Predictors of overall survival among patients treated with sirolimus/tacrolimus vs methotrexate/tacrolimus for GvHD prevention.

Sirolimus (SIR)/tacrolimus (TAC) is an alternative to methotrexate (MTX)/TAC. However, rational selection among these GvHD prophylaxis approaches to optimize survival of individual patients is not possible based on current evidence. We compared SIR/TAC (n=293) to MTX/TAC (n=414). The primary objective was to identify unique predictors of overall survival (OS). Secondary objective was to compare acute and chronic GvHD, relapse, non-relapse mortality, thrombotic microangiopathy (TMA), hepatic veno-occlusive disease (VOD/SOS), and acute kidney injury. Day 100 grades II-IV acute GvHD was significantly reduced in SIR/TAC vs MTX/TAC group (63 vs 73%, P=0.02). An interaction between GvHD prophylaxis groups and comorbidity index (hematopoietic cell transplantation (HCT)-CI) significantly impacted OS. Patients with HCT-CI⩾4 had significantly worse OS with MTX/TAC (HR 1.86, 95% CI 1.14-3.04, P=0.01) while no such effect was seen for SIR/TAC (HR 0.78, 95% CI 0.48-1.26, P=0.31). Other end points did not significantly differ between groups except TMA and VOD/SOS were increased in the SIR/TAC group, but excess death from these complications was not observed. We conclude, GvHD prophylaxis approach of SIR/TAC is associated with reduced grades II-IV acute GvHD, comparable toxicity profile to MTX/TAC, and improved OS among patients with HCT-CI⩾4.

Pharmacokinetically-targeted BU and fludarabine as conditioning before allogeneic hematopoietic cell transplantation for adults with ALL in first remission.

Allogeneic hematopoietic cell transplantation offers improved survival in patients with ALL, but with regimens containing TBI, the nonrelapse mortality is 20-40%. Efforts to lessen transplant toxicities by reducing conditioning regimen intensity have led to increased relapse risk. Therefore, there is a need for less toxic regimens that maintain an anti-leukemia effect. We report here a retrospective review of 65 patients with ALL in first remission receiving grafts from allogeneic donors after fludarabine 40 mg/m(2)/day for 4 days and i.v. BU targeted to a median daily area under the concentration-time curve below 6000 µmoles min/L. At 2 years after transplantation, OS was 65% (95% confidence interval (CI): 52-77%), relapse-free survival was 61% (95% CI: 48-73%), cumulative incidence of relapse was 26% (95% CI: 17-39%) and cumulative incidence of nonrelapse mortality was 14% (95% CI: 8-26%). Age over 35 years, Ph chromosome positivity and minimal residual disease at transplant did not adversely affect outcomes. Pharmacokinetically targeted BU and fludarabine can provide intensive pre-transplant conditioning for adults with ALL in first remission, with promising relapse-free and OS rates.

A novel clofarabine bridge strategy facilitates allogeneic transplantation in patients with relapsed/refractory leukemia and high-risk myelodysplastic syndromes.

Patients with relapsed/refractory leukemias or advanced myelodysplastic syndrome (MDS) fare poorly following allogeneic hematopoietic cell transplant (HCT). We report prospective phase II study results of 29 patients given clofarabine 30 mg/m(2)/day i.v. × 5 days followed immediately by HCT conditioning while at the cytopenic nadir. A total of 15/29 patients (52%) were cytoreduced according to pre-defined criteria (cellularity <20% and blasts <10%). Marrow cellularity (P<0.0001) and blast% (P=0.03) were reduced. Toxicities were acceptable, with transient hyperbilirubinemia (48%) and gr3-4 infections (10%). In all, 28/29 proceeded to transplant; 27 received ATG or alemtuzumab. Post HCT, 180 day non-relapse mortality (NRM) was 7% (95% confidence interval (CI): 1-21), relapse was 29% (95% CI: 13-46) and OS was 71% (95% CI: 51-85), comparing favorably to published data for high-risk patients. Two-year graft vs host disease incidence was 40% (95% CI: 21-58) and 2 year OS was 31% (95% CI: 14-48). Disease at the nadir correlated with inferior OS after HCT (HR=1.22 for each 10% marrow blasts, 95% CI: 1.02-1.46). For AML/MDS patients, there was a suggestion that successful cytoreduction increased PFS (330 vs 171 days, P=0.3) and OS (375 vs 195 days, P=0.31). Clofarabine used as a bridge to HCT reduces disease burden, is well tolerated, and permits high-risk patients to undergo HCT with acceptable NRM. Late relapses are common; thus, additional strategies should be pursued. NCT-00724009.

