ORIGINAL ARTICLE

http://dx.doi.org/10.5546/aap.2016.eng.337

Validation of the Hematopoietic Cell Transplantation-Specific Comorbidity Index in a retrospective cohort of children and adolescents who received an allogeneic transplantation in Argentina

 

Carlos M. Figueroa Turienzo, M.D.^a, Carolina Cernadas, M.D.^b, Mariana Roizen, M.D.^a, Silvia Pizzi, M.D.^a and Raquel Staciuk, M.D.^a

a. Division of Bone Marrow Transplant of Hospital Garrahan.
b. Research Coordination of Hospital Garrahan.

E-mail address: Carlos M. Figueroa Turienzo, M.D.: cfigueroa59@yahoo.com.ar

Funding: None.

Conflict of interest: None.

Received: 12-13-2015
Accepted: 02-10-2016

 

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ABSTRACT

Introduction. Hematopoietic cell transplantationis a therapy with a risk of transplant-related mortality (TRM), which may vary depending on prior comorbidities. The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) is an instrument developed to measure this risk. There are very few reports on its use in pediatrics. The objective of this study was to validate the HCT-CI in a pediatric cohort of allogeneic hematopoietic-cell transplantation recipients in Argentina.
Population and methods. Retrospective cohort made up of 140 transplant patients at Hospital J. P. Garrahan between 2008 and 2012. Medical records were reviewed to identify patient history and course. The HCT-CI was estimated for each patient, who was classified as having a low (score: 0), intermediate (score: 1-2) or high (score: >3) risk. Survival was estimated for each group using the Kaplan-Meier method and compared with the log-rank test. For malignancies, relapse was considered an event consistent with TRM. A p value <0.05 was considered significant.
Results. The median score in the HCT-CI was 1 (r: 0-6). A score of 0 was observed in 45.7% of patients, 1-2 in 40.7%, and >3 in 13.6%. The most common comorbidities included obesity, infection, pulmonary and liver involvement. TRM was 14.1% among patients with a score of 0; 43.7% with a score of 1-2, and 52.6% with a score >3. Differences were observed among the survival curves of the three groups (p = 0.01).
Conclusion. The HCT-CI demonstrated to be an effective tool to predict the risk of TRM in our setting.

Key words: Comorbidity; Hematopoietic stem cell transplantation; Non-relapse mortality; Pediatrics.

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INTRODUCTION

In spite of advances in support therapy, hematopoietic-cell transplantation (HCT) still presents a high risk of mortality.¹

Previous organ involvement or a history of infection may increase the likelihood of complications or transplant-related mortality (TRM).^2-5

When a patient has several concurrent risk factors, it becomes difficult to estimate their individual risk. Reducing the level of uncertainty in this regard may help to define a patient's eligibility for HCT, to select a more acceptable conditioning regimen, and to facilitate an adequate consent process.

In 2005, Sorror et al. published the results of the validation of a new instrument to solve such uncertainty, the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI)⁶, based on the general comorbidity index developed by Charlson.⁷ Taking the HCT-CI into account, authors were able to define three TRM risk categories according to comorbidities existing before transplantation. Several subsequent studies, including two multicenter, prospective studies, confirmed the usefulness of the HCT-CI,^8-12 although dissimilar results were reported by some sites.^13,14

In 2011, Smith et al. described the results of implementing the HCT-CI in a retrospective cohort of 252 pediatric patients followed up at four sites in the USA.¹⁵ In this study, the HCT-CI demonstrated adequate power to predict TRM and overall survival.

The primary objective of this study was to assess HCT-CI effectiveness to predict TRM risk and survival in a retrospective cohort of children and adolescents who received an allogeneic HCT in an Argentinean site. The secondary objectives included exploring TRM causes and the impact of a pre- and post-transplant invasive fungal infection (IFI).

POPULATION AND METHODS

Retrospective cohort made up of a consecutive sample of 140 patients who received an allogeneic HCT between January 1^st, 2008 and December 31^st, 2012 at the Division of Bone Marrow Transplant of Hospital de Pediatría Prof. Dr. Juan P. Garrahan.

All patients received antibiotic prophylaxis with ciprofloxacin and fluconazole during the neutropenia period, acyclovir prophylaxis for herpes simplex, and trimethoprimsulfamethoxazole or pentamidine prophylaxis for Pneumocystis jiroveci. The management of cytomegalovirus infection consisted of its early treatment, based on viral load surveillance weekly. Low-dose heparin prophylaxis was administered for hepatic veno-occlusive disease. Prevention of graft-versus-host disease (GvHD) consisted in the administration of a calcineurin inhibitor (cyclosporin A for related donor transplants or tacrolimus for unrelated donor transplants) in association with methotrexate for bone marrow or peripheral blood recipients. For umbilical cord blood recipients, GvHD prophylaxis consisted of the combination of a calcineurin inhibitor and methylprednisolone or mycophenolate.

