Clinical Outcomes of Patients with Primary Myelofibrosis in Japan: A Nationwide Survey over a 17-Year Study Period

Abstract Backgrounds: Primary myelofibrosis (PMF) is associated with poor prognosis and a marked reduction in life expectancy, with median survival durations ranging from 3.5 to 6 years, according to previous studies with great variation. We conducted a 17-year nationwide survey (1999-2015) to elucidate the clinical outcomes of patients with PMF in Japan, and evaluated the change of survival duration over time. Patients and Methods: Questionnaires were sent annually to approximately 500 hematology departments of board-certified member institute of the Japanese Society of Hematology to collect data about clinical features and prognoses of patients with PMF. Newly diagnosed patients with PMF were enrolled in this study and were followed up annually to collect prognostic information. Approximately 50 patients were enrolled per year, yielding an eventual total of 780 patients with PMF that were included in a 17-year study period (1999-2015). Results: The median age at diagnosis was 66 years. At the time of the analysis, 374 enrolled patients (48%) had died after a median survival duration of 47 months (95% CI, 41-53 months). Of the patients for whom the final cause of death was known, infection (n = 89) and transformation into acute leukemia (n = 91) were the most frequent causes. The 3-year overall survival (OS) rate was 59% (95% CI, 55%-63%). Significant improvements in the 3-year OS rate were not observed during the 17-year period of analysis (p = 0.235)(Figure A). Among the proposed prognostic models for predicting the outcomes of PMF patients, the Dynamic International Prognostic Scoring System of PMF (DIPSS) plus model was the most feasible for our cohort. However, the calculated areas under ROC curves were 0.609, and only modest accuracy was observed in this regard. Forty-three patients (median age of 52 years; range, 24-66 years) received allogeneic hematopoietic stem cell transplantation (alloSCT) at a median of 343 days after diagnosis. The estimated median survival duration after first alloSCT was 134 months (range, 71 to not reached), with a 3-year OS rate of 84% (95% CI, 68%-93%). The median survival duration after diagnosis among patients who received alloSCT was 207 months (range, 105 to not reached), and this is significantly longer than that calculated for patients who did not receive alloSCT (median: 45 months; range, 38-49 months; p < 0.001)(Figure B). Ruxolitinib therapy was given to 47 patients, but did not have an impact on survival duration. Conclusions: The survival curves of patients diagnosed during different subperiods of our study period exhibited complete overlap, indicating a lack of improvement in survival duration over time. However, only alloSCT among current treatment modalities had an impact on the natural course of PMF. Regarding prognostic prediction, DIPSS plus was the optimal model for survival prediction even among Japanese patients with PMF. However, the ROC analysis indicated that the prognostic covariates in DIPSS plus were not sufficient, and additional information regarding gene mutation statuses (e.g., CALR and ASXL1) might be required to predict the precise outcomes of PMF patients. A long-term registration study is required for further evaluations of prognosis and the impact of treatments on survival. Figure Figure. Disclosures Shibayama: Novartis Pharma: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau. Ozawa:Sumitomo Dainippon Pharma Co. Ltd: Research Funding; Takara Bio Inc: Research Funding; Celgene Japan: Consultancy; JCR Pharmaceutical Inc: Consultancy.

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Improved Survival in Chronic Myeloid Leukemia (CML) Since the Introductin of Imatinib Therapy - A Single Institution Historical Experience

Blood ◽

10.1182/blood.v118.21.2750.2750 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2750-2750

Author(s):

Hun Lee ◽

Jorge E. Cortes ◽

Susan O'Brien ◽

Elias Jabbour ◽

Guillermo Garcia-Manero ◽

...

Keyword(s):

Prognostic Factors ◽

Median Survival ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Imatinib Therapy ◽

Blastic Phase ◽

Group A ◽

The Impact ◽

Over Time

Abstract Abstract 2750 Background: Outcome of CML since introduction of imatinib therapy has improved. Aims: analyze improvement of CML outcome in different phases. Study Group: A total of 1,569 patients with CML referred since 1965, within 1 month from diagnosis, were reviewed and used to identify phase-specific prognostic factors: 1,148 chronic, 175 accelerated, 246 blastic. Results: The median survival was 8.9 years in chronic, 4.8 years in accelerated, and 6 months in blastic phase. In chronic phase, the 8-year survival was ≤ 15% before 1983, 42–65% from 1983 to 2000, and 87% since 2001 (Figure 1). Survival was worse in older patients (p=0.004), but less significant since 2001 (p=0.07). Survival by Sokal risk was significantly different before 2001 (p<0.001), but not since 2001 (p=0.4). In accelerated phase, survival improved over time (p<0.001); the 8-year survival in patients treated since 2001 was 75% (Figure 2). Survival by age was not different in years < 2001 (p=0.09), but was better since 2001 in patients ≤ 70 years (p=0.004). Multivariate analysis derived adverse factors since 2001: older age (p=0.049), increased marrow blasts (p=0.03). In blastic phase, the median survival improved over time (p<0.001), although it is only 7 months since 2001. Conclusions: Survival in CML significantly improved significantly since 2001, particularly so in chronic and accelerated phases. Imatinib therapy minimized the impact of known prognostic factors and Sokal risk in chronic phase, and accentuated the impact of age in accelerated and blastic phases. Disclosures: Cortes: Novartis: Consultancy; Novartis: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