Race/ethnicity affects the probability of finding an HLA-A, -B, -C and -DRB1 allele-matched unrelated donor and likelihood of subsequent transplant utilization.

Factors relevant to finding a suitable unrelated donor and barriers to effective transplant utilization are incompletely understood. Among a consecutive series of unrelated searches (n=531), an 8/8 HLA-A, -B, -C and -DRB1-matched unrelated donor was available for 289 (54%) patients, 7/8 for 159 (30%) and no donor for 83 (16%). Patients of Caucasian race (P<0.0001) were more likely to find a donor. Younger age (P=0.01), Caucasian race (P=0.03), lower CIBMTR (Center for International Blood and Marrow Transplantation Research) risk (P=0.005), and 8/8 HLA matching (P=0.005) were associated with higher odds of reaching hematopoietic cell transplantation (HCT). In a univariate analysis of OS, finding a donor was associated with hazard ratio (HR) of 0.85 (95% CI 0.63-1.2), P=0.31. Karnofsky performance status (KPS) accounted for interaction between having a donor and survival. Patients with KPS 90-100 and a donor had significantly reduced hazard for death (HR 0.59, 95% CI 0.38-0.90, P=0.02). These data provide estimates of the probability to find an unrelated donor in the era of high-resolution HLA typing, and identify potentially modifiable barriers to reaching HCT. Further efforts are needed to enhance effective donor identification and transplant utilization, particularly in non-Caucasian ethnic groups.

Feasibility of clofarabine cytoreduction before allogeneic transplant conditioning for refractory AML.

To control disease before allogeneic hematopoietic cell transplantation (HCT) for relapsed/refractory AML, we used clofarabine cytoreduction. Seventeen patients received clofarabine 30-40 mg/m(2) i.v. daily for 5 days with plans to initiate conditioning during the nadir, 14 days later. Bone marrow biopsy 12 days after clofarabine showed effective cytoreduction (that is,<20% cellularity with <10% blasts) in 10 of 17 patients (59%). Ineffective cytoreduction correlated with lower PFS (3.8 vs 6.4 months; HR=2.7, 95% CI=1.10-14.29, P=0.035) and OS (5.1 vs 16.6 months; HR=2.5, 95% CI=0.98-12.17, P=0.053). Significant toxicities before HCT, attributable to clofarabine, were grade 1-2 hyperbilirubinemia (18%); grade 1-2 (59%) or grade 3-4 (18%) transaminitis; and grade 1-2 (18%) creatinine elevation. Sixteen patients proceeded to HCT infusion 22 days (median) after initiation of clofarabine. Day 100 and 2-year transplant-related mortality were 6 and 36%. Nine patients relapsed. One year PFS and OS were 25 and 38%, respectively. Two patients are alive in remission at 18 and 52 months. Clofarabine cytoreduction followed by immediate HCT is feasible with acceptable toxicity and TRM. Outcomes for this cohort of patients with refractory AML remain poor and we are studying this approach in a prospective manner.

Diet and blood nutrient correlations with ischemic heart, hypertensive heart, and stroke mortality in China.

