Higher Initial White Blood Cell Research Articles

Changes in White Blood Cell Counts Early during Treatment of Acute Leukemia Using Differentiating Chemotherapies

Background: Differentiation syndrome (DS) is a life-threatening complication that can occur with a number of therapies used for the treatment of acute myeloid leukemia (AML). It is best characterized in patients treated with All-trans retinoic acid (ATRA) and Arsenic for acute promyelocytic leukemia (APL), or for patients receiving an IDH inhibitor for IDH1/2 mutant AML, but can also be seen with other therapies such as with FLT3 inhibitors, and in novel therapies under development such as menin inhibitors. It is critical to identify DS early, as corticosteroids can mitigate complications. The diagnosis of DS is made by recognizing a constellation of symptoms, typically including a rising white blood cell count, peripheral edema, rash, shortness of breath, pulmonary edema, and fevers. We evaluated white blood cell (WBC) count changes during treatment according to whether patients DS or not on chemotherapy. Methods: We identified adult patients who received ATRA+Arsenic for newly diagnosed APL, as well as patients with AML harboring a mutation in IDH1 or IDH2 who were treated with monotherapy IDH inhibitors (enasidenib or ivosidenib) at any point during their treatment for active AML and treated at MGH. Patients were treated at MGH between 2015 and 2023. Patients were 18 or older and had a confirmed pathological diagnosis. We interrogated the medical record to identify patients with clinical documentation of DS during treatment, as well as the treatments used for management and clinical complications. Descriptive statistics were used to identify differences in median WBC counts between patients with DS and those without DS, and comparisons were made using Wilcoxon or chi square testing as appropriate. Results: We identified 33 patients with APL who received ATRA+Arsenic, and 35 patients with AML harboring an IDH1/2 mutation treated with monotherapy IDH inhibition. Our analysis revealed that 26% (18/68) of patients had clinical documentation of differentiation syndrome, including 21% (14/33) of patients treated with ATRA+Arsenic and 11% (4/35) of patients on IDH inhibitors. In APL, the median day of a recorded diagnosis of DS was 4 days after treatment start (range 1-14 days). Patients with APL who developed DS had a higher initial WBC at treatment start compared to those who did not develop DS (6.7 vs 1.05 K/uL, p=0.03). There was no difference in hemoglobin, platelets, ANC, and percentage of peripheral blood blasts (Table 1). The WBC in DS patients started rising during the first week of treatment and peaked on Day 15 (Figure 1). Regarding treatment approaches for DS, the majority of patients were treated with steroids, (78%, 11/14) while 43% (6/14) received cytoreduction, most commonly with gemtuzumab. In IDH-mutant AML, the median day of a recorded diagnosis of DS was 35 days after treatment start (range 16-69 days). Patients with IDH-mutated AML on IDH Inhibitor monotherapy who experienced DS had a similar finding of an early temporal rise in WBC to those with APL on ATRA+Arsenic, although this rise started on day 12 and peaked on day 16 of monotherapy. Of note, these peaks occurred prior to the documentation of a clinical DS diagnosis. In contrast to APL, patients with IDH-mutant AML who developed DS had a lower baseline ANC (p=0.03) and higher percentage of peripheral blasts circulating than those without DS (p=0.03). All patients with IDH inhibitor associated DS received dexamethasone. Discussion: Patients with DS during treatment for APL on ATRA+Arsenic, as well as patients with DS with IDHmut AML on IDH inhibitors, had similar early peaks in the WBC count, occurring around 2 weeks from the start of treatment. In this small group, the IDHmut AML showed a rise in WBC that preceded the actual DS diagnosis. Understanding the timing of and risk factors for DS may help to identify at risk patients early for mitigation strategies.

Feasibility and Outcome of Post-Induction Therapy Incorporating Dasatinib for Patients with Newly Diagnosed ABL-Class Fusion B-Lymphoblastic Leukemia (ABL-class Fusion B-ALL): Children's Oncology Group AALL1131

