Preliminary Results from CPX-351 Italian Compassionate Use Program Show High Response Rate and Good Tolerability in Poor Prognosis AML Patients

Background: Therapy-related acute myeloid leukemia (t-AML) or AML evolving from a myelodisplastic syndrome are characterized by a low response rate to conventional chemotherapy and high relapse rate with poor overall survival (OS) despite intensive treatment and allogeneic stem cell transplantation consolidation (HSCT). CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin, in a fixed synergistic 1:5 molar ratio. CPX-351 has been approved by FDA for the treatment of patients affected by t-AML or AML with myelodisplasia-related changes (MRC-AML) based on the results of a randomized phase III trial where the drug was compared with conventional 3+7 induction (Lancet et al, JCO 2018). Notably, CPX-351 proved to increase survival probabilities in comparison with standard chemotherapy even among patient achieving complete remission (CR) and proceeding to HSCT, suggesting that CPX-351 may allow deeper responses. However, few information is available on minimal residual disease (MRD) assessment after CPX-351 treatment, or on the impact of molecular alterations on response probability. Aims: The aim of this study was to evaluate the clinical activity of CPX-351 in a real life setting, with particular focus on molecular characterization at diagnosis and MRD evaluation in responding patients. Methods: Seventy five patients were enrolled in a compassionate use program (CUP) in 37 Italian Hematology Centers. CUP started on December 2018 and closed on June 2019. Data collection began on July 2019 and was completed, at the time of writing, for 25/75 patients, enrolled in 9 Centers. Median age was 69 years (56-73), 10 patients were female. Molecular and MRD analysis were performed in each Center as per internal standard. MRD was assessed in most Centers with multicolor flow cytometry. NPM1 mutation was found in 2/22 assessed patients, FLT3-ITD in 3/22, with low allelic burden in 2/3 patients. TP53 mutations have been found in 4/12 patients.Four patients had complex Karyotype, one had isolated del(7q) whereas the remaining 19 had normal karyotype. Six patients had t-AML; 15 patients were previously diagnosed with MDS and 5 of them had already received hypomethilating agents for a median of 5 cycles (2-49). European Leukemia net risk score was low in 2 (8%), intermediate in 12 (48%) and high in 11 (44%) patients. Most patients (20/25) had relevant comorbidities upon enrollment, mostly COPD, diabetes and/or hypertension. As per CUP inclusion criteria, all patients had normal left ventricular function at the time of enrollment (defined by a normal ejection fraction). Results: Induction-related mortality was 2/25 (8%). Fourteen patients experienced grade >1 extra hematological adverse event during induction (mainly infections). Alopecia was observed in 4/25 patients (16%).Response was assessed in 20 patients:2 patients died during induction and 3 patients were not yet evaluated for response at the time of analysis. CR or CRi was observed in 19/22 (86.3%). MRD was performed in 11 patients, with 4 of them achieving flow MRD negativity after first cycle (defined as <0.1%, Minetto et al. BJH 2019). Median time to neutrophil and platelets recovery in responding patients were 29 (18-60) and 24.5 (19-60) days, respectively. Among responding patients, 10 received further CPX-351 consolidation, which was very well tolerated. One patient proceeded directly to HSCT, one is currently waiting for HSCT to be performed and one patient received a conventional chemotherapy consolidation. The remaining patients are currently waiting for administration of consolidation therapy with CPX-351. Four patient had completed so far all planned consolidation therapy with CPX-351 and 2/4 of them were flow MRD negative at the end of therapy. Of note, 3/4 patients with mutated TP53 achieved MRD negative CR. After a median follow-up of 5 months, relapse was observed in 2/20 responding patients and 21 patients are alive at the time of analysis. Conclusions: Our preliminary data confirm the high clinical activity and good tolerability of CPX-351 in a challenging AML cohort. The high median age and the high incidence of severe comorbidities did not result in unacceptable risk of death during induction. With the limitation of very small numbers, CPX-351 showed good antileukemic activity among TP53 mutated patients. Disclosures No relevant conflicts of interest to declare.

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Consolidation Therapy Based on Conventional Chemotherapy and Corticoids Do Not Provide Therapeutic Advantage for Newly Diagnosed Patients after Autologous Transplantation.

