Scholarly article on topic 'Prognostic Factor and Quality of Life Analysis in 160 Patients Aged ≥60 Years with Hematologic Neoplasias Treated with Allogeneic Hematopoietic Cell Transplantation'

Prognostic Factor and Quality of Life Analysis in 160 Patients Aged ≥60 Years with Hematologic Neoplasias Treated with Allogeneic Hematopoietic Cell Transplantation Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Barbara Deschler, Kristin Binek, Gabriele Ihorst, Reinhard Marks, Ralph Wäsch, et al.

Toxicity-reduced conditioning is a curative treatment option for medically compromised or elderly patients ineligible for myeloablative hematopoietic cell transplantation (HCT). The aim of this study was to detect prognostic factors for overall survival (OS) and to evaluate quality of life (QOL) in a large homogeneous cohort of 160 consecutive patients aged ≥60 years treated with allogeneic HCT. We evaluated age, sex, performance status, comorbidities, pulmonary function, lactic dehydrogenase concentration, type of donor, disease status, CD34+ cells transplanted, cytomegalovirus status, time from diagnosis to HCT, and the development of acute and chronic graft-versus-host disease (GVHD). All patients who survived for ≥6 months (n = 79) were asked to complete a QOL survey. All patients (median age, 64.7 years; range, 60.1-76 years) received pretransplantation conditioning with fludarabine, BCNU, and melphalan. With a median follow-up of 35 months, the 1-year OS was 62.4% and 3-year OS was 47.4%. Multivariate analysis revealed compromised performance status as the most significant negative prognostic parameter for OS (P < .003), whereas male donor (P = .008) and chronic GVHD (P = .024) were associated with better OS. The 89% of survivors who returned the QOL questionnaire rated their global QOL as good-to-excellent despite impaired functional capabilities and such symptoms as fatigue, dyspnea, and loss of appetite. The main prognostic factor was performance status, not age. Our data suggest that toxicity-reduced conditioning offers a chance for enhanced OS with an adequate QOL.

Similar topics of scientific paper in Clinical medicine , author of scholarly article — Barbara Deschler, Kristin Binek, Gabriele Ihorst, Reinhard Marks, Ralph Wäsch, et al.

Academic research paper on topic "Prognostic Factor and Quality of Life Analysis in 160 Patients Aged ≥60 Years with Hematologic Neoplasias Treated with Allogeneic Hematopoietic Cell Transplantation"

ASBMI

American Society for Blood and Marrow Transplantation

Prognostic Factor and Quality of Life Analysis in 160 Patients Aged $60 Years with Hematologic Neoplasias Treated with Allogeneic Hematopoietic Cell Transplantation

Barbara Deschler,1 Kristin Binek,1 Gabriele Ihorst,2 Reinhard Marks,1 Ralph Wasch,1

Hartmut Bertz,1 JUrgen Finke1

Toxicity-reduced conditioning is a curative treatment option for medically compromised or elderly patients ineligible for myeloablative hematopoietic cell transplantation (HCT). The aim of this study was to detect prognostic factors for overall survival (OS) and to evaluate quality of life (QOL) in a large homogeneous cohort of 160 consecutive patients aged $60 years treated with allogeneic HCT. We evaluated age, sex, performance status, comorbidities, pulmonary function, lactic dehydrogenase concentration, type of donor, disease status, CD34 cells transplanted, cytomegalovirus status, time from diagnosis to HCT, and the development of acute and chronic graft-versus-host disease (GVHD). All patients who survived for $6 months (n = 79) were asked to complete a QOL survey. All patients (median age, 64.7 years; range, 60.1-76 years) received pretransplan-tation conditioning with fludarabine, BCNU, and melphalan. With a median follow-up of 35 months, the 1-year

OS was 62.4% and 3-year OS was 47.4%. Multivariate analysis revealed compromised performance status as the most significant negative prognostic parameter for OS (P \.003), whereas male donor (P = .008) and chronic GVHD (P = .024) were associated with better OS. The 89% of survivors who returned the QOL questionnaire rated their global QOL as good-to-excellent despite impaired functional capabilities and such symptoms as fatigue, dyspnea, and loss of appetite. The main prognostic factor was performance status, not age. Our data suggest that toxicity-reduced conditioning offers a chance for enhanced OS with an adequate QOL. Biol Blood Marrow Transplant 16: 967-975 (2010) © 2010 American Society for Blood and Marrow Transplantation