Though major differences exist in subcategory mortality levels, cardiovascular disease remains a leading cause of death among both Asian Chinese and Westerners. This paper examines the possible relationship between cardiovascular mortality and biochemical, diet and lifestyle factors based on two surveys in China. Statistically significant associations indicate five variables negatively correlated: molybdenum, oleic acid, liquor consumption (males), legumes, and age at first pregnancy with ischemic heart disease; molybdenum, oleic acid (females) and age at first pregnancy with hypertensive heart disease; and legumes and age at first pregnancy with stroke. Five variables were positively correlated: triglycerides and herpes antibodies with ischemic heart disease; salt and phosphorus (females) with hypertensive heart disease; and only albumin (males) with stroke. Some findings confirm those observed in the West (salt, triglycerides, herpes, legumes, oleic acid, and liquor), but molybdenum and age at first pregnancy have not been emphasized previously. Still others significant in the West have not been observed here, such as cholesterol and smoking.

The National Mortality Survey of China: implications for cancer control and prevention.

Findings of the People's Republic of China (PRC) Cancer Mortality Survey were reviewed for historic background, implications for etiologic-interventive clues, and transitional experience among Chinese migrants. Rates, calculated using the 10% sample census, were all age-adjusted. Cancer comprised about 10% of total deaths, with stomach cancer as the top killer. Minority rates, adjusted to the 1964 China population, ranged from 26.7 (Miao) to 127.5 (Kazak). Multiple high-risk areas were noted for cancer of the esophagus and other sites, and urban rates exceeded those for rural areas. The transitional experience among U.S. Chinese was examined at geographic-generational levels. Among U.S. Chinese, downward trends were found for cancers known as to be high-risk for Asian-Chinese (nasopharynx, esophagus, liver, uterus, and perhaps stomach). The reverse was true for low-risk sites (colon, lung leukemia, and female breast). Lung and colorectal cancers among females were the only major sites for which foreign-born Chinese had higher rates than U.S.-born.

Patterns of site-specific displacement in cancer mortality among migrants: the Chinese in the United States.

Taking advantage of the information gathered for the 1975 National Mortality Survey in China, this paper compares the levels of cancer mortality among foreign-born and United States-born Chinese around 1970 with those of the communities of origin of the majority of Chinese migrants to the US. Age-adjusted rates indicate two distinctive site-specific patterns among US Chinese: a downward trend for cancers of high risk among Guangdong and Hong Kong Chinese (nasopharynx, esophagus, liver, uterus, and perhaps stomach) and an upward trend for those sites of low risk among Chinese in Guangdong and Hong Kong (colon, lung, leukemia, and female breast). Further field studies are needed with emphasis on the birthplace of migrants and environmental changes in host countries.

American white Protestant clergy as a low-risk population for mortality research.

An examination of 28,134 clergymen in five predominantly white Protestant denominations, 1950--60, showed a more favorable mortality for these clergymen for all causes of deaths, total cancers, and cardiovascular-renal diseases compared with the mortality for U.S. white males, total U.S. males with work experience, and total U.S. white clergymen. The standardized mortality ratios for cancer of the lung and non-motor-vehicle accidents were particularly depressed. However, those for diabetes, leukemia, and cancers of the prostate gland and, to a lesser extent, lymphoma and cancers of the intestine and pancreas were not significantly different from 100. The findings were interpreted in the social class contest, with emphasis on cross-national investigations and critical assessment of clerical statistics.

Cancer mortality among Chinese in the United States.

A total of 1,824 cancer deaths among the Chinese in California, Hawaii, and New York City, 1968--72, was examined against 96,635 Taiwanese dying from cancer for the corresponding years. Emphasis was placed on patterns of displacement by nativity between 1960 and 1970. Much of the transitional experiences were similar to those reported for Japanese and European migrants to the United States, such as the rise of cancers of the lung and colon in males. However, the upward displacement of cancers of the female breast and corpus uteri failed to occur among the Chinese. In general, the pattern of transition for Idai and Erdai was less apparent, compared with the mortality experiences of Issei and Nisei. Perhaps longer periods are needed to achieve full displacement of cancer risks in the advanced ages.