Background: Approximately 2-3% of B-ALL patients have Philadelphia chromosome like (Ph-like) B-ALL with an ABL-class fusion ( ABL1, ABL2, PDGFRB, or CSF1R fusions), but lacking BCR::ABL1. These patients are predicted to be sensitive to ABL-class tyrosine kinase inhibitors, such as imatinib or dasatinib. Ph-like B-ALL is associated with male sex, older age, higher initial white blood cell (WBC) count, elevated end of induction (EOI) minimal residual disease (MRD), and poor outcome. The AALL1131 Dasatinib arm was designed to evaluate response to therapy following induction of patients with ABL-class fusion B-ALL, when given dasatinib continuously on a modified Berlin-Frankfurt-Münster (MBFM) backbone. Methods: Between February 2012 and March 2019, AALL1131 enrolled patients 1-30 years with newly diagnosed high risk (HR) B-ALL. AALL1131 was amended in August 2016, to include the Dasatinib arm for patients with ABL-class fusions involving ABL1, ABL2, PDGFRB, and CSF1R. Patients with Down Syndrome were not eligible for the Dasatinib arm. ABL-class fusion B-ALL patients with a predicted TKI-sensitive mutation were screened by low density array (LDA) PCR and confirmed by additional molecular testing. Following 4-drug induction, patients with HR B-ALL and ABL-class fusions received MBFM with dasatinib (60 mg/m 2, maximum 140 mg) daily from start of consolidation through end of maintenance. Dasatinib was held only for toxicity. Results: Twenty-two evaluable patients with HR B-ALL were non-randomly assigned to the Dasatinib arm. ABL-class 3' partners included ABL1 (n=4), ABL2 (n=4), PDGFRB (n=12), and CSF1R (n=2). Compared to all patients on AALL1131, patients treated on the Dasatinib arm were older (median age at diagnosis 14 versus 10 years, p=0.008), more often male (77% versus 56%, p=0.046), and had a trend towards an increased initial WBC (median WBC at diagnosis 44,000/µL versus 19,000/µL, p=0.086). Patients with ABL-class fusions had EOI MRD > 0.01% in 20 of 22 patients and available end of consolidation MRD >0.01% in 6 of 10 patients. Only 5 of 22 (22.7%) patients completed prescribed protocol therapy. Reasons for therapy discontinuation included induction failure (n=2), relapse (n=1), alternate therapy (n=1), determined to be in the patient's best interest (n=10), death (n=1), unknown (n=2). Compared to all patients on AALL1131, four-year disease-free survival was 52.5+18.1% versus 86.8+0.7% (p<0.0001) and overall survival 79.4+13.6% versus 89.2+0.4% (p<0.0001). Dasatinib was well tolerated with no unexpected treatment related toxicities. Conclusion: Patients with ABL-class fusions were more likely male, EOI MRD+, and had poorer outcomes. Seventy-seven percent of patients enrolled on the Dasatinib arm did not complete prescribed therapy. While dasatinib was well tolerated, treatment failures occurred early, indicating alternate strategies are needed.

Clinical Study on the Relationship between Gene Mutation Profile and Prognosis in Pediatric Acute Lymphocyte Leukemia

To analyze the gene mutation profile in children with acute lymphocyte leukemia (ALL) and to explore its prognostic significance. Clinical data of 249 primary pediatric ALL patients diagnosed and treated in the Department of Hematological Oncology of Wuhan Children's Hospital from January 2018 to December 2021 were analyzed retrospectively. Next-generation sequencing (NGS) was used to obtain gene mutation data and analyze the correlation between it and the prognosis of children with ALL. 227 (91.2%) were B-ALL, 22 (8.8%) were T-ALL among the 249 cases, and 178 (71.5%) were found to have gene mutations, of which 85 (34.1%) had ≥3 gene mutations. NRAS(23.7%), KRAS (22.9%),FLT3(11.2%), PTPN11(8.8%), CREBBP (7.2%), NOTCH1(6.4%) were the most frequently mutated genes, the mutations of KRAS, FLT3, PTPN11, CREBBP were mainly found in B-ALL, the mutations of NOTCH1 and FBXW7 were mainly found in T-ALL. The gene mutation incidence of T-ALL was significantly higher than that of B-ALL (χ2= 5.573，P＜0.05) and were more likely to have co-mutations (P＜0.05). The predicted 4-year EFS rate (47.9% vs 88.5%, P＜0.001) and OS rate (53.8% vs 94.1%, P＜0.001) in children with tp53 mutations were significantly lower than those of patients without tp53 mutations. Patients with NOTCH1 mutations had higher initial white blood cell count （128.64×109/L vs 8.23×109/L，P＜0.001）, and children with NOTCH1 mutations had a lower 4-year EFS rate than those of without mutations (71.5% vs 87.2%, P＝0.037). Genetic mutations are prevalent in childhood ALL and mutations in tp53 and NOTCH1 are strong predictors of adverse outcomes in childhood ALL, with NGS contributing to the discovery of genetic mutations and timely adjustment of treatment regimens.

Does time from diagnosis to treatment affect the prognosis of patients with newly diagnosed acute myeloid leukemia?

AbstractIn fit patients with newly diagnosed acute myeloid leukemia (AML), immediate treatment start is recommended due to the poor prognosis of untreated acute leukemia. We explored the relationship between time from diagnosis to treatment start (TDT) and prognosis in a large real-world data set from the German Study Alliance Leukemia–Acute Myeloid Leukemia (SAL-AML) registry. All registered non–acute promyelocytic leukemia patients with intensive induction treatment and a minimum 12 months of follow-up were selected (n = 2263). We analyzed influence of TDT on remission, early death, and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0 to 5, 6 to 10, 11 to 15, and >15 days of TDT, adjusted for influence of established prognostic variables on outcomes. Median TDT was 3 days (interquartile range, 2-7). Unadjusted 2-year OS rates, stratified by TDT of 0 to 5, 6 to 10, 11 to 15, and >15 days, were 51%, 48%, 44%, and 50% (P = .211). In multivariable Cox regression analysis accounting for established prognostic variables, the TDT hazard ratio as a continuous variable was 1.00 (P = .617). In OS analyses, separately stratified for age ≤60 and >60 years and for high vs lower initial white blood cell count, no significant differences between TDT groups were observed. Our study suggests that TDT is not related to survival. As stratification in intensive first-line AML treatment evolves, TDT data suggest that it may be a feasible approach to wait for genetic and other laboratory test results so that clinically stable patients are assigned the best available treatment option. This trial was registered at www.clinicaltrials.gov as #NCT03188874.