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Cancer Research Campaign phase II trial of temozolomide in metastatic melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.1995.13.4.910 ◽

1995 ◽

Vol 13 (4) ◽

pp. 910-913 ◽

Cited By ~ 187

Author(s):

N M Bleehen ◽

E S Newlands ◽

S M Lee ◽

N Thatcher ◽

P Selby ◽

...

Keyword(s):

Phase I ◽

Total Dose ◽

Metastatic Melanoma ◽

Median Survival ◽

Phase Ii ◽

Lung Metastases ◽

Interleukin 2 ◽

Survival Duration ◽

Median Response ◽

Median Survival Duration

PURPOSE Sixty patients with metastatic melanoma were treated in a phase II study with the imidazotetrazine derivative temozolamide to assess further the efficacy demonstrated in previous phase I studies. PATIENTS AND METHODS Fifty-five of 56 eligible patients were assessable for toxicity and 49 for response. The patients received temozolomide 150 mg/m2/d over 5 successive days orally (total dose, 750 mg/m2) in the first course. Courses were repeated every 4 weeks and the dose was escalated to 200 mg/m2/d x 5 (total dose, 1 g/m2) after the first course if toxicity was acceptable. Patients were all chemotherapy-naive, except for two who had previously received interferon alfa and one who had received interleukin-2 (the latter patient had also received two phase I drugs some time previously). RESULTS A complete response (CR) was documented in three patients (all with lung metastases) and a partial response (PR) in nine patients (21% CR plus PR rate). Seven of 56 patients were not assessable for response because of early death or deterioration. The overall response rate excluding these patients is 12 of 49 (24%). The median response duration was 6 months (range, 2.5 to 22+). Toxicity of the regimen, which was mainly hematopoietic, was low. The median survival duration for all patients was 5.5 months (range, 0.5 to 29.5). For responders, the median survival duration was 14.5 months (range, 3 to 28+), with four patients still alive. CONCLUSION Temozolomide in the schedule used has as good activity in chemotherapy-naive metastatic melanoma as the other most active agents currently in use. Further studies of the drug on its own and in combination with other agents is recommended.

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Preoperative chemoradiation followed by transhiatal esophagectomy for carcinoma of the esophagus: final report.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.6.1118 ◽

1993 ◽

Vol 11 (6) ◽

pp. 1118-1123 ◽

Cited By ~ 275

Author(s):

A A Forastiere ◽

M B Orringer ◽

C Perez-Tamayo ◽

S G Urba ◽

M Zahurak

Keyword(s):

Median Survival ◽

Squamous Cell ◽

Curative Resection ◽

Survival Rates ◽

Residual Tumor ◽

Transhiatal Esophagectomy ◽

Preoperative Chemoradiation ◽

Survival Duration ◽

Median Survival Duration

PURPOSE In 1990 we published the results of an intensive 3-week preoperative chemoradiation regimen for locoregional esophageal cancer that suggested improved survival compared with historical controls. We now report the long-term results at a median follow-up of 78.7 months. PATIENTS AND METHODS Forty-three patients with locoregional squamous cell carcinoma or adenocarcinoma of the esophagus or cardia were treated with fluorouracil (5-FU), cisplatin, and bolus vinblastine concurrent with radiation administered over 21 days. Transhiatal esophagectomy was performed on day 42. RESULTS Forty-one patients (95%) completed the preoperative treatment, and 36 (84%) had a potentially curative resection. Ten of 41 (24%) had no tumor in the resected esophagus and nodal tissues (path-negative group). The median survival duration of all 43 patients registered on study was 29 months; 34% were alive at 5 years. By histology, median survival durations were 32 months for 21 adenocarcinoma patients and 23 months for 22 squamous cell patients, with corresponding 5-year survival rates of 34% and 31%, respectively. Analysis of the 36 patients who underwent a potentially curative resection demonstrated median survival durations of 32 and 44 months and 5-year survival rates of 36% and 43%, respectively, for adenocarcinoma and squamous cell histologies. Path-negative (complete response [CR]) patients had a median survival duration of 70 months and 60% were alive at 5 years, while those patients with residual tumor in the resected esophagus had a median survival duration of 26 months and 32% were alive at 5 years (P = .114 by the log-rank test and P = .04 by the Wilcoxon test). CONCLUSION The results of this regimen appear improved over those reported with surgery alone, with an approximate doubling of the 5-year survival rate. Thirty-two percent of patients with residual tumor in the esophageal specimen are long-term survivors, which suggests a benefit from esophagectomy. A randomized trial is in progress to compare this preoperative regimen with immediate surgery.