Cancer mortality risk among Japanese in the United States.

Earlier findings on cancer mortality experiences of Nisei and Issei were updated to around 1970. Compared with U.S. whites, Japanese in Japan had a high standardized mortality ratio (SMR) for cancers of the esophagus, stomach, biliary passages, and cervix, whereas they had low ratios for cancers of most other sites. Among U.S. Japanese, the direction and magnitude of the SMR transition varied by site, but generally the SMR moderated toward that of U.S. whites. Specifically, mortality from stomach cancer was elevated through the ratio has been reduced. In addition, mortality from cancers of the liver and biliary passages remained high. In contrast to a sharp decline in the SMR for esophageal cancer, the SMR for cancer of the colon and lymphomas rose closer to the levels for whites. The SMR for cancers of the ovary and prostate gland represented a rise above that of Japan. A higher Issei than Nisei SMR was observed for most cancer sites, regardless of the risk level in Japan. The reverse was true for cancers of the liver and nasopharynx among males, cancers of the breast and ovary among females, and lymphosarcoma and leukemia among both sexes.

A case-control study of large bowel cancer in Japan.

This investigation of diet and other environmental factors reports on 588 patients with colorectal cancer and 1,176 hospitalized controls in three prefectures of Japan. Weak (not statistically significant) positive effects were found for social class and urbanization. The significant association of colorectal cancer with consumption of beef, string beans, or starches previously described for Hawaiian Japanese were not reproduced here. An association with hakusal (cabbage) agreed with other reports on a negative association with cruciferous vegetables. An analysis of the subset of cases in the low rectum yielded results similar to those for the total series. The failure to uncover important food effects in Japan is attributed to the difficulty of detecting case-control differences in areas with homogeneous diet practices. Further epidemiologic research aided by leads from ongoing work with animals may provide ideas for more sharply defined questions, should stress new approaches for more accurate diet histories, and should continue to emphasize tumor localization.

Epidemiologic pathology of gastric ulcer and gastric carcinoma among Japanese in Hawaii.

This case-control study of Hawaiian Japanese indicated that gastric ulcer in the proximal portion of the pyloric antrum has features similar to those of gastric cancer. Such ulcers occurred at sites most frequently and most severely affected by intestinal metaplasia, although metaplasia tended to be more extensive with cancer than with ulcer. Metaplastic mucosa was more vulnerable to the action of pepsin and acid than was normal mucosa. The risk of ulceration would rise when a sufficiently lagrge area of the antrum was intestinalized and when the corpus continued to produce significant quantities of these substances. This study showed a strong association between salt intake, ulcer, and metaplasia. Significant but less dramatic associations were demonstrated between metaplasia and the use of traditional Japanese foods and smoking. The question was raised as to whether salt promotes ulceration or whether it potentiates the action of a mutagen that causes intestinal metaplasia.

Stomach cancer in Japan.

A study of 783 patients with stomach cancer and 1,566 hospital controls in Hiroshima and Miyagi prefectures of Japan showed that farmers, representing mostly the lowest socioeconomic class, had higher risk of developing stomach cancer. The usual inverse gradient in risk by social class was in the urban population of Miyagi, but not Hiroshima, prefecture. The study in Japan did not reproduce the association of stomach cancer with consumption of salted/dried fish and salt-pickled vegetables described for the Hawaiian Japanese. Salted/dried fish and pickled vegetables were more widely used by farmers than by nonfarmers in Japan or by Japanese migrants to Hawaii. The ability to detect associations for these typical Japanese foods in Hawaii stemmed from the fact that these reduced levels of use were more completely expressed by the Hawaiian-Japanese controls than by patients. The lower risk of developing stomach cancer for lettuce and celery users agreed with the Hawaiian-Japanese findings, and the combined results supported conjectures on possible protective food effects. Lettuce, in particular, warranted attention from this viewpoint, since similar findings have been consistently reported.