What Is the Life Expectancy of a Stem Cell Baby

J Clin Oncol. 2010 Feb 20; 28(6): 1011–1016.

Life Expectancy in Patients Surviving More 5 Years After Hematopoietic Jail cell Transplantation

Paul J. Martin, George W. Counts, Jr, Frederick R. Appelbaum, Stephanie J. Lee, Jean E. Sanders, H. Joachim Deeg, Mary Eastward.D. Flowers, Karen L. Syrjala, John A. Hansen, Rainer F. Storb, and Barry E. Storer

Paul J. Martin

From the Fred Hutchinson Cancer Research Centre and the University of Washington, Seattle, WA.

George Westward. Counts, Jr

From the Fred Hutchinson Cancer Enquiry Center and the Academy of Washington, Seattle, WA.

Frederick R. Appelbaum

From the Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, WA.

Stephanie J. Lee

From the Fred Hutchinson Cancer Research Center and the Academy of Washington, Seattle, WA.

Jean E. Sanders

From the Fred Hutchinson Cancer Inquiry Eye and the University of Washington, Seattle, WA.

H. Joachim Deeg

From the Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, WA.

Mary Eastward.D. Flowers

From the Fred Hutchinson Cancer Inquiry Center and the University of Washington, Seattle, WA.

Karen L. Syrjala

From the Fred Hutchinson Cancer Enquiry Center and the Academy of Washington, Seattle, WA.

John A. Hansen

From the Fred Hutchinson Cancer Enquiry Heart and the University of Washington, Seattle, WA.

Rainer F. Storb

From the Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, WA.

Barry Due east. Storer

From the Fred Hutchinson Cancer Inquiry Center and the University of Washington, Seattle, WA.

Received 2009 Aug 12; Accepted 2009 Oct 7.

Abstract

Purpose

Hematopoietic cell transplantation can cure hematologic malignancies and other diseases, but this treatment tin also cause late complications. Previous studies take evaluated the cumulative furnishings of tardily complications on survival, simply longer-term effects on life expectancy subsequently hematopoietic cell transplantation accept not been assessed.

Patients and Methods

Nosotros used standard methods to evaluate mortality, projected life expectancy, and causes of death in a cohort of 2,574 patients who survived without recurrence of the original disease for at to the lowest degree 5 years afterward allogeneic or autologous hematopoietic cell transplantation from 1970 through 2002. Sex activity- and age-specific comparisons were made with United states population data.

Results

Estimated survival of the cohort at 20 years after transplantation was 80.4% (95% CI, 78.ane% to 82.6%). During 22,923 person-years of follow-up, 357 deaths occurred. Mortality rates remained four- to nine-fold college than the expected population charge per unit for at to the lowest degree 30 years after transplantation, yielding an estimated 30% lower life expectancy compared with that in the general population, regardless of current age. In rank order, the leading causes of excess deaths were second malignancies and recurrent disease, followed by infections, chronic graft-versus-host disease, respiratory diseases, and cardiovascular diseases.

Conclusion

Patients who accept survived for at to the lowest degree 5 years after hematopoietic cell transplantation without recurrence of the original illness accept a high probability of surviving for an additional 15 years, simply life expectancy is not fully restored. Farther attempt is needed to reduce the burden of disease and treatment-related complications in this population.

INTRODUCTION

Hematopoietic cell transplantation (HCT) has been used for more than 40 years to treat hematologic malignancies and nonmalignant diseases that could non be cured by other therapies.ⁱ Since the first iii cases of successful allogeneic HCT in 1968, more than than 800,000 patients take had allogeneic or autologous transplantation.² These treatments are now used worldwide for more than than 60,000 patients each yr.

Since the early 1970s, bloodshed during the offset 100 days after HCT has decreased because of changes in selection criteria, refinement of pretransplantation workout regimens, and improvements in prevention and management of graft-versus-host disease (GVHD) and infection. One-yr survival rates now exceed 60% for patients with human leukocyte antigen–identical sibling donors.ⁱⁱ With decreased early bloodshed and more widespread utilise of HCT, the number of 5-twelvemonth survivors now exceeds 150,000 and will keep to grow.

Mortality rates among patients who take had HCT remain higher than those for the general population for at least 10 years after the procedure.^3–vii The leading causes of late deaths include recurrent or second malignancy, chronic GVHD, infection, and other complications that result from the pretransplantation illness, its handling before the transplantation, or the transplantation itself. In this written report, nosotros evaluated the cumulative effects of tardily complications on life expectancy later HCT.

PATIENTS AND METHODS

Study Population

The initial patient population comprised all 7,984 patients who had HCT afterwards high-dose conditioning regimens at our centre through the year 2002, with no restrictions on diagnosis or donor type. Outcomes were based on information available as of Feb 2008. Within 5 years later the transplantation, 4,851 patients died, 381 had recurrent malignancy, 81 received a second transplantation, and 96 had no follow-upwards beyond five years. The study cohort of 5-year survivors comprised the remaining two,574 patients, 32% of the original cohort.

A sustained and systematic program of long-term follow-up at our middle includes annual attempts to contact all surviving patients and periodic searches of public sources for patients without recent contact. At the time of assay, 357 deaths (14%) had been documented in the study accomplice. The median time since last contact in the surviving 2,217 patients was seven.8 months, and 2,097 survivors (94.6%) had been contacted within the by v years. The institutional review lath of the Fred Hutchinson Cancer Research Center canonical the procurement and apply of information regarding causes of death for this written report.

