Incidence Of Chronic Myeloid Leukemia Research Articles

Higher Incidence of Chronic Myeloid Leukemia (CML) Among Blacks Compared to Whites in the Post-Imatinib Period (2002–2009) Corresponds with Worse Survival Observed within the Surveillance, Epidemiology and End Results 18 Registries

AbstractAbstract 3773 Background:Age at diagnosis of CML varies by race in the United States with median occurring around ages 54 and 63 among Black and White patients, respectively. The treatment paradigm shifted when Imatinib was approved in 2001 for treatment of CML. More recently, second generation tyrosine kinase inhibitors (TKI) have also been used for treatment of CML. Differences in outcomes by race have been previously reported prior to the TKI treatment period. We aimed to assess whether the earlier age at diagnosis resulted in differential trends in age-adjusted incidence rates and survival outcomes by race in the post-Imatinib treatment period. Methods:Data from the Surveillance, Epidemiology, and End Results (SEER) 18 Registries were extracted for diagnoses between 2002 and 2009 based on the assumption that cases diagnosed after 2002 would be treated with TKI's. CML was defined according to the International Classification of Diseases for Oncology 3rd edition code 9863 (CML-NOS) and 9875 (CML-Philadelphia Chromosome Positive). Cases diagnosed by autopsy or death certificate only were excluded. Incidence rates are expressed per 100,000 person-years and age-adjusted to the 2000 US Standard Population. Black/White incidence rate ratios (IRRBW) are shown with corresponding 95% confidence intervals (CI). Kaplan-Meier estimates of CML-specific survival (CPS) and overall survival (OS) were estimated at 5-years post-diagnosis with the event being time to CML-specific death or any death, respectively. Stratified Cox proportional hazards models were constructed to assess the impact of age and race on the risk of death expressed as a hazard ratio (HR). Results:Since 2002, 6,632 patients diagnosed with CML were reported to the SEER 18 registries including 5,829 White patients (87.9%) and 803 Black patients (12.1%) with 57% being male. The age-adjusted incidence rate for Blacks was 1.18 (95% CI, 1.10–1.27) per 100,000 and 1.12 (95% CI, 1.09–1.27) per 100,000 for Whites. The corresponding IRRBW was 1.06 (95% CI, 0.98– 1.14). When considering 20-year age-groups, Blacks had higher incidence rates in the 20–39 and 40–59 age groups; IRRBW of 1.26 (95% CI, 1.06–1.49; p=0.0073) and 1.23 (95% CI, 1.09–1.39; p=0.0007), respectively. No statistically significant differences in IRRBW were seen within the 0–19, 60–79 and 80+ age-groupings although Whites have higher non-significant incidence rates in the latter 2 age-groups. Differences in IRRBW prompted an assessment of survival to determine if the excess incidence observed in the younger age groups corresponded with a worse survival. CPS at 5-years was 85.5% (95% CI, 84.3–86.6). In univariate analysis, age was an important predictor of outcome (p<0.0001) with patients diagnosed after age 80 having the worse outcomes (OS: 58.3%), followed by patients diagnosed between 60 and 79 years (OS 84.7%), 0–19 years (OS: 87.1%), 40–59 years (OS: 90.2%), and 20–39 years (OS: 92.6%). When considering all age-groups, race was not a significant predictor of death (HR 0.91; 95% CI, 0.72–1.15). However, in a stratified analysis with 20-year age groups, Blacks had an increased risk of death as compared to Whites (Figure 1) in the 20–39 age group (HR: 2.94; 95% CI, 1.72–5.26; p<0.0001) and the 40–59 age group (HR: 1.67; 95% CI, 1.22–2.27; p=0.0069) while no differences were seen within the 0–19, 60–79 and 80+ age groups. Conclusions from OS models were similar to that of the CPS models. Conclusions:Through this analysis of population-based cancer registry data collected in the US between 2002 and 2009, we show that Blacks have a younger age at diagnosis with higher incidence rates observed in the 20–39 and 40–59 age-groups as compared to Whites. Both CPS and OS outcomes differed by race and age. Similar to the differences observed with the incidence rates, survival was worse in Blacks diagnosed within the 20–39 and 40–59 age-groups as compared to Whites. Although outcomes have globally improved in patients with CML since the advent of tyrosine kinase inhibitors, the persistence of incidence heterogeneity and poorer survival among Blacks warrants further attention. Access to care may be a possible reason for the differences observed but further studies are warranted to rule out biological differences which may be causing an earlier age at onset and poorer survival. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Chronic myeloid leukemia incidence trends among Caucasians in the United States.