Blood ◽

10.1182/blood.v110.11.531.531 ◽

2007 ◽

Vol 110 (11) ◽

pp. 531-531 ◽

Cited By ~ 1

Author(s):

Roman Hajek Prof ◽

Ivan Spicka ◽

Vlastimil Scudla ◽

Evzen Gregora ◽

Vladimir Maisnar ◽

...

Keyword(s):

Maintenance Therapy ◽

Response Rate ◽

Autologous Transplantation ◽

Phase Iii ◽

Primary Therapy ◽

Consolidation Therapy ◽

Newly Diagnosed ◽

Conventional Chemotherapy ◽

Significant Difference ◽

Phase Iii Study

Abstract Benefit of maintenance and/or consolidation therapy after autologous transplantation (AT) is unclear. CMG 2002 is randomized phase III study comparing efficacy and safety of consolidation therapy versus interferon alfa (IFN) maintenance therapy after AT in patients with newly diagnosed multiple myeloma (MM). Methods: A total of 545 patients were enrolled to the trial in the period of April 2002 to April 2007. This first analysis (patients enrolled until December 31, 2005) was done in cohort of 269 patients randomly assigned after AT to either IFN 3x3 MU s.c. weekly alone (IFN group) until relapse or four cycles of chemotherapy CED (cyclophosphamide 300–400 mg/m2 i.v., etoposide 30–40mg/m2 i.v., and dexamethasone 40mg on days 1–4; month 4,8,12 and 16 after transplantation; CED group) followed by IFN 3x3 MU s.c. weekly starting month 18 after AT. All patients received primary therapy with four cycles of VAD regimen (vincristine, doxorubicine, and dexamethasone) followed by mobilization with cyclophosphamide 2.5g/m2 and G-CSF 5–10 μg/kg. The conditioning regimen with melphalan 200mg/m2 was used for single AT. Response was defined according to Blade’s criteria. Median of follow up is 41 months (range 6.2–56.1) Results: All basic parameters including median age, gender distribution, measures of disease burden, renal function and also response rate before/after AT, and basic prognostic factors (beta2microglobulin, albumin, LDH, CRP) were comparable between randomized IFN group (n=134) and CED group (n=135) as follows: median age 57.0 vs. 57.0; stage I: 8.1% vs. 5.5%, stage II: 27% vs. 27.3%, stage III: 64.9% vs. 66.7%; stage B 12.8% vs. 17.1%; ISS I: 37.2% vs. 34.0%, ISS II: 29.7% vs. 34.0%, ISS III: 17.6% vs.21.8%, ISS not available: 15.5 vs.10.2%; IgA: 25.7% vs. 29.9%, IgG: 61.5% vs. 51.8%; ORR after AT (CR+PR): 72.3% vs.72.1%, CR: 23.0% vs. 19.0%, VGPR: 17.6 vs. 24.5%, PR 31.8% vs. 28.6%). Four cycles of CED consolidation treatment after AT did not significantly increase response rate achieved after AT in comparison with IFN group (response rate improved in 14,8% in CED group vs. 15,1% in IFN group at 4 months, respectively in 81,5% vs. 75,8% at 18 months after AT). There was no significant difference between CED and IFN groups in time to progression [TTP] (median 34.5 vs.38.2 months, p=0.622), in progression free survival [PFS] (median 32.4 vs. 36.8 months, p=0.515) and also in duration of response [DOR] (29.6 vs. 36.2 months). Median of overall survival was not yet reached (25th percentile 40.8 months for all patients). CED consolidation had acceptable toxic profile. Conclusions: In the first analysis of CMG 2002 randomized phase III study consolidation therapy based on conventional chemotherapy and corticoids followed by IFN maintenance therapy did not show any benefit for patients if compared with IFN maintenance alone.

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Efficacy of BRAF and MEK Inhibition in Patients with BRAF-Mutant Advanced Melanoma and Germline CDKN2A Pathogenic Variants

Cancers ◽

10.3390/cancers13102440 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2440

Author(s):

Francesco Spagnolo ◽

Bruna Dalmasso ◽

Enrica Tanda ◽

Miriam Potrony ◽

Susana Puig ◽

...