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Decitabine Is Effective and Safe In Patients with Chronic Myelomonocytic Leukemia

Blood ◽

10.1182/blood.v116.21.4032.4032 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4032-4032

Author(s):

Elias Jabbour ◽

Hagop M. Kantarjian ◽

Farhad Ravandi ◽

A. Megan Cornelison ◽

Tapan Kadia ◽

...

Keyword(s):

Median Survival ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Chronic Myelomonocytic Leukemia ◽

Phase Iii ◽

White Blood Count ◽

Survival Duration ◽

Overall Response ◽

Myelomonocytic Leukemia

Abstract Abstract 4032 Background: Chronic myelomonocytic leukemia (CMML) is a rare yet indolent disease. The median survival duration in CMML is 12 to 18 months and patients with poor prognostic features do even worse, with median survival time ranging 3 to 6 months. Activity with decitabine in CMML has been previously reported. We sought to analyze the clinical experience of 17 adults with a diagnosis of CMML treated on two decitabine studies. Methods: A subset of patients with CMML from a pivotal phase III 3-day dosing and an open-label trial of 5-day dosing were identified and reviewed to determine the overall response rate (ORR, based on IWG 2006 criteria), duration of response, time to response, and overall survival (OS). Results: A total of 17 patients with CMML were included in this review. Mean age at diagnosis was 71 years (range, 47 to 81 years) with a mean time from diagnosis of 406.4 days. The majority of CMML patients had de novo (94.1%), good risk cytogenetics (58.8%) with an IPSS classification of Intermediate-1 (64.7%). Baseline mean white blood count (WBC), hemoglobin (HGB), and platelets (plts) were 7.5 × 103/μ L, 14.6 g/dL and 81.9 × 103/μ L, respectively. A larger proportion of CMML patients at baseline were plt and RBC transfusion independent. Objective response rate (ORR) was 41% [17.6% complete response (CR) and 23.5% marrowCR (mCR)]; Hematologic improvement (HI) was observed in 11.7% and stable disease in 29.4% of patients. Median survival was 391 (95% CI 239, 678) days and 2 (11.7%) patients progressed to AML. The adverse event profile was similar to observations in previous trials with myelosuppression and infectious complications. Conclusions: This retrospective review of responses in CMML patients supports previous findings of decitabine experience in this population. In this analysis an overall response rate of 41.4% was achieved. Decitabine provided anti-CMML activity with an acceptable safety profile. Disclosures: Jabbour: Eisai Inc.: Editorial and statistical support from Eisai Inc., Honoraria. Kantarjian:Novartis: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy. Ravandi:Eisai Inc.: Research Funding; Eisai Inc.: Honoraria. Borthakur:Eisai Inc.: Research Funding. Cortes:Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding.

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24-Month Analysis of the Impact of Chelation on Clinical Outcomes in a 600 Patient Registry of Lower-Risk MDS Patients

Blood ◽

10.1182/blood.v118.21.2800.2800 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2800-2800 ◽

Cited By ~ 4

Author(s):

Roger M. Lyons ◽

Billie J. Marek ◽

Surabhi Sharma ◽

Carole Paley ◽

Jason Esposito ◽

...

Keyword(s):

