The introduction of reduced-intensity conditioning regimens has allowed elderly patients with preexisting comorbidities access to the potentially curative allogeneic stem cell transplantation. Patient’s comorbidities at the time of treatment consideration play a significant role in transplant outcome in terms of both overall survival (OS) and nonrelapse mortality (NRM). The hematopoietic stem cell transplantation comorbidity index (HCT-CI) quantifies these patient specific risks and has established itself as a major tool in the pretransplant assessment of patients. Many single center and multicenter studies have assessed the HCT-CI score and reported conflicting outcomes. The present study aimed to evaluate the HCT-CI in a single large European transplant centre. 245 patients were retrospectively analyzed and the predictive value of the score was assessed with respect to OS and NRM. We confirm that the HCT-CI predicts outcome for both OS and NRM. Moreover, we identified age of the patient as an independent prognostic parameter for OS. Incorporation of age in the HCT-CI would improve its ability to prognosticate and allow the transplant physician to assess the patient specific risks appropriately at the time of counseling for transplant.
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapeutic option for a variety of haematological malignancies [
The Charlson Comorbidity Index (CCI) has been used to predict treatment-related mortality (TRM) risks for various solid tumours by assigning weights for 19 chronic conditions based on their association with mortality [
We retrospectively analyzed all patients treated with HSCT between 2000 and 2009 at our Stem Cell Transplant Unit, University Hospital of Cologne, Germany. All consecutive patients identified within the timeframe, irrespective of the underlying disease and conditioning regimen, were included in the study. All patients gave their informed consent to the planned treatment schedule as well as to anonymized data collection and analysis. Antibiotics were routinely administered as prophylaxis against bacterial (Ciprofloxacin), fungal (Fluconazole), pneumocystis carinii (Pentamidine), and herpes virus (Aciclovir) infections. Early detection of cytomegalovirus antigenemia by twice weekly screening and preemptive ganciclovir therapy, in patients with early signs of reactivation, were routinely performed in all patients.
All relevant investigations were performed within the routine workup for transplant. A questionnaire was developed based on the HCT-CI scoring system [
Results were analyzed as of November 30, 2013. Overall survival (OS) was defined as time to death from transplantation irrespective of cause. Nonrelapse mortality (NRM) was defined as time to death from transplant without evidence of disease relapse or recurrence. Survival curves for OS and NRM were estimated by the Kaplan-Meier method and differences tested by log rank test. A two-sided
We identified 245 patients, 109 female and 136 male, who consecutively received an allogeneic HSCT between 2000 and 2009 in our institution. The demographic data is summarised in Table
Patient characteristics.
Characteristic |
|
---|---|
Male/female | 136/109 (56/44) |
Age | |
<31 | 40 (16.3) |
31–40 | 48 (19.6) |
41–50 | 74 (30.2) |
51–60 | 56 (22.8) |
61–70 | 27 (11) |
Diagnoses | |
AML | 98 (40.2) |
ALL | 45 (18.3) |
MDS/sAML | 13 (5.3) |
CML | 19 (7.7) |
CLL | 15 (6.1) |
NHL | 18 (7.3) |
HD | 18 (7.3) |
MM | 8 (3.3) |
SAA/FA | 7 (2.8) |
MPN | 4 (1.6) |
Conditioning regimen | |
BuCy | 44 (18) |
Cyc/TBI | 27 (11) |
TBI/VP16 | 9 (3.7) |
FLAMSA/TBI | 42 (17.1) |
FLU/MEL140 | 23 (9.4) |
FLU/TREO | 16 (6.5) |
FLAMSA no TBI | 6 (2.4) |
TBI 2 Gy | 7 (2.9) |
TBI 2 Gy/FLU | 28 (11.4) |
Other | 43 (17.6) |
Donor type | |
Related | 87 (35.5) |
Unrelated | 158 (64.5) |
Cell source | |
PBMC | 230 (94) |
Marrow | 12 (4.9) |
N.a. | 3 (1.1) |
Prior HSCT | |
No prior HSCT | 223 (91) |
Prior autologous PBSC | 22 (9) |
AML: acute myeloid leukaemia; ALL: acute lymphocytic leukaemia; MDS/sAML: myelodysplastic syndrome/secondary AML; CML: chronic myeloid leukaemia; CLL: chronic lymphocytic leukaemia; NHL: non-Hodgkin’s lymphoma; HD: Hodgkin’s lymphoma; MM: multiple myeloma; SAA/FA: severe aplastic anemia/fanconi anemia; MPN: myeloproliferative neoplasm; Bu: busulfan, Cy: cyclophosphamide, TBI: total body irradiation, VP16: etoposide, FLAMSA: fludarabine, Ara-C and Amsacrine, Mel: melphalan, Flu: fludarabine, Treo: treosulfan, PBMC: peripheral blood mononuclear cells; HSCT: hematopoietic stem cell transplantation.