Keyword(s):

Real World ◽

Response Rate ◽

Suppressor Gene ◽

Phase Iii ◽

Clinical Activity ◽

P Value ◽

Pathogenic Variants ◽

Phase Iii Trials ◽

The Difference ◽

First Time

Inherited pathogenic variants (PVs) in the CDKN2A tumor suppressor gene are among the strongest risk factors for cutaneous melanoma. Dysregulation of the p16/RB1 pathway may intrinsically limit the activity of MAPK-directed therapy due to the interplay between the two pathways. In our study, we assessed, for the first time, whether patients with germline CDKN2A PVs achieve suboptimal results with BRAF inhibitors (BRAFi)+/−MEK inhibitors (MEKi). We compared the response rate of nineteen CDKN2A PVs carriers who received first-line treatment with BRAFi+/−MEKi with an expected rate derived from phase III trials and “real-world” studies. We observed partial response in 16/19 patients (84%), and no complete responses. The overall response rate was higher than that expected from phase III trials (66%), although not statistically significant (p-value = 0.143; 95% CI = 0.60–0.97); the difference was statistically significant (p-value = 0.019; 95% CI = 0.62–0.97) in the comparison with real-world studies (57%). The clinical activity of BRAFi+/−MEKi in patients with germline CDKN2A PV was not inferior to that of clinical trials and real-world studies, which is of primary importance for clinical management and genetic counseling of this subgroup of patients.

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Clinical Activity of Pertuzumab (rhuMAb 2C4), a HER Dimerization Inhibitor, in Advanced Ovarian Cancer: Potential Predictive Relationship With Tumor HER2 Activation Status

Journal of Clinical Oncology ◽

10.1200/jco.2005.05.4221 ◽

2006 ◽

Vol 24 (26) ◽

pp. 4324-4332 ◽

Cited By ~ 181

Author(s):

Michael S. Gordon ◽

Daniela Matei ◽

Carol Aghajanian ◽

Ursula A. Matulonis ◽

Molly Brewer ◽

...

Keyword(s):

Response Rate ◽

Advanced Ovarian Cancer ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Ca 125 ◽

Enzyme Linked Immunosorbent Assay ◽

Clinical Activity ◽

Her2 Overexpression ◽

Ventricular Ejection Fraction ◽

Tumor Biopsies

PurposeOvarian cancers (OCs) frequently have HER2 activation in the absence of HER2 overexpression. Pertuzumab, a humanized antibody that prevents HER2 dimerization and inhibits multiple HER-mediated pathways, was studied in a phase II, multicenter trial in advanced, refractory OC.Patients and MethodsSixty-one patients (cohort 1) with relapsed OC received a loading dose of 840 mg pertuzumab intravenously followed by 420 mg every 3 weeks; 62 patients (cohort 2) received 1,050 mg every 3 weeks. Response rate was the primary end point. Fresh tumor biopsies were obtained in cohort 1 to assay for phosphorylated HER2 (pHER2).ResultsMedian age was 57 years and median number of prior chemotherapy regimens was five. Fifty-five patients in cohort 1 and 62 patients in cohort 2 were assessable for efficacy. There were five partial responses (response rate [RR] = 4.3%; 95% CI, 1.7% to 9.4%), eight patients (6.8%) with stable disease (SD) lasting at least 6 months, and 10 patients with CA-125 reduction of at least 50% (includes two partial responses and four patients with SD ≥ 6 months; total clinical activity, 14.5%). Median progression-free survival (PFS) was 6.6 weeks. Eight of 28 tumor biopsies (28.6%) were pHER2+ by enzyme-linked immunosorbent assay (ELISA; without gene amplification). Median PFS for pHER2+ patients was 20.9 weeks (n = 8) versus 5.8 weeks for pHER2− (n = 20; P = .14) and 9.1 weeks for unknown pHER2 status (n = 27). Pertuzumab was well tolerated with diarrhea in 69.1% (11.4% grade 3, no grade 4). Five patients had asymptomatic left ventricular ejection fraction decreases to less than 50% (one confirmed by central facility).ConclusionPertuzumab is well tolerated with a RR of 4.3% in heavily-pretreated OC patients. Further studies on pHER2 as a diagnostic are warranted.