Prognostic Role of Postinduction Minimal Residual Disease and Myeloid Sarcoma Type Extramedullary Involvement in Pediatric RUNX1-RUNX1T1 (+) Acute Myeloid Leukemia.

Acute myeloid leukemia with the t(8;21)(q22;q22) rearrangement (RUNX1-RUNX1T1 (+) AML) is known to have a favorable prognosis. Our study aimed to determine the most important prognostic variables among an aggregate of clinical, genetic, and treatment response-based factors in pediatric RUNX1-RUNX1T1 (+) AML. We analyzed the characteristics and outcome of 40 patients who were diagnosed with and treated for RUNX1-RUNX1T1 (+) AML from April 2008 to December 2016 at our institution. A<-2.2 log fusion transcript decrement after remission induction, myeloid sarcoma type extramedullary involvement (EMI) at diagnosis, higher initial white blood cell count, and presence of KIT mutation predicted lower event-free survival. Both lower fusion transcript decrement after remission induction and the presence of EMI at diagnosis proved to be significant adverse factors in the multivariate study. The 5-year event-free survival was 70.0±7.2% (28/40); 8 of the 12 relapsed patients survive disease-free, resulting in 5-year overall survival of 89.5±5.0% (36/40). Kinetics of response to remission induction chemotherapy, measured in terms of the PCR value for the fusion transcript, and the presence of myeloid sarcoma type EMI at diagnosis may predict the risk of relapse in pediatric RUNX1-RUNX1T1 (+) AML.

Demographics and Outcome of Philadelphia-positive ALL in a Pediatric Population in North India: a Single-center Experience.

Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) in children had a worse outcome before the use of tyrosine kinase inhibitors. We have evaluated the demographics and outcome of Ph+ ALL patients treated with imatinib without blood marrow transplantation. Of the 206 children with ALL registered for treatment, the demographic data of 15 Ph+ ALL patients were compared with the remaining Ph- patients. Imatinib (340 mg/m) was started on day 5 (D5) of induction in Ph+ patients, and their overall survival was compared with Ph- high-risk patients treated on similar protocols. Statistical analysis was carried out by the Fisher exact test and the t test. The Kaplan-Meier test was used for survival analysis. Philadelphia positivity noted in 15/206 (7.28%) ALL patients was higher than reported earlier. Median initial total leukocyte count and central nervous system positivity were significantly higher in Ph+ patients. Myeloid markers, CD13 and CD33, were also positive in 33.3% Ph+ patients. D15 and D35 marrow showed remissions in a larger proportion of Ph+ ALL, as compared with Ph- patients, but chemotherapy interruptions and neutropenic deaths were significantly higher after starting imatinib, as compared with Philadelphia high-risk patients. Overall survival was similar in Ph+ and Ph- high-risk ALL patients. Ph+ ALL, noted in 7.28%, presented with high initial white blood cell counts, high central nervous system positivity, poor steroid response, and higher induction deaths, as compared with high-risk Ph- ALL, and raised the question about the appropriate dose and time of introduction of imatinib to prevent toxicity.

Genetic variants and clinical significance of pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, is characterized by molecular aberrations. Recently, genetic profiling has been fully investigated on ALL; however, the interaction between its genetic alterations and clinical features is still unclear. Therefore, we investigated the effects of genetic variants on ALL phenotypes and clinical outcomes. Targeted exome sequencing technology was used to detect molecular profiling of 140 Chinese pediatric patients with ALL. Correlation of genetic features and clinical outcomes was analyzed. T-cell ALL (T-ALL) patients had higher initial white blood cell (WBC) count (34.8×109/L), higher incidence of mediastinal mass (26.9%), more relapse (23.1%), and enriched NOTCH1 (23.1%), FBXW7 (23.1%) and PHF6 (11.5%) mutations. Among the 18 recurrently mutated genes, SETD2 and TP53 mutations occurred more in female patients (P=0.041), NOTCH1 and SETD2 mutants were with higher initial WBC counts (≥50×109/L) (P=0.047 and P=0.041), JAK1 mutants were with higher minimal residual disease (MRD) level both on day 19 and day 46 (day 19 MRD ≥1%, P=0.039; day 46 MRD ≥0.01%, P=0.031) after induction chemotherapy. Multivariate analysis revealed that initial WBC counts (≥50×109/L), MLLr, and TP53 mutations were independent risk factors for 3-year relapse free survival (RFS) in ALL. Furthermore, TP53 mutations, age (<1 year or ≥10 years), and MLLr were independently associated with adverse outcome in B-cell ALL (B-ALL). MLLr and TP53 mutations are powerful predictors for adverse outcome in pediatric B-ALL and ALL. Genetic profiling can contribute to the improvement of prognostication and management in ALL patients.