e17005 Background: Information on trend of Chronic Myeloid Leukemia (CML) incidence rate is scant. This study was conducted to evaluate the time trends of CML incidence rates among Caucasians in the U.S. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) Program to extract annual age-adjusted incidence rates of CML from 1973-2008 for &lt;60yr and &gt;60yr age groups classified by gender. Trends of incidence rates were evaluated using the National Cancer Institute’s Joinpoint Regression Program (v 3.5.2). The maximum number of joinpoints used was 4. The annual percentage change (APC %) for the final selected joinpoint model for each cohort is shown in the table. Results: The annual age-adjusted CML incidence rates for 1973 vs. 2008 were 0.72/0.67, 5.67/4.47, 0.93/0.67, and 10.5/8.5 per 100,000 population for the 4 cohorts: women (&lt;60yr, &gt;60yr) and men (&lt;60yr, &gt;60yr), respectively. Among Caucasian women (&gt;60yr), the incidence rate decreased significantly from 5.58/100,000 in 2001 to 4.47/100,000 in 2008 (APC= -3.08, CI -5.8 to -0.3, p = 0.004). The incidence trend from 1973-2001 was stable for this cohort (APC=0.1, CI -0.3 to 0.5). The incidence trends among women &lt;60yr, men &lt;60yr, and men &gt;60yr were stable from 1973-2008. Conclusions: The annual age-adjusted incidence rates of chronic myeloid leukemia among older (&gt;60 year) Caucasian women has declined sharply from 2001-2008. The rate change is unexplained. It may help generate hypotheses regarding risk factors for CML. [Table: see text]

Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy

The annual incidence of chronic myeloid leukemia (CML) in the United States is approximately 4800 cases. With the success of tyrosine kinase inhibitor (TKI) therapy, the all-cause annual mortality rate was reduced to 2%. Therefore, the prevalence of CML is increasing over time. Estimating the CML prevalence and plateau prevalence is important in the implementation of health care strategies and future therapeutic trials. The objective of this report was to estimate the increasing prevalence and plateau prevalence of CML in future years. The prevalence of CML was estimated based on several parameters: the annual mortality rate on TKI therapy compared with a age-matched, normal population; the incidence of CML; the anticipated population growth in the United States; and aging of the population. On the basis of these calculations, the mortality ratio of patients with CML compared with an age-matched normal population was approximately 1.53. The estimated prevalence of CML is approximately 70,000 in 2010, 112,000 in 2020, 144,000 in 2030, 167,000 in 2040, and 181,000 in 2050, when it will reach a near plateau prevalence. The current results indicated that the prevalence of CML will continue to increase to reach a near plateau prevalence 35 times the annual incidence. These estimates should be considered in health care policies and in the design of future studies in CML.

Changing trends of chronic myeloid leukemia in greater Mumbai, India over a period of 30 years

Background:Little is known about burden of chronic myeloid leukemia (CML) in India. There is a recent interest to observe incidence and mortality because of advent of new diagnostic and treatment policies for CML.Materials and Methods:We extracted data from the oldest population-based cancer registry of Mumbai for 30 years period from 1976−2005 to observe incidence and mortality rates of CML. We classified the data into four age groups 0–14, 15–29, 30–54 and 55–74 to observe incidence rates in the respective age groups.Results:The age specific rates were highest for the age group of 55–74 years. No significant change in trends of CML was observed for 30 years period. However, there was a significant reduction in incidence rate for recent 15-years period (Estimated average annual percentage change=-3.9). No significant reduction in mortality rate was observed till 2005.Conclusion:The study demonstrates that age-specific rates for CML are highest in age group of 55-74 years, although they are lower compared to western populations. Significant reduction in incidence of CML in recent periods might be because of reduced misclassification of leukemias. The data of CML has to be observed for another decade to witness reduction in mortality because of changes in treatment management.