KEY WORDS: Elderly, RIC, Performance status, Outcome

INTRODUCTION

Hematopoietic cell transplantation (HCT) in elderly persons remains controversial, primarily because of its assumed applicability to a small minority of affected patients, as well as the fear of high treatment-related mortality and poor overall outcome [1]. Because age is considered the key risk factor, there

From the 'Department of Hematology/Oncology, Albert-Ludwigs University of Freiburg, University Medical Center Freiburg ; and 2Institute of Medical Biometry, Medical Informatics and Center of Clinical Trials, Albert-Ludwigs University of Freiburg, Freiburg, Germany. Financial disclosure: See Acknowledgments on page 974. Correspondence and reprint requests: Barbara Deschler, MD, Albert-Ludwigs University Medical Center, Department ofHe-matology and Oncology, Hugstetter Str 55, D-79106 Freiburg, Germany (e-mail: barbara.deschler@uniklinik-freiburg.de). Received September 29, 2009; accepted February 1, 2010 © 2010 American Society for Blood and Marrow Transplantation 1083-8791/$36.00 doi:10.1016/j.bbmt.2010.02.004

are limited data on other prognostic parameters and quality-of-life (QOL) outcomes in older patients undergoing this procedure; however, patients aged >60 years are at greatest need of such intensive treatment [2], and issues related to QOL are among the most serious concerns in cancer survivors [3]. Despite advances in reducing nonrelapse mortality (NRM) through reduced-intensity conditioning (RIC) before transplantation [4], data on NRM vary widely, and toxicity remains a major concern. Supportive measures for anticipating individual treatment tolerability and treatment-related complications are highly desirable [5]. Along with disease-specific parameters, such as remission status and cytogenetics [6,7], patient- and age-specific factors are now being increasingly considered [8-13].

Our previous experience has demonstrated that elderly patients and patients with comorbidities can be successfully treated using a RIC regimen comprising fludarabine, BCNU, and melphalan (FBM) [14,15]. Here we present a systematic overview of readily available patient- and disease-specific

parameters of 160 consecutive patients aged $60 years, along with a cross-sectional QOL survey of the survivors, which together compose the largest data set yet reported on homogeneously treated elderly HCT patients.

METHODS

Patients

All 160 patients were aged $60 years at the time of transplantation and thus ineligible for conventional myeloablative (MA) conditioning; all were assigned to the FBM RIC protocol, described in detail later. Because 45 of our patients had previously participated in a 2-center prospective, nonrandomized, opened-label, phase II clinical trial [15], patient characteristics and survival data were evaluated in that context.

During the latest outpatient follow-up visit, survivors of the cohort (n = 79) were asked to provide aself-rated QOL assessment according to the European Organization for the Recognition and Treatment of Cancer (EORTC) QLQ-C30 questionnaire. The local Ethics Committee approved the study design, and all patients provided informed consent.

Performance Status and Comorbidity

Data from medical records were extracted to identify each patient's pretransplantation Karnofsky Index (KI) performance status and comorbidities documented by the treating physician at the time of hospital admission for HCT. For the KI, each patient was given a score on a linear scale of 0 (dead) to 100 (normally active) summarizing his or her ability to perform daily activities. The Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) was used to evaluate comorbidities, as described previously [9]. The HCT-CI assigns points for 17 common medical conditions relevant in the transplantation setting, yielding in a total score of 0-29. Suspecting an independently strong impact, we also documented cytomegalovirus (CMV) status, serum lactate dehydrogenase (LDH) concentration, and pulmonary function (ie, forced expiratory volume in 1 minute [FEVi]).

Conditioning, Transplantation Procedure, GVHD Prophylaxis, and Toxicity Grading

All patients received the toxicity-reduced FBM regimen as conditioning chemotherapy [15,16]. The dosage was modified twice during the study period. Before 2005, 89 patients received fludarabine (Flu) 5 x 30 mg/m2 from days -9 to -5, BCNU 2 x 150 mg/m2 on days —7 and -6, and melphalan (Mel) 110 mg/m2 on day —4. Between July 2005 and August 2006, 36 patients received Flu 4 x 30 mg/m2 from days —8 to —5, BCNU 2 x 150 mg/m2 on days —7

and —6, and Mel 110 mg/m2 on day -4. Since August 2006, 35 patients received Flu 4 x 30 mg/m2 from days —7 to —4, BCNU 2 x 150 mg/m2 on days —7 and —6, and Mel 110 mg/m2 on day —4. Initially, GVHD prophylaxis consisted of cyclosporine A (CsA) and methotrexate; the latter was later replaced by mycophenolate mofetil (MMF). All patients with an unrelated donor received CsA in addition to MMF and rabbit anti-T-lymphocyte globulin.