Clinical Outcomes ◽

Lower Risk ◽

Research Funding ◽

Chelation Therapy ◽

Iron Chelation ◽

Disease Status ◽

Cardiac Events ◽

Leukemic Transformation ◽

The Impact

Abstract Abstract 2800 Introduction: Many patients with MDS require regular transfusions. Several reviews have documented poorer clinical outcomes and overall survival (OS) in transfusion-dependent MDS patients. A US registry of 600 lower-risk MDS patients prospectively collected data on clinical outcomes in chelated and non-chelated transfused patients. This 24-month interim analysis reports on cardiac events, leukemic transformation and OS. Methods: This is a 5-year, non-interventional registry in MDS patients (aged ≥18 years) with lower-risk MDS (based on WHO, FAB and/or IPSS criteria) from 107 US centers. Patients had to have transfusional iron overload (serum ferritin ≥1000 μg/L and/or ≥20 packed red blood cell units and/or ongoing transfusion requirement of ≥6 units every 12 weeks). Follow-up was every 6 months for up to 60 months or death. Use of chelation therapy was not required. Chelated patients were those who had ever used iron chelation; a sub-analysis was done on patients with ≥6 months chelation. Assessments included demographics, disease status, MDS therapy, comorbidities, and causes of death. Differences between non-chelated and chelated patients are reported. Results: 600 patients enrolled; as of May 26, 2011, 249 continued in the registry. 351 patients discontinued due to: lost to follow-up (n=51, 8.5%); death (n=278, 46.3%); other (n=22, 3.7%). 263/600 patients received chelation therapy, of whom 191 received ≥6 months. Leukemic transformation and cardiac events were more common in non-chelated patients (Table 2). Time to leukemic transformation was significantly shorter in non-chelated versus chelated patients. A greater percentage of deaths occurred in non-chelated patients; time to death was significantly shorter in non-chelated versus chelated patients. The most frequent reasons for death were MDS/AML, cardiac, and infection. At baseline, non-chelated patients had a higher incidence of cardiac disorders than chelated patients (51.3% vs 35%). While on the registry, non-chelated patients had a higher incidence of comorbidities than did chelated patients, predominantly vascular, cardiac and endocrine. Lifetime use of MDS therapies (pre- and on-registry) was lower among non-chelated versus chelated patients (88.4% vs 94.3%). Conclusions: At the 24-month analysis, use of chelation was associated with lower AML transformation, fewer cardiac events, and better OS. The two patients groups had similar age, gender, and risk status breakdown (IPSS); however the non-chelated group had a higher prevalence of cardiac comorbidities. Ongoing follow-up for the 5-year duration of this registry will provide further data on differences in outcomes between chelated and non-chelated patients. Disclosures: Lyons: Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Telik: Research Funding; Alexion: Consultancy, Honoraria; Novartis: Research Funding. Sharma:Novartis: Employment. Paley:Novartis: Employment. Esposito:Novartis: Employment.

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Final Results From SENSOR: Switch to Nilotinib After Molecular Suboptimal Response (SoR) to Frontline Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽

10.1182/blood.v124.21.1815.1815 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1815-1815 ◽

Cited By ~ 1

Author(s):

Mitsune Tanimoto ◽

Koichi Miyamura ◽

Toshihiro Miyamoto ◽

Kazuhito Yamamoto ◽

Masafumi Taniwaki ◽

...

Keyword(s):

