3-month Landmark Research Articles

Benefit of Long-Term Dual Anti-Platelet Therapy in Patients Treated With Drug-Eluting Stents: From the NHLBI Dynamic Registry

The optimal duration of dual-antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation is an important, unanswered question. This study was designed to evaluate the association of varying durations of DAPT on clinical outcomes after DES implantation for the treatment of coronary artery disease. Using the National Heart, Lung, and Blood Institute Dynamic Registry, patients enrolled in the last 2 waves after index percutaneous coronary intervention with DES and who were event free at the time of landmark analysis were included. Landmark analysis was performed 12 and 24 months after percutaneous coronary intervention, and patients were stratified according to continued use of DAPT or not. Subjects were evaluated for rates of death, myocardial infarction, and stent thrombosis at 4 years from their index procedures. The numbers of evaluable patients were 2,157 and 1,918 for the 12- and 24-month landmarks, respectively. In both landmark analyses, there was a significantly lower 4-year rate of death or myocardial infarction in the group that continued DAPT compared to the group that did not (12 months: 10.5% vs 14.5%, p=0.01; 24 months: 5.7% vs 8.6%, p= 0.02). Beneficial differences in the group that continued on DAPT were preserved after multivariate and propensity adjustment. There were no significant differences in definite stent thrombosis in either landmark analysis. In conclusion, at 12 and 24 months after DES implantation, continued use of DAPT was associated with lower 4-year risk for death and myocardial infarction.

Treatment of AL Amyloidosis with Bendamustine

AbstractAbstract 4057Combinations of older drugs and novel agents are constantly improving the outcome of chemotherapy in AL amyloidosis. Bendamustine has demonstrated activity in multiple myeloma and Waldenström macroglobulinemia. In the present study we evaluated the safety and efficacy of Bendamustine and prednisone (BeP) in 36 patients with AL amyloidosis from two European referral centers, the Amyloidosis Center (Heidelberg, Germany) and the Amyloidosis Research and Treatment Center (Pavia, Italy).The databases of the two centers were systematically searched for patients with AL amyloidosis treated with BeP. Nineteen patients were treated in Heidelberg and 17 in Pavia. The patients received 28-day cycles of bendamustine (60–100 mg/m2 on days 1 and 2) and prednisone (100 mg on days 1–4). The target dose of bendamustine was 100 mg/m2, and lower doses were used in 20 patients (55%) who had baseline cytopenia. Ten patients (28%) had IgM clones. Of them, 8 received rituximab associated with BeP. Response was evaluated according to the novel criteria of the International Society of Amyloidosis. Patients’ characteristics are reported in Table 1. Severe (grade 3 or 4) adverse events (SAE) were observed in 33% of subjects, most common being cytopenia (17%). Other SAEs were fever (6%), portal vein thrombosis, skin rash, renal failure, and weight loss, in 1 patient each. By intention to treat, 17 patients (47%) achieved hematologic response, with complete remission (CR) in 1 case (3%), and very good partial response in 2 (6%). The median time to response was 3 months. The dose of bendamustine administered in each cycle was not associated with response. Three out of 5 treatment-naïve patients responded. Interestingly, amongst the 8 subjects with IgM clones receiving BeP combined with rituximab, 6 (75%) responded (1 CR), including 1 out of 3 subjects who were refractory to previous rituximab. Amongst 10 patients who were refractory to melphalan, bortezomib and lenalidomide, 4 responded to BeP. Cardiac responses were observed in 3 patients (12%), two of whom also had liver response and one improvement of peripheral neuropathy. Overall, 12 patients (33%) died, and 65% of patients are alive after 3 years. Two subjects died within 3 months from treatment initiation due to advanced cardiac amyloidosis. A troponin I concentration >0.1 ng/mL or a high-sensitivity troponin T level >77 ng/L negatively affected survival (median 5 vs. 45 months, P=0.003). In a 3-month landmark analysis, response to BeP conferred a significant survival advantage (Figure 1).Treatment with bendamustine is effective and well tolerated, representing an additional treatment option in AL amyloidosis, particularly as salvage therapy. Its use in combination with rituximab in IgM patients is very promising, and warrants further studies in prospective international trials.Table 1Patients' characteristicsVariableN (%)/median (range)Newly diagnosed5 (14)Refractory to previous therapy24 (67)Relapsed after previous therapy7 (19)Number of prior therapies2 (0–5)Previous treatment type:alkylating agents29 (81)bortezomib16 (44)lenalidomide12 (33)thalidomide6 (17)rituximab*6 (17)Male gender18 (50)Age, years66 (33–80)Organ involvementheart25 (69)kidney20 (56)soft tissues13 (36)liver10 (28)peripheral nervous system8 (22)Two or more organs involved22 (61)New York Heart association class III or IV14 (39)Cardiac Stage°I9 (28)II19 (59)III4 (13)Estimated glomerular filtration rate22 (61)≥60 mL/min per 1.73 m211 (31)30–59 mL/min per 1.73 m23 (8)<30 mL/min per 1.73 m2Bone marrow infiltration15 (3–30)*Used in patients with IgM clones.°Available in 32 patients. Cardiac staging was based on N-terminal pro-natriuretic peptide type-B (cutoff 332 ng/L) and cardiac troponin I (cutoff 0.1 ng/mL) or high-sensitivity troponin T (cutoff 77 ng/L). Stage I patients had both markers below the cutoffs, stage II only one marker above the cutoffs and stage III patients both markers above the cutoffs. [Display omitted] Disclosures:Off Label Use: Use of bendamustine in AL amyloidosis.