Transplantation of stem cell grafts, supportive care, antimicrobial prophylaxis and treatment, and transfusion of blood products were performed according to standard good clinical practice procedures [14].

Acute GVHD (aGVHD) was assessed using the criteria of Przepiorka et al. [17]. Chronic GVHD (cGVHD) was defined as GVHD occurring 100 days or more after allogeneic HCT and was graded as none, limited, or extensive [16,18].

HLA Matching

Patients and their related or unrelated donors were matched for HLA-A and -B class I loci by serologic techniques (2 digits) and for HLA-DRB1 and -DQB1 class II alleles by high-resolution DNA-typing techniques (4 digits). Patients received granulocyte colony-stimulating factor-mobilized, unmanipulated peripheral blood stem cells (PBSCs) or bone marrow from matched unrelated and related donors.

Disease-Specific Parameters

Disease-specific risk stratification was performed as described previously [15]. The low-risk group included patients with chronic myelogenous leukemia (CML) in chronic phase, acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) in first remission, and myelodysplastic syndrome (MDS) with refractory anemia (RA) or RA with ringed sideroblasts (RARS). The high-risk group comprised patients with non-Hodgkin lymphoma (NHL); chronic lymphocytic leukemia (CLL); multiple myeloma (MM); CML in accelerated phase or blast crisis; AML or ALL in second or further remission, partial remission, or relapse; and MDS with RA with excess blasts (RAEB I and II). MDS and AML cytogenetics were documented as described previously [19,20].

QOL Aspects

QOL was evaluated using the EORTC QLQ C 30 version 3.0, which has demonstrated good psychometric utility in evaluating physical aspects of QOL and associated symptomatology [21,22]. The questionnaire contains 1 subscale for global QOL, 5 functioning subscales, and 9 symptom subscales, with each subscale linearly converted to a scale of 0-100. Published reference data for an age- and sex-matched average German population were used for comparison

[23]. A recommended approach to overcoming the difficulty of presenting 2 means that differ statistically but may not be clinically significant or overly important from a QOL standpoint is to specify a change of a specific number of points (eg, $10 or 15; usually 1 standard error of measurement, or 10% of the scale), which equates to a clinically important difference between groups. This suggestion is consistent with what has been identified as the minimally important difference (MID), the degree of change in a symptom or aspect of functioning that is recognizable and important to patients [24-26]. In the EORTC QLQ C30 questionnaire, a difference of 5-10 points is considered small, and a difference of 10-20 points is considered moderate [27]. Thus, in the present study, mean results of the cross-sectional patient analysis are interpreted in comparison to the reference population, focusing on between-group differences of >10 points.

Statistical Methods

Patient data were collected between December 1999 and February 2008. Overall survival (OS) was calculated as the time from transplantation until death from any cause, or censored at the time of last contact with the patient. The Kaplan-Meier method was used to estimate OS with accompanying 95% confidence intervals (CIs). Cox proportional hazards regression analysis of potential prognostic factors for OS for the patient cohort was performed with available variables. Univariate calculations were performed first, and variables with a univariate P <.10 were entered into a multivariate model, in which a backward-selection strategy (P <.10) was applied. aGVHD and cGVHD were considered time-dependent covariates.

Patients who died with no evidence of relapse or disease progression were considered cases of NRM. NRM and relapse mortality were considered competing risks, and cumulative incidence rates were calculated to estimate the respective rates. Associations between prognostic factors were investigated using continuity-corrected c2 tests from 2 x 2 tables. All calculations were made using SAS version 9 (SAS Institute, Cary, NC).

RESULTS

Patient, Donor, and Transplant Characteristics

Table 1 presents baseline characteristics of the 160 consecutive patients. The study group had a median age of 64.8 years (range, 60-76 years) and was 55.6% male. Median donor age was 40 years (range, 19-79 years), and 51.3% of donors were male. The median donor age was 63 years in cases of matched related transplantation (n = 51) and 35 years in cases of matched unrelated donor (MUD) transplantation (n = 109);

thus, donor age was significantly associated with the type of donor (P <.0001). In contrast, recipient age was not associated with the type of donor (P =.92). Eight patients received a bone marrow graft, and 152 patients received a PBSC graft. The median CD341 cell count in the PBSC grafts was 6.12 x 106/kg body weight (range, 1.3-23 x 106/kg).