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The impact of non-steroidal anti-inflammatory drugs use in elderly cardiovascular patients: an observational study from tertiary care in South India

International Journal of Research in Medical Sciences ◽

10.18203/2320-6012.ijrms20191677 ◽

2019 ◽

Vol 7 (5) ◽

pp. 1787

Author(s):

Sadhna Sharma ◽

Biju Govind ◽

Kondal Rao

Keyword(s):

Observational Study ◽

Elderly Patients ◽

Tertiary Care ◽

The Elderly ◽

Left Ventricular ◽

Risk Of Death ◽

Increased Risk ◽

High Prevalence ◽

One Year ◽

The Impact

Background: Long-term use of NSAIDs, by patients having cardiovascular conditions, has shown to increase the risk of cardiovascular events and increased risk of death. Hence, the study was conducted to determine the complications related to NSAID use by the elderly patients with cardiovascular disease (CVD).Methods: The study was a single-center prospective observational study conducted November 2017 to October 2018. Elderly patients (>60 years) suffering from various CVDs and reported NSAID intake daily for at least one month were included. A questionnaire included demographic, treatment related history and complete details of NSAIDs intake including nature, dose, indication, source etc. The same questionnaire was again filled at the end of one-year follow-up.Results: A total of 100 participants were included in the study. The mean age was 72±8.6 years. Majority of the patients (93%) had hypertension, and 69% of the patient had previous MI. Five NSAIDs (diclofenac, ibuprofen, mefenamic acid, naproxen, and ketorolac) were used routinely. At least one over the counter NSAID used was reported by 86%, 57% were prescribed at least one NSAIDs by their orthopaedics and physicians. At the end of 1-year follow-up, authors found that 71% had MI (2% increase), 4% developed reinfarction, 20% had severe left ventricular failure (4% increase), 7% had atrial fibrillation (1% increase), and 2% patients died and 63% patients reported raise in systolic blood pressure by 5mmHg.Conclusions: High prevalence of concomitant NSAID use among elderly CVD patients, which might be contributing towards increase in CVS morbidity and mortality.

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Evaluation of local control strategies in patients with localized Ewing sarcoma of bone: A report from the Children’s Oncology Group.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.9537 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 9537-9537 ◽

Cited By ~ 1

Author(s):

Steven G. DuBois ◽

Mark D. Krailo ◽

Mark C. Gebhardt ◽

Sarah S. Donaldson ◽

Karen Chayt Marcus ◽

...

Keyword(s):

Local Control ◽

Ewing Sarcoma ◽

Propensity Scores ◽

Phase Iii ◽

Tumor Site ◽

Control Groups ◽

Cox Models ◽

Adjusted Risk ◽

Risk Of Death ◽

The Impact

9537 Background: Patients (pts) with Ewing sarcoma (EWS) require local control, either with surgery alone (S), radiation alone (R), or a combination of surgery + radiation (S+R). Optimal choice of local control for disease control remains unclear. Our primary aim was to determine the mode of local control associated with the highest event-free survival (EFS). Methods: Pts with localized EWS of bone treated on INT0091, INT0154, or AEWS0031 phase III trials were included if they had complete local control data, did not have cranial tumors, received local control starting 2-6 months after enrollment, and were randomized to receive standard dose 5-drug chemotherapy every 3 weeks. We used propensity scores to control for differences in age, tumor site, and year of diagnosis between local control groups. We constructed Cox models controlling for local control propensity scores to assess the impact of local control type on EFS and overall survival (OS) from the start of local control. Results: 465 pts were included. Pts selected for S were treated more recently (p < 0.001), more likely to have appendicular tumors (p < 0.001), and younger (p = 0.02). Pts treated with R, compared to S, had higher unadjusted risk of any event (HR 1.70; 95% CI 1.18 - 2.44; p = 0.004) or death (HR 1.84; 95% CI 1.18 – 2.85; p = 0.006). Pts treated with S+R, compared to S, had higher unadjusted risk of death (HR 1.75; 95% CI 1.10 – 2.76; p = 0.02). After adjusting for propensity scores, there was a trend of higher risk of any event for pts treated with R (HR 1.42; 95% CI 0.94 – 2.14; p = 0.10) compared to S, though this was not statistically significant. No other differences in adjusted risk of event or death between local control groups were statistically significant. We confirmed these results with standard Cox models using age, tumor site, and year of diagnosis as covariates. Conclusions: In this large group of uniformly treated pts, investigator choice of local control approach was not significantly related to EFS. These data support current practice of surgical resection when feasible, while validating radiotherapy as a reasonable alternative in selected pts.