Pre-transplant assessment included lab tests, renal and liver function tests, an echocardiogram, an abdominal ultrasound, chest and sinus computed tomography, and lung function tests as of six years old.

Strategy: One of the investigators reviewed each patient's medical record, including an assessment record sheet completed at the time of admission to the transplant unit. Sorror's recommendations¹⁶ were followed to record data regarding the HCT-CI.

If necessary, the lab database was also reviewed. In the case of uncertainty regarding a score assignment, a discussion was held among all investigators.

The following data were recorded: sex, age at the time of transplant, diagnosis, date of HCT, date of transplant-related death, date of relapse, date of most recent control, donor type, conditioning type, and source of hematopoietic stem cells. The history of pre-HCT IFI and the following post-transplant events were also recorded: acute GvHD (grade 2-4 and 3-4), chronic GvHD (limited and extensive), IFI, and known TRM risk factors.^1,5

HCT-CI: The index score is the result of assessing 17 items at the time of patient's admission for HCT, and each result is assigned a specific score, which is the result of its relevance as a risk factor in the original study.⁶ The results for each of these items were recorded based on authors' specifications and the index score was estimated for each patient. The same risk categories used in the original study were used here: mild for a score of 0, intermediate for a score of 1-2, and high for a score ≥3.

Statistical analysis: The different outcome measures were summarized as percentage or median and range, as applicable. The rate of acute and chronic GvHD, IFI, and TRM were compared between related and unrelated donor HCT using the Fisher's test. Logistic regression was used to analyze the association between TRM and the following risk factors: grade 2-4 and grade 3-4 acute GvHD, extensive chronic GvHD, and pre-and post-transplant IFI. The association between the HCT-CI risk category and the risk of TRM was assessed by estimating survival of each group using the Kaplan-Meier method, and it was then compared to a log-rank test. For malignancies, relapse was considered an event consistent with TRM. A p value <0.05 was regarded as significant. The statistical software used was Stata 9.

The protocol was assessed and approved by the Research Review Committee and Ethics Committee of the hospital.

RESULTS

Table 1 describes the general characteristics of the sample. As observed, the main indication for HCT was acute leukemia; 45.8% were in second remission, and 2.7%, in third remission.

Table 1. General characteristics of patients

Also, 55% of patients had grade 2-4 GvHD, and 11.4% grade 3-4 GvHD (8.3% in related donor HCT versus 18.3% in unrelated donor HCT, p= 0.14).

The rate of chronic extensive GvHD was 28.6% (25% in related donor HCT versus 36.4% in unrelated donor HCT, p = 0.23).

A history of pre-HCT IFI was observed in 7.8% of patients while 19.3% had post-transplant IFI (15.3% in related donor HCT versus 27.3% in unrelated donor HCT, p= 0.11).

The TRM was 27.1%, and a worse clinical course was observed in unrelated donor HCT (19.8% in related donor HCT versus 42.8% in unrelated donor HCT, p= 0.007).

The most common causes of TRM were infections (92%), in association with active or corticosteroid-refractory GvHD in 39% of cases. The latter was observed in 21% of GvHD cases.

Table 2 describes the rate of documented infections that caused TRM.

Table 2. Infections documented as a cause of mortality related to hematopoietic cell transplantation

The presence of acute grade 3-4 GvHD (odds ratio [OR]: 7.8, confidence interval [CI]: 2.4-25.1, p= 0.001) and post-HCT IFI (OR: 2.7, CI: 1.1-7, p= 0.039) was associated with a greater TRM. No association was demonstrated between TRM and a history of IFI (OR: 1.4, CI: 0.4-5.9) or the presence of chronic extensive GvHD (OR: 1.1, CI: 0.4-2.3).

Hematopoietic Cell Transplantation-Specific Comorbidity Index

The median score was 1 (r: 0-6). A score of 0 was assigned to 45.7% of patients; of 1-2, to 40.7%; and >3 to 13.6%. No significant differences were observed between related and unrelated donor HCT recipients.

Table 3 describes comorbidities observed in the sample. The most common comorbidities included obesity, infection, and pulmonary and liver involvement.

