Thrombocytopenia Is a Biomarker for Response in Patients Treated with Anti PD-1/Pdl-1 Therapy

Abstract Background: Immunotherapy directed against the PD-1/PDL-1 (programmed cell death protein [ligand] 1) pathway has shown activity across a range of malignancies. Immune-related adverse events have been shown to be associated with the efficacy of PD-1/PDL-1 inhibitors in patients with melanoma and non-small cell lung cancer. Thrombocytopenia has been reported in up to 33% of patients receiving anti PD-1/PDL-1 therapy. Our hypothesis is that immune-mediated thrombocytopenia may be a biomarker for response to anti PD-1/PDL-1 therapy. Methods: We collected data on 250 patients aged 18 years and older who were treated with anti PD-1/PDL-1 therapy at the University of Oklahoma Health Sciences Center between January 2014 and January 2016. Initial platelet count at baseline as well as nadir platelet count during treatment were examined. Patient's clinicopathologic characteristics were analyzed using simple descriptive statistics [median (range) for continuous covariates and n (%) for categorical variables]. Kaplan Meier Analysis was performed to assess how thrombocytopenia was associated with overall survival (OS) and progression free survival (PFS). Patients were grouped according to their nadir platelet count: normal platelets (≥150k), grade 1 (75k-150k), and combined grades 2, 3, 4 (<75k). Cox proportional hazard regression models were used to assess the association of thrombocytopenia with OS and PFS adjusted for various covariates. The objective of the study is to assess whether the degree of thrombocytopenia correlates with the PFS and OS in patients receiving anti PD-1/PDL-1 therapy. Results: A total of 250 patients were reviewed in this study. After excluding 27 patients with baseline platelet count <100k and 14 patients with missing platelet count data, 209 patients were included in the analysis. Fifty-five percent were females. Median age at diagnosis was 62 (23-91) years. The most common cancer diagnoses were lung cancer (21.1%), melanoma (17%), and ovarian cancer (9%). Nivolumab was the most commonly used agent (40.9%), followed by Pembrolizumab (38.4%). Median number of treatments received was 5. Median platelet count at baseline was 227 (102-535). Median nadir platelet count was 180 (4-552). Thrombocytopenia of any grade was observed in 70 (33%) patients .The number of patients with grade 1, 2, and 3/4 were 56 (26.8%), 1 (0.5%) and 13 (6.2%), respectively. Median follow-up time was 226 days. Univariate analysis showed that patients with grade I thrombocytopenia had higher PFS and OS when compared to patients who did not develop thrombocytopenia [HR 0.48 (95% CI, 0.29-0.81), P = 0.0053 and HR 0.49 (95% CI, 0.27-0.9), P = 0.0209, respectively]. When adjusted for age, cancer type, performance status, and line of treatment, grade 1 thrombocytopenia remained positively associated with survival outcome [HR 0.50 (95% CI, 0.29-0.87), P = 0.0146 for PFS and HR 0.40 (95% CI, 0.21-0.77), P = 0.0061 for OS]. Only 14 patients had grade 2-4 thrombocytopenia, and there was no statistically significant difference in survival compared to patients with no thrombocytopenia [adjusted HR 0.52 (95% CI, 0.2-1.38), P = 0.189 for OS]. Conclusion: Our study shows that in patients treated with anti PD-1/PDL-1 therapy, grade 1 thrombocytopenia appears to be positively correlated with survival outcomes. This survival advantage was not seen with higher grades of thrombocytopenia. PD-L1 was recently shown to be expressed on human platelets; thus, thrombocytopenia is likely immune-mediated. Thrombocytopenia may be a biomarker for efficacy of immune checkpoint therapy. The predictive significance of thrombocytopenia in patients receiving PD-1/PDL-1 therapy warrants further investigations. Disclosures No relevant conflicts of interest to declare.

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Effects Of Helicobacter Pylori Eradication In Adult Patients With Acute Idiopathic Thrombocytopenic Purpura (ITP)

Blood ◽

10.1182/blood.v122.21.2321.2321 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2321-2321

Author(s):

Minoosh Moghimi ◽

Saeid Razavi Dizaji ◽

Yousef Mortazavi ◽

Saeideh Mazloomzadeh ◽

Shaharbano Keyhanian ◽

...