BCR‐ABL positive cells and chronic myeloid leukemia in immune suppressed organ transplant recipients

The constitutively activated tyrosine kinase activity of the p210(bcr-abl) fusion protein, generated by a t(9;22)(q34;q11) chromosomal translocation, is pathogenetically associated with chronic myeloid leukemia (CML). However, mechanisms contributing to the expansion of a BCR-ABL positive clone are largely obscure. In the presence of an impaired immune surveillance, cells carrying any of these alterations may become phenotypically relevant. Therefore, immunosuppressed solid organ recipients represent an optimal population to investigate the frequency of mRNA products of this translocation. Blood leukocytes were studied in 201 individuals (100 organ recipients and 101 control individuals) for the presence of BCR-ABL transcripts by a nested-reverse transcriptase-polymerase chain reaction assay, routinely used in our institution. In 5/100 immunosuppressed patients, at least one out of two RT-PCR products was bcr-abl positive while all controls were negative. These findings were extended by four CML cases of organ transplant recipients (three renal and one liver transplants). Three of these cases developed CML in a total of 2088 transplantations in 9 yr, suggesting a higher incidence of CML in these patients.

Obesity, Weight Gain, and Risk of Chronic Myeloid Leukemia

To date, little is known about the risk factors for the development of chronic myeloid leukemia (CML). Obesity, measured as body mass index, has been identified as a possible risk factor for several solid tumors as well as some adult hematopoietic malignancies. This case-control study (N = 253 cases and 270 controls), conducted at the University of Texas M. D. Anderson Cancer Center, investigated the role of obesity and adulthood weight gain in CML risk. Cases and controls were similar with respect to smoking, alcohol consumption, and occupational solvent and ionizing radiation exposure. Cases were significantly more likely to have a history of occupational exposure to agricultural chemicals (11% cases versus 3% controls, P = 0.001). Cases were more likely to be obese during adulthood compared with controls at age 25 [odds ratios (OR) = 4.29; 95% confidence intervals (95% CI), 1.63-11.3], at age 40 (OR = 5.12; 95% CI, 1.92-13.6), and at diagnosis (OR = 3.09; 95% CI, 1.56-6.13). Obesity at all ages was found to be an independent risk factor, with a significant dose-response effect. Among participants > or =45 years, cases gained significantly more weight each year between ages 25 and 40 compared with controls (0.78 versus 0.44 kg/y, P < 0.001) with the association strongest among those who gained >1 kg/y between 25 and 40 years of age (OR, 3.63; 95% CI, 1.46-9.04). Our results suggest that obesity and adulthood weight gain play important roles in CML risk. Several plausible biological mechanisms have been proposed and warrant further investigation. In the future, cancer prevention interventions aimed at reducing the incidence of CML could be developed.

Targeted treatment of chronic myeloid leukemia: role of imatinib.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by clonal expansion of pleuripotent hematopoetic stem cells. The incidence of CML is 1 to 2 cases per 100,000 people per year; in the Western Hemisphere, CML accounts for 15% of leukemias in adults. Discovery of the specific karyotypic abnormality of the Philadelphia (Ph) chromosome in the pathogenesis of CML has led to a better understanding of the disease and hence to an advancement of targeted therapeutics. Availability of imatinib as an accepted targeted therapy in newly diagnosed patients has changed the treatment paradigm in CML. The majority of CML patients in chronic phase achieve excellent and durable responses with standard-dose imatinib. Mechanisms of primary and secondary resistance to imatinib in CML have been extensively studied and newer tyrosine kinase inhibitors are now being evaluated for clinical use. It is important that at any time the CML treatment and response remain optimal and thus patients on imatinib require continuous monitoring for early detection of resistance. This review will discuss the treatment and guidelines for monitoring CML patients in the imatinib era.

Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997–2002

Efforts to prevent leukemia have been hampered by an inability to identify significant risk factors. Exploring incidence patterns of leukemia subtypes by sex and race/ethnic group may generate new etiologic hypotheses and identify high-risk groups for further study. Data from the North American Association of Central Cancer Registries for 1997-2002 were used to assess patterns of leukemia incidence by subtype, sex, age, race and ethnicity. A total of 144,559 leukemia cases were identified, including 66,067 (46%) acute and 71,860 (50%) chronic leukemias. The highest rates of acute myeloid leukemia with and without maturation were observed in Asian-Pacific Islanders (API). Hispanics had a higher incidence of acute lymphocytic leukemia, particularly in childhood, and promyelocytic leukemia than did non-Hispanics. African-Americans had the highest rates of HTLV-1 positive adult T-cell leukemia/lymphoma. A sharp increase in the incidence of chronic myeloid leukemia was observed for both APIs and Hispanics, 85 years and older. Known risk factors are unlikely to explain the observed disparities in leukemia incidence. Further studies of differences in environmental and genetic risk factors in these populations by specific leukemia subtype may provide clues to the etiologies of these malignancies.

Clinical Trials Underestimate Age of Chronic Myeloid Leukemia (CML) Patients: Epidemiological Study in a Representative Area in Germany.

Epidemiological information on chronic myeloproliferative disorders (CMPD), notably Philadelphia (Ph) and/or bcr/abl positive chronic myeloid leukemia (CML), is rare. National cancer registries and clinical trials differ with regard to median age of CML patients by 10 to 20 years (Table). Therefore, an evaluation was conducted in a defined area in Germany between 1998 and 2000 to determine incidences and compare clinical characteristics of Ph and/or bcr/abl positive CML patients participating and not participating in trials. 68 (37.4%) hospitals and 241 specialty practices (16.4%) reported 893 newly diagnosed CMPD patients. CML patients represented 24.9% of all cases with CMPD. The crude incidence of CML cases (n=218) was 0.79, that of the 172 Ph and/or bcr/abl positive CML cases 0.62 and that of CMML (n=61) 0.22. The incidence of CML and CMML cases combined was 1.01. 110 (64.0%) of the 172 Ph and/or bcr/abl positive CML patients participated in clinical studies, mainly CML Studies III and IIIA of the German CML Study Group. Median age was significantly different between patients participating and not participating in clinical trials: (54.1 vs. 64.8 years, p=0.0001). The chance for a Ph and/or bcr/abl positive CML patient < 65 years to be enrolled in a clinical study was 3.8 times higher than for a CML patient ≥ 65 years (OR=3.8, CI: 1.9–7.3). Male patients had a slightly higher probability to be enrolled in a study than females (OR=1.5 (CI: 0.8–2.8)). Our data indicate that 36% of the Ph and/or bcr/abl positive CML patients registered in a defined area of Germany are not treated in clinical trials, that elderly patients have a lower probability to be included in trials than younger patients and that patients participating in trials are 10.7 years younger than those who do not.Age of CML Patients in Population based Registries and in Clinical TrialsA) RegistriesAge mean (years ± S.D.) /Thames Cancer Registry, U.K.65 (20–98)SEER Cancer Statistics Review, 1975–200468 (range not available)SEER cancer statistics review, 1973–199864 (range not available)B) TrialsThe Italian Cooperative Study Group on Chronic Myeloid Leukemia. N Engl J Med 199448 ± 14Hehlmann et al., Blood 199448 (17–85)Guilhot et al., N Engl J Med 199750 (7–70)Hasford et al., JNCI 199849 (10–85)The Benelux CML Study Group. Blood 199856 (20–83)Baccarani et al., Blood 200245 ± 13Hehlmann et al., Leukemia 200348 (10–83)O'Brien et al., N Engl J Med 200350 (18–70)Hehlmann et al., Blood 200749 (11–90)

A Retrospective 20-Year Survey of the Incidence of Chronic Myeloid Leukemia in the Northern France Region.