Table 3. Rate of comorbidities evaluated with the Hematopoietic Cell Transplantation-Specific Comorbidity Index

The TRM in patients whose score was 0 was 14.1% (10.6% in related donor HCT versus 23.5% in unrelated donor HCT, p= 0.23); in those whose score was 1-2, 43.7% (27.3% in related donor HCT versus 80% in unrelated donor HCT, p= 0.1); and in those whose score was ≥3, 52.6% (50% in related donor HCT versus 57.1% in unrelated donor HCT).

A score of 0 was associated with a lower risk of TRM in both related donor HCT (OR: 0.30, CI: 0.090.9, p= 0.03) and unrelated donor HCT (OR: 0.25, CI: 0.06-0.95, p= 0.04) recipients.

Patients with comorbidities (score >0) tended to have post-transplant IFI more frequently than those without comorbidities (25% versus 12.5%, p= 0.08) and grade 3-4 acute GvHD (15.79 versus 6.25%, p= 0.1).

Figure 1 shows survival curves with significant differences among groups (p= 0.01)

Figure 1. Survival curves by risk group according to the Hematopoietic Cell Transplantation-Specific Comorbidity Index

DISCUSSION

The study findings show that the HCT-CI predicts the risk of TRM in pediatric patients seen in our setting.

The possibility of unrelated donors, advances made in support management, and diversified conditioning regimens have allowed widening the base of HCT-eligible patients.¹⁷ This results in HCT candidates being more heterogeneous and in the inclusion of patients with a more significant organ involvement prior to transplant, so it becomes more difficult to compare different groups and to make individual predictions regarding the likelihood of survival and risk of TRM.

The Charlson Comorbidity Index, which is used to measure different diseases, was combined with the performance status and demonstrated an adequate predictive power for TRM, but its sensitivity to detect comorbidities in HCT candidates was limited.¹⁸ Based on the index developed by Charlson, Sorror et al. designed a new indicator, the HCT-CI, which includes common comorbidities in HCT recipients, such as infections and psychiatric disorders, and demonstrated a higher sensitivity and predictive power.⁶

Although the sample used to develop and validate the HCT-CI included pediatric patients (authors described that the age ranged from 0.8 to 72.7 years old), the median age of patients was 44 years old, and children and adolescents were not assessed as a sub-group. In 2011, Smith et al. published the only study we could find using the HCT-CI exclusively in a population of children and adolescents.¹⁵ Authors described, with variations among the different participating sites, that 55% of patients had a score of 0, 21% a score of 1-2, and 24% a score of 3 or more. The percentage of patients without comorbidities in that sample was higher than that observed in the original study conducted to validate the HCT-CI, where the percentage of patients with a score of 0 was 38%, and that with a score of 3 or more was also 38%.⁶

In our sample, the percentage of patients with a score of 0 was 46%, which is an intermediate value; however, the percentage of patients with a high risk was smaller than that observed in the above-mentioned studies.

A question arises from these data: do pediatric HCT recipients have fewer comorbidities than older patients and/or do they have specific comorbidities undetected by the HCT-CI? Even though comorbidity prevalence increases with age¹⁹, some factors may lessen the HCT-CI's sensitivity in pediatric patients. Firstly, some pediatric conditions which are an indication for HCT, such as inborn errors of metabolism or constitutional bone marrow failure syndrome, are associated with comorbidities, such as developmental disorders or malformations not recorded by the HCT-CI. Secondly, a 2 mg/dl limit for blood creatinine (which at our site is considered an exclusion criterion for transplant eligibility) to define severe kidney involvement may undervalue significant reductions in glomerular filtration rate in toddlers whose creatinine values are lower. Estimating glomerular filtration rate by combining blood creatinine values with correction factors that account for age and/or anthropometric data is common practice in pediatrics, but should be assessed in future studies.²⁰ Performing pulmonary function tests in preschoolers is difficult, and this may be another reason why pulmonary involvement is underrecorded in this age group. Implementing new pulmonary function test techniques in infants and preschoolers, which are now being used more and more to follow-up patients with a significant clinical history in clinical practice, may improve this aspect of the assessment.²¹

Pulmonary and liver involvement, together with infections, were the most common comorbidities observed in the pediatric cohort studied by Smith et al.¹⁵ In our cohort, these comorbidities were less common than obesity, which reached a prevalence of 20% and was the most common. This percentage is much higher than that referred in the sample studied by Smith et al., where obesity is somewhat above 1.1%, but such difference may be due to methodological aspects. While in the study by Smith et al. obesity was defined as a body mass index of 35 kg/ m² or more, criterion used for adults, in our study we set the limit at the 95^th percentile for age in accordance with the recommendations later published by Sorror.¹⁶ As per this criterion, obesity prevalence in our sample is even lower than that observed by other authors, such as White et al.²²