Keyword(s):

Helicobacter Pylori ◽

Platelet Count ◽

Conflicts Of Interest ◽

Eradication Therapy ◽

Adult Patients ◽

Standard Triple Therapy ◽

Number Of Patients ◽

Significant Difference ◽

Acute Itp

Abstract Background Different studies have investigated the link between helicobacter pylori and extra digestive diseases suchas ITP. Aims In most studies chronic ITP has been investigated, therefore in the present study, we focused on the effect of H.pylori eradication on chronicity of ITP in adult patients with acute ITP. Methods After obtaining informed consent, eighty five patients with acute ITP whose platelet count were less than 30 ×103 /μl were enrolled to the study. Urea breath test (UBT) was carried out for all the patients. Based on the UBT results,the patients were divided into 3 groups: 1- H.pylori positive patients who underwent standard triple therapy. 2- ITPpatients negative for H.pylori and 3- ITP patients positive for H.pylori, but without eradication therapy. Evaluation of the H.pylori eradication was done 4 weeks after the treatment and also at the end of month 6. Results 52(61.2%) of patients were female and 33(38.8%) were male with mean age of 34.8±12.2 years. There was nosignificant difference between the mean age and sex in different groups. No significant difference was seen in mean platelet count at the baseline among the groups, but there was a significant statistical difference in mean platelet betweenthe groups at the end of the first month. However, a significant difference was not seen in mean platelet count in months 2to 6. Chronicity in the first group was less than the 3rd group which statistically was significant. Also, the chronicity rate in non-infected ITP patients was lower than the H.pylori positive patients (P=0.03). Summary / Conclusion Our results show that eradication of H.pylori can reduce the chronicity rate in adult patients with acute ITP. Further studies on larger number of patients with longer follow-up are recommended. Disclosures: No relevant conflicts of interest to declare.

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Acute Erythroid Leukemia: A Distinctive Subtype of AML? Outcome and Prognostic Factors in Comparison with Non-M6 AML. The Gimema Experience.

Blood ◽

10.1182/blood.v114.22.1019.1019 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1019-1019

Author(s):

Alessandro Pulsoni ◽

Massimo Breccia ◽

Sonia Maria Orlando ◽

Massimo Bernardi ◽

Marco Borgia ◽

...

Keyword(s):

Platelet Count ◽

Cumulative Incidence ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Treatment Strategies ◽

Disease Free Survival ◽

The Other ◽

Significant Difference ◽

Few Data ◽

Epidemiologic Features

Abstract Abstract 1019 Poster Board I-41 INTRODUCTION: Erythroleukemia is characterized by a peculiar marrow feature: a proliferation of erythroblasts greater than 50% and of myeloblasts greater than 30%, according to the FAB classification. Treatment strategies are usually indistinct from other forms of acute myeloid leukemia (AML), with the exception of acute promyelocytic leukemia. Although generally considered as a very aggressive subtype of AML, very few data are available concerning epidemiologic features and specific outcome of erythroleukemia among AMLs. MATERIALS AND METHODs: Adult patients with AML consecutively enrolled in the GIMEMA trials AML10 and LAM99p were retrospectively analyzed with the aim of evaluating the epidemiologic features and outcome of acute erythroid leukemia (FAB M6) characterized by morphological/cytochemical criteria after central revision, in comparison with non-M6 AML. RESULTs: Among 1675 AML patients, 59 (3.6%) were identified as M6; 39 were males and 20 females, the median age was 49 years (range 25.9-60.8), the median WBC count at diagnosis 2.7 × 109/l (range 0.7-41.8), the median Hb level 7.8 gr/dl (range 5.1-11.8) and the median platelet count 38 × 109/l (range 6-245). Univariate analysis showed a statistical difference between the M6 cases and the non-M6 series enrolled in these two clinical trials with regard to: incidence of male gender (p=0.03), prevalence of older age (p=0.001), leukopenia at diagnosis (p<0.0001), decreased levels of Hb (p=0.0006), lower platelet count (p=0.05), peripheral blast count (p<0.0001) and increased PMN count (p<0.0001). A previous myelodisplastic phase was reported in 5.6% of M6 cases compared to 1.7% in the other AML subtypes (p=0.07). Analysis of response to intensive chemotherapy, evaluated as ITT, showed that 64.4% of M6 patients achieved a complete remission (CR) compared to 69.6% in the other FAB subtypes (p=0.39); a similar induction death rate (13.5%) was observed in both groups. Overall survival (OS) at 60 months was 29.5% in M6 patients and 34% in the other FAB types (p=0.75), as shown in the figure; no significant difference was recorded also with regard to disease-free survival (DFS): 44% in M6 vs 39.7% in the other FAB types after 60 months of follow-up (p=0.59). For patients who obtained a CR, the cumulative incidence of relapse (CIR) showed no statistical differences: 45% at 60 months in M6 vs 46.9% in the other types, p=089). Also the cumulative incidence of non-relapse mortality (CINRM) at 60 months was similar in both groups: 10.7% in M6 vs 13.4% in the other types, p=0.62. CONCLUSIONs: Despite the higher incidence of some risk factors - higher age, higher proportion of myelodisplastic pre-phase and cytopenias - in this rare form of AML the CR duration and the OS are similar to those observed in the other more frequent forms of AML. Based on this analysis, the prognosis of this form of acute leukemia does not differ from that of the other subtypes. Disclosures: No relevant conflicts of interest to declare.

