Median survival was 22 months with a 5‐years overall survival (OS) of 35%. Factors with a negative impact on OS were older age (P = 0.0001), unfavorable cytogenetic (P = 0.005), ABCG2 overexpression (P = 0.03) and high BAALC levels (P = 0.01). We observed a worse outcome in patients with high BAALC expression through all cytogenetic risk categories: 5‐years OS was 100% vs. 71% in patients with favorable cytogenetics (P = 0.05), 55% vs. 40% in cases with intermediate karyotype (P = 0.04) and 34% vs. 23% in unfavorable cytogenetic subgroup (P = 0.02). BAALC overexpression identified AML patients with poor prognosis in all cytogenetic groups. Though relatively rare, BAALC positivity in patients with favorable or unfavorable karyotype significantly worsened survival. Am. J. Hematol. 88:848–852, 2013. © 2013 Wiley Periodicals, Inc.     

Outcomes in obese and overweight acute myeloid leukemia patients receiving chemotherapy dosed according to actual body weight

Cytotoxic chemotherapy dosages are traditionally calculated according to body surface area (BSA). No guidelines exist for chemotherapy dosing of acute myeloid leukemia (AML) patients at extremes of weight. We investigated the efficacy and safety of chemotherapy dosed according to BSA based on actual body weight (ABW) among under/normal weight, overweight, and obese AML patients. AML patients (excluding acute promyelocytic leukemia) treated with anthracycline and cytarabine‐based remission induction chemotherapy from 2002 to 2009 at Cleveland Clinic were divided into three body mass index (BMI) groups: under/normal weight (BMI ≤ 24.9), overweight (BMI 25.0–29.9), and obese (BMI ≥30.0). Among 247 AML patients, 81 (33%) were under/normal weight, 81 (33%) were overweight, and 85 (34%) were obese. Complete remission (CR) rates were similar among these groups (69.1, 79.0, and 76.5%, respectively; P = 0.321), as was median survival (10.7, 16.7, and 14.2 months, respectively, P = 0.352) and 30‐day mortality (3.7, 2.5, 7.1%, respectively, P = 0.331). There was no difference among groups in days to neutrophil or platelet recovery, hospitalization days for induction chemotherapy, and bacteremia. After adjustment for confounders (age, sex, BMI, white blood cells, cytogenetic risk, etiology, and bacteremia), overall survival was significantly shorter for normal weight compared to overweight (P = 0.006) and obese (0.038) patients. Response rates and adverse events were not significantly different among AML patients of all weight classes when induction chemotherapy was dosed according to ABW. Induction chemotherapy in these patients can be safely dosed using ABW. Am. J. Hematol. 88:906–909, 2013. © 2013 Wiley Periodicals, Inc.     

Clinical features and outcomes of hypocellular acute myeloid leukemia in adults: A Korean AML registry data

The hypocellular variant of acute myeloid leukemia (AML) is defined as bone marrow cellularity of <20% in a biopsy specimen at presentation. We performed a retrospective analysis of the clinical features and survival outcomes of hypocellular AML in a Korean population. We reviewed the medical records of all patients diagnosed with AML at nine hospitals participating in the Korean AML registry from 2006 to 2012. Overall survival (OS) and event-free survival (EFS) rates were calculated from the time of diagnosis until death or an event, respectively. In total, 2110 patients were enrolled and 102 (4.8%) were identified as having hypocellular AML. Patients with hypocellular AML were older than those with non-hypocellular AML (median age: 59 vs 49 years; P < .001) and presented with leukopenia more frequently (mean white blood cell count: 5810/μL vs 40549/μL; P < .001). There was no difference between patients with and without hypocellular AML in terms of the presence of antecedent hematologic disorders (5.9% vs 5.3%; P = .809). FLT3-ITD and NPM1 mutations were less common in hypocellular than non-hypocellular AML (FLT3-ITD mutations: 1.2% vs 14.3%, P < .001; NPM1 mutations: 0% vs 9.5%, P = .019). No differences were seen between the hypocellular and non-hypocellular AML groups in the complete remission rate (53.9% vs 61.3%, P = .139) or early death rate (defined as any death before 8 weeks; 14.7% vs 13.0%, P = .629). The OS and EFS did not differ between the hypocellular and non-hypocellular AML groups (median OS: 16 vs 23 months, P = .169; median EFS: 6 vs 9 months, P = .215). Hypocellular AML is more frequently observed in older-aged patients and have fewer FLT3-ITD and NPM1 mutation, but the clinical outcomes of hypocellular AML do not differ from those of non-hypocellular AML.     