DURATION OF DUAL ANTIPLATELET THERAPY AND OUTCOMES AFTER LEFT MAIN PERCUTANEOUS CORONARY INTERVENTION

ObjectivesDespite treatment recommendations for at least 12 months of dual antiplatelet therapy (DAPT) following drug-eluting stent revascularisation, the optimal duration of DAPT after left main percutaneous coronary intervention remains controversial....

Prolonged Clopidogrel Use After Bare Metal and Drug-Eluting Stent Placement

Current guidelines recommend combining clopidogrel with aspirin for up to 1 year after coronary stenting, but the value of clopidogrel beyond this time is uncertain. We evaluated all patients in the Veterans Administration healthcare system receiving either drug-eluting or bare metal stents from 2002 to 2006. The Veterans Administration National Patient Care and Pharmacy databases were used to extract patient characteristics, duration of clopidogrel use, and outcomes for up to 4 years after the index procedure. We used Cox proportional hazards to estimate hazard ratios for death, myocardial infarction, revascularization, and bleeding from a 12-month landmark after stenting that excluded patients with events within the first 12 months. Of 42,254 patients, 29,175 met the study inclusion criteria. Compared with ≤12 months of clopidogrel, prolonged clopidogrel (>12 months) was associated with a lower adjusted risk of death for both drug-eluting stents (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.61, 0.82; P<0.01) and bare metal stents (HR, 0.85; 95% CI, 0.76, 0.96; P=0.01) as well as for death and myocardial infarction but was unrelated to stroke or major bleeding. The effect of prolonged clopidogrel on death or myocardial infarction was significantly greater among patients receiving drug-eluting (HR, 0.70; 95% CI, 0.64, 0.84) compared with bare metal stents (HR, 0.88; 95% CI, 0.79, 0.98; interaction P=0.024). Patients receiving clopidogrel beyond 12 months had a lower risk of death or myocardial infarction compared patients receiving clopidogrel ≤12 months. The risk reduction was greater for drug-eluting stents. These data support longer durations of dual antiplatelet therapy for patients receiving a stent, particularly for those receiving a drug-eluting stent.

Abstract No. 243: Alpha-fetoprotein response correlates with EASL response and survival in hepatocellular carcinoma patients treated with locoregional therapies