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288. Follow-Up Blood Cultures in Gram-Negative Bacteremia: How Do They Impact Outcomes

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.331 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S144-S144

Author(s):

Azza Elamin ◽

Faisal Khan ◽

Ali Abunayla ◽

Rajasekhar Jagarlamudi ◽

aditee Dash

Keyword(s):

Clinical Outcomes ◽

Antibiotic Treatment ◽

Readmission Rate ◽

Blood Cultures ◽

Categorical Variables ◽

Gram Negative ◽

Number Of Patients ◽

Significant Difference ◽

The Impact

Abstract Background As opposed to Staphylococcus. aureus bacteremia, there are no guidelines to recommend repeating blood cultures in Gram-negative bacilli bacteremia (GNB). Several studies have questioned the utility of follow-up blood cultures (FUBCs) in GNB, but the impact of this practice on clinical outcomes is not fully understood. Our aim was to study the practice of obtaining FUBCs in GNB at our institution and to assess it’s impact on clinical outcomes. Methods We conducted a retrospective, single-center study of adult patients, ≥ 18 years of age admitted with GNB between January 2017 and December 2018. We aimed to compare clinical outcomes in those with and without FUBCs. Data collected included demographics, comorbidities, presumed source of bacteremia and need for intensive care unit (ICU) admission. Presence of fever, hypotension /shock and white blood cell (WBC) count on the day of FUBC was recorded. The primary objective was to compare 30-day mortality between the two groups. Secondary objectives were to compare differences in 30-day readmission rate, hospital length of stay (LOS) and duration of antibiotic treatment. Mean and standard deviation were used for continuous variables, frequency and proportion were used for categorical variables. P-value < 0.05 was defined as statistically significant. Results 482 patients were included, and of these, 321 (67%) had FUBCs. 96% of FUBCs were negative and 2.8% had persistent bacteremia. There was no significant difference in 30-day mortality between those with and without FUBCs (2.9% and 2.7% respectively), or in 30-day readmission rate (21.4% and 23.4% respectively). In patients with FUBCs compared to those without FUBCs, hospital LOS was longer (7 days vs 5 days, P < 0.001), and mean duration of antibiotic treatment was longer (14 days vs 11 days, P < 0.001). A higher number of patients with FUBCs needed ICU care compared to those without FUBCs (41.4% and 25.5% respectively, P < 0.001) Microbiology of index blood culture in those with and without FUBCs Outcomes in those with and without FUBCs FUBCs characteristics Conclusion Obtaining FUBCs in GNB had no impact on 30-day mortality or 30-day readmission rate. It was associated with longer LOS and antibiotic duration. Our findings suggest that FUBCs in GNB are low yield and may not be recommended in all patients. Prospective studies are needed to further examine the utility of this practice in GNB. Disclosures All Authors: No reported disclosures

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Heparin-induced thrombocytopenia: when a low platelet count is a mandate for anticoagulation

Hematology ◽

10.1182/asheducation-2009.1.225 ◽

2009 ◽

Vol 2009 (1) ◽

pp. 225-232 ◽

Cited By ~ 14

Author(s):

Thomas L. Ortel

Keyword(s):

Platelet Count ◽

Heparin Therapy ◽

Severe Thrombocytopenia ◽

Drug Induced ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Immune Mediated ◽