Purpose: To assess the incidence of chronic myeloid leukemia (CML) in the Nord-Pas de Calais Region in Northern France (~ 4 millions inhabitants) and to describe the patients (pts) characteristics and evolution.Methods: A retrospective study was conducted to record all confirmed diagnosis of CML that occurred during the period 1985–2004. All pts were actually living in the region at the diagnosis. CML was diagnosed by cytogenetic and molecular tests (Philadelphia chromosome and/or BCR-ABL fusion gene). Pts were screened through the results of the two cytogenetic and molecular laboratories of the region. The possibility of pts diagnosed outside the region is negligible and under study. Age-standardized incidence rate calculation was based on the standard world population.Results: 783 pts with confirmed diagnosis of CML were included. Age-standardized incidence rate is 0.82/100,000 people during the 1990–2004 period, with a raw incidence rate of 1.02/100,000 people during the same period. In the whole 20 years cohort, 55.7% of the pts are of male gender and the median age at diagnosis is 55.3 years (5.4–93.4). Haematological status at diagnosis was available for 83.5% of pts: chronic phase (CP) for 623 pts (95.3%), accelerated phase (AP) for 21 pts (3.2%), and blastic crisis (BC) for 10 pts (1.5%). Sokal index was available for 67% of pts, and was low for 40.5%, intermediate for 35.9%, and high for 23.6% of them. At December 31th 2004, 331 (42.3%) pts were still alive, 370 (47.2%) were deceased and 82 (10.5%) of unknown status. Taking into account the patients who have left the region, the raw prevalence rate is 8.1/100,000 people at this date. During the follow-up, an advanced phase was documented for 206 pts (26.5%) of the whole cohort and 189 (48.5%) of deceased patients. Allogeneic bone marrow transplantation was performed in 140 (17.9%) pts with a 5-years overall survival rate of 60%. 354 pts (45.2%) received interferon alfa (IFN) (median treatment duration 13.5 Mo (0.5–157.1)) with 24.6% pts achieving a major cytogenetic response (MCyR). 302 pts (38.6%) were treated by imatinib mesylate (IM) (median treatment duration 31.3 Mo (0.5–72.3)) with a rate of MCyR of 75.2% for pts in CP at IM initiation (206 informative pts). The overall median survival of the whole cohort was 72 months. For the diagnosis periods 1985–1989, 1990–1994, 1995–1999, and 2000–2004, the 5-years overall survival rates were respectively 41.6%, 51%, 57.5%, and 78.5% (p<0.0001).Conclusion: our findings in a well defined region corroborate the results of other cancer registries for the CML incidence. The prognosis of this disease has been modified by bone marrow transplantation and the use of interferon alfa but the major survival improvement seems related to the large use of tyrosine kinase inhibitors since 2000–2001, suggesting a great increase of CML prevalence in the future. [Display omitted]

The age incidence of chronic myeloid leukemia can be explained by a one-mutation model

Chronic myeloid leukemia (CML) is associated with the Philadelphia chromosome, which arises by a reciprocal translocation between chromosomes 9 and 22 and harbors the BCR-ABL fusion oncogene. It is unknown whether any other mutations are needed for the chronic phase of the disease. The CML incidence increases as a function of age with an exponent of approximately 3. A slope of 3 could indicate that there are two mutations, in addition to the Philadelphia translocation, that have not yet been discovered. In this work, we explore an alternative hypothesis: We study a model of cancer initiation requiring only a single mutation. A mutated cell has a net reproductive advantage over normal cells and, therefore, might give rise to clonal expansion. The cancer is detected with a probability that is proportional to the size of the mutated cell clone. This model has three waiting times: (i) the time until a mutated cell is produced, (ii) the time of clonal expansion, and (iii) the time until the clone is detected. Surprisingly, this simple process can give rise to cancer incidence curves with exponents up to 3. Therefore, the CML incidence data are consistent with the hypothesis that the Philadelphia translocation alone is sufficient to cause chronic phase CML.

Efficacy and Safety of Imatinib Treatment in Elederly Patients with Chronic Myeloid Leukemia.