PurposeAlpha-fetoprotein (AFP) is a universally recognized tumor marker in hepatocellular carcinoma (HCC). Its utility in assessing response to treatment remains controversial. We sought to study the: a) correlation between AFP response and imaging response, and b) ability of AFP, European Association for the Study of the Liver disease (EASL) and World Health Organization (WHO) response guidelines to predict survival outcomes in patients with HCC.Materials and Methods629 HCC patients were treated with transarterial locoregional therapies over an 11-year period. To eliminate confounding factors, we included patients with single tumors, baseline AFP≥200 ng/mL, and no extrahepatic disease; this identified our study cohort of 51 patients. AFP response was defined as >50% decrease from baseline; this was correlated to EASL and WHO response criteria by Kappa agreement, Pearson correlation and receiver operating curves. Survival analyses were performed by Landmark, risk-of-death and Mantel-Byar methodologies.ResultsThree months post-treatment, AFP and EASL response correlated well (Kappa: 0.83; Pearson: 0.84); the sensitivity, specificity, positive and negative predictive values of AFP in predicting EASL response at 3 months were 96.6%, 85.7%, 92.3% and 93.3% respectively. Correlation with WHO response was low. From the 3-month landmark, WHO, EASL and AFP responders survived longer than nonresponders (P=0.006, 0.0001 and <0.0001 respectively). The risk of death was lower for EASL and AFP responders by both risk-of-death and Mantel-Byar methodologies (P<0.05).ConclusionResponse by AFP and EASL is a strong predictor of survival outcomes. AFP correlates with imaging response assessment by EASL guidelines. Achieving AFP response should be one of the therapeutic intents of locoregional therapies. PurposeAlpha-fetoprotein (AFP) is a universally recognized tumor marker in hepatocellular carcinoma (HCC). Its utility in assessing response to treatment remains controversial. We sought to study the: a) correlation between AFP response and imaging response, and b) ability of AFP, European Association for the Study of the Liver disease (EASL) and World Health Organization (WHO) response guidelines to predict survival outcomes in patients with HCC. Alpha-fetoprotein (AFP) is a universally recognized tumor marker in hepatocellular carcinoma (HCC). Its utility in assessing response to treatment remains controversial. We sought to study the: a) correlation between AFP response and imaging response, and b) ability of AFP, European Association for the Study of the Liver disease (EASL) and World Health Organization (WHO) response guidelines to predict survival outcomes in patients with HCC. Materials and Methods629 HCC patients were treated with transarterial locoregional therapies over an 11-year period. To eliminate confounding factors, we included patients with single tumors, baseline AFP≥200 ng/mL, and no extrahepatic disease; this identified our study cohort of 51 patients. AFP response was defined as >50% decrease from baseline; this was correlated to EASL and WHO response criteria by Kappa agreement, Pearson correlation and receiver operating curves. Survival analyses were performed by Landmark, risk-of-death and Mantel-Byar methodologies. 629 HCC patients were treated with transarterial locoregional therapies over an 11-year period. To eliminate confounding factors, we included patients with single tumors, baseline AFP≥200 ng/mL, and no extrahepatic disease; this identified our study cohort of 51 patients. AFP response was defined as >50% decrease from baseline; this was correlated to EASL and WHO response criteria by Kappa agreement, Pearson correlation and receiver operating curves. Survival analyses were performed by Landmark, risk-of-death and Mantel-Byar methodologies. ResultsThree months post-treatment, AFP and EASL response correlated well (Kappa: 0.83; Pearson: 0.84); the sensitivity, specificity, positive and negative predictive values of AFP in predicting EASL response at 3 months were 96.6%, 85.7%, 92.3% and 93.3% respectively. Correlation with WHO response was low. From the 3-month landmark, WHO, EASL and AFP responders survived longer than nonresponders (P=0.006, 0.0001 and <0.0001 respectively). The risk of death was lower for EASL and AFP responders by both risk-of-death and Mantel-Byar methodologies (P<0.05). Three months post-treatment, AFP and EASL response correlated well (Kappa: 0.83; Pearson: 0.84); the sensitivity, specificity, positive and negative predictive values of AFP in predicting EASL response at 3 months were 96.6%, 85.7%, 92.3% and 93.3% respectively. Correlation with WHO response was low. From the 3-month landmark, WHO, EASL and AFP responders survived longer than nonresponders (P=0.006, 0.0001 and <0.0001 respectively). The risk of death was lower for EASL and AFP responders by both risk-of-death and Mantel-Byar methodologies (P<0.05). ConclusionResponse by AFP and EASL is a strong predictor of survival outcomes. AFP correlates with imaging response assessment by EASL guidelines. Achieving AFP response should be one of the therapeutic intents of locoregional therapies. Response by AFP and EASL is a strong predictor of survival outcomes. AFP correlates with imaging response assessment by EASL guidelines. Achieving AFP response should be one of the therapeutic intents of locoregional therapies.

Alpha-fetoprotein response correlates with EASL response and survival in solitary hepatocellular carcinoma treated with transarterial therapies: A subgroup analysis

Alpha-fetoprotein (AFP) is a universally recognized tumor marker in hepatocellular carcinoma (HCC). Its utility in assessing response to treatment remains controversial. We sought to study the: (a) correlation between AFP response and imaging response, and (b) ability of AFP, EASL, and WHO response to predict survival outcomes in patients with solitary HCC. Six hundred and twenty-nine HCC patients were treated with transarterial locoregional therapies over an 11-year period. To eliminate confounding factors, we included patients with single tumors, baseline AFP ≥200ng/ml, and no extrahepatic disease; this identified our study cohort of 51 patients. AFP response was defined as>50% decrease from baseline; this was correlated to EASL and WHO response criteria by Kappa agreement, Pearson correlation and receiver operating curves. Survival analyses were performed by Landmark, risk-of-death and Mantel-Byar methodologies. None of the patients received sorafenib. Three months post-treatment, AFP and EASL response correlated well (Kappa: 0.83; Pearson: 0.84); the sensitivity, specificity, positive and negative predictive values of AFP in predicting EASL response at 3 months were 96.6%, 85.7%, 92.3%, and 93.3%, respectively. Correlation with WHO response was low. From the 3-month landmark, WHO, EASL, and AFP responders survived longer than non-responders (p=0.006, 0.0001, and <0.0001, respectively). The risk of death was lower for EASL and AFP responders by both risk-of-death and Mantel-Byar methodologies (p <0.05). Response by AFP and EASL are predictors of survival outcome in patients with solitary HCC. AFP correlates with imaging response assessment by EASL guidelines. Achieving AFP response should be one of the therapeutic intents of locoregional therapies (LRTs).

