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

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.

The Clinical and Biological Studies of Myelodysplastic Syndrome

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.

Individualizing IPSS Risk Assessment in Myelodysplastic Syndromes, by Additionally Taking into Account Age, Gender and French-American-British (FAB) Classification - A Multicenter Analysis.

In Myelodysplastic Syndromes (MDS) the International Prognostic Scoring System (IPSS) is the golden standard to assess the patients risk profile. Although only three parameters were included in the score, namely the medullary blast cell count, the karyotype and the amount of cytopenias, multiple risk factors, among others age and gender, were discussed in its original publication (Greenberg et al., Blood89,6,1997:p2079–88). Their additional predictive importance was stated there, but not formally quantified. In a retrospective multicenter analysis (for sample details see below) the modulating impact of age, gender and FAB classification on the IPSS was studied and individualized score values of the IPSS for each age*gender*FAB group were estimated (see table below). While without consideration of age, gender and FAB classification the risk of a patient at the four IPSS levels is best represented by the values 0 to 3, these values vary considerably between age*gender*FAB subgroups, as e.g. an IPSS ‘low’ scoring female patient <66 years with RA/RARS would be assigned a score of −2.3, an otherwise equal male patient −0.4, indicating that especially the female patient faces a much lower risk than the average IPSS ‘low’ patient. The estimation of these scores is based on a Cox-PH model predicting survival and including significant main effects for the IPSS, age (<=66 years vs >66 years), gender and FAB classification (RA/RARS vs RAEB/RAEBT/CMML), as well as interactions between IPSS and gender, and age and FAB, expressed by the formula RR = ipss*.44 + sex*−.27+age66*.47+fab_gr*.41+(ipss:sex)*.36+(age66:fab_gr)−.60. The IPSS/gender interaction shows that the IPSS differentiates much better in women than in men, the age/FAB interaction underlines that the FAB classification has more relevance in younger as compared to older patients. Sample details: In a series of 897 primary MDS patients treated with supportive care only, median survival was 47 months and the median follow up 56 months. The median age was 68 years. According to the FAB classification the distribution and the median survival duration were as follows: RA 341 pts, 70 mo; RARS 152 pts, 77 mo; RAEB 172 pts 20 mo; CMML 148 pts, 25 mo; RAEBT 84 pts, 11 mo. According to the IPSS the distribution and the median survival duration were as follows: low 268 pts (29,9%), 86 mo; int-1 285 pts (31,8%), 55 mo; int-2 158 pts (17,6%), 23 mo; high 186 pts (20,7%), 13 mo. These results are concordant with other published data, especially the original publication of the IPSS. Conclusion: The reported table and formula are useful and convenient to substantially enhance the precision of the IPSS in predicting the risk of MDS patients. IPSS Low Int-1 Int-2 High n.a. not applicaple all patients 0.0 1.0 2.0 3.0 male,<66,RA/RARS −0.4 0.2 0.8 n.a. female,<66,RA/RARS −2.3 −0.9 0.6 n.a. male,>66,RA/RARS 1.3 1.9 2.5 n.a. female,>66,RA/RARS −0.5 0.9 2.3 n.a. male,<66,RAEB/RAEBT/CMML n.a. 1.8 2.4 3.0 female,<66,RAEB/RAEBT/CMML n.a. 0.8 2.2 3.6 male,>66,RAEB/RAEBT/CMML n.a. 2.2 2.8 3.3 female,>66,RAEB/RAEBT/CMML n.a. 1.1 2.5 4.0

The Clinical Characteristics and Therapeutic Status of Multiple Myeloma in China- a 23 Years Retrospective Analysis in One Single Center.

The clinical characteristics and treatment results of the multiple myeloma patients admitted to our hospital from January 1980 to December 2002 were retrospectively analyzed and compared in order to put forward a feasible therapeutic strategy for MM in China. Results: 1. Clinical characteristics (1) 432 cases with full follow-up statistics were analyzed. The median age was 57 years (20 to 80).The peak onset age were 50 to 60 years. The ratio of male to female was 2.35:1. (2) 81% patients had anemia(Hb<100 g/L) at diagnosis. The median proportion of tumor cells in the bone marrow was 0.38 (0.005–0.970). 72.1% with high β2-MG (>3mg/L), 60% of the patients had abnormities in X-rays. (3) M-protein peak was detected in 78.5% patients. IgG made up the majority in classification(48.1%), IgA (21.8%)and light-chain(20.5%)next to it. 144 patients were in stage IIIA(40%), and 87 cases in IIIB(24.1%)at first diagnosis. (4) The median survival duration was 27 months (1–137months). 2. Treatment results: 206 cases had integral therapeutic records in 432 patients. (1) 200 patients were administered with drugs therapy, and their 3-year and 5-year survival were 32.01% and 15.8% respectively. The OS, median survival, 3-year and 5-year survival in MP group(n=46) were 30.4%, 30 months, 21.96% and 13.2% respectively. 149 cases(72.3%)received multi-drug combined chemotherapy(CCT).The overall response was 50.3% and significant higher than that of MP group(P=0.01).While the median survival duration(30.5 months), 3-year and 5-year survival rates (35% and 16.7% respectively) were as same as MP group (P>0.05. (2). 38/200 cases (19%) were treated with interferon in combination with chemotherapy over 6 months. The overall response rates were 53.6%, and the median survival duration was 52 months, and presented an increased response(P=0.02)and a prolonged survival duration (P=0.0003) compared with the no interferon group(34.4%,27months respectively. (3)Thalidomide was administered to 29 cases(14.5%), including 5 who took it alone(2.5%). The overall response rates were 50.3%. (4) 6 patients received hematopoietic stem cell transplantation. 5 patients with autologous peripheral blood stem cell transplantation were alive averagely in 73±12.5 months by the end of the follow-up. Conclusion: 1) MM patients in China had poor prognostic characteristics except of younger age compared with the westerns, especially most patients were diagnosed at III phase with significant lower survival. 2) CCT yielded higher response rates but no longer duration of survival benefit than MP when used as treatment for MM. INF-a and Thalidomide could benefit MM by combination with chemotherapy. Among patients who are <60 years old with good performance, HSC could prolong survival duration.