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Lenalidomide/Dexamethasone Improves Response and Prolongs Time to Progression, Even in Patients with IgA Multiple Myeloma: A Sub-Analysis of the MM-009/010 Studies.

Blood ◽

10.1182/blood.v110.11.4839.4839 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4839-4839 ◽

Cited By ~ 3

Author(s):

Robert Foa ◽

Donna Weber ◽

Meletios Dimopoulos ◽

Marta Olesnyckyj ◽

Zhinuan Yu ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Response Rate ◽

Complete Response ◽

High Response Rate ◽

Response To Therapy ◽

Phase Iii ◽

Time To Progression ◽

Phase Iii Trials ◽

The Impact

Abstract Background: Historically, patients with IgA multiple myeloma (MM) respond poorly to treatment. In 2 recent phase III trials, Lenalidomide (Len) in combination with Dexamethasone (Dex) led to an overall response (OR) rate of approximately 60% (61% in MM-009 and 60% in MM-010), a complete response (CR) rate of about 15% (14% and 16%, respectively), an overall survival (OS) of at least 29.5 months (29.5 and not yet reached), and a median time to progression (TTP) of at least 11.1 months (11.1 months and 11.3 months, respectively) in patients with relapsed/refractory MM. In both studies, OR, CR, OS and TTP were significantly better with Len/Dex than with Dex alone. Here, we assess the impact of IgA disease on the efficacy and tolerability of treatment with Len/Dex versus Dex alone. Methods: Data were pooled from the MM-009 and MM-010 studies. Patients were randomized to receive Len (25 mg/day on days 1–21 of each 28-day cycle) or placebo. Both groups received Dex 40mg PO q.d. on days 1–4, 9–12, and 17–20 (for the first four cycles). After four cycles, Dex 40 mg/day was administered only on days 1–4. Response to therapy, TTP, OS, and adverse events were assessed. Response rate and TTP were based on data obtained before unblinding (June 2005 [MM-009] and August 2005 [MM-010]). Results: Of 154 patients with IgA at baseline, 72 were treated with Len/Dex and 82 with Dex alone. Among those without IgA, 281 received Len/Dex and 269 received Dex alone. Baseline characteristics were balanced between treatment groups. Len/Dex was associated with a significantly higher OR and longer median TTP than Dex alone in patients with and without IgA (Table). In the non-IgA group, patients treated with Len/Dex had a significantly longer OS than those treated with Dex alone. Response, TTP and OS were comparable between IgA and non-IgA patient groups. There was no difference in the incidence of adverse events between patients with and without IgA. Among those with IgA, the most common grade 3–4 adverse events with Len/Dex and Dex alone were neutropenia (37.5% and 2.4%), thrombocytopenia (16.7% and 8.5%), and anemia (11.1% and 7.3%). The respective rates for patients without IgA were 46.5% and 14.5%, 12.1% and 5.7%, and 11.0% and 5.7%. Conclusion: In patients with and in those without IgA MM, Len/Dex treatment induces a high response rate and a prolonged TTP compared with Dex. IgA non-IgA Clinical response, % Len/Dex (n=72) Dex alone (n=82) P Len/Dex (n=281) Dex alone (n=269) P OR 68.1 18.3 <0.001 57.7 23.0 <0.001 CR 18.1 0 NS 14.2 2.6 NS PR 38.9 15.9 NS 35.6 19.3 NS Median TTP, wks 44.3 16.4 <0.001 52.1 20.1 <0.001 Median OS, wks 130.4 102.4 NS 156.0 136.1 <0.05

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Head-to-Head Comparison of 5-Azacitidine Versus Decitabine for the Treatment of Myelodysplastic Syndrome.