Number Of Patients ◽

Increased Risk ◽

Antibody Levels

Abstract Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder caused by the development of antibodies to platelet factor 4 (PF4) and heparin. The thrombocytopenia is typically moderate, with a median platelet count nadir of ~50 to 60 × 109 platelets/L. Severe thrombocytopenia has been described in patients with HIT, and in these patients antibody levels are high and severe clinical outcomes have been reported (eg, disseminated intravascular coagulation with microvascular thrombosis). The timing of the thrombocytopenia in relation to the initiation of heparin therapy is critically important, with the platelet count beginning to drop within 5 to 10 days of starting heparin. A more rapid drop in the platelet count can occur in patients who have been recently exposed to heparin (within the preceding 3 months), due to preformed anti-heparin/PF4 antibodies. A delayed form of HIT has also been described that develops within days or weeks after the heparin has been discontinued. In contrast to other drug-induced thrombocytopenias, HIT is characterized by an increased risk for thromboembolic complications, primarily venous thromboembolism. Heparin and all heparin-containing products should be discontinued and an alternative, non-heparin anticoagulant initiated. Alternative agents that have been used effectively in patients with HIT include lepirudin, argatroban, bivalirudin, and danaparoid, although the last agent is not available in North America. Fondaparinux has been used in a small number of patients with HIT and generally appears to be safe. Warfarin therapy should not be initiated until the platelet count has recovered and the patient is systemically anticoagulated, and vitamin K should be administered to patients receiving warfarin at the time of diagnosis of HIT.

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The Use of Milrinone Versus Conventional Treatment for the Management of Life-Threatening Bronchial Asthma

The Open Anesthesia Journal ◽

10.2174/2589645801913010012 ◽

2019 ◽

Vol 13 (1) ◽

pp. 12-17 ◽

Cited By ~ 2

Author(s):

Amr Sobhy ◽

Doaa M. K. Eldin ◽

Hany V. Zaki

Keyword(s):

Bronchial Asthma ◽

Conventional Treatment ◽

Controlled Trial ◽

Blood Gases ◽

Categorical Variables ◽

Chi Square ◽

Arterial Blood ◽

Number Of Patients ◽

Significant Difference ◽

Life Threatening

Background and Aims: In our study, we investigated the effectiveness of intravenous milrinone in life-threatening bronchial asthma as compared to conventional treatment. Methods: Fifty patients aged 18-50 years, presenting with life-threatening asthma were enrolled in a Randomised Controlled Trial (RCT). They were randomly allocated into Group C (25 patients): who received the standard pharmacotherapy and placebo, and Group M (25 patients): who in addition to the standard therapy, received 25 μg milrinone as an initial slow IV bolus diluted in 10 ml of normal saline. The following data were recorded: PEFR (Peak Expiratory Flow Rate) expressed as a percentage of the patient’s previous value, Respiratory Rate (RR), MABP (Mean Arterial Blood Pressure), arterial blood gases, and the number of patients requiring mechanical ventilation. Differences between groups were tested using Analysis of Variance (ANOVA) for quantitative variables with post hoc using the Least Significant Difference (LSD) test, and Chi square test for categorical variables. Results: Group M showed marked improvement in PEFR that was highly significant (P < 0.001) 10 min after injection and significant after one hour from the start of treatment in comparison to Group C. There was also an improvement in RR and PO2 that was significant in group M. Milrinone was associated with a reduction in MABP only after 10 min from injection, and showed a statistically significant decrease in the number of patients requiring mechanical ventilator support (P ˂ 0.05). Conclusion: Milronine is a promising agent as a rescue drug in the treatment of life-threatening bronchial asthma.

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Is There a Role for Autologous Stem Cell Transplantation (Auto SCT) for Patients with Acute Myelogenous Leukaemia? A Retrospective Analysis.

Blood ◽

10.1182/blood.v116.21.1689.1689 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1689-1689

Author(s):

Nicolas Novitzky ◽

Valda Thomas ◽

Cecile du Toit ◽

Andrew McDonald

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Mononuclear Cells ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Entire Group ◽