Outcomes of Burkitt lymphoma with central nervous system involvement: evidence from a large multicenter cohort study

Central nervous system (CNS) involvement in Burkitt lymphoma poses a major therapeutic challenge, and the relative ability of contemporary regimens to treat CNS involvement remains uncertain. We describe the prognostic significance of CNS involvement and the incidence of CNS recurrence/progression after contemporary immunochemotherapy using real-world clinicopathological data from adults with Burkitt lymphoma diagnosed between 2009 and 2018 in 30 institutions in the USA. We examined associations between baseline CNS involvement, patients’ characteristics, complete response rates, and survival. We also examined risk factors for CNS recurrence. Of 641 patients (aged 18 to 88 years), 120 (19%) had CNS involvement. CNS involvement was independently associated with human immunodeficiency virus infection, poor performance status, involvement of ≥2 extranodal sites, and bone marrow involvement. Selection of the first-line treatment regimen was unaffected by CNS involvement (P=0.93). Patients with CNS disease had significantly lower rates of complete response (59% vs. 77% for patients with and without CNS involvement, respectively; P<0.001), worse 3-year progression-free survival (adjusted hazard ratio [aHR]=1.53, 95% confidence interval [95% CI]: 1.14-2.06; P=0.004) and overall survival (aHR=1.62, 95% CI: 1.18-2.22; P=0.003). The 3-year cumulative incidence of CNS recurrence was 6% (95% CI: 4-8%) and was significantly lower among patients receiving other regimens (CODOX-M/IVAC, 4%, or hyperCVAD/MA, 3%) compared with DA-EPOCH-R (13%; adjusted sub-distribution HR=4.38, 95% CI:, 2.16-8.87; P<0.001). Baseline CNS involvement in Burkitt lymphoma is relatively common and portends inferior prognosis independently of the first-line treatment regimen selected. In real-world practice, regimens including intravenous systemic agents with pronounced CNS penetrance were associated with a lower risk of CNS recurrence. This finding may be influenced by observed suboptimal adherence to the strict CNS staging and intrathecal therapy procedures incorporated in the DA-EPOCH-R regimen.     

Salvage therapy for acute myeloid leukemia with fludarabine,cytarabine, and idarubicin with or without gemtuzumab ozogamicin and with concurrent or sequential G‐CSF

The current salvage therapies for relapsed/refractory acute myeloid leukemia (AML) are unsatisfactory. Over the past 7 years, we have used two salvage regimens: fludarabine, cytarabine, and idarubicin with (FLAG‐IM) or without gemtuzumab ozogamicin (GO) (9 mg/m² on Day 8) (FLAG‐I) in relapsed/refractory AML. Three‐quarters of patients also received concurrent G‐CSF. Seventy‐one patients were treated, 23 with FLAG‐I and 48 with FLAG‐IM. The median duration of follow‐up was 30.6 months. The treatment groups were well balanced with median ages of 48 years (range 18–70) and 47 years (range 20–68), unfavorable cytogenetics in 57% and 35%, prior allogeneic stem cell transplant in 43% and 42%, and CR1 duration <1 year in 60% and 67%, respectively, for FLAG‐I and FLAG‐IM. The complete remission (CR) rate in the FLAG‐I group was 39% with an additional 13% achieving a CRp [overall response rate (ORR) 52%]; the CR rate in the FLAG‐IM group was 29% with an additional 27% achieving a CRp (ORR 56%). The median duration of response (DOR; 16.8 vs. 8.3 months), event‐free survival (EFS; 7.4 vs. 4.1 months), and overall survival (OS; 8.8 vs. 5.0 months) trended to favor FLAG‐I over FLAG‐IM. The patients who received G‐CSF concurrent with chemotherapy had superior overall response rate (ORR; 62% vs. 29%, P = 0.026), median EFS (6.2 vs. 3.4 months, P = 0.010), and OS (8.8 vs. 3.9 months, P = 0.004) when compared with those who sequentially received G‐CSF and chemotherapy, regardless of chemotherapy regimen. The addition of GO, at this dose and schedule, to FLAG‐I failed to improve the outcomes in patients with relapsed/refractory AML. The patients who received G‐CSF concurrently with chemotherapy had improved outcomes. Am. J. Hematol., 2009. © 2009 Wiley‐Liss, Inc.     