Calculation of Mortality Rates and Life Expectancy

Details of the calculations are provided in the Appendix (online only). The mortality rate for an interval of fourth dimension defined either by time since transplantation or by historic period was estimated equally the number of deaths in the interval divided by the number of person-years of observation time in the interval among patients alive at the get-go of the interval. Smoothed estimates of the mortality rates and associated CIs were obtained past plumbing equipment a Poisson regression model to the observed counts, using cubic spline terms for time.

Although the offset patient entered the report cohort in 1975, the midpoint of the 22,923 person-years of follow-upward in the cohort occurred late in the year 2000 (Appendix Fig A1, online just). Expected population mortality rates and life expectancy were based on sexual activity-specific 2001 United states life table data from the National Eye for Health Statistics. Calculation of life expectancy required estimates of mortality rates beyond the historic period range of transplantation survivors. We used the spline-smoothed Poisson model and extrapolated estimated bloodshed rates to historic period 100, at which signal the subsequent survival probability is as well modest to have a significant issue on life expectancy.

Cause of Death

The National Death Index (NDI) returned cause of death data for 285 patients identified through matching criteria. International Classification of Diseases nine (ICD-9) codes were mapped to equivalent ICD-10 codes. Sex- and age-specific mortality rates using ICD-10 coding were obtained from the National Center for Health Statistics for 1999 to 2003, spanning the midpoint of cumulative follow-up. Expected numbers of deaths in broad ICD categories were calculated by applying the population rates to the person-years of follow-up in the corresponding sex- and age-specific intervals in the study cohort.

Standardized mortality ratios were calculated as the ratio of observed deaths to expected deaths, each summed across sex and age. Deaths attributable to recurrent affliction were removed from the adding, and the counts of observed deaths were adjusted upward in proportion to the number of patients whose cause of decease was unknown. A separate analysis incorporated all information in the available records to refine the cause of expiry, including chronic GVHD, which is not recognized every bit a cause of death in the population data. In this analysis, causes of death matching the pretransplantation diagnosis were attributed to recurrent disease. Deaths due to cancerous diseases differing from the pretransplantation diagnosis were categorized equally 2d malignancies.

Gamble Factor Analysis

Cox regression assay with historic period as the time axis was used to analyze factors that might touch mortality rates and to evaluate their effect on life expectancy. Staggered entry by age was accommodated via left truncation, with the usual right censoring.

RESULTS

Study Population

Characteristics of the transplantation cohort of seven,984 patients, the report accomplice of 2,574 five-twelvemonth survivors, and the 357 deceased patients are described in Table 1. The median follow-up afterward transplantation in surviving members of the study cohort was thirteen.1 years (range, five.0 to 36.one years), and their median attained age at analysis was 46 years (range, 6 to 80 years). Overall, the estimated survival of the study cohort was 80.4% (95% CI, 78.1% to 82.6%) at 20 years afterward transplantation. Survival across v years correlated inversely with age at transplantation (Fig one).

Table one.

Patient Characteristics

Characteristic	Overall Accomplice (Northward = 7,984)		5-Twelvemonth Survivors* (north = 2,574)		Deaths† (n = 357)
	No.	%	No.	%	No.	%
Transplant blazon
Related allogeneic	iv,736	59	1,623	63	241	68
Unrelated allogeneic	1,576	20	537	21	45	13
Autologous or syngeneic	one,672	21	414	16	71	20
Year of transplantation
1994-2002	3,097	39	1,109	43	86	24
1984-1993	3,497	44	1,074	42	153	43
1969-1983	1,390	17	391	xv	118	33
Sex activity
Male	4,479	56	ane,395	54	203	57
Female	3,505	44	one,179	46	154	43
Historic period at transplantation, years
Median	33		32		32
Range	0-73		0-73		two-64
< eighteen	one,773	22	607	24	73	xx
18-45	iv,437	56	one,481	58	202	57
> 45	1,774	22	486	nineteen	82	23
Diagnosis
Acute lymphoblastic leukemia	1,260	sixteen	279	11	46	13
Acute myeloid leukemia	1,935	24	552	21	97	27
Chronic myeloid leukemia	ane,863	23	799	31	87	24
Lymphoma	907	xi	244	ix	34	x
Myelodysplastic syndrome	564	vii	214	8	19	5
Other hematologic malignancy	346	4	67	3	21	6
Chest cancer	280	4	68	3	12	3
Other malignancy	230	3	40	1	1	< 1
Aplastic anemia	439	6	233	9	32	9
Other nonmalignant disease	160	2	78	3	eight	two
Total body irradiation
No	ii,552	32	974	38	113	32
Yes	v,432	68	1,600	62	244	68
Chronic graft-versus-host affliction
No‡	4,033	51	947	37	108	30
Yes‡	2,279	29	1,213	47	178	50
Not applicable	1,672	21	414	sixteen	71	20

Survival and bloodshed rates for patients younger than age 18 years (solid line), xviii to 45 years (short-dashed line), and older than age 45 years (long-dashed line) at the time of transplantation.

Mortality Rates and Life Expectancy

Annual mortality rates for the study cohort exceeded the expected rates throughout the entire length of follow-up after transplantation and showed a trend toward greater divergence from expected rates amid the longest surviving fraction of the cohort (Fig ii). For comparison to other studies, Appendix Figure A2 (online only) shows the ratios of observed to expected mortality rates for the entire transplantation cohort. Equally expected, mortality rates in the written report cohort increased with age (Appendix Fig A3 [A], online just). The number of deaths per 1,000 person-years inflected upward at approximately fifty years of historic period, which was x to 15 years earlier than expected (Appendix Fig A3 [B]). The ratios of observed to expected mortality rates were highest in younger historic period groups, reflecting the depression expected mortality rates in these age groups (Appendix Fig A3 [C]). Although the mortality ratios declined in older patients (Appendix Fig A3 [C]), the number of backlog deaths per one,000 person-years increased among patients age 50 years or older (Appendix Fig A3 [D]). Overall patterns were similar for patients younger than 18 years of age at transplantation (Appendix Fig A4, online only).