The Role of Day 14 Bone Marrow Analysis in Determining Leukemia Free Survival and Overall Survival

IntroductionIn the treatment of acute myeloid leukemia, initial induction guidelines frequently include performing a day 14 bone marrow biopsy to assess response. A second induction is then recommended for patients with morphologic residual leukemia (≥5% blasts). Recent retrospective reviews have shown no difference in complete response (CR) rates amongst patients with residual leukemia based on day 14 marrow assessment who were and were not given a second induction. In our single center retrospective study, we compared patients with residual blast counts ≥5% to identify differences in leukemia free survival (LFS) and overall survival (OS) in those who did and did not receive a second induction. In addition we examined the cytogenetic profile of Day 14 and remission bone marrows.Methods:Consecutively treated patients with newly diagnosed primary and secondary AML over the age of 18 who received daunorubicin based induction with a curative intent from 2006 to 2014 were obtained via cancer center medical records. Outcome data was followed until May 1st 2015. We reviewed demographic (age, sex, ECOG PS, co-morbidities) as well as AML specific data (daunorubicin dose, use of etoposide, initial bone marrow blast count, initial white blood cell count, bone marrow blast count at day 14, cytogenetic stratification, CR rate, allogeneic stem cell transplant, LFS and OS). Patients included in survival analysis were required to have an initial and day 14 bone marrow biopsy with morphologic identification of residual leukemia on the day 14 marrow. Cytogenetic risk stratification was based on NCCN guidelines. Morphological CR was defined based on International Working Group criteria (Cheson, JCO, 2003). Positive (PPV) and negative predictive value (NPV) for CR were calculated by considering a BM of less than 5% at Day 14 a positive screening test for obtaining CR. Data was analyzed using Mann Whitney U test and chi square analysis as appropriate. LFS and OS were estimated using the Kaplan Meier method and compared using the log rank test. All calculations and graphs were obtained using STATA/SE 12.1.Results:Of the 91 patients initially identified, 67 had Day 14 marrows performed and 31 had residual blast counts ≥5%. For our overall cohort, we found a PPV of 76% and NPV of 65% for Day 14 marrows in determination of CR, which is in line with previous studies. No statistical differences were seen between the groups (Table 1), although patients who were reinduced trended toward higher initial white blood cell counts while those who were not reinduced trended towards improved CR rates. Comparing patients with residual disease at Day 14 who were or were not reinduced, we found no statistical difference for LFS and OS between the two groups (p 0.87 and 0.96 respectively). Interestingly, in comparing cytogenetics, two patients with unfavorable cytogenetics on initial BM converted to normal/intermediate cytogenetics after induction despite a residual blast count greater than 5%. Both obtained CR, one with and one without reinduction. Another patient with unfavorable cytogenetics at day 14 obtained CR with normal cytogenetics without reinduction.Conclusions:Although of limited size, our study suggests that reinduction based on Day 14 marrow is of limited use in predicting LFS and OS in AML. Better methods to determine residual leukemia following initial induction therapy are required in order to help guide treatment decisions.Table 1Demographics of patients with and without reinduction chemotherapy with residual disease on repeat bone marrow biopsyNo Reinduction(n=17)Reinduction(n=14)p valueAge (Median)6357.50.46Male:Female8:98:60.58ECOG PS011161040.69Initial WBC (Median)5.211.70.06Initial % Bone Marrow Blast (Median)0.530.480.56DNR Dose60mg/m290mg/m2116860.67Etoposide Given540.96Cytogenetic RiskIntermediateUnfavorable98770.87Complete Response1040.09Allo-SCT780.38 [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Identification of novel kinase fusion transcripts in paediatric B cell precursor acute lymphoblastic leukaemia with IKZF1 deletion.

Activating tyrosine kinase mutations or cytokine receptor signalling alterations have attracted attention as therapeutic targets for high-risk paediatric acute lymphoblastic leukaemia (ALL). We identified two novel kinase fusions, OFD1-JAK2 and NCOR1-LYN, in paediatric ALL patients with IKZF1 deletion, by mRNA sequencing. The patient with CSF2RA-CRLF2 also harboured IGH-EPOR. All these patients had high-risk features, such as high initial white blood cell counts and initial poor response to prednisolone. The functional analysis of these novel fusions is on-going to determine whether these genetic alterations can be targeted by drugs.

Prognostic Value of Prednisone Response in CCLG-ALL 2008

To ovaluate the prognostic value of prednisone response in treatment regimes of children with acute lymphoblastic leukemia. A total of 598 newly diagnosed ALL patients were enrolled and received prednisone pre-treatment. Based on the peripheral lymphoblast count on day 8, these patients were divided into 2 groups: prednisone good response (PGR) and prednisone poor response (PPR). PPR patients were classified into high risk group immediately and then received intensed chemotherapy. The all enrolled patients were followed up and the clinical features and treatment outcomes of the two groups were analyzed. Compared with PGR group, PPR group had different characteristics. They were older in age and had higher initial white blood cell count (P<0.05). T-cell ALL (T-ALL) and Philadelphia chromosome positive ALL (Ph+ ALL) were frequent in PPR group (P<0.05). Event-free survival (EFS) rate of PPR group was significantly lower than that of PGR group (P<0.05). 2 year event-free survival(EFS) rate of PGR group was (88.3±1.5)%, while the 2-year EFS rate of PPR group was (58.4±5.3)%. 5 year EFS rates of PGR and PPR were (80.8±2.1)% and (53.4±6.0)%, respectively. The EFS rate of PPR group was falling rapidly within 2 years. PPR group had higher relapse rate, and most relapses occurred within 18 months (P<0.05). PPR group had more high incidence of minimal residual disease (MRD) both on day 33 and on week 12 (P<0.05). No significant difference of EFS and relapse time was found between PPR and high risk PGR patients (P>0.05). In multi-variate regression analysis, the PPR, the presence of BCR-ABL1 and MLL were significantly unfavorable factors (P<0.05). Prednisone response has been confirmed to be still great prognostic value and PPR children patients have poor outcomes generally. It is likely that the response to prednisone does not make much sense to high risk ALL patients.