The increase of median survival of the general population results in a higher incidence of Chronic Myeloid Leukemia (CML) in the elderly. In our series of 260 cases from a single institution the mean age of CML cases was 52.5 from 1977 to 1987 and 61.9 from 1999 to 2003; in other words, in the last 5 years 39.6% of our CML cases was over 70 years of age. The introduction of Imatinib (STI) has changed the treatment strategy in CML elderly patients, previously treated with hydroxyurea (HU). Efficacy, tolerability and cost of STI therapy in this CML setting are worth to be considered. For this purpose we retrospectively evaluated our elderly CML patients treated with STI. Our series consists in 24 cases, M/F 18/6, with a median age at diagnosis of 70.1 yrs (60–83), and 73.4 (65–83) at time of STI therapy; Co-morbidity included hypertension (5 cases), renal failure (2), cardiovascular diseases (4), diabetis (1), psoriasis (1), B-cell chronic lymphocytic leukaemia (B-CLL) (1).The mean interval from diagnosis to STI was 2.6 yrs (0-7). Sokal index was low in 4 cases, intermediate in 18, high in 2; Euro index was low in 15, intermediate in 7, high in 2. All cases were bcr/abl positive (p210), 19 Ph1+, 4 Ph1-. Four patients, one in AP, were untreated. Six cases had received HU, 3 in accelerate phase (AP). Out of 14 cases previously treated with interferon (IFN) for 1 to 43 months, 5 patients were intolerant, 7 resistant (1 in AP), while 2 patients obtained haematological and cytogenetic complete response and received IFN treatment for 24 and 29 months, respectively. STI was administered at 400 mg/day in CP and 600 mg/day in AP, for a mean period of 2 yrs (1 to 46 months). All cases but 3, 2 in AP and 1 in chronic phase (CP), either obtained or maintained the hematological response. After 6 to 12 months of STI therapy, out of 24 cases, 11 obtained complete cytogenetic (CG) response (1 case in AP), 1 minor, 3 no CG response; in the remaining cases CG response was not evaluable, in 2 cases because CG response was already obtained after IFN therapy, in 3 because of short period of therapy, and in 4 because Ph1 negative at onset. Quantitative molecular response, evaluated in 9 out of 11 patients achieving CG response, was obtained in 8 cases; notably, in 4 cases bcr/abl was so low to become undetectable. Tolerability was generally good in all but 2 cases, requiring STI permanent withdrawal; one patient presented subdural hemorrage needing surgery, the other one presented hepatic failure The remaining toxicity consisted of grade 3 cough, scrotal oedema, reversible lethargy because of cerebral oedema; and fatigue requiring temporary withdrawal or dose reduction in 7 patients. Also hematological toxicity required temporary drug withdrawal 2 cases. Out of 4 patients requiring permanent dose reduction to 300 mg/day, 3 are maintaining CG and molecular response, while one patients lost CG response. In detail, out of 5 cases in AP, 3 died of progressive disease, one maintains haematological and the last CG complete response. Interestingly the patients affected by psoriasis demonstrated a clear improvement of skin lesions and the patient with concomitant B-CLL achieved a response at phenotypic level.At the time of the present report 3 patients died, all in AP because of disease progression. According to the present data STI therapy is indicated in CML elderly patients.

Biologically-based risk estimation for radiation-induced chronic myeloid leukemia.

Radiation cancer risks are typically determined by the use of simple statistical descriptions of epidemiological data. It is important in risk assessment in general, however, to attempt to incorporate as much biological information into the risk models as possible. We illustrate this by presenting a biologically-based linear-quadratic-exponential (LQE) incidence rate model for radiation-induced chronic myeloid leukemia (CML). The model consists of a linear-quadratic dose-response for the induction of BCR-ABL, a waiting time distribution between BCR-ABL formation and detection of CML, and an exponential cell-killing term that multiplies both the background and induced incidence rates. Using data exclusive of the A-bomb survivor cohort, Bayesian priors are defined for each of the nine parameters in this LQE model. The priors are based on chromosomal translocations in lymphocytes, hematopoietic stem cell survival experiments, CML waiting times in women irradiated for benign disease, the background CML incidence rate in the U.S. population, and genomic DNA target sizes of BCR and ABL. Fixing three of the LQE model parameters to the means of their priors, maximum likelihood estimates of the remaining six parameters were obtained using A-bomb survivor incidence data for Hiroshima males. The likelihood estimates and the corresponding six prior distributions, both approximated as multivariate normal, were then used to form Bayesian posteriors for the six parameters not fixed. With these posteriors the LQE model yields Qgamma*=0.0042 Gy(-1) where Qgamma* is the upper 95% confidence bound of the lifetime CML risk per person-gray in the limit of low doses of gamma-rays. This value is slightly less than Qgamma*=0.0049 Gy(-1) obtained from likelihood estimates of the LQE parameters, and substantially less than Qgamma*=0.0158 Gy(-1) obtained for a simple statistical model linear in dose for kermas less than 4 Gy.