Blood ◽

10.1182/blood.v120.21.2843.2843 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2843-2843

Author(s):

Yun-Gyoo Lee ◽

Inho Kim ◽

Sung-Soo Yoon ◽

Seonyang Park ◽

June-Won Cheong ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Lower Risk ◽

Overall Response Rate ◽

Response Rate ◽

Hazard Ratio ◽

Phase Iii ◽

Comparable Efficacy ◽

Overall Response ◽

Risk Of Death ◽

Grade 3

Abstract Abstract 2843 Introduction The hypomethylating agents (HMAs) 5-azacitidine (AZA) and decitabine (DAC) provided significant overall response rates (40–60%) in myelodysplastic syndrome (MDS), and improved the outcome of higher risk MDS. However, phase III trials comparing AZA or DAC to conventional treatment including best supportive care have shown discrepant results. The aim of this study is to compare the efficacy and safety between AZA and DAC in patients with MDS. Methods We evaluated 203 patients in lower risk with significant cytopenia and higher risk MDS who received AZA and 97 patients who received DAC in Korea between January 2004 and December 2011. AZA 75mg/m2/day was given subcutaneously for 7 days every 4 weeks. DAC 20mg/m2/day was given intravenously over one hour for 5 days every 4 weeks. We compared overall response rate (complete responses, partial responses, marrow complete responses, and hematologic improvements), overall survival (OS) and adverse outcomes with the use of propensity-score matching in the overall cohort according to HMAs. Results Among 300 patients, propensity matching for the entire cohort created 97 matched pairs of patients. The International Prognostic Scoring System risk category was Intermediate-2/High in 40.2%. A median of 5 courses (range 1–24) were delivered in AZA and 5 courses (range 1–14) in DAC. In the overall matched cohort, there was no significant difference between AZA and DAC in overall response rate (44.2% vs. 52.1%, P=.28), OS (28 vs. 23 months; hazard ratio for AZA, 1.14; 95% confidence interval [CI], 0.75 to 1.72, P=.54) with a median follow-up duration of 29.6 months. Among the patient under 65, no significant differences were noted for OS between AZA and DAC group. Among the patient over 65, however, the patients who received DAC showed higher risk of death than those who received AZA with borderline significance (hazard ratio for AZA, 1.58; 95% CI 0.91 to 2.73, P=.10). The cumulative hazard of transformation to acute myeloid leukemia (AML) was 16.3% in AZA and 21.9% in DAC at one year, and 32.2% in AZA and 55.3% in DAC at two year. The incidence of grade 3 & 4 neutropenia was significantly higher in DAC than AZA (P=.026). Among 1151 assessable treatment courses (604 in AZA, 547 in DAC), AZA group have less likely to experience fever episodes requiring intravenous antibiotics than DAC group (8.6 vs. 15.7 episodes per 100 courses; risk ratio, 0.55; P<.001). Conclusions In a cohort of patients in lower risk with significant cytopenia and higher risk MDS, AZA and DAC showed comparable efficacy in terms of overall response rate, OS and risk of transformation to AML. However, patients receiving DAC experienced more frequent grade 3 & 4 neutropenia and fever episodes than patient receiving AZA. When both AZA and DAC are available, safety profiles as well as treatment efficacy need to be considered. Disclosures: No relevant conflicts of interest to declare.

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Negative Prognostic Impact Of High CD33 Expression Is Negated With The Use Of Gemtuzumab Ozogamicin: A Report From The Children’s Oncology Group

Blood ◽

10.1182/blood.v122.21.491.491 ◽

2013 ◽

Vol 122 (21) ◽

pp. 491-491 ◽

Cited By ~ 3

Author(s):

Jessica Pollard ◽

Todd A. Alonzo ◽

Robert B. Gerbing ◽

Susana C Raimondi ◽

Betsy Hirsch ◽

...

Keyword(s):