Factors Predictive of Relapse of Acute Leukemia in Children after Allogeneic Hematopoietic Cell Transplantation

The presence of minimal residual disease (MRD) before transplantation is the most important prognostic risk factor predictive of post-transplantation relapse in hematologic malignancies. However, MRD alone does not adequately predict relapse in all patients. To improve upon the ability to identify patients likely to relapse, we evaluated risk factors, in addition to MRD, that may be associated with development of post-transplantation relapse. In this single institution, retrospective cohort study of children with acute leukemia or myelodysplastic syndrome who had undergone a first allogeneic transplantation and had pretransplantation MRD evaluation, 40 of 93 patients (43%) experienced relapse. Univariate analysis demonstrated that African American race, high initial white blood cell count, central nervous system (CNS) disease at diagnosis, short first complete remission, nonmyeloablative (NMA) conditioning, lack of remission, and MRD before transplantation were associated with worse relapse-free survival (RFS). In a Cox multivariable analysis, CNS disease (P = .009), lack of remission (P = .01), and NMA conditioning (P = .04) were independently associated with inferior RFS. Among those in a morphologic complete remission who underwent a myeloablative transplantation, having both CNS disease at diagnosis (specifically in acute lymphoblastic leukemia) and MRD positivity was an independent risk factor predictive of relapse, which has not been previously reported. Results from our study support the existence of risk factors complimentary to pretransplantation MRD. Validation in a larger independent homogenous cohort is needed to develop a prognostic tool for clinical use to predict post-transplantation relapse.

Expression of CD56 is an unfavorable prognostic factor for acute promyelocytic leukemia with higher initial white blood cell counts

Expression of CD56 has recently been introduced as one of the adverse prognostic factors in acute promyelocytic leukemia (APL). However, the clinical significance of CD56 antigen in APL has not been well elucidated. We assessed the clinical significance of CD56 antigen in 239 APL patients prospectively treated with all-trans retinoic acid and chemotherapy according to the Japan Adult Leukemia Study Group APL97 protocol. All patients were prospectively treated by the Japan Adult Leukemia Study Group APL97 protocol. The median follow-up period was 8.5 years. Positive CD56 expression was found in 23 APL patients (9.6%). Expression of CD56 was significantly associated with lower platelet count (P = 0.04), severe disseminated intravascular coagulation (P = 0.04), and coexpression of CD2 (P = 0.03), CD7 (P = 0.04), CD34 (P < 0.01) and/or human leukocyte antigen-DR (P < 0.01). Complete remission rate and overall survival were not different between the two groups. However, cumulative incidence of relapse and event-free survival (EFS) showed an inferior trend in CD56+ APL (P = 0.08 and P = 0.08, respectively). Among patients with initial white blood cell counts of 3.0 × 109/L or more, EFS and cumulative incidence of relapse in CD56+ APL were significantly worse (30.8% vs 63.6%, P = 0.008, and 53.8% vs 28.9%, P = 0.03, respectively), and in multivariate analysis, CD56 expression was an unfavorable prognostic factor for EFS (P = 0.04). In conclusion, for APL with higher initial white blood cell counts, CD56 expression should be regarded as an unfavorable prognostic factor.

Leptomeningeal Carcinomatosis in Non–Small-Cell Lung Cancer Patients: Impact on Survival and Correlated Prognostic Factors

The incidence of leptomeningeal carcinomatosis (LC) has increased in patients with metastatic non-small-cell lung cancer (NSCLC) because of recent improvements in survival. The clinical features and prognostic factors of LC in NSCLC patients, however, have not been well identified. The aim of this study was to identify the clinical features and prognostic factors of NSCLC patients with LC. One hundred and forty-nine consecutive NSCLC patients with cytologically proven LC diagnoses between 2001 and 2009 at Samsung Medical Center were retrospectively reviewed. The median age was 58 years (range, 34-80) with most patients (135, 95%) having histology indicating adenocarcinoma. Twenty-six patients (17.4%) had LC at the initial presentation of lung cancer. Treatment for LC consisted of intrathecal chemotherapy (ITC) alone in 44 patients, ITC plus systemic therapy in 18 patients, ITC plus radiotherapy in 29 patients, all three treatments in 18 patients, and other treatments without ITC in 20 patients. Twenty patients received only supportive care. The median follow-up duration was 34 months and the median overall survival from diagnosis of LC was 14 weeks (95% confidence interval [CI] 12, 16). In univariate analysis, encephalopathy, Eastern Cooperative Oncology Group (ECOG) performance status, low initial cerebrospinal fluid (CSF) glucose, high initial CSF protein, high initial CSF white blood cell count, treatment with ITC, systemic therapy with epidermal growth factor receptor tyrosine kinase inhibitors or cytotoxic chemotherapy, whole-brain radiotherapy (WBRT), ventriculoperitoneal (VP) shunt operations, and negative cytologic conversion after ITC were identified as variables that had prognostic influence on survival. In multivariate analysis, poor ECOG performance status (p = 0.026), high protein level of CSF (p = 0.027), and high initial CSF WBC count (p = 0.015) remained significant predictors of poor prognosis for survival, whereas ITC (p < 0.001), EGFR-TKI use (p = 0.018), WBRT (p = 0.009), and VP shunt operation (p = 0.013) remained significant predictors of favorable prognosis for survival. Even though the prognosis of LC from NSCLC is poor, small subsets of these patients survive longer. Our results suggest that more active treatment strategies including ITC, WBRT, and EGFR-TKI use might improve clinical outcomes in NSCLC patients with LC and good performance status, low initial CSF protein and WBC counts.