Dasatinib and Imatinib-Induced Reductions in BCR-ABL Transcript Levels Below 10% At 3 Months Are Associated with Improved Responses in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Analysis of Molecular Response Kinetics in the DASISION Trial

Abstract▪2767▪This icon denotes a clinically relevant abstract Background:In the randomized phase 3 DASISION trial in patients (pts) with newly diagnosed CML-CP, dasatinib showed superior efficacy over imatinib (IM), including higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR) at 24 months, and acceptable tolerability (Hochhaus et al. Haematologica 96: 2011 [Suppl 2; abstract 1011]). Previous studies have shown that molecular response after 3 months of imatinib therapy is predictive for treatment failure and transformation (Hanfstein et al, ASH 2010, abstract 360). Here, an analysis of BCR-ABL kinetics in pts from DASISION after a minimum 24 months of follow-up and a 3-month landmark analysis are presented. Methods:Pts with CML-CP diagnosed within 3 months were randomized to receive dasatinib 100 mg once daily (QD; n=259) or IM 400 mg QD (n=260). Levels of BCR-ABL b2a2 and b3a2 transcripts in peripheral blood were assessed using real-time quantitative PCR by a central independent laboratory (MolecularMD, Portland, OR). For the current analysis, pts with atypical BCR-ABL transcripts were excluded (5 in the dasatinib arm, 3 in the imatinib arm). MMR was defined as a BCR-ABL transcript level of ≤0.1% on the international scale (IS) (≥3-log reduction from the standardized baseline). For PCR negative samples an at least 4.5 log test sensitivity was confirmed. The following events were considered in the progression-free survival (PFS) analysis: increasing WBCs, loss of complete hematologic response or major cytogenetic response, transformation to accelerated/blast phase (AP/BP), or death. Results:In the dasatinib vs imatinib arms, 24-month cumulative response rates were MMR in 65% vs 47%, BCR-ABL ≤0.01% (MR4, ≥4-log reduction) in 29% vs 19%, and BCR-ABL ≤0.0032% (MR4.5, ≥4.5-log reduction) in 17% vs 9%, respectively. The advantage in MMR rates for dasatinib over imatinib was maintained between 12 and 24 months (18–19% difference). Median time to MMR in all pts irrespective of response (calculated by competing risk analysis) was 20 months shorter for dasatinib compared with imatinib (15 vs 35 months). The median BCR-ABL transcript level decreased faster in the dasatinib arm compared with the imatinib arm (Table). By 3 months, 84% vs 64% of evaluable pts in the dasatinib vs imatinib arms, respectively, had achieved a BCR-ABL level ≤10%. Compared with pts who had not achieved this degree of response, a landmark analysis found that pts who had achieved BCR-ABL ≤10% at 3 months had a higher probability of achieving CCyR by 12–18 month and MMR by 18–24 months, a higher probability of 24-month PFS, and a lower probability of transformation to AP/BP, both in the dasatinib and imatinib arms (Table). Probabilities of subsequent CCyR and MMR among pts who had a BCR-ABL level ≤10% at 3 months showed a higher trend in dasatinib-treated pts compared with imatinib-treated pts. Conclusions:In pts with newly diagnosed CML-CP, first-line dasatinib results in faster and deeper molecular responses compared imatinib. For pts treated with either dasatinib or imatinib, BCR-ABL reduction to ≤10% at 3 months is associated with increased likelihood of achieving CCyR by 12 months and MMR by 24 months, decreased progression to AP/BP, and increased PFS at 24 months.Table:Molecular kinetics with dasatinib and imatinib, and landmark analysis of response/outcome based on achieving a BCR-ABL level ≤10% at 3 monthsDasatinib 100 mg QD armImatinib 400 mg QD armMedian BCR-ABL level, %3 months1.265.516 months0.301.0112 months0.130.3918 months0.060.1524 months0.040.09BCR-ABL at 3 months (evaluable patients)≤1% (n=112)>1–10% (n=86)≤10% (n=198)>10% (n=37)≤1% (n=32)>1–10% (n=122)≤10% (n=154)>10% (n=85)CCyR by 12 months, n110 (98%)81 (94%)191 (96%)10 (27%)31 (97%)107 (88%)138 (90%)38 (45%)MMR by 24 months, n99 (88%)51 (59%)150 (76%)6 (16%)28 (88%)73 (60%)101 (66%)16 (19%)AP/BP at any time, n2 (2%)1 (1%)3 (2%)3 (8%)0 (0%)4 (3%)3 (3%)8 (9%)PFS at 24 months*96%98%97%83%100%95%96%85%*PFS rates were obtained from Kaplan-Meier estimates. PFS included death from any cause as a progression event. Disclosures:Hochhaus:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Pfeizer: Consultancy. Chuah:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Pavlovsky:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Bradley Garelick:Bristol-Myers Squibb: Employment. Lambert:Bristol-Myers Squibb: Employment. Shah:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy; Ariad: Consultancy, Research Funding.