The median KI score was 80 (range, 30-100), and the median HCT-CI score was 2 6 1.7 (range, 0-7). The most common comorbidities were cardiovascular disease (68.2%) and diabetes mellitus (12.7%).

Diagnoses included AML (n = 111), MDS (n = 24), CML (n = 3), NHL (n = 11), CLL (n = 7), MM (n = 2), and MPS (n = 2). Based on disease status, 18 patients were in the low-risk group and 142 were in the high-risk group. Cytogenetic data were available in 106 patients with AML or MDS (78.5%); aberrations were identified in 49 cases (46.2%). Nine patients died before having completed full hematologic engraft-ment. Documented best responses to treatment were 141 complete remission (CR), 4 partial response (PR), and 6 stable disease.

At a median follow-up of 35 months, 79 patients (49.4%) were alive. Median OS was 889 days (95% CI, 428-1404 days). OS was 62.4% (95% CI, 54.7%-70.1%) after 1 year, 54.1% (95% CI, 45.9%-62.4%) after 2 years, and 47.7% (95% CI, 38.5%-56.2%) after 3 years.

Cumulative incidence rates for relapse mortality were 15.5% after 1 year, 19.8% after 2 years, and 22% after 3 years. Median relapse-free survival was 418 days, or 84.4% at 100 days, 52% at 1 year, 42.6% at 2 years, and 39.2% at 3 years.

Of the 81 patients who died, 36 (44.4%) died of relapse and 45 (55.6%) died ofNRM (Figure 1). NRM was 8.1% at 100 days, 22.1% at 1 year, and 30.6% at 3 years. Fatal infection was the leading cause of death (64.4%), whereas cardiovascular complications accounted for 15.6% ofNRM and cGVHD (n = 5) accounted for 11% ofNRM.

Prognostic Factor Analysis

Table 2 summarizes the results ofunivariate analysis for risk factors for OS. Multivariate regression analysis for variables that had a P <.10 in univariate analysis was performed as illustrated in Table 2. A KI score of #80 was associated with an elevated hazard ratio (HR) of 2.01 (95% CI, 1.27-3.18; P =.0026), with markedly reduced survival in the entire follow-up period, as shown in Figure 2. For patients with a KI #80, the cause-specific HR was 2.66 for relapse mortality (P =.0069) and 1.61 for NRM (P = .118). A KI of #70 was associated with even poorer prognosis (HR, 2.36; 95% CI,

Table 1. Characteristics of Patients, Donors, and Grafts

Patient-specific parameters

Age, years, median (range) 64.8 60.1-76)

Male, n (%) 89 55.6)

KI score, median range) 80 30-100)

HCT-CI, median (range) 2 0-7)

Disease-specific parameters

Diagnosis, n %)

CML 3 19)

Chronic phase 1 0.63)

Blast crisis 1 0.63)

Accelerated phase 1 0.63)

MDS 24 15)

RA 6 37)

RAEB/t, CMMoL 18 11.2)

AML 111 69.4)

CRI 11 6.9)

Relapse/refractory 67 41.9)

CR2 or greater 6 37)

Untreated 27 16.8)

MPS/OMF 2 12)

MM PR) 2 12)

NHL* 11 6.9)

Primary induction failure 3 19)

Progression after standard treatment 8 5)

CLL 7 4.4)

Risk group, n (%)f

High 142 88.75)

Low 18 11.25)

Cytogenetics in MDS/AML, n (%) 106 78.5)

Normal 57 53.8)

Favorable 4 3.8)

Intermediate 7 6.6)

Poor 38 35.8)

Donors and grafts

Donor age, years, median range) 40 19-79)

Related donor, n %) 51 31.9)

Age, years, median range) 63 35-79)

Unrelated donor, n %) 109 68.1)

Age, years, median range) 35 19-66)

Sex match, n %)

Patient male/donor female 41 25.62)

Patient female/donor male 34 21.25)

Patient female/donor female 37 23.13)

Male patient/male donor 48 30.0)

Graft source, n %)

Bone marrow stem cells 8 5)