Predictors of outcome and methodological issues in children with acute lymphoblastic leukaemia in El Salvador

Background Most children with cancer live in low-income countries (LICs) where risk factors in paediatric acute lymphoblastic leukaemia (ALL) developed in high-income countries may not apply. Methods We describe predictors of survival for children in El Salvador with ALL. We included patients <16 years diagnosed with ALL between January 2001 and July 2007 treated with the El Salvador–Guatemala–Honduras II protocol. Demographic, disease-related, socioeconomic and nutritional variables were examined as potential predictors of event-free survival (EFS) and overall survival (OS). Results 260/443 patients (58.7%) were classified as standard risk. Standard- and high-risk 5-year EFS were 56.3 ± 4.5% and 48.6 ± 5.5%; 5-year OS were 77.7 ± 3.8% and 61.9 ± 5.8%, respectively. Among standard-risk children, socioeconomic variables such as higher monthly income (hazard ratio [HR] per $100 = 0.84 [95% confidence interval (CI) 0.70–0.99; P = 0.04]) and parental secondary education (HR = 0.49, 95% CI 0.29–0.84; P = 0.01) were associated with better EFS. Among high-risk children, higher initial white blood cell (HR per 10 × 10 9/L = 1.03, 95% CI 1.02–1.05; P < 0.001) predicted worse EFS; socioeconomic variables were not predictive. The difference in EFS and OS appeared related to overestimating OS secondary to poor follow-up after abandonment/relapse. Conclusion Socioeconomic variables predicted worse EFS in standard-risk children while disease-related variables were predictive in high-risk patients. Further studies should delineate pathways through which socioeconomic status affects EFS in order to design effective interventions. EFS should be the primary outcome in LIC studies.

Which AML subsets benefit from leukemic cell priming during chemotherapy? Long‐term analysis of the ALFA‐9802 GM‐CSF study

: Priming with granulocytic hematopoietic growth factors may modulate cell cycle kinetics of leukemic cells and render them more susceptible to phase-specific chemotherapeutic agents. In a first report, we have shown that priming with granulocyte-macrophage colony-stimulating factor (GM-CSF) may enhance complete remission (CR) rate and event-free survival (EFS) in younger adults with acute myeloid leukemia (AML). : In this randomized trial, 259 patients with AML were randomized at baseline to receive or not receive GM-CSF concurrently with all cycles of chemotherapy. The effects of GM-CSF on survival were reported herein with a long-term follow-up and studied according to distinct biological subgroups defined on cytogenetics and molecular markers. : The EFS rate was better in the GM-CSF group (43% vs 34%; P = .04). GM-CSF did not improve the outcome in patients from good risk subgroups, while patients from poor risk subgroups benefited from GM-CSF therapy. In this population, the difference in terms of EFS probability was mainly observed in patients with high initial white blood cell count and in those with FLT3-ITD or MLL rearrangement. When combining these 2 molecular abnormalities for comparison of the effect of GM-CSF priming, the difference in terms of EFS was highly significant (5-year EFS, 39% with GM-CSF vs 8% without GM-CSF; P = .007). : Sensitization of leukemic cells and their progenitors by GM-CSF appears as a plausible strategy for improving the outcome of patients with newly diagnosed AML. Patients with poor-prognosis FLT3-ITD or MLL rearrangement might be a good target population to further investigate priming strategies. Cancer 2010. (c) 2010 American Cancer Society.

High incidence of FLT3 mutations in adults with Acute Promyelocytic Leukemia (APL): Correlation with diagnostic features and treatment outcome (CALGB 9710)

7002 Background: Studies have associated activating mutations of FLT3 (FLT3+) with adverse outcomes in patients (pts) with APL, but little is known about the impact of adding Arsenic Trioxide (As2O3) to frontline APL treatment on the clinical outcome of pts harboring these mutations. Methods: We examined the incidence of FLT3+ in a subset of 78 adults with newly diagnosed APL entered onto CALGB 9710, a North American Intergroup phase III randomized trial that demonstrated a significant survival benefit from adding two 25-day courses of As2O3 to post-remission consolidation therapy (Powell, et al. ASCO 2007). FLT3 internal tandem duplications (ITD) and activation loop point mutations (D835) were identified using standard methods (InVivoScribe, San Diego). FLT3+ was correlated with other diagnostic/prognostic features including PML-RARA isoform type, initial white blood cell (WBC) count, and pt age, and with treatment response. Results: FLT3+ was identified in 42 pts (54%); 28 (36%) had an ITD, 17 (22%) had a D835, and 3 (4%) had both. FLT3+ was not associated with increasing age; 55% of FLT3+ pts were male. There was a strong association of FLT3+ with high initial WBC count > 10K/μl (p= 0.0002), and with the S-isoform of PML-RARA (p < 0.0001). Overall, FLT3+ was not associated with early deaths during induction, lower CR rate, or inferior disease free survival (DFS) or survival (S). However, when analyzed by treatment arm, relapses occurred in only 2/21 (10%) FLT3+ pts who received As2O3 compared to a very high relapse rate of 13/21 (62%) among FLT3+ pts who did not receive As2O3 (p = 0.0004). Conclusions: FLT3+ occurs with high frequency (54%) in our APL cohort and is very strongly associated with high initial WBC count and S-isoform, both of which correlated with adverse outcomes for pts on CALGB 9710 (Stock et al, ASCO 07). In contrast to previous reports, we did not find an association of FLT3+ with high induction death rates, DFS, or S. Treatment with As2O3 appeared to decrease markedly the relapse rate in FLT3+ pts. These results will be examined in a larger cohort of 9710 pts. Given the high frequency of FLT3+ APL, targeted therapy with FLT3 inhibitors is an attractive strategy to further improve relapse-free survival for pts with FLT3+ APL. No significant financial relationships to disclose.