Mortality rates later on transplantation. Empirical mortality rates during each twelvemonth (solid circles) are shown with fitted rates from the spline-smoothed Poisson regression model (solid line) and associated bespeak-wise 95% CIs (short-dashed line), and the expected bloodshed rates for each interval based on sex- and age-specific data for the United states population in 2001 (long-dashed line).

The college mortality rates in the report cohort translate to shorter projected life expectancies compared with the general population. The absolute decrease in estimated residual life expectancy ranges from 17.0 years for survivors at xx years of age to 6.4 years for survivors at 60 years of historic period (Fig iiiA). The proportionate reduction in life expectancy is approximately 30% at whatever attained age (Fig threeB). Autologous transplantation, prior chronic GVHD, and transplantation before 1984 were associated with higher bloodshed rates and greater effect on life expectancy. Transplantation for chronic myeloid leukemia in chronic stage or nonmalignant diseases was associated with lower mortality rates and lesser effect on life expectancy (Table 2).

Projected reduction in life expectancy in the study accomplice relative to U.s. population data as a role of attained age. (A) Absolute reduction in years; (B) percentage reduction.

Tabular array two.

Multivariate Analysis of Risk Factors for Mortality

Variable*	Hazard Ratio†	95% CI	P	Reduction in Life Expectancy (%)‡
Transplant type
Related allogeneic	one.0			24
Unrelated allogeneic	1.1	0.8 to 1.half dozen	.54	27
Autologous/syngeneic	2.0	one.4 to 2.8	< .0001	44
Year of transplantation
1994-2002	1.0			28
1984-1993	0.8	0.6 to 1.1	.25	23
1969-1983	1.5	1.1 to 2.3	.02	41
Diagnosis
Other malignancies	1.0			32
Chronic myeloid leukemia in chronic phase	0.6	0.v to 0.ix	.004	twenty
Nonmalignant diseases	0.6	0.4 to 0.9	.02	18
Prior chronic graft-versus-host affliction
No	i.0			21
Aye	ane.6	1.2 to two.0	.0002	35
Age at transplantation, years§
< 18	0.9	0.vi to one.five	.73	28
18-45	1.0			thirty
> 45	0.8	0.v to 1.3	.xl	25
Sex
Male	one.0			31
Female	0.8	0.7 to ane.0	.12	26
Total torso irradiation
No	ane.0			30
Yeah	0.ix	0.vii to 1.3	.70	28

Causes of Decease

Although the study cohort was defined by the absence of documented recurrent malignancy inside 5 years, recurrent malignancy contributed the largest fraction of deaths as classified by the NDI (Table 3). All deaths attributed to hematologic malignancy by the NDI occurred among patients originally diagnosed with a hematologic malignancy, merely the NDI coding does not distinguish whether these represented new malignancies or recurrence. Amongst reviewed causes, 29 (45%) of the 65 ascertained deaths among survivors after autologous transplantation were attributed to recurrent disease compared with xl (15%) of the 274 deaths among survivors later allogeneic transplantation (Appendix Table A1, online only).

Table 3.

Expected and Observed Deaths According to Cause

Crusade	Expected	National Decease Index		Reviewed*		Excess†
		Observed	SMR‡	Observed	SMR‡	No.	%
Major ICD disease categories
Cardiovascular	22.0	31	1.8	39	one.nine	19.i	7
Congenital	0.3	0	0	0	0
Digestive	4.0	six	i.9	5	1.3	1.iii	0
Endocrine	three.iv	three	1.1	2	0.6
External (eg, accident)	13.three	12	1.1	14	1.1	1.5	one
Genitourinary	1.two	3	three.ii	3	2.seven	2.0	1
Infection, hepatitis C	0.four	12	35.6	17	42.4	17.5	6
Infection, other	iii.0	12	5.0	35	12.3	33.9	12
Mental	one.two	0	0	0	0
Musculoskeletal	0.5	0	0	0	0
Neoplasm, nonhematologic	20.3	72	four.four	84	4.4	68.1	24
Neoplasm, hematologic	ii.two	—§	—§	9¶	4.3	7.3	3
Neurologic	ane.8	2	1.four	iv	2.4	ii.4	1
Pregnancy	0.1	0	0	0	0
Respiratory	4.7	22	5.9	25	five.6	21.half dozen	8
Skin	0.ane	0	0	0	0
Other	ane.vii	4	ii.9	1	0.6
Undefined ICD categories
Recurrent affliction	—	106	—	69¶	—	72.7	26
Chronic GVHD	—	—	—	32	—	33.seven	12
Unknown	—	72	—	xviii	—
All causes	80.1	357	four.5	357	4.5

Causes of backlog deaths in rank order included a wide variety of second malignancies and recurrent disease, followed by infections, chronic GVHD, respiratory diseases, and cardiovascular diseases, all broadly associated with transplantation (Table three). Oropharyngeal cancers (n = 17), GI cancers (n = 16), and encephalon tumors (n = 12) deemed for more than half the 85 fatal nonhematologic 2d malignancies. The chance of recurrent malignancy was not uniform among different subgroups (Appendix Table A2, online merely). Pulmonary fibrosis was implicated in 16 of the 25 reviewed causes of death attributed to respiratory disease. Deaths attributed to 2d malignancies and respiratory diseases occurred more ofttimes amid survivors between 5 and 44 years of historic period than among older survivors, as measured past mortality ratios (Appendix Table A3, online but). As measured past the number of excess deaths per 1,000 person-years, the differences between the 2 age groups are less hit, suggesting that the decrease in mortality ratios reflects the historic period-associated increase in mortality attributed to cancer and pulmonary affliction in the full general population. All deaths related to hepatitis C infection occurred among patients who had transplantation earlier 1990, before hepatitis C screening of transplantation and transfusion donors became bachelor. Deaths due to other infections were more prominent among survivors with prior chronic GVHD (reviewed causes: northward = 28; standardized mortality ratio, twenty.0) than among other survivors (reviewed causes: due north = 7; standardized mortality ratio, 4.viii).