The patients could be classified into eight groups based on their HCT-CI score (Table
Risk groups based on HCT-CI score.
Number (%) | |
---|---|
HCT-CI score | |
0 | 49 (20) |
1 | 82 (33.5) |
2 | 38 (15.5) |
3 | 38 (15.5) |
4 | 20 (8.2) |
5 | 12 (4.9) |
6 | 5 (2) |
7 | 1 (0.4) |
Risk groups according to HCT-CI | |
Low (score 0) | 49 (20) |
Intermediate (score 1-2) | 120 (49) |
High (score >2) | 76 (31) |
Overall survival based on HCT-CI score. (a) Patients are categorised into three risk groups: HCT-CI 0 = low risk; HCT-CI 1-2 = intermediate risk; HCT-CI > 2 = high risk. (b) Patients are categorised into five risk groups HCT-CI 0, 1, 2, 3, and >3.
Nonrelapse mortality based on HCT-CI. (a) Patients are categorised into three risk groups: HCT-CI 0 = low risk; HCT-CI 1-2 = intermediate risk; HCT-CI >2 = high risk. (b) Patients are categorised into five risk groups HCT-CI 0, 1, 2, 3, and >3.
Cardiac, pulmonary, and hepatic comorbidities were most commonly observed within the study population. In the HCT-CI scoring system, patients with a history of cardiac arrhythmias, coronary vascular disease, myocardial infarction or congestive heart failure, or an ejection fraction below 50% are given a score of 1, whereas heart valve disease of grade 3 or 4 excluding mitral valve prolapse is given a score of 3. In our cohort 20/245 (8%) patients scored 1 due to cardiac comorbidities and 2/245 (0.8%) with heart valve disease had a score of 3. 19 of the 20 patients with a score of 1 and both patients with a score of 3 died during followup highlighting the significant role that cardiac comorbidities play in relation to transplant outcome (
Overall survival based on scores assigned for (a) cardiac or (b) pulmonary comorbidities.
HCT-CI score allows the classification of the patients based on their lung function tests into three groups irrespective of the underlying cause. Moderate pulmonary comorbidity defined as diffuse lung capacity (DLCO) and/or FEV1 66–80% or dyspnoea on slight activity allocates a score of 2 and severe pulmonary comorbidity defined as (DLCO) and /or FEV1 ≤ 65% or dyspnoea at rest or oxygen requirement allocates a score of 3. Mild pulmonary comorbidity is defined as (DLCO) and/or FEV1 81–90% or dyspnoea at moderate activity is not included in the HCT-CI scoring system. We analysed the impact of pulmonary function prior to transplant on transplant outcome. 179/245 (73%) patients had a normal lung function prior to transplantation (score 0), 45 a moderate pulmonary comorbidity (score 2), and 21 severe pulmonary comorbidity (score 3). Pulmonary comorbidity had a statistically significant influence on overall survival (
17 (7%) patients had a mild hepatic comorbidity (score 1) (bilirubin > ULN to 1.5 × ULN or AST/ALT > ULN to 2.5 × ULN) and 1 patient additional liver cirrhosis with portal hypertension (score 3). 6/17 patients with a score of 1 and the patient with score 3 died during followup. In our cohort hepatic comorbidity was not associated with a statistically significant impact on OS after transplant. 27 (11%) patients had a prior malignancy; however this did not influence OS following transplant. A preexisting infection requiring treatment at day 0 was identified in 124 (50%) patients giving these patients a score of 1. After transplant more patients (92/121, 76%) died in the subgroup without infections, that is, with a score of 0 in comparison to the group with infections (72/124, 58%). Lack of influence of preexisting infections requiring treatment on OS may be because of the longer duration of followup and the influence of the underlying disease as well as other comorbidities on outcome.