Infections, either associated with GvHD or not, were the main cause of TRM in our sample. This is consistent with previous studies on TRM.²³ Data obtained from the literature are useful to understand the relationship between pre-HCT comorbidities and these events. Sorror et al. reported, in a recent multicenter study, an association between HCT-CI and the risk for more severe forms of GvHD²⁴, consistent with the trend observed in our sample. In addition, Bayraktar et al. observed that the HCT-CI was associated with a higher TRM among HCT recipients who were admitted to the intensive care unit.²⁵ Given that severe GvHD is a risk factor for infections²⁶, it is logical to consider that the most common association between comorbidities and TRM in pediatric patients is the result, in most cases, of multiple organ failure secondary to an interaction between GvHD and infections rather than the primary multiple organ failure caused by conditioning regimens.

The rate of TRM in our sample shows a significant difference between related and unrelated donor HCT recipients. Although studies conducted in sites with major experience in unrelated donor transplants have reported similar survival rates with both donor types²⁷, other studies have found differences in TRM by donor type, a difference that has tended to reduce over the past years.²⁸

During the study period, the median time at our site, since the start of the search for an unrelated donor and transplantation was six months. Such delay exposes patients with malignancies to higher cumulative chemotherapy doses, and those with hematologic failure or immunodeficiencies, to a higher risk for infections or iron overload. However, in our study, such delay was not observed to be reflected in a higher HCT-CI score among recipients of unrelated donor transplants. This may be either due to the reduced number of unrelated donor HCT recipients in our sample or is a limitation of the HCT-CI's sensitivity.

In this regard, it is worth noting a recently published study by Vaughn et al., which shows that combining the HCT-CI with biological markers, such as ferritin, albumin, and platelet count, increases the instrument's discriminating power.²⁹

In conclusion, according to our study, the HCT-CI is a useful tool to predict survival and assess the mortality risk among children and adolescents who received an HCT in our setting. Its use in clinical practice and research may help to improve consent processes and decisionmaking in planning and managing transplants.³⁰ ■

REFERENCES

1. Gooley TA, Chien JW, Per gam SA, Hingorani S, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010;363(22):2091-101.         [ Links ]

2. Mancuzo EV, Rezende NA. Hematopoietic stem cell transplantation: pulmonary function tests and posttransplant mortality. J Bras Pneumol 2011;37(5):598-606.         [ Links ]

3. Hertenstein B, Stefanic M, Schmeiser T, Scholz M, et al. Cardiac toxicity ofbone marrow transplantation: predictive value of cardiologic evaluation before transplant. J Clin Oncol 1994;12(5):998-1004.         [ Links ]

4. Lee SH, Yoo KH, Sung KW, Koo HH, et al. Hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation: incidence, risk factors, and outcome. Bone Marrow Transplant 2010;45(8):1287-93.         [ Links ]

5. Martino R, Parody R, Fukuda T, Maertens J, et al. Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: a retrospective survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Blood 2006;108(9):2928-36.         [ Links ]

6. Sorror ML, Maris MB, Storb R, Baron F, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005;106(8):2912-9.         [ Links ]

7. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40(5):373-83.         [ Links ]

8. Raimondi R, Tosetto A, Oneto R, Cavazzina R, et al. Validation of the Hematopoietic Cell Transplantation-Specific Comorbidity Index: a prospective, multicenter GITMO study. Blood 2012;120(6):1327-33.         [ Links ]

9. Sperr WR, Wimazal F, Kundi M, Baumgartner C, et al. Comorbidity as prognostic variable in MDS: comparative evaluation of the HCT-CI and CCI in a core dataset of 419 patients of the Austrian MDS Study Group. Ann Oncol 2010;21(1):114-9.         [ Links ]

10. Sorror Ml, Giralt S, Sandmaier BM, De Lima M, et al. Hematopoietic cell transplantation specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences. Blood 2007;110(13):4606-13.         [ Links ]

11. Zipperer E, Pelz D, Nachtkamp K, Kuendgen A, et al. The hematopoietic stem cell transplantation comorbidity index is of prognostic relevance for patients with myelodysplastic syndrome. Haematologica 2009;94(5):729-32.         [ Links ]

12. Sorror ML, Logan BR, Zhu X, Rizzo JD, et al. Prospective validation of the predictive power of the hematopoietic cell transplantation comorbidity index: a center for International Blood and Marrow Transplant Research Study. Biol Blood Marrow Transplant 2015;21(8):1479-87.         [ Links ]