Give-and-take

Mortality rates improve dramatically during the first v years after HCT simply remain four- to nine-fold higher than in the general population for at least 25 years thereafter. The ratio of mortality among transplantation survivors compared with the expected population charge per unit decreases with increasing historic period, as mortality increases in the general population, just the number of excess deaths per 1,000 person-years increases sharply, especially afterward fifty years of age. The excess mortality charge per unit translates to an estimated thirty% lower life expectancy than that of the United states of america population, regardless of current historic period. The major causes of excess deaths include recurrent disease, second malignancies, infections, chronic GVHD, respiratory diseases, and cardiovascular diseases.

Pond et al⁶ observed that the 95% CI for the ratio of observed and expected deaths overlapped 1.0 beginning later on the tenth year from HCT, which was interpreted as suggesting no deviation in survival compared with that of the general population. Our overall bloodshed rates fall within the CIs of their results (Appendix Fig A2), but with a larger number of patients, longer follow-upwardly, and the added precision of model-derived estimates, our data betoken that mortality rates practice not reach expected levels at any fourth dimension afterward transplantation, even among patients without recurrent affliction during the beginning 5 years. Our results exercise not exclude the possibility that mortality rates in certain subgroups of patients could arroyo population rates at some point subsequently HCT.^iv,5

Five other studies have evaluated late mortality afterwards HCT,^iii–7 all showing that bloodshed rates were higher amidst transplantation survivors than mortality rates expected in the general population. Mortality ratios from these studies cannot be straight compared with our results, because our cohort was divers by survival without recurrence of the original disease for at least 5 years after the transplantation, whereas the cohorts for other studies were defined by survival for 2 years^4,five,7 or included patients with recurrence of the original disease earlier entry into the cohort.^3,5,6

Our results confirm that the leading causes of excess late deaths subsequently HCT include 2nd malignancies, recurrent malignancy, infections, chronic GVHD, and respiratory diseases.^3–7 Other studies^3,iv,7 take also shown that late bloodshed rates for survivors who had more advanced malignancies or a prior history of chronic GVHD are college than those for survivors without these take a chance factors. Conflicting results have been reported for the association of total-body irradiation with late mortality later on HCT. Duell et alⁱⁱⁱ found that full-torso irradiation was associated with an increased risk of belatedly mortality amongst 5-yr survivors who had allogeneic transplantation before 1986, whereas Bhatia et al⁵ found that total-trunk irradiation was associated with a decreased risk of mortality amid 2-year survivors who had autologous transplantation between 1981 and 1998. In the study past Duell et al,³ 67% of the patients who received total-body irradiation had a single exposure compared with 7% in our study, which might explicate why full-body irradiation was non significantly associated with late mortality in our study.

Previous studies accept shown that the take chances of recurrent malignancy decreases with fourth dimension afterward transplantation, while the risk of second malignancies increases with time subsequently transplantation.⁸ In all three previous studies that assessed late bloodshed after transplantation in 2-year survivors and in 1 of the two studies that assessed tardily mortality in 5-year survivors, deaths related to recurrent malignancy were more prevalent than deaths related to second cancers.^three–5,7 In the study by Pond et al,⁶ recurrent malignancy and second malignancies accounted for similar proportions of the deaths in patients surviving for more than half-dozen years. In this context, our results indicate that with further time from transplantation and with increasing patient historic period, 2nd cancers will surpass recurrent malignancy every bit the predominant cause of excess deaths. As discussed by Rizzo et al,⁸ efforts are needed to develop pretransplantation conditioning regimens that minimize the take a chance of 2nd cancers without jeopardizing control of the underlying disease. Physicians caring for survivors should encourage age-appropriate screening, especially for oropharyngeal and GI cancers, and patients should be advised to avoid carcinogenic exposures.

Our results enhance the question of whether similar findings might use to patients who take other types of treatment for malignant diseases. Previous studies have evaluated belatedly mortality among 5-year survivors after babyhood cancer^9–16 simply no comparable effort has been fabricated for adult cancer survivors. Patients who had recurrent malignancy earlier the 5-yr landmark were excluded from our report merely non from most studies of childhood cancer survivors. For this reason, mortality rates among childhood cancer survivors cannot exist directly compared with those in our results. As measured past both the mortality ratio and the absolute excess risk of mortality, death rates amongst childhood cancer survivors are highest from v to 10 years afterwards the diagnosis and so decrease sharply.^x–13,15,16 The high mortality rate during this interval partly reflects deaths among patients who had recurrent malignancy before 5 years from diagnosis. Cardous-Ubbink et al¹² showed that both the mortality ratio and the absolute excess risk of mortality decreased throughout follow-upwards after diagnosis to more thirty years of attained age among 5-year survivors after babyhood cancer. Among patients who had transplantation before 18 years of age, the bloodshed ratio showed less striking changes over time from transplantation, and the absolute excess risk of mortality showed petty change earlier 40 years of attained age (Appendix Fig A4). Follow-upwardly in the report by Cardous-Ubbink et al¹² was not sufficient to determine whether the college mortality ratios and absolute excess risk of mortality associated with attained historic period across 40 years in babyhood transplantation recipients too occurs in babyhood cancer survivors.