Primary Endpoint ◽

Research Funding ◽

Direct Sequencing ◽

Assay Method ◽

Manuscript Preparation ◽

Molecular Response ◽

Molecular Responses ◽

Mutation Status ◽

The Impact ◽

Over Time

Abstract Background: Nilotinib elicits faster, deeper molecular responses than imatinib as frontline treatment for CML-CP and is also approved as second-line treatment for patients (pts) intolerant of or resistant to imatinib.However, the optimal management of pts with SoR to frontline imatinib treatment has not been determined. Here, we present final data from the Study to Evaluate Nilotinib in CML pts with SubOptimal Response (SENSOR, NCT0104387), in which adult pts with molecular SoR to frontline imatinib switched to nilotinib. Methods: In this multicenter, open-label study, 45 pts received nilotinib 400 mg twice daily with 24 mo of follow-up. All pts had SoR per 2009 European LeukemiaNet criteria—complete cytogenetic response (CCyR) but no major molecular response (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [IS]) after ≥ 18 mo of frontline imatinib. The primary endpoint was rate of MMR at 12 mo after switch to nilotinib. BCR-ABL1IS transcript levels using ABL1as a control gene were centrally evaluated monthly (mo 1-3), then every 3 mo. Durable MMR at 24 mo was defined as MMR at both 12 and 24 mo with no intermediate loss of MMR. MR4 and MR4.5 were defined as BCR-ABL1IS ≤ 0.01% and ≤ 0.0032%, respectively. Mutation analyses by direct sequencing were performed at baseline (BL) and at end of study for all pts. Retrospective mutational analyses were performed even in pts who did not have any mutations identified at BL or at the end of study visit. Results: Pts were enrolled from Dec 2009 to Feb 2012; 39 pts completed the study and 6 discontinued. Reasons for discontinuation were adverse events (AEs; n = 3), disease progression (n = 1), and withdrawn consent (n = 2). Median dose intensity of nilotinib was 748.9 mg /day (range, 183-799 mg) for a median duration of exposure of 22.1 mo (range, 0.1-22.7 mo). The primary endpoint was met; the rate of MMR at 12 mo was 51.1% (the expected value was 40%). Median time to first MMR among pts who achieved MMR (N = 23) was 2.28 mo, and 51.1% of pts had durable MMR. The proportion of pts achieving MMR as well as deeper molecular responses (MR4, MR4.5) increased over time (Figure). Rates of MMR, MR4, and MR4.5 were 66.7%, 11.1%, and 6.7%, respectively, at 24 mo. By 24 mo, the cumulative rates of MMR, MR4, and MR4.5 were 75.6%, 13.3%, and 6.7%, respectively. Overall, BCR-ABL1 levels decreased during treatment. The median BCR-ABL1IS ratio was 0.24% (range, 0.1%-3.5%) at BL (n = 45) and 0.06% (range, ≤ 0.0032%-2.3%) at 24 mo (n = 40). The slope of BCR-ABL decline was steepest in the first 3 mo after switch to nilotinib. Univariate and multivariate analyses of factors associated with molecular responses at 24 mo will also be presented. Among 30 pts with MMR at 24 mo, 4 pts (13.3%) had BCR-ABL1 mutations at BL, and 17 pts (56.7%) had newly detected (post-BL) mutations (Table). One pt with a newly detected T315I mutation never achieved MMR, progressed to blast crisis after 5.4 mo, and died at 9.4 mo. No other pt progressed or died. The most common any-grade AEs were hyperbilirubinemia (53.3%), nasopharyngitis (46.7%), and headache (37.8%). Elevated lipase level (20.0%) and hypophosphatemia (15.6%) were the most common grade 3/4 AEs. Conclusions: Switching from imatinib to nilotinib resulted in 66.7% of pts achieving MMR at 24 mo and a cumulative incidence of MMR of 75.6% by 24 mo. Some pts achieved even deeper molecular responses. These responses were achieved regardless of BL mutation status and new mutations/splicing abnormalities detected on treatment, except for T315I. Further study is required to determine the impact of the mutations on the efficacy of nilotinib. The safety profile of nilotinib was consistent with prior studies. Figure. Molecular Responses Over Time Figure. Molecular Responses Over Time Table. MMR at 24 mo by BCR-ABL1 Mutation Status (Assay Method: Direct Sequencing) With MMRn = 30 Without MMRn = 15 BLn (%) Post-BLn (%) BLn (%) Post-BLn (%) No mutation 26 (86.7) 13 (43.3) 15 (100) 6 (40.0) Any mutation 4 (13.3) 17 (56.7) 0 9 (60.0) Insensitive T315I 0 0 0 1 E255K 1 0 0 0 Others (occurring in > 2 pts) Exon 8/9 35 base pair insertion 1 9 0 9 Exon 7 deletion 1 4 0 3 Disclosures Yamamoto: Novartis Pharma K.K.: Honoraria, Research Funding; Pfizer Inc.: Research Funding, Speakers Bureau, support with manuscript preparation, support with manuscript preparation Other; ARIAD Pharmaceuticals, Inc: Research Funding. Taniwaki:Novartis: Honoraria, Research Funding. Kimura:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Ohyashiki:Novartis Pharma K.K.: Honoraria, Research Funding, Speakers Bureau. Kawaguchi:Novartis Pharma: Honoraria. Matsumura:Novartis Pharma KK: Honoraria, Research Funding; Bristol-Myers Squibb Company: Honoraria. Hino:Novartis Pharma: Research Funding. Kondo:Novartis Pharma K.K.: Employment. Aoki:Novartis Pharma K.K.: Employment. Okada:Novartis: Employment. Yanada:Novartis: Consultancy.

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The Clinical and Biological Studies of Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v126.23.5247.5247 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5247-5247

Author(s):

Aining Sun ◽

Tongtong Zhang ◽

Suning Chen ◽

Wu Depei

Keyword(s):