Myeloablative Conditioning ◽

Post Transplant ◽

Significant Difference

Abstract Abstract 1689 Introduction: To better counsel our patients on the role of auto SCT for patients with AML we studied consecutive individuals in CR 1 who had tissue compatible siblings and underwent allogeneic (allo) SCT with subjects who had no HLA donor and actually underwent auto SCT. Methods: Patients were in CR 1 following induction combinations containing 7 days of cyatarabine and etoposide with 3 days daunorubicin followed by similar consolidation therapy. The choice for the type of graft was based on availability of HLA identical siblings. Allogeneic donors underwent PBPC mobilisation with filgrastim and for GvHD prophylaxis grafts were exposed ex vivo to alemtuzumab 1mg/1010 mononuclear cells. Patients were prescribed cyclosporin until day 90 post transplant. Individuals lacking a donor underwent PBPC mobilization with etoposide 2 gr/m2 and harvested PBPC were cryopreserved. Patients received similar myeloablative conditioning followed by infusion of the grafts. Patients were stratified by clinical and laboratory factors as well as cytogenetic risk. The end points were TRM, DFS and OS. Results: The median presentation age for both transplant groups was 35 (14-60) years. Of the 112 consecutive patients achieving remission 37 had HLA identical siblings, but 3 relapsed and donors became unavailable in 2. Thus, autologous or allogeneic grafts were actually transplanted to 43 and 32 patients respectively. There was no significant difference in the presentation clinical features, laboratory parameters, marrow morphology or proportion of low and intermediate cytogenetic risk for both transplant options. Treatment mortality as well as relapse rate was similar (14 and 15%; 39 and 27%, respectively). At a median of 1609 and 1819 post transplant days, 56% and 63% in each group survive. In univariate analysis performance status, cytogenetic risk, morphological features of dysplasia, blast count and LDH were significant factors for survival. While for the entire group there was no difference in survival between both modalities, all patients with unfavourable cytogenetics receiving an autologous graft died of disease recurrence (3 year survival 35% vs 0%; p= 0.05). Conclusions: We conclude that patients with AML who have low or intermediate cytogenetic risk undergoing myeloablative conditioning followed by autologous or allogeneic T-cell depleted stem cell transplantation appeared to have similar outcome. However, those with unfavourable karyotype are unlikely to be cured with autologous grafts and are candidates for experimental modalities. Disclosures: No relevant conflicts of interest to declare.

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Outcome of Patients (pts) Treated for Myelodysplastic Syndrome (MDS) and Secondary Acute Myeloid Leukemia (s AML) After Azacitidine (AZA) Failure

Blood ◽

10.1182/blood.v116.21.443.443 ◽

2010 ◽

Vol 116 (21) ◽

pp. 443-443 ◽

Cited By ~ 1

Author(s):

Thomas Prebet ◽

Steven D. Gore ◽

Benjamin Esterni ◽

Raphael Itzykson ◽

Sylvain Thepot ◽

...

Keyword(s):