Strengths of our written report include the long duration of follow-up, the inclusion of both adults and children, and the effort to validate data from decease certificates. Other studies have noted the limitations of death certificates in ascertaining causes of death.^17,eighteen Limitations of our study include the use of sex- and historic period-specific mortality rates for 2001 in estimating the ratio of observed and expected mortality, rather than using mortality rates for each twelvemonth. Bloodshed rates in the U.s. population have shown but small changes over time, especially for the early on to midlife ages where the bulk of follow-up occurs in our written report. Our transplantation cohort was heterogeneous with respect to the underlying disease and treatment, only the removal of deaths and recurrent malignancies during the first 5 years lessens the heterogeneity in our study cohort, and the consequence of heterogeneity remaining after 5 years was modest in comparing to the overall reduction in life expectancy. Some diseases represented in the study accomplice, such every bit breast cancer, are no longer treated with HCT, but these patient groups however contribute relevant data regarding tardily effects. Our estimates of life expectancy involve an uncertain extrapolation of mortality rates to age groups older than those observed in our cohort. Further studies will be needed to test the validity of this extrapolation and to strengthen the data for translation of bloodshed rates into estimates of life expectancy after HCT.

The lower life expectancy among 5-yr transplantation survivors compared with that in the The states population reflects not only effects of transplantation but also effects of the underlying affliction and the treatment before the transplantation. In our study, 75% of the 5-year survivors who were between 36 and 50 years of age at the fourth dimension of the transplantation were alive at 20 years after the transplantation. These results compare favorably with a study of late survival amidst patients who were potentially cured iii years later conventional treatment for acute myeloid leukemia.¹⁹ In that cohort, with a median age of 40 years, the projected survival at 20 years after the original diagnosis was approximately 50%.

Individual risk factors for mortality in our study had simply limited effects on the overall reduction in life expectancy after HCT. Replacement of single-exposure total-body irradiation past fractionated regimens in the early 1980s probable contributed to the comeback in late mortality and life expectancy in patients who had transplantation after 1983. The introduction of screening for hepatitis C in hematopoietic cell and transfusion donors during the early on 1990s is likely to yield further improvement in the future. The estimated reductions in life expectancy among v-twelvemonth survivors later on HCT for chronic myeloid leukemia in chronic stage and nonmalignant diseases highlight the contribution of late transplantation–related complications, apart from the effects of prior treatment and recurrent malignancy. Further endeavor is needed to minimize the burden of belatedly handling–related complications. Patients who are surviving for more than v years after HCT should be offered both precautions and hope during discussions of longer-term outcomes. Increased mortality rates emphasize the importance of ready access to high-quality health care and abstention of exposures that might exacerbate the risks of 2d malignancies, infections, and respiratory diseases. Even though life expectancy does not render to normal, healthy survivors have a high probability of surviving for many boosted years.

Acquittance

Nosotros thank members of the research and clinical staff for their dedication and for their many years of service contributing to the long-term intendance of our patients after hematopoietic jail cell transplantation; and M. Scott Bakery, MD, for reviewing the manuscript.

Appendix

Methods

Adventure charge per unit analysis.

Empirical estimates of the bloodshed charge per unit for an interval of fourth dimension i (defined either past time since the transplantation or by age) were estimated as $\widehat{\lambda }$ _i = d_i/y_i , where d_i is the number of deaths in the interval and y_i is the number of person-years of observation time in the interval among patients alive at the showtime of the interval, truncated at the time of death or final contact if either occurred during the interval. These estimates correspond to estimates of the chance rate under an exponential (constant adventure) supposition, just this assumption is not disquisitional for purposes of this study. The interval estimates were smoothed by plumbing fixtures a Poisson regression model to the observed counts d_i , first by the log of y_i and including cubic spline terms for time. From the fitted models, we generated smoothed point estimates of the bloodshed rates, denoted $\tilde{\lambda }$ _i , and associated betoken-wise CIs.

Expected population rates.

For each fourth dimension interval i of involvement since transplant, the probability of surviving the interval p_i was determined for each patient live at the start of the interval based on US population rates for their sex and age at that fourth dimension. These probabilities were converted to mortality rates λ _i = −log(p_i ) and and then averaged beyond the patients at take chances to yield a weighted mortality rate for the interval λ _i . The expected mortality rates at each age represent a simple weighted average of sexual activity-specific rates at each historic period, weighted past the overall proportion of full person-years of follow-up in males and females (53.5% and 46.five%, respectively).

Life expectancy calculation.

We used the spline-smoothed Poisson model to extrapolate estimated mortality rates to age 99. For a patient just turning age x, the probability of dying while aged y > 10 is

The residue life expectancy at age 10 is then calculated equally

that is, the weighted average of possible death ages out to historic period 99, with the historic period of decease assigned to the midpoint of the rounded death age. The effects of take chances factors on life expectancy were calculated by applying a abiding hazard ratio multiplier to each of the $\tilde{\lambda }$ _i . To derive the hazard ratio multiplier, the hazard ratio relative to the baseline category in Table 2 was re-expressed equally a take a chance ratio relative to a blended weighted hazard ratio, with weights reflecting the pct of patients in each category of the risk cistron.

The accurateness of our life expectancy calculation depends partly on the validity of the extrapolation of decease rates in transplant survivors older than 70 years of historic period. Adequate data are not available for this historic period group, and the data for younger age groups practice not support the use of a abiding mortality ratio or a abiding excess expiry rate as the footing for a model. Estimated differences in life expectancy between transplantation survivors and the general population will exist smaller if the truthful mortality rates among older transplantation survivors are lower than projected in Appendix Figure A3. Likewise, estimated differences will be larger if the true mortality rates among older transplant survivors are higher than projected in Appendix Effigy A3.