Outcomes after curative treatment for cryptogenic cirrhosis-associated hepatocellular carcinoma satisfying the Milan criteria

Background and Aim: The prognosis of cryptogenic cirrhosis‐associated hepatocellular carcinoma (CC‐HCC) was reported to be poor because many of them were discovered at the advanced stage. The aim of this study is to reveal the clinical features of early CC‐HCC. Methods: Consecutive 36 curatively treated CC‐HCC patients satisfying the Milan Criteria were compared with corresponding 211 HCV‐associated HCC (HCV‐HCC) patients. The clinical background, tumor recurrence rate, overall survival rate, and prognostic values of the patients were assessed. Results: The size of CC‐HCCs was larger than that of HCV‐HCCs (P = 0.01). The respective tumor recurrence rates at 1, 3, and 5 years were 11%, 32%, and 46% in the CC‐HCC, and 21%, 59%, and 81% in the HCV‐HCC. The respective overall survival rates at 1, 3, and 5 years were 94%, 85%, and 80% in the CC‐HCC, and 98%, 81%, and 61% in the HCV‐HCC. CC‐HCC patients had a lower tumor recurrence rate and a higher survival rate compared to the HCV‐HCC patients (P = 0.001 and P = 0.02, respectively). Via multivariate analysis, significant factors for high recurrence rate were number of HCCs (P = 0.02) and serum alpha fetoprotein levels (P = 0.03) in CC‐HCC, whereas multiple tumors (P < 0.001), large tumor size (P = 0.01), and high alanine aminotransferase (P = 0.04) in HCV‐HCC. The factor for survival was albumin in both groups. Conclusion: The size of CC‐HCC was larger than that of HCV‐HCC even in patients who received curative treatment; however, the risk for recurrence and the mortality of the patients with CC‐HCC was lower than those with HCV‐HCC.     

Adult acute megakaryocytic leukemia: an analysis of 37 patients treated at M.D. Anderson Cancer Center

To characterize acute megakaryocytic leukemia (FAB M7 AML), we identified 37 patients with M7 AML treated at M.D. Anderson Cancer Center between 1987 and 2003 and compared them with 1800 patients with non-M7, non-M3 AML treated during the same period. The median age of the M7 AML group was 56 years (range, 21-78 years); 22 patients (59%) had an antecedent hematologic disorder or myelodysplastic syndrome or both, and 7 patients (19%) had previously received chemotherapy for other malignancies. Extensive bone marrow fibrosis was found in 23 patients (62%). Poor cytogenetic characteristics were observed in 49% of patients with M7 AML versus 33% of others (P < .001). Complete remission rates were 43% with M7 AML and 57% with non-M7 AML (P = .089). Median overall survival (OS) was 23 and 38 weeks, respectively (P = .006). Median disease-free survivals were 23 versus 52 weeks, respectively (P < .001). By multivariate analysis, M7 AML was an independent adverse prognostic factor for OS, independent of other factors including cytogenetic abnormalities (hazard ratio 1.51, P = .049). These results confirm the poor prognosis of M7 AML and indicate that other biologic characteristics beyond cytogenetic abnormalities likely play a role in this disease.     

Survival benefit of implantable cardioverter-defibrillators in left ventricular assist device-supported heart failure patients