Low Dose ◽

Response Rate ◽

Univariate Analysis ◽

Initial Response ◽

Multivariate Model ◽

Published Data ◽

High Dose ◽

Number Of Patients ◽

Significant Difference ◽

Number Of Cycles

Abstract Abstract 443 Background: AZA is the current standard of care for IPSS int-2 and high (“higher”) risk MDS. However, most pts will experience primary or secondary treatment failure. To date, there is no published data on the outcome of those pts. Design: 565 patients from 4 independent cohorts, who had not responded to or relapsed after response to AZA, were included. The datasets included 3 prospective trials (AZA001 (n=138; Lancet Onc, 2009), J9950 (n=26; Cancer Res 2006), J0443 (n=32; NCT00101179) trials) and data from the French ATU compassionate use program (n=369). Two cohorts administered AZA as single agent (AZA001 and French ATU) while two combined AZA with a histone deacetylase inhibitor (J9950, sodium phenylbutyrate; J0443, entinostat). 339 patients had no clinical response to AZA while 226 relapsed after initial response. The influence of pre treatment variables and salvage treatment options on the outcome after AZA failure was analyzed. Survival was measured from the date of failure of AZA. Results: The cohort included 475 MDS (including 117 RAEB-T) and 90 sAML (AML secondary to MDS). Median age was 69 years and the median number of cycles of AZA before failure was 6 (range [1-41]). Patients were randomly assigned to one learning (n=377) and one validation (n=188) set stratified on the number of deaths. There was no difference in the baseline characteristics of the 2 sets. With a median follow-up of 15 months after AZA failure, the median overall survival (OS) was 6 months and the 2-year probability of OS was 15%. The multivariate model constructed with the learning set showed that age (HR 1.02/y, 95%CI [1.01-1.03], p=0.002), sex (female 7 months vs male 5.6 months HR 1.3 [1.01-1.67] p=0.04), cytogenetics (favorable 8 months vs intermediate 5.9 months HR 1.49 [1.06-2.08] p=0.02, vs high risk 4.6 months HR 2.19 [1.63-2.91] p<0.001), bone marrow blast % before AZA (below 10% 7.8 months vs 10 to 20% 5.8 months HR 1.34 [0.97-1.84] p=0.07, vs 21%+ 4.3 months HR 1.92 [1.36-2.7] p<0.001), and the number of cycles of AZA (6 or less 4.7 months vs more 7.2 months HR 0.69 [0.54-0.9] p=0.005) were significantly associated with survival. Initial response to AZA was significant in univariate analysis (non responders 4.7 m vs 7.3 m in responders, p=0.02) but did not retain significance in the multivariate model. These results were confirmed with the validation set. Data on the treatment administered after AZA failure were available for 350 patients. Allogeneic transplantation (n= 50) (median OS 18.3 months, range [3-55+]) and investigational therapies (n= 56, including epigenetic drugs, IMIDs, and non registered compounds; median OS 13.2 months, range [1-36+]) were associated with significantly better survival than palliative care (median OS 3.3 months) or conventional cytotoxic chemotherapy (median OS 7.6 months, including AML like induction chemo and low dose chemo such as cytarabine or 6-MP). Conclusions: Outcome of patients with AZA failure was poor, although pts receiving allo SCT or investigational treatments had a somewhat better outcome. This work highlights the potential predictors of outcome and defined the baseline survival data that will help in the design of second line trials in higher risk MDS having failed treatment with AZA. *: Overall response rate for each treatment group is presented with the number of patients evaluable for response in each cohort. For the CT group, response rate for low dose chemotherapy and high dose (AML like, marked with **) chemo have been individualized. Univariate analysis (log-rank test) showed significant difference between PC and CT (p=0.002), IT (p<0.001) or ASCT (p<0.001). There was also significant differences between CT and IT (p=0.004) or ASCT(p=0.001). Difference between IT and ASCT reached borderline significance (p=0.053). Disclosures: Gore: Celgene: Research Funding, Stock options. Beach:Celgene: Employment.

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The Pro-Inflammatory IL23/IL23R/IL17 Axis Is Active in IL23R-Expressing Circulating CLL Cells in Patients with Poor Prognosis

Blood ◽

10.1182/blood.v120.21.3889.3889 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3889-3889

Author(s):

Fortunato Morabito ◽

Giovanna Cutrona ◽

Anna Grazia Recchia ◽

Sonia Fabris ◽

Serena Matis ◽

...

Keyword(s):

Lymph Node ◽

Lymph Nodes ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Prognostic Significance ◽