Fig A1.

Distribution of follow-up according to calendar yr. In the article, mortality and life expectancy information for the Usa population in single-year historic period intervals are taken from 2001 (blackness). Crusade-specific mortality data for the Us population in five- or 10-twelvemonth age intervals are taken from 1999 to 2003 (nighttime blueish).

Fig A2.

Bloodshed ratios for the unabridged initial cohort of 7,984 patients as a part of time since transplantation. The standardized annual mortality ratios are plotted at the midpoint during each year later on hematopoietic cell transplantation at the Fred Hutchinson Cancer Research Center (reddish circles), with the fitted rates from the spline-smoothed Poisson regression model (gold line) and the associated point-wise 95% conviction limits (bluish line). Blackness points and confined betoken standardized mortality ratios and 95% conviction limits for the accomplice reported by Pond et al.^vi The horizontal black line indicates a standardized mortality ratio of 1.0, indicating no excess take chances of death compared with sex activity- and age-specific data for the full general population.

Fig A3.

Bloodshed equally a function of age in the study cohort. (A) and (B) Empirical almanac bloodshed rates during each 5-twelvemonth interval of historic period, plotted at the midpoint of each interval (black circles), fitted rates from the spline-smoothed Poisson regression model (solid lines) and associated betoken-wise 95% CIs (short-dashed lines), with projection of model estimates to 100 years of historic period (gray dashed lines), and the expected mortality rates for each interval based on an average of sexual activity-specific US population rates at each age in 2001 (long-dashed lines), weighted by the overall proportion of follow-upward person-years for males and females in the study accomplice (53.5% and 46.5%, respectively). Results are shown on log (A) and arithmetic (B) scales. (C) Standardized mortality ratio (the ratio of observed to expected deaths) on a log calibration, representing the difference betwixt the 2 curves in the panel higher up. The horizontal black line indicates a standardized mortality ratio of 1.0, indicating no backlog risk of death compared with the general population. In younger age groups, the standardized bloodshed ratio is influenced more past changes in expected mortality rates than by changes in the mortality rates of transplantation survivors. (D) Excess deaths per 1,000 person-years of follow-upwardly (the difference between observed and expected deaths), representing the difference betwixt the 2 curves in the panel to a higher place. The number of excess deaths per 1,000 person-years of follow-up is constant in younger historic period groups and increases in older age groups, because the decease rate increases at an earlier age in transplantation survivors than in the United states of america population. Patient groups younger than x years of historic period and older than 70 years of age contained as well few events to provide meaningful estimates for comparisons with the US population.

Fig A4.

Mortality ratios and excess deaths among v-year survivors who had hematopoietic cell transplantation before xviii years of historic period. Bloodshed ratios (A and C) and backlog deaths per 1,000 person-years (B and D) are shown as a function of time since transplantation (A and B) or attained historic period (C and D). Empirical annual bloodshed rates during each 1-year or 5-year interval are plotted at the midpoint of the interval (black circles), with fitted rates from the spline-smoothed Poisson regression model (solid lines) and the associated betoken-wise 95% CIs (dashed lines). The horizontal blackness lines indicate a standardized bloodshed ratio of 1.0, indicating no excess risk of mortality compared with sexual practice- and age-specific information for the full general population in 2001. Reddish circles point information from Cardous-Ubbink et al.^eleven

​ ​ ​

Table A1.

Expected and Observed Deaths Co-ordinate to Crusade for Person-Years at Risk Later on Autologous Transplantation (two,519 total person-years) or Allogeneic Transplantation (twenty,409 total person-years)

Cause	Expected	National Death Alphabetize		Reviewed
		Observed	SMR*	Observed	SMR*
Later autologous transplantation
Major ICD disease categories
Cardiovascular	iv.1	six	1.eight	ix	2.4
Congenital	0
Digestive	0.6	2	four.0	one	1.8
Endocrine	0.half dozen	i	2.one
External	ane.3	1	0.nine	1	0.eight
Genitourinary	0.two
Infection, hepatitis C	0.1			ii	38.viii
Infection, other	0.4	2	6.four	2	5.6
Mental	0.2
Musculoskeletal	0.1
Neoplasm, nonhematologic	iii.8	8	2.6	9	2.6
Neoplasm, hematologic	0.4	—†	—†	5	13.six
Neurologic	0.iii			two	6.8
Pregnancy	0
Respiratory	1.0	3	three.8	v	5.5
Peel	0
Other	0.ii
Undefined ICD categories
Recurrent illness	—	34	—	29	—
Chronic GVHD	—	—	—		—
Unknown	—	xiv	—	vi	—
All causes	xiii.four	71	5.3	71	5.3
Subsequently allogeneic transplantation
Major ICD illness categories
Cardiovascular	17.8	25	i.viii	30	1.eight
Congenital	0.3
Digestive	3.4	four	1.five	4	1.2
Endocrine	ii.8	2	0.9	2	0.8
External	eleven.9	11	1.two	13	i.one
Genitourinary	0.9	3	4.0	3	iii.3
Infection, hepatitis C	0.4	12	41.1	xv	42.eight
Infection, other	2.six	10	four.eight	33	13.2
Mental	1.0
Musculoskeletal	0.4
Tumour, nonhematologic	16.five	64	4.9	75	4.7
Neoplasm, hematologic	1.viii	—†	—†	4	ii.3
Neurologic	1.4	ii	1.seven	2	i.5
Pregnancy	0
Respiratory	three.7	19	vi.iv	twenty	five.6
Pare	0.1
Other	1.5	4	3.3	1	0.7
Undefined ICD categories
Recurrent Illness	—	72	—	40	—
Chronic GVHD	—	—	—	32	—
Unknown	—	58	—	12	—
All causes	66.6	286	four.3	286	4.iii

Table A2.