BackgroundImplantable cardioverter-defibrillators (ICDs) reduce mortality in heart failure (HF). In patients requiring a ventricular assist device (VAD), the benefit from ICD therapy is not well established. The aim of this study was to define the impact of ICD on outcomes in VAD-supported patients.Methods and ResultsWe reviewed data for consecutive adult HF patients receiving VAD as a bridge to transplantation from 1996 to 2003. The primary outcome was survival to transplantation. A total of 144 VADs were implanted [85 left ventricular (LVAD), 59 biventricular (BIVAD), mean age 50 ± 12 years, 77% male, left ventricular ejection fraction 18 ± 9%, 54% ischemic]. Mean length of support was 119 days (range 1–670); 103 patients (72%) survived to transplantation. Forty-five patients had an ICD (33 LVAD, 12 BIVAD). More LVAD patients had an appropriate ICD shock before implantation than after (16 vs 7; P = .02). There was a trend toward higher shock frequency before LVAD implant than after (3.3 ± 5.2 vs 1.1 ± 3.8 shocks/y; P = .06). Mean time to first shock after VAD implant was 129 ± 109 days. LVAD-supported patients with an ICD were significantly more likely to survive to transplantation [1-y actuarial survival to transplantation: LVAD: 91% with ICD vs 57% without ICD (log-rank P = .01); BIVAD: 54% vs 47% (log-rank P = NS)]. An ICD was associated with significantly increased survival in a multivariate model controlling for confounding variables (odds ratio 2.54, 95% confidence interval 1.04–6.21; P = .04).ConclusionsShock frequency decreases after VAD implantation, likely owing to ventricular unloading, but appropriate ICD shocks still occur in 21% of patients. An ICD is associated with improved survival in LVAD-supported HF patients.     

In vitro growth in acute myeloblastic leukaemia: relationship with other clinico-biological characteristics of the disease

The in vitro growth characteristics of a large series of acute myeloid leukaemia (AML) patients and their relationship with other clinical and biological disease characteristics were analysed. Patients with AML were studied, 181 with de novo AML and 45 with secondary AML (24 myelodysplastic syndrome, sAML-MDS, 21 myeloproliferative disorder, sAML-MPD). Leukaemic colony forming units (L-CFU) were assayed by plating peripheral blood (PB) blast cells in methyl-cellulose and using LCM-PHA as stimulant. In each case parallel cultures were made with and without stimulating factors. Plating efficiency (PE) was defined as the number of clusters plus colonies/10⁵ cells plated. Autonomous growth (AG) was the number of colonies plus clusters growing without stimulant. The autonomous proliferative index (API) was calculated as the number of clusters + colonies without stimulating factor divided by the number of clusters + colonies with stimulating factor. No significant differences in the PE between de novo and secondary AML were found. Autonomous growth was significantly higher in sAML-MPD. The FAB subtype M3 leukaemias displayed a significantly greater PE and a significantly lower API when compared with the other FAB subgroups (P = 0.0002). Upon analysing the relationship with the immunophenotype, only CD33 expression showed a significant relationship with the in vitro growth pattern; CD33⁺ cases displayed a higher PE (P = 0.0002) and AG (P = 0.0003) than CD33^? cases. When patients were grouped according to the level of rh123 efflux (MDR1) it was observed that cases with >30% elimination showed a higher AG and API than those with <30% (P = 0.03). Finally we found that patients with higher API (>0.05) displayed a significantly shorter overall survival as compared with patients with API < 0.05 (P = 0.04). The in vitro study properties of clonogenic cells produces relevant clinical information of leukaemic cell biology in AML patients.     

Clinical significance of chromatin-spliceosome acute myeloid leukemia: a report from the Northern Italy Leukemia Group (NILG) randomized trial 02/06

Secondary acute myeloid leukemia (sAML) after myelodysplastic or myeloproliferative disorders is a high-risk category currently identified by the clinical history or specific morphological and cytogenetic abnormalities. However, in the absence of these features, uncertainties to identify the secondary nature of some cases, otherwise defined as de novo AML, remain. In order to test whether a chromatinspliceosome (CS) mutational signature might better define the de novo AML group, we analyzed a prospective cohort of 413 newly diagnosed AML patients who were enrolled in a randomized clinical trial (NILG AML 02/06) and who provided samples for accurate cytogenetic and molecular characterization. Among clinically defined de novo AML, 17.6% carried CS mutations (CS-AML) and showed clinical characteristics closer to sAML (older age, lower white blood cell counts and higher rate of multilineage dysplasia). Outcomes in this group were adverse, more similar to those of sAML as compared to de novo AML (overall survival, 30% in CS-AML and 17% in sAML vs. 61% in de novo AML, P<0.0001; disease-free survival, 26% in CS-AML and 22% in sAML vs. 54% of de novo AML, P<0.001) and independently confirmed by multivariable analysis. Allogeneic transplant in first complete remission improved survival in both sAML and CS-AML patients. In conclusion, these findings highlight the clinical significance of identifying CS-AML for improved prognostic prediction and potential therapeutic implications. (NILG AML 02/06; clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00495287","term_id":"NCT00495287"}}NCT00495287).