Clinical trial results of the HER‐2/neu (E75) vaccine to prevent breast cancer recurrence in high‐risk patients

The authors conducted exploratory phase 1-2 clinical trials vaccinating breast cancer patients with E75, a human leukocyte antigen (HLA) A2/A3-restricted HER-2/neu (HER2) peptide, and granulocyte-macrophage colony-stimulating factor. The vaccine is given as adjuvant therapy to prevent disease recurrence. They previously reported that the vaccine is safe and effective in stimulating expansion of E75-specific cytotoxic T cells. Here, they report 24-month landmark analyses of disease-free survival (DFS). These dose escalation/schedule optimization trials enrolled lymph node-positive and high-risk lymph node-negative patients with HER2 (immunohistochemistry [IHC] 1-3(+) ) expressing tumors. HLA-A2/A3(+) patients were vaccinated; others were followed prospectively as controls for recurrence. DFS was analyzed by Kaplan-Meier curves; groups were compared using log-rank tests. Of 195 enrolled patients, 182 were evaluable: 106 (58.2%) in the vaccinated group and 76 (41.8%) in the control group. The 24-month landmark analysis DFS was 94.3% in the vaccinated group and 86.8% in the control group (P = .08). Importantly, because of trial design, 65% of patients received a lower than optimal vaccine dose. In subset analyses, patients who benefited most from vaccination (vaccinated group vs control group) had lymph node-positive (DFS, 90.2% vs 79.1%; P = .13), HER2 IHC 1+-2+ (DFS, 94.0% vs 79.4%; P = .04), or grade 1 or 2 (DFS, 98.4% vs 86.0%; P = .01) tumors and were optimally dosed (DFS, 97.3% vs 86.8%; P = .08). A booster program has been initiated; no patients receiving booster inoculations have recurred. The E75 vaccine has clinical efficacy that is more prominent in certain patients. A phase 3 trial enrolling lymph node-positive patients with HER2 low-expressing tumors is warranted.

Covering the Cover

Covering the Cover

Impact of Cardiac Rehabilitation on Mortality and Cardiovascular Events After Percutaneous Coronary Intervention in the Community

Although numerous studies have reported that cardiac rehabilitation (CR) is associated with reduced mortality after myocardial infarction, less is known about its association with mortality after percutaneous coronary intervention. We performed a retrospective analysis of data from a prospectively collected registry of 2395 consecutive patients who underwent percutaneous coronary intervention in Olmsted County, Minnesota, from 1994 to 2008. The association of CR with all-cause mortality, cardiac mortality, myocardial infarction, or revascularization was assessed with 3 statistical techniques: propensity score--matched analysis (n=1438), propensity score stratification (n=2351), and regression adjustment with propensity score in a 3-month landmark analysis (n=2009). During a median follow-up of 6.3 years, 503 deaths (199 cardiac), 394 myocardial infarctions, and 755 revascularization procedures occurred in the study subjects. Participation in CR, noted in 40% (964 of 2395) of the cohort, was associated with a significant decrease in all-cause mortality by all 3 statistical techniques (hazard ratio, 0.53 to 0.55; P<0.001). A trend toward decreased cardiac mortality was also observed in CR participants; however, no effect was observed for subsequent myocardial infarction or revascularization. The association between CR participation and reduced mortality rates was similar for men and women, for older and younger patients, and for patients undergoing elective or nonelective percutaneous coronary intervention. We found that CR participation after percutaneous coronary intervention was associated with a significant reduction in mortality rates. These findings add support to published clinical practice guidelines, performance measures, and insurance coverage policies that recommend CR for patients after percutaneous coronary intervention.

Amenorrhea from Breast Cancer Therapy — Not a Matter of Dose

To the Editor: In our article on concurrent versus sequential administration of chemotherapy drugs for women with operable, node-positive, early-stage breast cancer (June 3 issue),1 we report that premenopausal women in whom amenorrhea developed as a consequence of receiving adjuvant chemotherapy had a superior outcome to those without amenorrhea. In response to questions regarding our data analyses, we have performed two additional analyses. One is a 12-month landmark Kaplan–Meier analysis to address the concern that our previous results may have been biased by the misclassification of women without amenorrhea who had a relapse or died before reaching 24 months of . . .