Characteristics of Patients Who Died, According to Crusade

Characteristic	Full (N = 357)		Recurrence (n = 69)		Other Causes (n = 288)
	No.	%	No.	%	No.	%
Transplant type
Related allogeneic	241	68	32	46	209	73
Unrelated allogeneic	45	thirteen	8	12	37	xiii
Autologous or syngeneic	71	xx	29	42	42	15
Year of transplantation
1994-2002	86	24	29	42	57	20
1984-1993	153	43	31	45	122	42
1969-1983	118	33	9	13	109	38
Sexual practice
Male	203	57	29	42	174	60
Female	154	43	40	58	114	40
Age at transplantation, years
Median	32		43
Range	2-64		ii-62
< 18	73	twenty	6	9	67	23
18-45	202	57	37	54	165	57
> 45	82	23	26	38	56	19
Diagnosis
Astute lymphoblastic leukemia	46	13	ii	3	44	xv
Astute myeloid leukemia	97	27	sixteen	23	81	28
Chronic myeloid leukemia	87	24	16	23	71	25
Lymphoma	34	ten	eight	12	26	9
Myelodysplastic syndrome	xix	five	2	3	17	vi
Other hematologic malignancy	21	6	11	16	x	three
Breast cancer	12	3	10	fourteen	2	1
Other malignancy	1	< i	1	ane	0	< 1
Aplastic anemia	32	ix	0	0	32	11
Other nonmalignant disease	viii	2	3	4	5	2
Full body irradiation
No	113	32	32	46	81	28
Yes	244	68	37	54	207	72
Chronic graft-versus-host disease
No	108	30	xx	29	88	31
Yes	178	fifty	twenty	29	158	55
Not applicable	71	20	29	42	42	xv

Table A3.

Expected and Observed Deaths According to Cause for Person-Years at Risk at Age 44 and Younger (14,821 full person-years) and at Age 45 Years and Older (viii,107 total person-years)

Cause	Expected	National Death Index		Reviewed
		Observed	SMR*	Observed	SMR*
Historic period 44 years and younger
Major ICD affliction categories
Cardiovascular	ii.ix	half dozen	two.7	eleven	3.9
Congenital	0.2	0	0	0	0
Digestive	0.8	4	6.ii	iv	4.9
Endocrine	0.half dozen	1	2.2	1	1.7
External	8.six	vii	1.i	8	1.0
Genitourinary	0.2	2	15.0	1	5.9
Infection, hepatitis C	0.1	iii	48.8	six	77.1
Infection, other	1.3	6	5.ix	17	13.3
Mental	0.iv	0	0	0	0
Musculoskeletal	0.1	0	0	0	0
Tumour, nonhematologic	two.2	37	22.0	45	21.1
Tumour, hematologic	0.4	—†	—†	iv	9.7
Neurologic	0.4	0	0	1	2.four
Pregnancy	< 0.1	0	0	0	0
Respiratory	0.five	12	29.nine	14	27.6
Skin	< 0.i	0	0	0	0
Other	0.eight	three	five.1	1	i.3
Undefined ICD categories
Recurrent illness	—	43	—	22	—
Chronic GVHD	—	—	—	22	—
Unknown	—	38	—	5	—
All causes	nineteen.7	162	8.2	162	8.2
Age 45 years and older
Major ICD disease categories
Cardiovascular	nineteen.one	25	1.6	28	1.6
Congenital	0.2	0	0	0	0
Digestive	three.two	2	0.8	one	0.three
Endocrine	2.8	2	0.9	1	0.iv
External	4.7	five	1.3	six	1.4
Genitourinary	1.0	1	1.2	2	2.2
Infection, hepatitis C	0.3	9	31.ix	xi	34.5
Infection, other	1.7	6	4.three	18	11.v
Mental	0.8	0	0	0	0
Musculoskeletal	0.3	0	0	0	0
Neoplasm, nonhematologic	eighteen.ane	35	2.3	39	2.3
Neoplasm, hematologic	one.8	—†	—†	five	three.0
Neurologic	1.3	two	one.8	3	2.four
Pregnancy	< 0.i	0	0	0	0
Respiratory	4.2	10	2.ix	11	2.eight
Pare	0.i	0	0	0	0
Other	ane.0	i	1.3	0	0
Undefined ICD categories
Recurrent disease	—	63	—	47	—
Chronic GVHD	—	—	—	10	—
Unknown	—	34	—	13	—
All causes	threescore.4	195	3.two	195	three.2

Footnotes

Supported by Grants No. CA18029 and CA15704 from the National Cancer Establish and HL36444 from the National Heart, Lung, and Blood Institute.