Peripheral blood stem cells 152 95)

CD34+ cell count, median (range)£ 6.12 x l06/kg 1.3-23 x l06/kg)

CMV status, n %)

Recipient-positive 112 70)

Donor-positive 81 50.6)

GVHD, n (%)

None 82 51.2)

Grade I 34 21.2)

Grade II 2l 13.1)

Grade III l7 10.6)

Grade IV 6 37)

None 7l 44.4)

Limited 35 21.9)

Extensive 35 21.9)

HCT-CI indicates Hematopoietic Cell Transplantation Comorbidity Index; KI, Karnofsky Index; CML, chronic myelogenous leukemia; MDS, myelodysplastic syndrome; RA, refractory anemia; RAEB, refractory anemia with excess blasts; AML, acute myelogenous leukemia; CRI, first complete remission; CR2, second complete remission; MM, multiple myeloma; NHL, non-hodgkin lymphoma; GVHD, graft-versus-host disease; aGVHD, acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease.

*NHL diagnoses included follicular lymphoma (n = 3), mantle cell lymphoma (n = 5), diffuse large cell lymphoma (n = 2), and T cell lymphoma (n = I) .

Months from HCT

# pailafits

at risk 160 82 51 37 24 19 12 9

P— Rgfapse ......NRVI [

Figure 1. Cumulative incidence: Relapse mortality versus NRM.

1.47-3.79; P = .0004); this group had a small number of patients, however (n = 33).

Half of the donors were male (with a slight predominance of male donors in MUD HCT [60:49] and of female donors in related HCT [29:22]). Female donor was identified as an adverse factor for OS (HR, 1.82; P =.0085). The negative impact was similar in the 41 male recipients and the 37 female recipients, with respective mortality rates of 56.1% and 56.8%. Female recipient was associated with an HR of 1.32 (P = not significant). No associations between donor sex and recipient age (P =.88), donor age (P =.09), cGVHD (P = 1.0), or type of donor (P =.21) were apparent; however, female donor was significantly associated with a CD341 cell count below the median level of 6.12 x 106/kg of body weight (P <.0001). Female recipient was associated with poorer respiratory function (P <.0001) and a higher median number of comorbidity factors (P = .06), but not with significantly poorer general performance status (P = .64).

aGVHD (defined as GVHD occurring before 100 days posttransplantation) was evident in 78 patients (grade I-II, 34.3%; grade III-IV, 14.3%) and was not associated with any significant decrease or increase in HR. Limited and extensive cGVHD were evaluable in 70 patients and were associated with a significantly reduced risk of death (HR, 0.52), because of a decreased rate of relapse mortality. Only 11% of patients with cGVHD died of relapse, as opposed to 31% of 71 patients without cGVHD.

Neither CD341 cell count nor type of donor had a statistically significant association with cGVHD (P =.862 and .789, respectively). Transplantation of

fTwo risk groups were defined. The low-risk group included CML in chronic phase, AML and ALL in first remission, and MDS-RA/RARS (n = 18). The high-risk group included NHL; MM; CLL; CML in accelerated phase or blast crisis; AML or ALL in CR2 or further remission, PR, or relapse; and MDS RAEB (n = 142). ^Peripheral blood HCT only.

Table 2. Risk Factors for OS after HCT

Variable

Incidence, n (%)

95% CI

KI #80 82 (51.2) 1.99 1.27-3.14 .0028

cGVHD (all grades)* 70 (43.8) 0.51 0.29-0.88 .0165

Patient age $65 years 76 (47.5) 0.58 0.37-0.93 .0229

Female donor 78 (48.7) 1.60 1.03-2.49 .0350

Female recipient 71 (44) 1.52 0.98-2.35 .0618

CD34+ <6 x I0E6j 80 (59) 1.53 0.98-2.36 .0619

HCT-CI $2 94 (58.7) 1.37 0.87-2.15 .I679

FEVI <80 49 (30.6) 1.38 0.86-2.20 .I777

MUD 109 (68.1) 0.74 0.46-1.17 .I955

Extensive cGVHD 35 (21.9) 0.73 0.38-1.38 .3336

Donor age $40 years 79 (49.4) 1.18 0.75-1.86 .4732

High-risk disease status 142(88.7) 1.32 0.60-2.86 .4829

HCT >1 year after initial diagnosis 46 (28.7) 1.16 0.73-1.86 .5256

CMV+ donor 81 (50.6) 1.20 0.77-1.86 .6637

CMV+ recipient 112 (70) I.II 0.69-1.79 .6637

aGVHD (all grades)* 77(48.1) 0.93 0.59-1.47 .7672

Median serum lactate dehydrogenase $215 IU/L 95 (59.37) I.05 0.67-1.64 .8210

Adverse cytogenetics^ 38 (35.8) I.06 0.62-1.81 .8298

Multivariate Cox regression analysis§ of pretransplantation factors for outcome,

all patients (n 5 160)