Survival Analysis ◽

Myelodysplastic Syndrome ◽

Median Survival ◽

Scoring System ◽

Chromosome Abnormalities ◽

Survival Duration ◽

International Prognostic Scoring System ◽

Male And Female ◽

Median Survival Duration ◽

Who 2008

Abstract Objective: To analyse systematically the clinical and biological characteristics of 2080 myelodysplastic syndrome patients in our laboratory from 1984 to 2013 and to reveal the unique features of MDS patient in our area. Methods: 1. Conventional cytogenetics were performed to investigated the cytogenetics changes in 2080 MDS patients. All patients were classified according to the FAB criterion, in which, 1493 cases were reclassified according to the WHO (2008) criterion; and 550 patients' outcomes were evaluated according to the International Prognostic Scoring System, WHO classification-based Prognostic Scoring System (WPSS) and the revised International Prognostic Scoring System (IPSS-R). 2. We analysed the clinical, cytogenetic characteristics and survival of 2080 MDS patients by statistical methods. Results: 1. According to the FAB criterion: 1040 (50.0%) patients with RA, 135 (6.5%) patients with RARS, 691 (33.2%) patients with RAEB, 145 (7.0%) patients with RAEB-t, and 69 (3.3%) patients with CMML. The median age was 51 years old (range, 5-93 years old). The ratio of male and female was 1.54. 40.3%(839/2080) patients had clonal chromosome abnormalities, in which 277 (13.3%) patients with complexed karyotype. The rate of karyotype abnormalities was higher in RAEB than that in other subtypes. Survival analysis show that the subgroup with RA had a longer median survival duration than the subgroup with RAS, RAEB, RAEB-t, their median survival duration was 50 months, 32 months, 13months and 16 months, respectively. 2. According to the WHO (2008) criterion: 220 patients (14.7%) with RA/RN/RT/RCUD, 75 patients (5.0%) with RARS, 385 patient (25.8%) with RCMD, 14 patient (0.9%) with 5q- syndrome, 282 patients (18.9%) with RAEB-1, 306 patients (20.5%) with RAEB-2, 211 patients (14.1%) with MDS-U. The ratio of male and female was 1.51 (898/595) and the median age was 54 years old (range, 6-93 years old). In all patients, the median hemoglobin level was 70g/L (11~167 g/L), the median platelet count was 51.5×109/L (2~1045 ×109/L) and the median WBC count was 2.65×109/L (0.11~52×109/L). The rate of clonal chromosome abnormalities was 42.1% (628/1493), in which 216 (14.5%) patients with complexed karyotype. There was statistically significant difference in the rate of chromosomal abnormalities among different subtypes (P<0.01). RA/RN/RT/RCUD had a longer median survival duration than other subgroups, in order of MDS-U, RCMD, RARS, RAEB-1 and RAEB-2. 3. Among 2080 patients, 839 patients with clonal chromosome abnormalities. chromosome aberration types mainly uneven anomalies, the most common trisomies or monomer. The most common abnormity was +8. Other aberrations in frequent order was -7/del(7q), del(20q), del(5q), and so on. 4. Stastistics for survival, 550 patients' outcomes were evaluated according to the IPSS, WPSS and IPSS-R. The results show the IPSS, WPSS and IPSS-R score were significantly affected OS (P<0.001). When comparing the prognostic value of the IPSS, WPSS, and IPSS-R, using the Cox regression model, a significantly higher predictive power for OS became evident for the IPSS-R, compared with the IPSS and WPSS. Conclusion: 1. In our study, the MDS patients showed the unique clinical and biological features. We found that the characteristics of cytogenetics has significant differences from western MDS patients. The most common abnormity was +8. Other aberrations in frequent order was -7/del(7q), del(20q), del(5q), and so on. 2. IPSS-R is a powerful tool in MDS survival analysis. Disclosures No relevant conflicts of interest to declare.

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Prognosis in Primary Myelofibrosis Patients According to Cytogenetic and Molecular Testing Results

Blood ◽

10.1182/blood.v128.22.5467.5467 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5467-5467

Author(s):

Liubov Polushkina ◽

Irina Martynkevich ◽

Vasily Shuvaev ◽

Mikhail Fominykh ◽

Dzhariyat Shikhbabaeva ◽

...

Keyword(s):