13. Guilfoyle R, Demers A, Bredeson C, Richardson E, et al. Performance status, but not the hematopoietic cell transplantation comorbidity index (HCT-CI), predicts mortality at a Canadian transplant center. Bone Marrow Transplant 2009;43(2):133-9.         [ Links ]

14. Birninger N, Bornhäuser M, Schaich M, Ehninger G, et al. The hematopoietic cell transplantation-specific comorbidity index fails to predict outcomes in high-risk AML patients undergoing allogeneic transplantation— investigation of potential limitations of the index. Biol Blood Marrow Transplant 2011;17(12):1822-32.         [ Links ]

15. Smith AR, Majhail NS, MacMillan ML, DeFor TE, et al. Hematopoietic cell transplantation comorbidity index predicts transplantation outcomes in pediatric patients. Blood 2011;117(9):2728-34.         [ Links ]

16. Sorror ML. How I assess comorbidities before hematopoietic cell transplantation. Blood 2013;121(15):2854-63.         [ Links ]

17. Storb RF, Champlin R, Riddell Sr, Murata M, et al. Non-myeloablative transplants for malignant disease. Hematology Am Soc Hematol Educ Program 2001:375-91.         [ Links ]

18. Artz AS, Pollyea DA, Kocherginsky M, Stock W, et al. Performance status and comorbidity predict transplant-related mortality after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2006;12(9): 954-64.         [ Links ]

19. Broemeling AM, Watson DE, Prebtani F. Population patterns of chronic health conditions, co-morbidity and healthcare use in Canada: implications for policy and practice. Healthc O 2008;11(3):70-6.         [ Links ]

20. Blufpand HN, Westland R, van Wijk JA, Roelandse-Koop EA, et al. Height-independent estimation of glomerular filtration rate in children: an alternative to the Schwartz equation. J Pediatr 2013;163(6):1722-7.         [ Links ]

21. Lum S. Lung function in preschool children: applications in clinical and epidemiological research. Paediatr Respir Rev 2006;7(Suppl 1):S30-2.         [ Links ]

22. White M, Murphy AJ, Hallahan A, Ware RS, et al. Survival in overweight and underweight children undergoing hematopoietic stem cell transplantation. Eur J Clin Nutr 2012;66(10):1120-3.         [ Links ]

23. Mateos MK, O'Brien TA, Oswald C, Gabriel M, et al. Transplant-related mortality following allogeneic hematopoeitic stem cell transplantation for pediatric acute lymphoblastic leukemia: 25-year retrospective review. Pediatr Blood Cancer 2013;60(9):1520-7.         [ Links ]

24. Sorror ML, Martin PJ, Storb RF, Bhatia S, et al. Pretransplant comorbidities predict severity of acute graft-versus-host disease and subsequent mortality. Blood 2014;124(2): 287-95.         [ Links ]

25. Bayraktar UD, Shpall EJ, Liu P, Ciurea SO, et al. Hematopoietic cell transplantation-specific comorbidity index predicts inpatient mortality and survival in patients who received allogeneic transplantation admitted to the intensive care unit. J Clin Oncol 2013;31(33):4207-14.         [ Links ]

26. Castagnola E, Bagnasco F, Bandettini R, Caviglia I, et al. Role of acute graft-versus-host disease in the risk of bacteremia and invasive fungal disease after allogeneic hemopoietic stem cell transplantation in children. Results from a singlecenter observational study. Biol Blood Marrow Transplant 2014;20(7):1068-73.         [ Links ]

27. Leung W, Campana D, Yang J, Pei D, et al. High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood 2011;118(2):223-30.         [ Links ]

28. Moore AS, Shaw PJ, Hallahan AR, Carter TL, et al. Haemopoietic stem cell transplantation for children in Australia and New Zealand, 1998-2006: a report on behalf of the Australasian Bone Marrow Transplant Recipient Registry and the Australian and New Zealand Children's Haematology Oncology Group. Med J Aust 2009;190(3): 121-5.         [ Links ]

29. Vaughn JE, Storer BE, Armand P, Raimondi R, et al. Design and validation of an augmented hematopoietic cell transplantation-comorbidity index comprising pretransplant ferritin, albumin, and platelet count for prediction of outcomes after allogeneic transplantation. Biol Blood Marrow Transplant 2015;21(8):1418-24.         [ Links ]

30. Bejanyan N, Bolwell BJ, Lazaryan A, Rybicki L, et al. Risk factors for 30-day hospital readmission following myeloablative allogeneic hematopoietic cell transplantation (allo-HCT). Biol Blood Marrow Transplant 2012;18(6):874-80.         [ Links ]