Authors' disclosures of potential conflicts of involvement and author contributions are plant at the end of this article.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Paul J. Martin, Barry E. Storer

Financial support: Paul J. Martin

Administrative support: Paul J. Martin, George Due west. Counts Jr, Frederick R. Appelbaum, Rainer F. Storb

Provision of report materials or patients: Paul J. Martin, Jean E. Sanders, H. Joachim Deeg, Mary E.D. Flowers, Rainer F. Storb

Collection and assembly of data: Paul J. Martin, George W. Counts Jr, H. Joachim Deeg, Barry E. Storer

Data analysis and interpretation: Paul J. Martin, Frederick R. Appelbaum, Stephanie J. Lee, Jean Eastward. Sanders, John A. Hansen, Barry Eastward. Storer

Manuscript writing: Paul J. Martin, Frederick R. Appelbaum, Stephanie J. Lee, Jean East. Sanders, H. Joachim Deeg, Mary E.D. Flowers, Karen L. Syrjala, John A. Hansen, Barry E. Storer

Final approving of manuscript: Paul J. Martin, George W. Counts Jr, Frederick R. Appelbaum, Stephanie J. Lee, Jean Eastward. Sanders, H. Joachim Deeg, Mary E.D. Flowers, Karen L. Syrjala, John A. Hansen, Rainer F. Storb, Barry E. Storer

REFERENCES

1. Thomas ED. A history of bone marrow transplantation. In: Appelbaum FR, Forman SJ, Negrin SJ, Blume KG, editors. Thomas' Hematopoietic Jail cell Transplantation. ed 4. Malden, MA: Blackwell Publishing; 2009. pp. 3–7. [Google Scholar]

2. Horowitz MM. Uses and growth of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin SJ, Blume KG, editors. Thomas' Hematopoietic Cell Transplantation. ed four. Malden, MA: Blackwell Publishing; 2009. pp. fifteen–21. [Google Scholar]

3. Duell T, van Lint MT, Ljungman P, et al. Health and functional status of long-term survivors of bone marrow transplantation. Ann Intern Med. 1997;126:184–192. [PubMed] [Google Scholar]

iv. Socié G, Stone JV, Wingard JR, et al. Long-term survival and late deaths later allogeneic bone marrow transplantation. N Engl J Med. 1999;341:14–21. [PubMed] [Google Scholar]

5. Bhatia Due south, Robison LL, Francisco L, et al. Late mortality of autologous hematopoietic-cell transplantation: Report from the Os Marrow Transplant Survivor Written report. Blood. 2005;105:4215–4222. [PMC gratuitous article] [PubMed] [Google Scholar]

6. Pond GR, Lipton JH, Messner HA. Long-term survival after claret and marrow transplantation: Comparison with an age- and gender-matched normative population. Biol Blood Marrow Transplant. 2006;12:422–429. [PubMed] [Google Scholar]

7. Bhatia S, Francisco 50, Carter A, et al. Late mortality subsequently allogeneic hematopoietic cell transplantation and functional status of long-term survivors: Study from the Bone Marrow Transplant Survivor Study. Claret. 2007;110:3784–3792. [PMC free article] [PubMed] [Google Scholar]

8. Rizzo JD, Curtis RE, Sobocinski KA, et al. Solid cancers after allogeneic hematopoietic jail cell transplantation. Blood. 2009;113:1175–1183. [PMC complimentary article] [PubMed] [Google Scholar]

9. Hudson MM, Jones D, Boyett J, et al. Late mortality of long-term survivors of childhood cancer. J Clin Oncol. 1997;15:2205–2213. [PubMed] [Google Scholar]

ten. Mertens Air conditioning, Yasui Y, Neglia JP, et al. Belatedly mortality in five-year survivors of childhood and adolescent cancer: The Babyhood Cancer Survivor Study. J Clin Oncol. 2001;19:3163–3172. [PubMed] [Google Scholar]

xi. Möller TR, Garwicz Due south, Barlow 50, et al. Decreasing tardily bloodshed amongst v-year survivors of cancer in childhood and boyhood: A population-based report in the Nordic countries. J Clin Oncol. 2001;19:3173–3181. [PubMed] [Google Scholar]

12. Cardous-Ubbink MC, Heinen RC, Langeveld NE, et al. Long-term cause-specific bloodshed among five-year survivors of childhood cancer. Pediatr Claret Cancer. 2004;42:563–573. [PubMed] [Google Scholar]

13. MacArthur AC, Spinelli JJ, Rogers PC, et al. Mortality amid five-twelvemonth survivors of cancer diagnosed during childhood or adolescence in British Columbia, Canada. Pediatr Claret Cancer. 2007;48:460–467. [PubMed] [Google Scholar]

fourteen. Bluhm EC, Ronckers C, Hayashi RJ, et al. Cause-specific mortality and second cancer incidence subsequently non-Hodgkin lymphoma: A report from the Childhood Cancer Survivor Written report. Claret. 2008;111:4014–4021. [PMC gratis article] [PubMed] [Google Scholar]

15. Mertens Air-conditioning, Liu Q, Neglia JP, et al. Cause-specific late mortality among 5-year survivors of babyhood cancer: The Babyhood Cancer Survivor Study. J Natl Cancer Inst. 2008;100:1368–1379. [PMC free commodity] [PubMed] [Google Scholar]

16. Armstrong GT, Liu Q, Yasui Y, et al. Late bloodshed amidst five-year survivors of childhood cancer: A summary from the Babyhood Cancer Survivor Written report. J Clin Oncol. 2009;27:2328–2338. [PMC free article] [PubMed] [Google Scholar]

17. Messite J, Stellman SD. Accuracy of death document completion: The need for formalized physician training. JAMA. 1996;275:794–796. [PubMed] [Google Scholar]

eighteen. Smith Sehdev AE, Hutchins GM. Bug with proper completion and accuracy of the cause of death statement. Arch Intern Med. 2001;161:277–284. [PubMed] [Google Scholar]

19. de Lima Chiliad, Strom SS, Keating M, et al. Implications of potential cure in astute myelogenous leukemia: Development of subsequent cancer and return to work. Blood. 1997;90:4719–4724. [PubMed] [Google Scholar]

brookscaloque.blogspot.com

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834427/

Share this post