KI #80 2.01 1.27-3.18 .0026

Female donor I.83 1.17-2.86 .0085

cGVHD* 0.52 0.29-0.92 .0235

Patient age $65 years 0.60 0.38-0.95 .0311

Multivariate Cox regression analysis§ of pretransplantation factors for outcome,

MDS/AML patients only (n 5 135)

KI #80 I.94 1.17-3.19 .0097

Female donor I.67 1.02-2.74 .0403

cGVHD* 0.60 0.33-1.09 .0976

Patient age $65 years 0.57 0.35-0.95 .0323

HCT-CI indicates Hematopoietic Cell Transplantation Comorbidity Index; KI, Karnofsky Index; CML, chronic myelogenous leukemia; MDS, myelodys-

plastic syndrome; AML, acute myelogenous leukemia; CMV, cytomegalovirus; FEVI, forced expiratory volume in 1 minute; GVHD, graft-versus-host

disease; aGVHD, acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease; MUD, matched unrelated donor.

*Time-dependent.

^Peripheral blood HCTonly.

^MDS/AML only.

§Factors considered for backward selection were P <.10 in univariate analysis.

less than the median dose of CD341 cells (6.12 x 106/ kg) in peripheral blood HCT was associated with an increased HR of survival (1.52; P = .06, univariate analysis). Donor age above the median of 40 years did not increase HR significantly. Forty-six patients underwent transplantation more than 1 year after initial diagnosis; delayed HCT was not associated with a significant increase in HR.

Concomitant diseases according to the HCT-CI were documented as follows: 34 patients (21.3%) had no relevant comorbidity, whereas 32 patients (14%) had a score of 1, 34 patients (21.3%) had a score of 2 points, and 60 patients (37.5%) had a score of $3 points. The categorization of patients with an HCT-CI score of $2 did not reach significance in univariate analysis (HR, 1.37; P =.17).

The HRs associated with disease-specific high-risk groups or poor-risk cytogenetics (in AML patients) did not reach significance; however, high-risk disease (present in 142 patients) was significantly associated with a lower performance status (P =.002). Patient age $65 years was associated with an HR decrease of

0.6, and was not associated with any negative prognostic factors (eg, poor performance status, female sex, absence of cGVHD).

0 12 24 3B 4H 60 72 B4 96 10B Months from Transplantation

# fttients at risk

>80 78 47 27 20 16 13 9 6 1 0

<=80 82 35 24 17 8 6 3 3 1 0

Kurnolsky Index - >80 ~ <=80

Figure 2. Survival distribution according to the KI. Good pretransplan-tation performance retains relevance in the protracted clinical course.

Table 3. EORTC QLQ C30: Comparison of Results of Survivors with the German Reference Population after a Median of 22.5 Months Posttransplantation

Patients (Median Age, 69 Years) Reference German Population (Age 60-69 Years) [23]

Total (n = 70) Male (n = 45) Female n = 25) Male (n = 193) Female (n = 197)

Functional scales

Physical functioning 72.9 78.7 63.5 86.5 83.8

Role functioning 64.4 68.2 58.3 84.5 82.1

Emotional functioning 72.6 74.8 68.7 80.5 75.9

Cognitive functioning 77.8 77.3 78.5 88.3 88.7

Social functioning 64.2 67.8 59.0 86.7 90.9

Global QOL 65.7 67.8 62.5 65.6 62.6

Symptom scales

Fatigue 38.7 34.4 45.8 18.6 23.0

Nausea/vomiting 4.9 2.6 10.4 2.2 2.8

Pain 24.4 18.9 33.3 20.3 23.9

Dyspnea 25.6 23.7 28.0 12.6 11.7

Insomnia 29.4 21.5 43.0 19.5 29.8

Appetite loss 19.3 12.6.7 32 6.2 6.6

Constipation 9.4 4.4 20.3 3.5 6.3

Diarrhea 19.6 14.8 27.8 2.1 2.2

For the functional and global QOL scores, a higher score presents a better functioning level. For the symptom scales and items, a higher score reflects more symptoms. A clinically relevant difference of $ 10 points between patients and reference population is apparent in the domains of role and social functioning, fatigue, insomnia, dyspnea, appetite loss, and diarrhea.