Lymphoid Cells ◽

Fish Analysis ◽

Number Of Patients ◽

Significant Difference

Abstract Abstract 3889 Inflammatory cytokines play a biological role in the pathogenesis of Chronic lymphocytic leukemia (CLL). IL23 is a pro-inflammatory cytokine involved in T-cell responses and in tissue remodeling. It has been shown that the IL23 receptor (IL23R) is up-regulated in primary acute lymphoblastic leukemia (ALL) cells, and that IL23 inhibits ALL cell growth. Nevertheless, the anti-tumor function of IL23 still remains controversial. The role of the IL23R/IL23 axis in CLL has not been investigated so far. Herein we evaluated the expression pattern of IL23R/IL23 axis and its correlation with progression free survival (PFS) in CLL patients. A total of 233 newly diagnosed Binet stage A CLL cases from Italian institutions (clinicaltrials.gov NCT00917540) were studied for IL23R expression by flow-cytometry (FC) (median percentage IL23R expression=22.7, range 1.2–91.1). The median follow-up was 23 months (range 1–47). PFS information was obtained in 203 patients. Using the median value of 23% of IL23R as threshold, 8/102 IL23Rneg and 23/101 IL23Rpos CLL cases progressed with therapy requirement. The 2-year PFS probability of IL23Rneg patients was 89.7% as compared to 80.7% of IL23Rpos cases [χ2 7.7, P=.006; HR=3.0, 95%CI (1.3–6.6)]. Cases were then stratified according to IL23R positivity [IL23Rneg (102 cases) versus IL23Rpos (101 cases)]. No significant difference in terms of CD38 and ZAP-70 positive cases was observed, however, the IGVH mutational status could distinguish the two groups: IGHV-mutated in 92 (78.6%) of IL23Rneg vs 70 (61.9%) IL23Rpos and IGHV-unmutated in 25 (21.4%) vs 43 (38.1%), p=.006]. FISH analysis showed that IL23Rneg and IL23Rpos cases carrying 13q14.3 were respectively 53 (51.4%) and 44 (42.7%), while the number of patients with trisomy 12 were 8 and 10 respectively in cases with low and high IL23R expression. Deletion of 11q was detected in 3.9% (4/103) of IL23Rneg and in 8.7% (9/103) of IL23Rpos cases. Only 3 cases with 17p deletion were seen in this cohort of early CLL patients and all belonged to the IL23Rpos group. Overall, no significant differences in the incidence of the major genetic lesions were observed between the two groups. Il23R expression still remained independently associated with PFS also in multivariate analysis. In situ expression analysis of IL23R and of its ligand IL23 was then performed by immunohistochemistry (IHC) in 16 CLL samples [10 lymph node (LN) and 6 bone marrow (BM) biopsies] collected on diagnosis and in 8 control biopsies (4 lymph nodes with reactive follicular hyperplasia and 4 normal BM biopsies). IL23R was variably expressed in CLL and significantly expressed in the neoplastic clones of 9 (6 lymph nodes and 3 BM biopsies) of the 16 cases tested; IL23R was diffusely present along the membrane and cytoplasm of neoplastic cells effacing the lymph node or BM architecture (Fig. 1, upper-left). In CLL cases with low IL23R expression, IL23R was detected in few scattered lymphoid cells intermingling with neoplastic lymphocytes (Fig. 1, upper-right). IL23 was also detected, with a variable staining intensity (Fig. 1, middle-left), paralleling in part that of IL23R. Double-marker analysis confirmed the concomitant expression of IL23 and IL23R in CLL neoplastic infiltrates highlighting the co-localization of the two markers (Fig.1 middle-right) and suggesting the possibility of an autocrine IL23/IL23R loop in CLL clones. We speculated that the microenvironment of CLL cases rich in IL23R and IL23 could be enriched in IL17-producing cells. The IHC expression of IL17 in CLL cases with low or high IL23R and IL23 expression showed that CLL cases rich in IL23Rpos cells, also characterized by high IL23 expression, displayed significantly higher numbers of IL17pos infiltrating cells (Fig. 1 bottom-left), as compared with CLL cases with no or low expression of IL23R or IL23 (Fig. 1 bottom-right). In conclusion, our study shows that high IL23R expression predicts a worse PFS. Furthermore, we linked this picture with, the in situ engendering of a clone-related microenvironment characterized by the preponderancy of pro-inflammatory signals such as those of the IL23/IL23R/IL17 axis, and its correlates in the peripheral blood (i.e. IL23R expression on circulating CLL cells), may endorse its strong prognostic significance. This analysis prompts further investigation into the specific function of the IL23/IL23R/IL17 axis and its targets in the context of CLL. Figure 1. Figure 1. Disclosures: No relevant conflicts of interest to declare.

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Augmented Berlin-Frankfurt-Muenster Based Therapy For Young Adults With Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood.v122.21.1400.1400 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1400-1400 ◽

Cited By ~ 1

Author(s):

Michael E. Rytting ◽

Deborah A. Thomas ◽

Susan O'Brien ◽

Kurt Schroeder ◽

Rebecca Garris ◽

...

Keyword(s):

Young Adults ◽

Acute Lymphoblastic Leukemia ◽

De Novo ◽

Conflicts Of Interest ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Univariate Analysis ◽