Disease Progression ◽

Median Survival ◽

Risk Group ◽

Primary Myelofibrosis ◽

Molecular Testing ◽

Sufficient Information ◽

Severe Thrombocytopenia ◽

Single Mutation ◽

Blast Phase ◽

The Impact

Abstract Introduction. The characteristics of pathological clone cells in the Primary Myelofibrosis (PMF) strongly influence on the variability of the clinical course and prognosis. The main of them are type of driver mutation in JAK2, MPL or CALR genes ("clonal markers" (CM)), cytogenetic and epigenetic alterations. It is very important to provide the physicians necessary and sufficient information about the molecular profile of the disease to select the appropriate therapy for the patient. The aim of our study was to investigate mutational diversity in PMF patients from the North-West region of the Russian Federation and to estimate overall survival (OS) depending on the type of CM, cytogenetic and epigenetic features. Materials and methods. We examined 115 patients with PMF (45 male, 70 female). Median age was 59 years (range 19-82). The detection of V617F mutation of JAK2 was carried out for all the patients. JAK2(-) samples were tested for MPL gene 515 codon mutations and 9th exon mutations in the CALR gene. All patients underwent the analysis of mutations in EZH2, ASXL1 and IDH1 genes. Karyotype research was done for 47 patients with suitable bone marrow samples. Differences of mutation/karyotype occurrence in groups were assessed using the χ2 test. Survival curves were estimated by the method of Kaplan-Meier. Differences were considered as statistically significant with p-value <0.05. Results. CM were detected in 87 patients: JAK2(+) 47% (54/115), CALR(+) 23% (26/115), MPL(+) 6% (7/115) cases. No CM were found in 24% (28/115) patients, who considered as triple-negative (TN). The median survival of TN patients was significantly shorter than in the group of patients with any CM: 4 years vs 14.5 years, p=0.005. Five-year OS in TN patients was 30.6%, JAK2(+) - 83.8% and CALR(+) - 93.5% (p=0.046) (Figure 1). Median survival in JAK2(+) patients was 14.7 years, CALR(+) - 9.8 years. In MPL(+) patients with follow-up of 4 years median survival has not been reached. Patients were divided into 2 groups based on the results of cytogenetic analysis: low-risk group (LR) included 27 patients with normal karyotype (NK) and 5 patients - with del(13)(q22), del(20)(q12), add(6)(p25), del(6)(q15) single features; high risk group (HR) consisted of 15 patients with complex abnormalities and unfavorable aberrations (+8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-). Median survival in the LR group was 7.5 years, in the HR group - less than 1.5 years (p=0.025). Unfavorable karyotype frequency was distinct in groups with different CM: CALR(+) - 9.1% (1/11), JAK2(+) - 35% (7/20), TN - 54% (7/14), MPL(+) - 0% (0/2) cases but these differences were not significant (p=0.107). We detected 28 mutations of the ASXL1 gene in 26/115 patients (22.6%): 24 patients had single mutation and two patients harbored two ASXL1 mutations at once. Mutation frequency was 13% (7/54) in JAK2(+) patients, 27% (7/26) in CALR(+), 32% in TN, 29% in MPL(+) (2/7). Differences in OS depending on the ASXL1-status were statistically significant in the TN group: median survival of the ASXL1(-) patients was 3.5 years, ASXL1(+) - 1.5 years (p=0.013). Two mutations in the EZH2 gene (1.7%) were observed - each one in TN and ASXL1(+) patients. Both cases were characterized by rapid disease progression. The first patient (a 61-year-old male, complex karyotype) progressed rapidly to the blast phase from diagnosis and died after 8 months. The second patient (a 75-year-old male, NK) had severe thrombocytopenia and died from a hemorrhagic stroke 5 months from diagnosis. We also detected 8 (7%) mutations in the IDH1 gene: 5 in CALR(+), 2 in TN, 1 in JAK2(+) patients. In seven cases it was a synonymous substitution G105 and in one case it was missense mutation R132C. The patient with the R132C mutation (a 74-year-old female, CALR(+), NK) had an unfavorable disease course: progression to blast phase was observed after 9 months from diagnosis. The patient died 13 months after disease progression. Conclusion. CM and epigenetic mutations frequencies in our PMF patients is consistent with international data. Type of CM, cytogenetic aberrations and epigenetic changes can be correlated with different prognosis of PMF. The absence of any CM, unfavorable karyotype and ASXL1-status in TN patient are associated with reduced OS. The impact of ASXL1-status in patients with CM as well as EZH2 and IDH1-status on the prognosis in PMF patients requires further studies. Figure OS in different groups of PMF patients. Figure. OS in different groups of PMF patients. Disclosures Shuvaev: Novartis pharma: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Fominykh:BMS: Honoraria; Novartis Pharma: Honoraria.

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Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience

Blood ◽

10.1182/blood-2011-08-358135 ◽

2012 ◽

Vol 119 (9) ◽

pp. 1981-1987 ◽

Cited By ~ 206

Author(s):

Hagop Kantarjian ◽

Susan O'Brien ◽

Elias Jabbour ◽

Guillermo Garcia-Manero ◽

Alfonso Quintas-Cardama ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Median Survival ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Imatinib Therapy ◽

Single Institution ◽

Historical Experience ◽

Blastic Phase ◽

The Impact ◽

Over Time

Abstract A total of 1569 patients with chronic myeloid leukemia (CML) referred to our institution within 1 month of diagnosis since 1965 were reviewed: 1148 chronic phase (CP), 175 accelerated phase (AP), and 246 blastic phase (BP). The median survival was 8.9 years in CP, 4.8 years in AP, and 6 months in BP. In CP, the 8-year survival was ≤ 15% before 1983, 42%-65% from 1983-2000, and 87% since 2001. Survival was worse in older patients (P = .004), but this was less significant since 2001 (P = .07). Survival by Sokal risk was significantly different before 2001 (P < .001), but not since 2001 (P = .4). In AP, survival improved over time (P < .001); the 8-year survival in patients treated since 2001 was 75%. Survival by age was not different in years < 2001 (P = .09), but was better since 2001 in patients ≤ 70 years of age (P = .004). In BP, the median survival improved over time (P < .001), although it has been only 7 months since 2001. In summary, survival in CML has significantly improved since 2001, particularly so in CP-AML and AP-CML. Imatinib therapy minimized the impact of known prognostic factors and Sokal risk in CP-CML and accentuated the impact of age in AP- and BP-CML.