Prediction of Cytogenetic Response to Second Generation TKI Therapy in CML Chronic Phase Patients Who Have Failed Imatinib Therapy and Early Identification of Factors That Influence Survival

Second generation tyrosine kinase inhibitors (2G-TKI) have displaced allogeneic stem cell transplant as the preferred therapy for patients with CML in chronic phase (CP) who fail imatinib. However a significant proportion of patients still fail to respond to 2G-TKI and may benefit from alternative therapy (including stem cell transplant). We have performed univariate and multivariate analyses in our cohort of 80 patients treated with dasatinib (n=67) or nilotinib (n=13) while still in first CP after imatinib failure in order to identify those patients who will benefit most with these therapies.The median age was 50 years and 46% were male; 72 patients were resistant to imatinib (2 primary haematological resistance, 40 primary cytogenetic, 32 secondary cytogenetic and 25 developed secondary hematologic resistance) and 8 were intolerant. 20 had developed kinase domain mutations while on imatinib therapy. 31 and 29 patients received maximal doses of imatinib 600 and 800 mg per day respectively. The median follow up was 28.3 months (range 6–42).The 3-year cumulative incidence of CCyR was 52.6%. The multivariate analysis identified four pre-2G-TKI independent predictive factors for CCyR, namely low Sokal risk score at diagnosis, the best cytogenetic response obtained on imatinib, G-CSF requirement during imatinib therapy and time from detection of imatinib failure (as defined by European LeukemiaNet criteria) to onset of second 2G-TKI therapy. Using these factors we devised a scoring system that could be used to predict the probability of achieving CCyR on 2G-TKI therapy. The score was calculated by allocating one point when any one of the following four features was present: (1) intermediate or high Sokal risk group, (2) need of G-CSF support during imatinib therapy, (3) institution of 2G-TKI more than 18 months after imatinib failure, and (4) failure to achieve a cytogenetic response on imatinib (≥95% Ph-pos). The 3-year cumulative incidence of CCyR for patients with 0–1 points was 95.6%, with 2 points 50% and with 3–4 points 18.7% (p<0.0001, Figure 1).For the 80 patients the probability of 3-year survival was 89.6%. We performed a 3-month landmark analysis to study the relationship between molecular response and subsequent outcome. The 44 patients with a BCR-ABL1/ABL ratio less than 15% at 3 months had a 3-year overall survival of 100% while the 36 patients with a ratio >15% had a survival of 77.4% (p=0.003, Figure 2). We performed a multivariate analysis including all relevant variables defined at the start of 2G-TKI and the 3-month transcript level. The 3-month transcript level was the only independent predictor for survival.Similarly we performed a 6-month landmark analysis where we explored the relationship between cytogenetic response and outcome. Patients who had achieved a McyR (n=38) or a CCyR (n=32) had a significantly better survival than those with lower levels of cytogenetic response (100% vs. 79.2% (p=0.006) and 100% vs 82.6 (p=0.02)) respectively. We also performed a multivariate analysis including the variables defined at the initiation of therapy, the 3-month transcript levels and the cytogenetic response at 6 months. Interestingly the 3-month molecular response was the only independent variable predicting for survival. Similar results were found for progression-free survival (data not shown).We conclude that factors measureable before starting treatment with 2G-TKI may be valuable for predicting response; molecular responses at 3-months and cytogenetic responses at 6 months provide further information about the value of continuing treatment with 2G-TKI. [Display omitted] [Display omitted]

Outcome, Prognostic Factors and Long-Term Follow-Up in 207 Chronic Phase CML Patients Receiving Front-Line Imatinib 400 mg at a Single Institution.

Imatinib is remarkably effective as single-agent treatment of newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) but most of the published data are based on a single multicenter study (acronym IRIS) carried out under the supervision of the manufacturer. We report here an independent validation of the IRIS results. At our institution from June 2000 and August 2006 207 consecutive newly diagnosed CML-CP patients were started on imatinib 400mg within 6 months from diagnosis, of whom 17 were included in the IRIS study. Their median age was 46.3 years. Their Sokal risk score was ‘low' in 59 (28.5%) patients, ‘intermediate' in 73 (35.3%) and ‘high' in 54 (26.1%). The median follow-up was 33 months (range 12–85). By intention to treat analysis the estimated overall survival (OS) and progression-free survival (PFS, defined by progression to accelerated or blastic phase) at 48 months were respectively 90.5% (95CI, 82.1–95.2%) and 90.2% (95CI, 84.5–94.0%) (data censored at the time of allografting). 34 (16%) patients discontinued imatinib at some point while still in CP and received a second generation TK inhibitor or an allograft. The cumulative incidence of complete cytogenetic response (CCyR) and major molecular response (MMolR) were 59.1% (95CI, 52.0–65.9%) and 11.9% (95CI, 8.0–17.4%) by 12 months, and 86.7% (95CI, 79.4–91.7%) and 58.4% (95CI, 47.6–68.5%) by 48 months respectively (data censored at the time of changing to another treatment). The cumulative incidence of loss of CCyR at 48 months was 17.5% (95CI, 9.9–29.1%). The imatinib dosage was increased in 70 (33.8%) patients to 600 mg/day and in 19 (11.6%) patients the dose was further increased to 800 mg/day during follow-up; in 5(2%) patients the dose of imatinib was directly escalated to 800mg/day. The only pre-therapy factor found to be predictive for PFS was the Sokal (and also Euro) score. A 12-month landmark analysis showed that patients who achieved a CCyR had significantly better OS and PFS at 48 months (OS - 95.2% vs 87.1%, p=0.026; PFS - 97.8% vs 87.3%, p=0.007 respectively), while the achievement of a MMolR by 18 months had no significant impact on OS or PFS. Nevertheless patients in CCyR who achieved a MMolR at any time during the follow-up were significantly less likely to lose their CCyR than CCyR patients who maintained higher BCR-ABL transcript levels (RR=0.08, p=0.0003). No plateau was seen either in the OS or in the PFS curves; however when analysis was restricted to patients who were on CCyR at 12 months the OS and PFS curves did achieve plateaux. Five patients (2.4%) achieved a complete molecular response (CMolR) during the follow up. When restricting the analysis to the 31 patients who had at least 4 years of follow-up only 2 patients (6.5%) had a sustained CMolR while on imatinib 400mg/day. In summary our findings confirm the results reported in the recent IRIS update, notably the high rates of CCyR and high rates OS and PFS at 48 months. Moreover, our results suggest that achieving a CCyR before 12 months is strongly associated with better OS, which accords with the recommendations published recently by the European LeukemiaNet. We showed moreover that once a patient has achieved CCyR, a further reduction in the transcript levels to MMolR is still clinically relevant, although the time-frame is not yet clear.