HLA-DR4 is associated with a diminished risk of the development of chronic myeloid leukemia (CML). Chronic Leukemia Working Party of the European Blood and Marrow Transplant Registry.

CML is characterized by the chromosomal translocation t(9;22) (q34;q11) resulting in the chimeric bcr-abl oncogene that encodes P210 fusion proteins with novel amino acid sequences in the breakpoint region. If these peptides derived from P210 are presented by HLA molecules on the cell membrane of leukemic cells an immunological response may occur. Recent studies using synthetic peptides identical to the bcr-abl fusion region revealed that some peptides are capable of binding to the class I molecules HLA-A2,-A3,-A11 and -B8 and the class II molecules HLA-DR1, -DR2, -DR3, -DR4 and -DR11. Moreover T cell responses have been induced against bcr-abl-derived synthetic peptides bound to some of these HLA molecules. For HLA class I, we have previously shown that individuals expressing HLA-A3 and -B8 have a diminished risk of development of CML. To assess a similar protective effect of class II molecules we performed a large multi-center study. This study compared the frequencies of HLA-DR1, -DR2, -DR3, -DR4 and -DR11 of patients with CML from the database of the EBMT (n = 1462) with unaffected individuals from the registry of Bone Marrow Donors Worldwide (n = 500 596). Patients and controls were matched per country. This analysis yielded significantly lower odds ratios (ORs) of 0.86 (95% CI 0.75-0.98) for HLA-DR3 and of 0.80 (95% CI 0.71-0.89) for HLA-DR4. The OR was 0.91 (95% CI 0.80-1.04) for HLA-DR1, 1.05 (95% CI 0.94-1.18) for HLA-DR2 and 0.87 (95% CI 0.74-1.01) for HLA-DR11. To assess a possible effect of the linkage disequilibrium between HLA-B8 and HLA-DR3 we found that coexpression of HLA-B8 and HLA-DR3 gave an OR of 0.84 (95% CI 0.72-0.98), whereas HLA-DR3 positive/HLA-B8 negative individuals showed an OR of 1.02 (95% CI 0.84-1.24). This means that the protective effect of HLA-DR3 of the development of CML was probably caused by its linkage disequilibrium with HLA-B8. In contrast, as there is no linkage disequilibrium of HLA-DR4 with HLA-A3 or HLA-B8, the results indicate that HLA-DR4 expression itself is associated with a diminished incidence of CML possibly by the presentation of bcr-abl breakpoint peptides in these HLA molecules on the membrane of the leukemic cells.

Trends in the incidence of leukaemia in Poland, 1963-90: an epidemiologic study.

An epidemiological study of the total population of patients with leukaemia in Poland during the period 1963-90 was performed with special emphasis on time trends. The material stemmed from the Polish National Cancer Registry and was believed to be virtually complete. Of the 38,200 patients, 50% had acute leukaemia, 25% had chronic lymphatic leukaemia, 15% had chronic myeloid leukaemia, and 10% of the patients had undefined lymphatic and myeloid leukaemia. Over the 28-year period, the incidence of leukaemia increased threefold in the age group 70-80+ years, and the increase in the age group 50-69 years was suspected. In the final 11 years of the study acute leukaemia increased in total age groups, mainly among those aged 70-80+ years, whereas the incidence of chronic myeloid leukaemia remained unchanged. The incidence of chronic lymphatic leukaemia increased only in the age group 70-80+ years.