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Incidence and Risk Factors for Nontuberculous Mycobacteria Infection after Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v126.23.1917.1917 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1917-1917 ◽

Cited By ~ 2

Author(s):

Jennifer M. Beswick ◽

Elizabeth Shin ◽

Jieun Uhm ◽

Fotios V. Michelis ◽

Auro Viswabandya ◽

...

Keyword(s):

Risk Factors ◽

Median Survival ◽

Research Funding ◽

Nontuberculous Mycobacteria ◽

Fungal Infections ◽

Conditioning Regimen ◽

Significant Risk ◽

Hematopoietic Cell ◽

Survival Duration ◽

Clinically Significant

Abstract Introduction: Nontuberculous mycobacteria (NTM) are ubiquitous environmental organisms that are increasingly recognized as clinically significant pathogens in the allogenic hematopoietic cell transplanted (alloHCT) population. The incidence of NTM infection post alloHCT has increased from 0.49-1.0% in early studies to 2.8-8.7% in more recent investigations, possibly due to improvements in NTM detection, varying pre-transplant conditioning regimens and regional epidemiology of different NTM species. We investigated incidence and risk factors of NTM infection after alloHCT. Methods & Patients: Medical records for 1097 consecutive patients who underwent alloHCT at Princess Margaret Cancer Centre from 2000 to 2013 were reviewed to determine the frequency, risk factors and outcomes associated with NTM infections. Clinically significant NTM infection was differentiated from colonization according to the American Thoracic Society guidelines, and was classified as pulmonary, non-pulmonary, or disseminated. Acute and chronic graft versus host disease (aGVHD and cGVHD) were diagnosed and graded using established and NIH consensus criteria respectively. The cumulative incidence of NTM was calculated considering competing risks of death. Multivariate analysis comprised Cox proportional hazards regression, modeling NTM risk. Statistical analyses were performed using EZR software (Saitama, Japan). Results: Of 1097 patients, NTM were isolated in 45 (4.1%) and judged clinically significant in 30 (2.7%). The incidence of NTM infection by competing risk analysis was 2.8% at 5 years (95% CI, 1.9-4.0%). The median (range) time to diagnosis was 343 (19-1967) days, and in 83% of patients, was diagnosed within 2 years of alloHCT. Of the 30 clinically significant NTM infections, 28 (93.3%) were pulmonary and 2 (6.7%) were disseminated. With respect to the latter group, one patient had NTM isolated from blood, while the second case was presumed disseminated based on characteristic skin findings, but with no confirmed microbiologic diagnosis. The most common species/groups isolated were Mycobacterium avium complex (n=11, 36.7%), M. xenopi (n=5, 16.7%), and M. fortuitum (n=5, 16.7%). 22/30 patients (73.3%) were on systemic immunosuppression at the time of diagnosis, and 95.7% had concurrent infections (30.4% pulmonary, 17.3% extra-pulmonary, and 47.8% both), with fungal infections occurring most frequently (53.3%). Significant risk factors (HR 95% CI) for NTM included aGVHD grades 2-4 (3.25 [1.33-7.96] p=0.036), cGVHD (3.20 [1.06-9.68] p=0.010), age (1.05 [1.02-1.07], p <0.001), and CMV viremia (4.64 [1.90-11.37] p=0.001). 76.7% of patients with clinically significant NTM had a diagnosis of cGVHD (23/30), in comparison to 47.4% (520/1097) of patients without a diagnosis of NTM infection (p=0.003), and cGVHD severity by NIH global score correlated with NTM risk. Among all patients with cGVHD, severe cGVHD was present in 39% (9/23) of NTM patients, versus 17% (89/520) of non-NTM patients (p=0.012). Pre-alloHCT diagnosis (p=0.34), conditioning regimen (p=0.81), T-cell depletion (p=0.66), HLA matching (p=0.62), or donor type (p=0.63), did not reach statistical significance. Median survival duration after a diagnosis of clinically significant NTM was 398 (range, 20-764) days, with a survival rate of 40.8±10.8% at 2 years. Conclusion: Clinically significant NTM infection after alloHCT was relatively common in our study population. GVHD (acute and chronic), age, and CMV bacteremia were significant risk factors. Given a median survival of approximately 1 year following diagnosis, NTM infection may be of greater clinical significance than previously thought. A high index of suspicion for NTM infection in patients with pulmonary symptoms, particularly within 2 years after HCT and in the presence of cGVHD, may lead to prompt diagnosis and treatment, and potentially better outcomes. Disclosures Lipton: Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding. Kim:Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.

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