Discussion generale : quels enjeux pour l’imagerie?

To test the prognostic role of treatment delay in patients affected by prostate cancer (PCa).The study included 2,653 patients treated with radical prostatectomy (RP) at a single institution between 2006 and 2011. The evaluated outcomes were biochemical recurrence (BCR) and clinical recurrence (CR). Multivariable Cox regression analysis was used to test the association between time from diagnosis to RP and oncological outcomes. Nonparametric curve fitting methods were used to graphically explore the relationship between time from diagnosis to RP and oncological outcomes. Sensitivity analyses were repeated in the subgroups of low-, intermediate-, and high-risk patients.At median follow-up of 56 months (interquartile range: 26, 92), 283 patients experienced BCR, and 84 patients developed CR. Median time from PCa diagnosis to surgery was 2.8 months (interquartile range: 1.6, 4.7). At multivariable Cox regression analysis, time from biopsy to RP was significantly associated with an increased risk of BCR (hazard ratio = 1.02, P = 0.0005) and CR (hazard ratio = 1.03, P = 0.0002). Using Nonparametric curve fitting methods, a significant increased risk of BCR and CR after approximately 18 months was observed. However, when sensitivity analyses were repeated according to risk groups, this effect was maintained in high-risk patients only, and such time interval was reduced to 12 months.Despite the overall trend on higher rate of cancer relapse after RP, the effect of treatment delay from biopsy to RP was significantly evident in high-risk patients only. Even in high-risk patients surgical treatment can be postponed safely, but not beyond the 12-month landmark.

Severe mucositis is associated with reduced survival after autologous stem cell transplantation for lymphoid malignancies

Mucositis is a known complication of autologous stem cell transplantation (ASCT). This study retrospectively reviewed 191 patients with lymphoid malignancies undergoing ASCT following a uniform mobilising regimen of etoposide (VP-16)/granulocyte colony-stimulating factor and a uniform high-dose preparative regimen of busulfan/cyclophosphamide/VP-16. Eighty-seven patients experienced severe mucositis (modified Oral Mucositis Assessment Scale > or =1). Patient characteristics compared between mucositis groups were balanced according to disease status, prior exposure to radiation therapy, time from radiation therapy and actual body weight. Log-rank analysis revealed that severe mucositis was associated with inferior overall survival (P = 0.002). A 12-month landmark analysis showed this difference in survival occurred within 1 year post-transplant. Multivariate analysis of all-cause mortality showed lower pretransplant albumin and severe mucositis to be significant risk factors. Multivariate analysis for relapse mortality revealed severe mucositis to be a risk factor (P = 0.047), while lower pretransplant albumin was significant for non-relapse mortality (NRM; P = 0.009). Kaplan-Meier estimates of survival based on relapse and NRM were significantly worse for patients with severe mucositis. Reduced pretransplant forced expiratory volume in 1 s (FEV(1)) and carbon monoxide (CO) diffusing capacity (DLCO) were also associated with severe mucositis. Our data suggest that studies of new treatment strategies for mucositis should include relapse and survival endpoints and that pretransplant factors, such as FEV(1) and DLCO may be useful to risk-stratify patients entered onto such trials.