Paclitaxel by 96-hour continuous infusion in combination with cisplatin: a phase I trial in patients with advanced lung cancer.

PURPOSE To determine the maximum-tolerated dose (MTD) of paclitaxel administered by 96-hour continuous infusion in combination with cisplatin, to determine if the addition of granulocyte colony-stimulating factor (G-CSF) permits significant paclitaxel dose escalation, and to assess the toxicity and preliminary activity of this combination in patients with advanced lung cancer. PATIENTS AND METHODS Fifty patients with untreated lung cancer were enrolled: 42 had advanced non-small-cell lung cancer (NSCLC) and eight had extensive-stage small-cell lung cancer (SCLC). Patients received paclitaxel doses of 100 to 180 mg/m2/96 hours and cisplatin doses of 60 to 80 mg/m2 as a single 30-minute bolus injection at the end of the paclitaxel infusion. RESULTS Two of six patients experienced dose-limiting neutropenia at a dose of paclitaxel 140 mg/m2/96 hours and cisplatin 80 mg/m2. With G-CSF support, one of three patients experienced both dose-limiting mucositis and fatal neutropenic sepsis at a dose of paclitaxel 180 mg/m2/96 hours and cisplatin 80 mg/m2. Significant peripheral neuropathy developed in five patients and occurred after six or more cycles of therapy. Thirty-three of 42 patients with NSCLC had measurable disease; the objective response rate was 55%, with two complete responses and 16 partial responses. For all 42 patients with NSCLC, the median time to progression and median survival duration were 5 months and 10 months, respectively. The actuarial 1-year survival rate was 41%. Of eight SCLC patients, four responded to therapy, and the median survival duration for all SCLC patients was 11 months. CONCLUSION The MTD without G-CSF is paclitaxel 120 mg/m2/96 hours and cisplatin 80 mg/m2, and the MTD with G-CSF is paclitaxel 160 mg/m2/96 hours and cisplatin 80 mg/m2. Infusional paclitaxel with cisplatin is well tolerated and active in patients with advanced NSCLC.

Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study.

PURPOSE The present intergroup phase III randomized study compared combined chemotherapy (CT) plus radiotherapy (RT) treatment versus RT only in patients with locally advanced esophageal cancer. MATERIALS AND METHODS Two courses of chemotherapy during 50 Gy RT followed by additional two courses of the same CT, versus 64 Gy RT alone were investigated. CT consisted of cisplatin 75 mg/m2 on day 1 [corrected] and fluorouracil (5FU) 1,000 mg/m2/d on days 1 to 4 every 4 weeks with RT and every 3 weeks post-RT. The main objective of the study was to compare overall survival between the two randomized treatment groups. Patients were stratified by tumor size, histology, and degree of weight loss. RESULTS Sixty-two assessable patients were randomized to receive RT alone, and 61 to the combined arm. Patients characteristics were as follows: squamous cell cancer, 90% versus 85%; weight loss greater than 10 lb, 61% versus 69%; and tumor size, > or = 5 cm, 82% versus 80% on the RT and CT-RT arms, respectively. Systemic side effects, which consisted of nausea, vomiting, and renal and myelosuppression, occurred more frequently on the combined arm, while local side effects were similar in both groups. With a minimum follow-up time of 5 years for all patients, the median survival duration was 14.1 months and the 5-year survival rate was 27% in the combined treatment group, while the median survival duration was 9.3 months with no patients alive at 5 years in the RT-alone group (P < .0001). Additional patients (69) were treated with the same combined therapy and were analyzed. The results of the last group confirmed all of the results obtained with combined CT-RT in the randomized trial, with a median survival duration of 17.2 months and 3-year survival rate of 30%. CONCLUSION We conclude that cisplatin and 5FU infusion given during and post-RT of 50 Gy is statistically superior to standard 64-Gy RT alone in patients with locally advanced esophageal cancer.