The Clinical Features and the Efficient Therapy of 66 Acute Promyelocytic Leukemia Patients with High Initial White Blood Cell Count.

Objective: To investigate the clinical features and the efficient therapy of acute promyelocytic leukemia(APL) with high initial white blood cell(WBC) count.Methods: The clinical features of 66 newly diagnosed APL patients with high initial WBC and 152 patients without high initial WBC were retrospectively analyzed. Additionally, 66 patients with high WBC were divided into different groups and the therapeutic effects were compared according to the different induction therapy.Results: The early death rate and the incidence of disseminated intravascular coagulation(DIC) and retinoic acid syndrome(RAS) were 30.3%,57.6% and 31.8% respectively for the group with initial high WBC, those were higher than the indexes of 7.2%,38.1% and 21.05% respectively for the group without initial high WBC (p <0.05),Whereas CR rate (63.6%) for the group with initial high WBC were lower than that (88.2%) for the group without initial high WBC (p <0.05). 61 of 66 patients with high WBC accepted induction therapy: 31 patients treated with all-trans retinoic acid(ATRA) alone ,21patients treated with the combination of ATRA and arsenic trioxide (ATO),9 treated with ATO alone, the early death rates were 27.3%,14.3%,55.6% respectively, CR rates were 67.7%,81.0%,44.4% respectively, the result showed there were the lowest rate of early death and the highest rate of CR in the combination group. Of 61 patients, 41 cases were given low-dose chemotherapy, the CR rate was 73.2%,total death rate was 19.5%, that of 20 patients without chemotherapy were 45.0%,55.0% respectively. The differences between two groups had statistical significance(p<0.05).Conclusions: Compared with APL without high initial WBC, APL with high initial WBC has lower CR rate, higher early death rate, higher incidence of DIC and RAS .The combination of ATRA,ATO and chemotherapy is the most efficient therapeutic approach to APL patients with high initial WBC, which can significantly reduce the early death rate and improve the CR rate.

Evaluation of Minimal Residual Disease Based on NPM1 Mutations in AML with Intermediate Risk Cytogenetics: A Prospective Study of 36 Patients.

Mutations in exon 12 of the nucleophosmin (NPM1) gene occur in approximately 50% of adult acute myeloid leukemia (AML) with normal karyotype. More than 40 mutant variants have been identified. Most of these mutations consist of a 4-bp insertion, which can be used as a target for minimal residual disease (MRD) monitoring. We previously checked the stability of NPM1 mutations at relapse in 21 NPM1-mutated patients at initial diagnosis. In this prospective study, we evaluated MRD by real-time quantitative PCR (RQ-PCR) in 36 NPM1-mutated AML patients corresponding to 33 adult and 3 pediatric cases, treated according to the French ALFA9801 or ALFA9802 and ELAM02 protocols, respectively. Out of these patients, 31/34 (91%) had normal karyotype, 13/33 (39%) had a high initial white blood cell count, and 10/36 (28%) were FLT3-Intern Tandem Duplication (FLT3-ITD) positive. 28 (78%) patients carry NPM mutation A, 3 (8%) mutation B and 5 (14%) other rare variants. RQ-PCR assays using a mutation-specific primer were performed on cDNA for mutation A and B and on genomic DNA for other NPM1 mutants. In our experiments, the maximal reproductible sensitivity of NPM1-based MRD detection is about 10−4 on genomic DNA and 10−5 to 10−6 on cDNA. The median follow-up was 260 days [40–791]. 2 to 9 follow-up samples from bone marrow and/or peripheral blood were analysed per patient. No correlation was found between leukocytosis at diagnosis and initial expression ratio of NPM1 mutation. The study of MRD log reduction after induction therapy shows that molecular responses are very heterogeneous (from 4.10−2 to more than 1.10−5), but 50% of patients reach at least a 4 log reduction in NPM1 levels. Patients with FLT3-ITD tend to have lower log reduction after induction than patients without FLT3-ITD, although not statistically significant (P=0.07). The analysis of NPM1-MRD in bone marrow and in peripheral blood at the same follow-up time-points shows that NPM1 levels can be until 1 log higher in bone marrow. This indicates that the evaluation of NPM1-MRD in bone marrow is more informative than in peripheral blood. We found all relapses had NPM1-MRD levels comparable to those observed at diagnosis. Among the 5 patients who relapsed so far, 2 were predictable by increasing MRD levels 1 to 4 months before hematological relapse. In 29 out of 36 cases, we could monitor MRD by both NPM1 mutation and WT1 gene expression. The comparison of the MRD profiles obtained by these two approaches reveals some discordant results, which can be, at least in part, explained by difference in the sensitivity of the RQ-PCR techniques, since the sensitivity of WT1 expression as MRD target is generally not higher than 10−3. In conclusion, NPM1 mutations are very specific and sensitive markers for MRD monitoring in AML. Further studies are required to determine if NPM1-MRD provides an independent prognostic factor and may be useful for therapeutic stratification in AML patients with intermediate risk cytogenetics.