The impact of local/regional radiotherapy (RT), and its timing, on survival following lumpectomy/mastectomy and systemic chemotherapy in patients with ≥10 positive axillary nodes: Analysis of CALGB 9082

In CALGB 9082, patients with breast cancer involving ≥10 axillary nodes without evidence of distant metastasis received 4 cycles of induction CAF chemo and were then randomized to receive either high dose cyclophosphamide, cisplatin, BCNU with autologous marrow/stem-cell support or intermediate-doses of the same drugs. All patients were prescribed to receive local-regional RT following chemo. We herein assess whether there was an association of overall survival with (1) receipt of RT and (2) the timeliness of RT among irradiated patients. This trial randomized 785 patients from 5/91–5/98. Of these, RT information was available for 747. The protocol-specified RT included 50 Gy to the chest wall, supraclavicular nodes in 1.8 Gy daily fractions using conventional techniques. IMN RT was encouraged but not required. Axillary RT was discouraged but permitted. We used proportional hazards models to assess two study questions. First, the overall survival in patients who received (+RT) or did not receive (−RT) were compared. Since patients were not randomized to ±RT, this comparison may be biased. For example, RT was often omitted due to chemo-associated morbidity that may bias against the −RT group. To address this, we used a landmark analysis in which a fixed time after a patient’s study-entry was selected as a landmark time. Patients who died prior to the landmark time were excluded from the analysis in an effort to remove the confounding effect of chemo-associated mortality/morbidity that may have impacted on the decision to use or not use RT. Patients were considered to have had RT only if they received it before the landmark. The dependent variable was survival measured from the landmark time until death due to any cause. We used landmark times of 9, 12, 18 and 24 months post study entry. Question 2: Among +RT patients, the survival in those who started RT within 45 days (the median) from the end of chemo, vs. >45 days were compared. The dependent variable was survival measured from 45 days after the end of chemo. All proportional hazards models controlled for treatment arm (high vs intermediate dose chemo), type of primary surgery (mastectomy vs other), age (<50 vs ≥50) and ER status (neg vs pos). The median follow-up was 8 yrs. For the 747 patients, median age was 44 yrs; 80% Caucasian; 65% stage II and 35% stage III; 69% receptor positive; 77% mastectomy. 91% of the 747 patients were irradiated. Of those who did not receive RT, 73% were on the HD-CPB arm. The survival hazard favored the +RT group at the 9 and 12 mo landmark analyses; hazard ratios [HR] were 1.36 (p = 0.098) and 1.28 (p = 0.31), respectively (the −RT group had an excess hazard of dying that was 36% or 28% higher than the +RT group). HRs favored the −RT group in the 18- and 24-month landmark analyses; HRs were 1.01 (p = 0.97) and 1.05 (p = 0.87), respectively. A test of the association of timeliness of RT with survival had p = 0.090. Patients whose RT started beyond 45 days after chemo had a hazard of dying that was 24% higher than those who started RT within 45 days of completing chemo (HR = 1.24, early RT better). In this comparison of non-randomized groups of patients, there was no definitive/consistent impact of RT, or its timeliness, on survival. Some of the p-values approached statistical significance (p = 0.09–0.10) suggesting that the use of RT, and its delivery within 45 days of chemo, may improve survival. The inability to demonstrate a statistically-significant association between RT usage/timing and survival may be due to 1) biases in selection/timing for RT that are not addressed by a landmark technique, 2) the relatively small number of patients, 3) competing risks of systemic spread in these patients with multiple positive axillary nodes, and 4) the lack of any real effect. Additional analyses of patterns of failure are underway and ill be presented

Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy

AbstractCytogenetic clonal evolution (CE) is a known poor prognostic factor in Philadelphia chromosome–positive chronic myelogenous leukemia (Ph-positive CML). However, its prognostic relevance in the era of imatinib therapy is unknown. We investigated the independent prognostic relevance of CE in 498 patients with Ph-positive CML treated with imatinib for chronic or accelerated phases. One hundred twenty-one patients had CE alone (n = 70) or with other accelerated phase criteria (n = 51). Patients were compared in 4 categories: chronic phase (n = 295), CE only (n = 70), accelerated phase without CE (n = 82), and accelerated phase with CE (n = 51). Statistical methods used established methodologies for univariate and multivariate analyses. In chronic and accelerated phases of CML, CE was not associated with significant differences in major or complete cytogenetic response rates, but it was an independent poor prognostic factor for survival by multivariate analyses in both chronic (P = .005) and accelerated phase (P = .03). Multivariate analyses conducted at the 3-month landmark (including the 3-month cytogenetic response) identified the lack of cytogenetic response at 3 months to be a stronger independent poor prognostic factor for survival than CE for both chronic (major cytogenetic response versus other) and accelerated phase (any cytogenetic response versus other). We conclude that cytogenetic CE is not an important factor for achieving major or complete cytogenetic response with imatinib mesylate therapy, but it is an independent poor prognostic factor for survival in both chronic and accelerated phases of CML. The 3-month cytogenetic response to imatinib mesylate refined the prognostic relevance of such studies in patients on imatinib mesylate therapy.