Calculations in the final multivariate model repeated for the largest subgroup of 135 patients with MDS/AML yielded results similar to those for all patients (Table 2).

QOL Aspects and Follow-Up

The 79 survivors were asked to complete the QLQ C30 questionnaire at last contact after a median of 22.5 months (range, 6-98 months); 70 (89%; 64.3% male) complied. The patients reported several symptoms, and most had decreased functional levels, yet impairment of global QOL was minimal. A comparison of the entire cohort to the published sex-matched German reference data (age cohort 60-69 years), summarized in Table 3, yielded similar values, with cutoff scores of 10 points difference indicating the MID [25]. In the subgroup of 32 patients aged $ 70 years at the time of the survey, global QOL values were higher than the reference values (74 vs 55 for females and 68 vs 61.5 for males). Patient impairment was most obvious in role and social functioning. The most prevalent symptoms were fatigue, pain, dyspnea, insomnia, and loss of appetite, with female patients persistently demonstrating greater impairment and more symptoms.

Only minimal differences in posttransplantation patient-rated global QOL values based on pretrans-plantation disease status or the occurrence of cGVHD were detected. However, a tendency toward improved global QOL values was seen in patients with a pretrans-plantation HCT-CI of <2 versus those with an HCT-CI of $2 (68.8 vs 61.6) and in those with an unrelated donor (68.3 vs 59.6). At last contact with the 79 survivors, 30 (38%) had a KI of 100, 32 (40.5%) had a KI of 90,12 (15.2%) had a KI of 80, and 5 (6.3%) had a KI of

70, indicating that all were able to live an independent life and few being compromised in daily activities.

DISCUSSION

The present evaluation of patient data after FBM conditioning and allogeneic HCT has focused on patients aged >60 years, because advanced age is postulated to be a major risk factor for intensive chemotherapeutic treatment [28,29]. The previously reported poor survival data in elderly patients with hematologic malignancies underscore the need to improve treatment options, particularly because >50% of these patients are considered unfit for intensive chemotherapeutic treatment [30]. The advent of RIC regimens has led to reduced toxicity and NRM [31,32].

In MA HCT, postulated risk factors include age, disease stage, cytogenetics, and pretransplantation serum ferritin concentration [13], as well as unrelated donor, high disease risk, impaired organ function

[33], disease duration, donor sex, and HLA disparity

[34] as predictors of NRM. We have found that FBM conditioning leads to high CR rates with acceptable toxicity in older patients and encouraging long-term effectiveness even in advanced disease [15]. Our evaluation of prognostic factors has revealed that older age does not necessarily translate into poorer outcome. In our patient cohort, NRM was 8% after 100 days, 22% after 1 year, and 31% after 3 years, demonstrating the feasibility or our approach. Others have published similar data in smaller trials using low-dose total body irradiation (2 Gy) and Flu in patients with a median age of 60-64 years [35-37]. Several trials that included

younger patients reported similar outcomes [11,38,39].

An age limitation has been suggested to be more important in unrelated donor transplantations than in sibling donor transplantations [40]. However, like others before us [4,41,42], we found no significant difference in risk between the 2 modalities. Recent data suggest that younger donor age is beneficial for outcome in patients receiving an RIC regimen [43]. In our study group, the unrelated donors were much younger than the sibling donors (Table 1), which might be one reason (even though it was not a significant parameter) why patients with an MUD fared no worse than the other patients.

Female sex ofboth recipient and (especially) donor was disadvantageous. Statistical calculations revealed no significant associations among female sex and other risk factors found to be relevant in our cohort. This finding is probably because of a combined effect of a lower transfused CD341 cell dose (a factor some believe to be adverse [44]), impaired organ function (eg, lower FEVj, higher HCT-CI), and perhaps reduced compensation strategies in our female patients. The latter may be implied by the lower QOL values in eg, role and social functioning and higher scores in most of the QOL symptom scales in elderly females compared with their male counterparts (Table 3). No data on smoking habits or other possible causes of pulmonary damage were available, precluding analysis of the poorer respiratory function seen in female patients. The small number of patients, the large number of prognostic factors studied, and the RIC regimen might explain why some previously proposed risk factors were not significant in our study. Screening of larger cohorts is needed to verify our findings.