Neoadjuvant therapy of high-risk gastric cancer: a phase II trial of preoperative FAMTX and postoperative intraperitoneal fluorouracil-cisplatin plus intravenous fluorouracil.

PURPOSE AND METHODS We identified patients with gastric cancer at high risk for recurrence before therapy using endoscopic ultrasonography (EUS). Neoadjuvant therapy using the fluorouracil, doxorubicin, and metrotrexate (FAMTX) regimen was given for three courses before planned laparotomy with the intention to perform curative resection. Postoperatively, intraperitoneal (IP) cisplatin and fluorouracil (FU) and intravenous (i.v.) FU were administered to patients undergoing resection. RESULTS Fifty-six assessable patients were treated. Preoperative FAMTX therapy was tolerable, with the major toxicity being neutropenic fever. One treatment-related death was seen. Eighty-nine percent of patients underwent surgical exploration and 61% had potentially curative resections. There were two postoperative deaths. Comparison of pathologic tumor (pT) stage with EUS-predicted tumor stage showed apparent downstaging in 51% of patients. Postoperative IP chemotherapy was delivered to 75% of eligible patients. Toxicity was acceptable. There was no increase in operative morbidity or mortality compared with concurrent nonstudy patients undergoing a similar operative procedure and not receiving preoperative therapy. With a median follow-up time of 29 months, the median survival duration was 15.3 months. For patients who underwent potentially curative resections, the median survival duration was 31 months. Peritoneal failure was seen in 16% of patients. CONCLUSION Chemotherapy with the FAMTX regimen is tolerable in patients with locally advanced gastric cancer, without an increase in operative morbidity or mortality. IP therapy can be successfully delivered to most resected patients. The intraabdominal failure pattern appears to be decreased compared with expected. This approach is an appropriate investigational arm to pursue in future studies.

Randomized trial of interferon maintenance in multiple myeloma: a study of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE To determine whether interferon maintenance therapy improves overall survival and response duration in patients with multiple myeloma who have responded to induction therapy with melphalan and prednisone. PATIENTS AND METHODS In a multicenter trial, patients with symptomatic clinical stage I and stage II and III multiple myeloma were registered at diagnosis and those who responded to melphalan-prednisone (MP) were randomized either to receive interferon (2 mU/m2) subcutaneously three times per week or no maintenance. MP was discontinued in both groups once a stable response plateau of the monoclonal protein was reached. Interferon was continued until relapse, and then was restarted on subsequent response to MP. Interferon toxicity was recorded using a self-report diary. Survival and response duration were calculated using life-table methods, and were adjusted in the analysis for imbalances in baseline prognostic factors. RESULTS Four hundred two patients were registered and 176 responders were randomized (85 to interferon and 91 to control). At a median follow-up time of 43 months, the median survival duration was 43 months for interferon and 35 months for control (P = .16), but when adjusted for chance imbalances in baseline prognostic factors (mainly performance status), the median survival duration was 44 months and 33 months for interferon and control, respectively (P = .049). Progression-free survival from randomization to first relapse also favored interferon (unadjusted P < .002; adjusted P < .003). Interferon toxicity caused 58% of patients to reduce their dose, of which 84% were able to return to the initial dose; 14% had to discontinue interferon treatment. CONCLUSION Interferon maintenance therapy improves progression-free and overall survival of patients with multiple myeloma who respond to melphalan and prednisone. Toxicity is substantial and must be weighed by patients against the potential benefits in response duration and survival.

Simple prognostic model to predict survival in patients with undifferentiated carcinoma of unknown primary site.

PURPOSE We performed this study to identify prognostic factors in a subgroup of patients with carcinoma of unknown primary site treated with cisplatin combination chemotherapy. PATIENTS AND METHODS Seventy-nine patients with poorly differentiated adenocarcinoma or undifferentiated carcinoma of unknown primary site were treated on two consecutive phase II chemotherapy protocols. The first protocol consisted of treatment with 3-week courses of cisplatin, etoposide, and bleomycin (BEP). In the second protocol, cisplatin was administered weekly combined with oral administration of etoposide (DDP/VP). To identify prognostic factors, univariate and multivariate analyses were conducted. RESULTS In the univariate analysis, performance status, histology, liver or bone metastases, and serum levels of alkaline phosphatase and AST were significant variables to predict survival. In the multivariate analysis, performance status and alkaline phosphatase were the most important prognostic factors. CONCLUSION Good-prognosis patients had a performance score of 0 (World Health Organization [WHO]) and an alkaline phosphatase serum level less than 1.25 times the upper limit of normal (N). These patients had a median survival duration greater than 4 years. Intermediate-prognosis patients were characterized by either a WHO performance status < or = 1 or an alkaline phosphatase level > or = 1.25 N. These patients had a median survival duration of 10 months and a 4-year survival rate of only 15%. The poor-prognosis group had both a WHO performance status > or = 1 and an alkaline phosphatase level > or = 1.25 N. These patients had a median survival duration of only 4 months and none survived beyond 14 months. Treatment strategies for these three groups are discussed. It is suggested that this prognostic model be validated in other patients series.