Disease Risk ◽

Risk Group ◽

Gemtuzumab Ozogamicin ◽

Phase Iii ◽

Study Cohort ◽

Prognostic Impact ◽

Cell Transplant ◽

Conventional Chemotherapy ◽

Hematopoietic Stem ◽

The Impact

Abstract CD33 is expressed on leukemic blasts of most patients with acute myeloid leukemia (AML) and is the target for gemtuzumab ozogamicin (GO), a toxin-conjugated anti-CD33 monoclonal antibody. CD33 expression of leukemic blasts was prospectively quantified within the context of COG AAML0531, a phase III randomized study for de novo AML in which patients were randomized to receive conventional chemotherapy (Arm A) vs. GO + conventional chemotherapy (Arm B) to determine the impact of CD33 expression on outcome within the context of this GO randomization. CD33 mean fluorescent intensity (MFI) of leukemic blasts was prospectively quantified in 825 diagnostic specimens. Patients were divided into quartiles (Q1-Q4) based on CD33 expression values and these levels were correlated with disease characteristics and outcome by treatment arm for the total study cohort and by cytogenetic/molecular disease risk-group. Analysis of 3 year outcome by treatment arm (N= 412 for Arm A vs. N=414 for Arm B) demonstrated that patients with high CD33 expression (Q4) in Arm A (no GO) had an overall survival (OS) from diagnosis of 55% vs. 70% for those with lower CD33 expression (Q1-3, P=.014) with a corresponding disease-free survival (DFS) from complete remission (CR) of 41% and 57%, respectively (P=.010). In contrast, for the patients in Arm B (receiving GO therapy) those with and without high CD33 expression had a similar OS from diagnosis (67% vs. 72%, P=.290) with a corresponding DFS from CR of 57% vs. 64%, respectively (P=.255). Comparison of the patients with the highest CD33 expression (Q4) who were treated with (N=105) and without (N=101) GO demonstrated that those who received GO had an OS from diagnosis of 67% versus 55% (P=.196) with a corresponding DFS from CR of 57% vs. 41% (P=.052). Analysis by cytogenetic/molecular disease risk group also showed that the effect of CD33 expression levels on outcome differed by treatment arm. Among intermediate risk (IR) patients on Arm A (N=200), those with high CD33 expression (Q4) had an OS from diagnosis of 52% vs. 62% for those with lower CD33 expression (P=0.194) with a corresponding DFS from CR of 28% vs. 53% respectively (P=.012). Conversely, for IR patients treated with GO (N=197), outcomes were similar for patients with high (Q4) and low (Q1-3) CD33 expression (OS from diagnosis of 65% vs. 64%, P=.923, DFS from CR of 50% vs. 53%, P=.687). The loss of prognostic impact of high CD33 expression for patients in Arm B may be due to improved response to GO in those with high CD33 expression (OS of IR patients in Q4 from study entry: Arm A (N=65) 52% vs. Arm B (N=70) 65%, P= .234, DFS from CR of IR patients in Q4: Arm A 28% vs. Arm B 50%, P=.033). Accurate sub analysis of the high-risk (HR) group was not feasible due to the very small number of HR patients with high CD33 expression (Q4) in Arm A (N=9) and Arm B (N=16). Similar trends were, however, observed in the low-risk (LR) group. LR patients with high (Q4) CD33 expression treated on Arm A (no GO) had an OS from diagnosis of 69% vs. 84% for those with lower CD33 expression (P=.092) with a corresponding DFS from CR of 68% vs. 64% respectively (P=0.803). For patients in Arm B (GO) those with and without high CD33 expression had an OS from diagnosis of 94% vs. 86%, respectively (P=.316) with a corresponding DFS from CR of 85% vs. 76% (P=.344). Like IR patients, those LR patients with high CD33 expression (Q4) who received GO trended towards improved outcome compared to Q4 patients treated without GO (LR OS from diagnosis: Arm A 69% vs. Arm B 94%, P= .069, LR DFS from CR: Arm A 68% vs. Arm B 85%, P=.195). However, given the small number of LR patients in Q4 (N= 27 Arm A, N=17 Arm B) we cannot state the significance of this finding with certainty. Taken together our results suggest that, for patients enrolled on AAML0531, high CD33 expression was associated with adverse outcome for those who received standard therapy and GO treatment negated the negative effect of high CD33 expression on clinical outcome for the entire study cohort and in IR and LR patients. This finding may reflect GO’s CD33 dependent mechanism of targeting and the potential for more efficient targeting in the setting of high antigen expression.It is also plausible that repeated exposure to GO, as seen within the context of treatment for all LR and some IR patients (e.g. those that did not undergo hematopoietic stem cell transplant), may also contribute therapeutic benefit within the context of high CD33 expression. Disclosures: No relevant conflicts of interest to declare.

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Pain Predicts Overall Survival in Men With Metastatic Castration-Refractory Prostate Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2007.15.0367 ◽

2008 ◽

Vol 26 (15) ◽

pp. 2544-2549 ◽

Cited By ~ 123

Author(s):

Susan Halabi ◽

Nicholas J. Vogelzang ◽

Alice B. Kornblith ◽

San-San Ou ◽

Philip W. Kantoff ◽

...