The epidemiology of leukemia in Kuwait

This study reports the occurrence of leukemia subtypes in Kuwait between 1979 and 1989. The cases were analyzed by age, sex, Kuwait and non-Kuwaiti nationality status. Of the total 723 cases, acute lymphoblastic leukemia (ALL) was the most frequent (44.2%), exhibited a peak incidence in the 0–4 years age group and was also the most common leukemia of childhood (90.5%). Acute myeloblastic leukemia (AML) constituted 32.4% of leukemia and showed a progressive increase in incidence with age. Chronic myeloid leukemia (CML) constituted 14.8% and chronic lymphocytic leukemia (CLL) 8.6% of all cases. The incidence, age and sex distribution of ALL, AML and CML was similar to that in the developed Western countries while the lesser frequency of CLL was similar to that in the Orient. This pattern of leukemia subtypes may be related to the population structure consisting of the predominantly young in Kuwait, and the peak incidence of ALL in the very young to the socio-economic conditions.

Patterns and temporal trends in the incidence of malignant disease in children: I. Leukaemia and lymphoma

Patterns and trends in incidence of leukaemia and lymphoma in children aged under 15 years and resident in the North Western Regional Health Authority area of England at diagnosis, over the 35-year time period 1954–1988, were analysed. The study included 1407 cases registered with the Manchester Children's Tumour Registry, 100% of which had a histologically or cytologically verified diagnosis. Log-linear modelling identified significant linear increases in acute lymphocytic leukaemia (ALL) (average quinquennial increase 4%) and Hodgkin's disease (HD) (10%), but not in acute non-lymphocytic leukaemia nor non-Hodgkin's lymphoma. Additionally, the χ 2 test for trend identified a significant increase in the incidence of chronic myeloid leukaemia. The possibility that the increases seen in ALL and HD are linked to increases in prevalence of unknown infectious agents is discussed.

Reclassification of Leukemia among A-Bomb Survivers in Nagasaki Using French-American-British (FAB) Classification for Acute Leukemia

The concordance rate for diagnoses of atomic bomb-related cases of leukemia in Nagasaki was determined using the French-American-British (FAB) classification for acute leukemias and myelodysplastic syndromes (MDS). Two Radiation Effects Research Foundation (RERF) hematologists and one of the members (JMB) of the FAB cooperative group reviewed independently the peripheral blood and/or bone marrow smears from 193 people with leukemia or a related disorder. There was 85% agreement in the identification of types and subtypes of acute leukemia. There was almost complete agreement for the diagnoses of non-FAB disorders (chronic myeloid leukemia (CML), adult T-cell leukemia (ATL) and others) resulting in overall concordance of 88.2%. The present study suggests that the previously established leukemia types for about a quarter of the cases of acute leukemia and related disorders except CML should be changed. Considerable numbers of cases of ATL and MDS were involved in this series. The frequency of the former disease was not high in the high-dose irradiated group, but that of the latter was considerably high. All subtypes of AML except M3 and M6 were present in the high-dose group. The striking difference in CML incidence between Nagasaki and Hiroshima may continue to be a problem in relation to biological response to radiation exposure.

Leukaemia and lymphoma in Kenya

This study reports the occurrence of leukemia subtypes in Kuwait between 1979 and 1989. The cases were analyzed by age, sex, Kuwait and non-Kuwaiti nationality status. Of the total 723 cases, acute lymphoblastic leukemia (ALL) was the most frequent (44.2%), exhibited a peak incidence in the 0–4 years age group and was also the most common leukemia of childhood (90.5%). Acute myeloblastic leukemia (AML) constituted 32.4% of leukemia and showed a progressive increase in incidence with age. Chronic myeloid leukemia (CML) constituted 14.8% and chronic lymphocytic leukemia (CLL) 8.6% of all cases. The incidence, age and sex distribution of ALL, AML and CML was similar to that in the developed Western countries while the lesser frequency of CLL was similar to that in the Orient. This pattern of leukemia subtypes may be related to the population structure consisting of the predominantly young in Kuwait, and the peak incidence of ALL in the very young to the socio-economic conditions.