Comorbidities related to inflammatory bowel disease, diabetes, cerebrovascular disease, psychiatric disturbance, peptic ulcer, obesity, preexisting rheumatologic disease, or renal impairment were infrequent and not associated with a significant impact on OS.
Age alone is an important factor that influences the decision to transplant as well as the conditioning regimen employed [
Risk groups based on HCT-CI and age along with the OS of each subgroup.
Age groups | HCT-CI |
|
Median OS (months) | Events |
---|---|---|---|---|
20–30 | 0–2 | 34 (85.0) | 62 | 17 |
>2 | 6 (15.0) | 11 | 4 | |
Total | 40 | 62 | 21 | |
|
||||
31–40 | 0–2 | 37 (77.1) | 22 | 23 |
>2 | 11 (22.9) | 13 | 7 | |
Total | 48 | 20 | 30 | |
|
||||
41–50 | 0–2 | 44 (59.5) | 8 | 26 |
>2 | 30 (40.5) | 8 | 21 | |
Total | 74 | 8 | 47 | |
|
||||
51–60 | 0–2 | 36 (64.3) | 6 | 26 |
>2 | 20 (35.7) | 5 | 19 | |
Total | 56 | 6 | 45 | |
|
||||
61–70 | 0–2 | 18 (66.7) | 6 | 14 |
>2 | 9 (33.3) | 6 | 8 | |
Total | 27 | 6 | 22 |
Overall survival based on HCT-CI scores and age. Patients are classified into different age groups from 20–39, 40–49, 50–59, 60–69, and >70.
Next, we allocated the patients within the different age groups to the calculated HCT-CI scores, HCT-CI low/intermediate with a score of 0–2, and high risk with a score above 2. HCT-CI of 0–2 was more frequent in each age group (Table
Increase in the average age of the cancer patients has led to a concerted effort in developing scoring systems which help in predicting outcomes following treatment [
Sorror et al. [
Comparison of data with Sorror et al. [
Chemnitz et al. | Sorror et al. [ |
Birninger et al. [ | |
---|---|---|---|
245 | 347 | 370 (only 340 included) | |
Median age | 45 | 44.5 | 53 |
Related donors (%) | 35.5 | 58 | 34.1 |
HCT-CI (low 0) | 49 (20%) | 132 (38%) | 18 (5%) |
HCT-CI (intermediate 1, 2) | 120 (49%) | 118 (34%) | 70 (21%) |
HCT-CI (High ≥3) | 76 (31%) | 97 (28%) | 252 (74%) |
Prevalence of pulmonary comorbidity | 27% | 34% | 34% |
Prevalence of cardiac comorbidity | 9% | 7% | 56% |
Prevalence of hepatic comorbidity | 7% | 20% | 51% |
Birninger et al. [
Age was excluded from the HCT-CI score as a comorbidity, as it is already an exclusion criteria for the transplant and crucial in deciding the conditioning regimen but was used to adjust the Cox regression hazards. The influence of age on transplant outcome has been disputed [
A big drawback of our data is the possibility of erroneous scoring which could have incurred due to false subjective interpretation during retrospective data collection. It is possible that comorbidities such as inflammatory bowel disease, cerebrovascular disease, obesity, peptic ulcer, and rheumatologic comorbidities were not documented and hence missed out resulting in a wrong final score. Wrong scoring based on subjective diagnosis criteria, for example, by assessing infectious or psychiatric comorbidities cannot be excluded. Thus, a strict and comprehensible web based calculation tool used prospectively is clearly helpful for standardized evaluation of the patients as suggested by Sorror et al. [
In conclusion we performed a retrospective analysis on a large single center patient cohort aiming to assess the HCT-CI as a predictive tool for OS and NRM post HSCT. HCT-CI was found to predict outcome for both OS and NRM, thereby representing a helpful instrument in patient counselling. The HCT-CI was developed on a patient cohort observed over a 2-year period. We observe the impact of pretransplant comorbidities persisting even after 65 months, further highlighting the importance of comorbidities on outcome. Possible errors in scoring the patients cannot be excluded and can be minimized by using a web based tool as well as prospective data collection.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Jens Chemnitz and Geothy Chakupurakal contributed equally to this work.