High Interleukin 15 Expression Characterizes Childhood Acute Lymphoblastic Leukemia with Involvement of the Central Nervous System.

Targeted but risk-adapted therapy to the central nervous system (CNS) has become a prerequisite for successful treatment of childhood acute lymphoblastic leukemia (ALL). Overt CNS involvement is a rare observation in childhood ALL and commonly associated with a poorer outcome when compared to CNS-negative patients. Although there are some known risk factors for CNS involvement of ALL such as T-cell-precursor immunophenotype and high initial white blood cell (WBC) count, the underlying biology leading to CNS disease is poorly understood. We hypothesized that leukemic cells crossing the blood-brain barrier early have distinct biological properties which are reflected in a specific gene expression pattern. To test this hypothesis, we generated leukemic gene expression profiles of 17 patients with CNS involvement using 26 CNS-negative patients as controls. Microarrays containing more than 39,000 distinct cDNA clones (SFGF, Stanford CA) were used. Data were analyzed applying Significance Analysis of Microarrays (PNAS 2001, 98, 5116–5121). Our analytical approach identified several differentially expressed genes. To control for possible T-cell contamination of the samples, we purified leukemic cells from four samples and repeated the analysis. Interleukin 15 (IL-15) was one of the genes for which differential expression could be confirmed with an up to 10-fold higher expression in CNS-positive patients. IL-15 is a pro-inflammatory cytokine known to stimulate proliferation and activation of T-lymphocytes and polymorphonuclear cells. Of importance with regard to the CNS, IL-15 was described to be highly expressed in peripheral blood (PBL) mononuclear cells in multiple sclerosis. The high expression of IL-15 in patients with CNS involvement was confirmed in an independent set of 13 CNS-positive and 26 CNS-negative patients by quantitative RT-PCR in a similar range as described above (P Mann-Whitney U-Test = <0.001). Therefore, we postulated that inflammatory processes might be involved in the pathogenesis of CNS disease by increasing the permeability of the blood-brain-barrier and reviewed differential PBL smears of 134 CNS-positive and 335 CNS-negative ALL patients. We observed a significantly higher ratio of immature to total myeloid cells in CNS-positive samples (P = <0.001). Next, we compared IL-15 expression at initial diagnosis of CNS-negative patients subsequently relapsing with CNS involvement (n = 22) to those without CNS disease and being in long-term remission (n = 18). Again, a significantly higher IL-15 expression was detected in patients with CNS relapse (P = 0.01). We conclude that measurement of IL-15 expression could serve as an additional tool to further tailor CNS-directed therapy in children newly diagnosed with ALL. Our results support a role for inflammatory processes, but additional studies are needed to finally elucidate the role of IL-15 and inflammation in the pathogenesis of CNS disease in childhood ALL.

Clinical and biological characteristics of acute promyelocytic leukemia in Taiwan: a high relapse rate in patients with high initial and peak white blood cell counts during all-trans retinoic acid treatment.

Acute promyelocytic leukemia (APL) patients treated with all-trans retinoic acid (ATRA) and chemotherapy have been shown to have better outcome than those treated with conventional chemotherapy alone. However, the biological characteristics of leukemic cells and their clinical implications in patients treated with ATRA have not been well established. In this study, the biological and clinical features of 30 APL patients were reported. The risk factors for relapse and for occurrence of retinoic acid (RA) syndrome, which might cause morbidity or mortality of patients after ATRA treatment, were also analyzed. All patients showed 15;17 translocation by cytogenetic and/or gene analysis. Patients in this study had higher white blood cell (WBC) counts and a higher incidence of additional abnormalities than those from other areas. The ratio of long (L) form to short (S) form PML-RAR alpha fusion transcript was 1.8:1, a value lower than that of Latino patients but higher than that of Italians. Leukemic cells from four patients showed coexpression of T cell-associated antigen CD2 which was highly correlated with S form fusion transcript. Nine (36%) of the 25 patients treated with ATRA developed RA syndrome; all but one were successfully controlled by corticosteroid. Complete remission (CR) rate was 84%. Patients with high WBC counts tended to develop RA syndrome and had increased risk of relapse. Isochromosome for the long arm of the derivative chromosome 17, ider(17q), as an additional chromosomal abnormality was also associated with poor outcome in this study. In conclusion, APL in this study showed some different biological characteristics compared with those reported in other areas. High WBC count was a risk factor for relapse and development of RA syndrome after ATRA treatment. The prognostic implication of the presence of ider(17q) needs further clarification.