Philadelphia Chromosome ◽

Significant Difference ◽

Grade Iii

Abstract Pediatric-based therapy of acute lymphoblastic leukemia (ALL) has been proposed as superior treatment for teen-agers and young adults with ALL. Several trials report improved survival rates in young adult ALL patients (pts) when treated with pediatric-based regimens. Augmented Berlin-Frankfurt-Muenster (ABFM) treatment is effective treatment for ALL in adolescents up to age 21. In an attempt to improve cure rates in AYA pts with ALL, we administered ABFM therapy to pts age 12 to 40 in a prospective, single institution trial. Results were then retrospectively compared to the HYPER CVAD regimen, the historical adult ALL regimen used at our institution. 85 pts with de novo Philadelphia chromosome negative ALL have completed at least 6 months of therapy. There are 69 (81%) pts with pre-B ALL and 16 (18%) pts with T-cell ALL/lymphoma. The age range is 13-39 with a median of 21. The median WBC at diagnosis is WBC=14 thousand/microliter (range 0.4-494). 80/85 (94%) pts entered remission (<5% blasts on day 29 marrow morphology). 1 patient died during induction. 61(72%) pts attained remission at day 15 of induction. 29 (22%) did not have morphological remission by day 15 of induction. At the end of induction, 46(58%) pts were minimal residual disease (MRD) negative by flow cytometry (<0.01% blasts). 25(31%) were positive for MRD and 6(7%) were not available or equivocal. By approximately day 84 of treatment, 55(69%) pts were negative for MRD and 13(16%) were positive or suspicious. Toxicities encountered include severe allergy to PEG-asparaginase in 17 (20%) pts, thrombosis in 18 (21%), hyperbilirubinemia grade III-IV in 31 (36%), elevated ALT grade III-IV in 28 (33%), hypofibrinogen grade III-IV in 30 (35%), pancreatitis in 9(11%), and avascular necrosis in 9 (11%). Grade III-IV hepatic toxicity is frequent but resolves within two weeks in almost all pts. For the entire cohort, the estimated 3 year overall survival (OS) is 75% and 3 year complete remission duration (CRD) is 71%. In univariate analysis, negative MRD at day 29 was associated with improved OS and day 84 negative MRD was associated with improved CRD. The presenting WBC was associated with OS and CRD. On multivariate analysis, only WBC over 50k/microliter maintained significance for OS and CRD. In comparing ABFM to HYPER CVAD, there is no significant difference in OS or CRD between the two regimens (fig. 1 and 2). This lack of difference in OS and CRD persists when patients are stratified for age > or </= 21 years, for presenting WBC over 50 thousand, and for MRD at the end of induction. In our hands, pediatric based therapy has significant though tolerable toxicity. Outcomes in AYA pts are similar but not superior to results obtained with historical ALL therapy. Disclosures: No relevant conflicts of interest to declare.

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Correlation between expression of MCM6, a new proliferative marker, and treatment outcome in patients with Hodgkin's disease

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e19547 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e19547-e19547

Author(s):

K. Khodadad ◽

S. Karimi ◽

Z. Esfahani Monfared

Keyword(s):

Treatment Outcome ◽

Hodgkin's Disease ◽

Hodgkin’S Disease ◽

Univariate Analysis ◽

Response To Treatment ◽

G1 Arrest ◽

Number Of Patients ◽

Significant Difference ◽

Proliferative Marker

e19547 Background: MCM6 is a proliferative marker, which in contrary to Ki67, is involved in all cell cycle phases, including early G1. We evaluated MCM6 expression in Hodgkin's disease (HD) patients in order to find any correlation between MCM6 expression and treatment outcome. Methods: Formalin-fixed paraffin-embedded lymph node specimens of 55 patients with HD treated with ABVD regimen (± radiotherapy) were assessed for MCM6 expression by IHC. The percentage of nuclear positivity in RS and mononuclear Hodgkin cells was evaluated in each case. Clinical data, response to treatment and relapse rates were obtained from patients’ medical records. These data were analyzed by SPSS software. Results: Mean MCM6 expression was 80.7% (ranging 35%-99%) with no significant difference between histology subtypes. In univariate analysis, MCM6 expression was not statistically significant for B-symptoms (P=0.27), sex (P=0.91), stage (P=0.18) and response to treatment (P=0.53), but was significant for age (P=0.008) (≤23 vs >23 yrs old). The MCM6 mean expression between relapsed and non-relapsed groups was marginally significant (21% vs 29.4%, P=0.057). In multivariate analysis, we evaluated MCM6 expression, B-symptoms, stage, response rate and age for relapse. None of risk factors were statistically significant predictor for relapse, including MCM6 expression (P=0.238), however, were significant regarding to response (P<0.001) and stage (P=0.048). We divided patients in 4 quartiles based on their MCM6 expression (Q1<74.25%, N=13, Q2=74.26–85.5%, N=14, Q3=85.6–91.75%, N=13, Q4>91.75%, N=12). Relapse and PFS were not significantly different between these quartiles (P=0.27 and P=0.83, respectively). Conclusions: Our study on a limited number of patients revealed MCM6 is not a strong predictor for treatment outcome in patients with HD. Our findings can be possibly explained by early G1 arrest of tumor cells and the role of cytokine production in pathogenesis of HD. We believe determining the accurate predictive role of proliferative markers needs to be focused on the markers which are exclusively involved in S phase. No significant financial relationships to disclose.

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