Keyword(s):

Prostate Cancer ◽

Overall Survival ◽

Group Performance ◽

Opioid Analgesic ◽

Objective Response ◽

Pain Interference ◽

Phase Iii ◽

Risk Of Death ◽

Pain Scores ◽

The Impact

PurposePain from castration-refractory prostate cancer (CRPC) bone metastases is a common event. Although it is assumed that pain represents an adverse prognostic factor, this variable has not been extensively evaluated. The objective of this study was to determine whether men with CRPC who had higher pain interference scores at baseline had worse clinical outcomes compared with men who had lower pain scores.Patients and MethodsData from three randomized phase III multicenter trials conducted by the Cancer and Leukemia Group B from 1992 to 1998 were combined. Eligible patients had progressive CRPC adenocarcinoma of the prostate, an Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate hematologic, renal, and hepatic functions. Seven items from the Brief Pain Inventory were used to assess the impact of pain on a range of daily activities and quality of life, each rated on a scale from 0 to 10.ResultsIn 599 men, the median pain interference scores was 17 (interquartile range, 4 to 34), and 38% of the men had opioid analgesic use at baseline. There was a statistically significant association between pain interference scores and risk of death. The median survival times were 17.6 months (95% CI, 16.1 to 19.1 months) and 10.2 months (95% CI, 8.6 to 11.3 months; P < .001) in men with low (< 17) and high (≥ 17) pain scores, respectively. Pain was inversely associated with likelihood of prostate-specific antigen decline, objective response, and time to bone progression.ConclusionThis analysis demonstrates that pain is a statistically significant predictor of overall survival in men with metastatic CRPC. These results need to be validated prospectively in future phase III trials.

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THE INFLUENCE OF GLYCEMIA ON SHORT-TERM PROGNOSIS IN MYOCARDIAL INFARCTION WITHOUT ANAMNESIS OF 2ND TYPE DIABETES

CARDIOVASCULAR THERAPY AND PREVENTION ◽

10.15829/1728-8800-2014-2-29-34 ◽

2014 ◽

Vol 13 (2) ◽

pp. 29-34

Author(s):

K. K. Kholmatova ◽

I. V. Dvoryashina ◽

T. V. Supryadkina

Keyword(s):

Myocardial Infarction ◽

Type Diabetes ◽

Glucose Metabolism ◽

Systolic Pressure ◽

Myocardial Damage ◽

Left Ventricular ◽

Glucose Metabolism Disorders ◽

Short Term ◽

Risk Of Death ◽

The Impact

Aim. To estimate the impact of glycemia recorded during myocardial infarction (MI) in-patient care on short-term prognosis of patients without 2nd type diabetes mellitus (2DM).Material and methods. Totally 296 patients were prospectively investigated. According to glucose levels patients were divided into three groups: 1st with ≤4,0 mM/l (7,4%); 2nd with 4,01–7,79 mM/l (69,9%); 3rd with ≥7,8 mM/l (22,6%). The rate of glucose metabolism disorders and complications during in-hospital care were studied.Results. In 2/3 of patients with glycemia ≥7,8 mM/l at hospitalization, later the changes of glucose metabolism were found by glucosetolerance test: prediabetes (36,9%), 2DM (32,3%). In the patients of 3rd group significantly higher was the rate of 3-vessel disease (41,8%) anf MI complications: congestive left-ventricular failure — 52,2% vs 27,3% in the 1st group and 34,1% in the second (p=0,017), cardiogenic shock — 26,9% vs 4,5% and 6,8% (p<0,001), conduction disorders — 27,3% vs 9,1% and 11,7% (p=0,006), in-hospital mortality — 13,8% vs 4,5% and 4,4% (p=0,025). The risk of death in subjects with glycemia ≥7,8 mM/l was 3,48 (95% CI: 1,41–8,60) times higher than in normoglycemic (p=0,007). The glycemia was independently linked with complications of MI during in-hospital period: OR = 1,128; 95% CI: 1,005–1,266 (p=0,042), — as also with the age, severity of myocardial damage and systolic pressure at admittance.Conclusion. There was higher prevalence of MI complications and 3 times higher risk of death in patients without 2DM, but having ≥7,8 mM/l glucose (22,6% of patients) at admittance. The glycemia parameter was an independent predictor for unfavorable prognosis of MI without previous 2DM diagnosis and should be used as part of secondary prevention care.

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