Patients who developed cGVHD had an OS benefit because of a decreased rate of relapse mortality, in agreement with a previous study [45]. This benefit was retained to a small degree even for extensive manifestations.

The HCT-CI is a recently defined patient-specific parameter. Although some authors consider the HCT-CI a significant predictor of posttransplantation NRM and OS [9,46], our data and those of others do not support this finding [47-49]. Notably, our patients' individual KIs were highly significant in predicting survival outcome. As shown in Figure 2, good pre-transplantation performance status retained its positive impact throughout the follow-up period. Interestingly, analysis of cumulative mortality incidence in patients with reduced performance status revealed an increased HR, especially for relapse mortality. The most likely explanation for this finding is the significant association between poor performance and high-risk disease, and thus an increased risk of relapse. Because clinicians may tend to focus on the burden of malignancy rather than on other medical

conditions when assigning performance status scores, these performance status scales may be of only limited value in identifying risks for NRM. We found that HCT-CI and performance status were independent of one another, in agreement with this assumption and other published findings [50]. Further studies that prospectively examine parameters so as to better define "performance status,'' as well as enhance its role in the clinical prediction of tolerability, NRM, and OS, are needed. Such trials may need to include parameters of a comprehensive geriatric assessment, such as in-depth measurement of functional abilities and independence [51].

Selection bias must be discussed when comparing our data with previously published results. The characteristics of our patients were comparable to the high-risk features of other RIC populations [15,38,43,46,52]. Because most of the patients referred to our unit underwent HCT as soon as a suitable donor was identified, selection processes might have been applied at earlier stages. Further work must focus on parameters considered to represent exclusion criteria for the presentation of a patient in a transplantation center.

The consideration of QOL is especially important in counseling, treatment, and posttreatment management of intensive therapies such as HCT [53]. These QOL data are the first to describe a large cohort of elderly patients who underwent RIC HCT. Our cross-sectional analysis has several shortcomings, because it can give only an impression of the posttransplantation QOL in long-term survivors. It must be followed by prospective investigations that also document individual dynamic QOL developments and acknowledge attrition.

Generally, our patients evaluated their global QOL as good and nearly equal to that in the German reference data (Table 3) [23]. Because the majority of patients were more than 1 year beyond transplantation, the good overall data may be a result of improved QOL during early recovery. As others have described, 2-year survivors report a return to baseline or better QOL by day 100 [54]. Even the presence of cGVHD did not diminish the subjective estimation of global QOL in our patients. Whereas patients reported several symptoms (especially fatigue, dyspnea, insomnia, and appetite loss), and most did not achieve functional levels quite as high as their average population counterparts, most judged their global QOL impairment to be minor. Further subgroup analyses (eg, patients age $70 years; n = 32) revealed that with increasing age, posttransplantation global QOL was even better than that in the average population. Moreover, compared with a much younger post-MA transplantation population (mean age: 45 years; n = 34), the variations in results did not demonstrate a relevant 10-point difference and were similarly satisfying [25,55]. In this context, the study of Lee et al. [56] and several older

QOL studies found that although certain distressing symptoms persisted, overall QOL and global measures of recovery at 6, 12, and 24 months were quite good in MA conditioning settings. As reported by Neitzert et al. [57], survival is associated with a high global QOL score; nevertheless, recovery from HCT is accompanied by a number of psychosocial difficulties. One reason for the positive interpretation of global QOL might be cognitive reappraisal as a response to a life-threatening disease [58]. Future investigations will need to develop therapeutic models that help eliminate debilitating symptoms.

Our aim in the present study was to highlight patient-specific factors that might be relevant to determining prognoses and in decision making processes. It is our experience that RIC HCT in patients aged $60 years, even those with advanced and high-risk hemato-logic diseases, is feasible and offers a chance for long-term survival and cure. Good performance status outweighs age as a prognostic marker. Importantly, surviving patients judge their QOL to be good to excellent despite some limitations in functional abilities and certain impairments.

ACKNOWLEDGMENTS

The authors thank Carole Curten for English language assistance.

Financial disclosure: This work was supported by the Jose Carreras Leukemia Foundation (Grant F06/04, to B.D.).

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