Outcomes in Patients Age 70 or Older Undergoing Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies

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Outcomes in Patients Age 70 or Older Undergoing

Allogeneic Hematopoietic Stem Cell Transplantation for

Hematologic Malignancies

Andrew M. Brunner

1

, Haesook T. Kim

2

, Erin Coughlin

1

, Edwin P. Alyea III

3

,

Philippe Armand

3

, Karen K. Ballen

1

, Corey Cutler

3

, Bimalangshu R. Dey

1

,

Brett Glotzbecker

3

, John Koreth

3

, Steven L. McAfee

1

, Thomas R. Spitzer

1

,

Robert J. Soiffer

3

, Joseph H. Antin

3

, Vincent T. Ho

3,y

, Yi-Bin Chen

1,*,y

1Bone Marrow Transplant Unit, Division of Hematology / Oncology, Massachusetts General Hospital, Boston, Massachusetts 2Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts

3Department of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts

Article history: Received 18 April 2013 Accepted 10 June 2013 Key Words: Allogeneic transplantation Aged Mortality Relapse

Graft versus host disease

a b s t r a c t

Allogeneic hematopoietic stem cell transplantation (HSCT) can achieve durable remissions in a number of patients with advanced hematologic malignancies. Little is known about the safety of HSCT in patients age 70 or older. Consecutive patients (n¼ 54) age 70 or older underwent HSCT between 2007 and 2012. Diseases included acute myelogenous leukemia (n¼ 25), myelodysplastic syndrome (n ¼ 12), chronic lymphocytic leukemia (n¼ 5), non-Hodgkin lymphoma (n ¼ 4), acute lymphoblastic leukemia (n ¼ 3), myeloproliferative neoplasm (n¼ 4), and chronic myelogenous leukemia (n ¼ 1). Median follow-up for survivors was 21 months. All patients received reduced-intensity conditioning regimens, primarily busulfan/fludarabine. All patients received unmanipulated peripheral blood stem cell grafts: 44 from 8/8 matched unrelated donors, 8 from matched related donors, and 2 from 7/8 matched unrelated donors. Graft-versus-host disease (GVHD) prophylaxis was calcineurin inhibitorebased in all patients. The median age at transplantation was 71 years (range, 70 to 76); the median HCT comorbidity index score was 1 (range, 0 to 5). Two patients died before hematopoietic recovery (1 with graft failure and 1 with disease progression), and 1 patient relapsed before hematopoietic recovery; otherwise, all engrafted with median donor chimerism of 94% at 1 month. Cumu-lative incidence of grades II to IV acute GVHD was 13% and of grades III to IV acute GVHD, 9.3%. At 2 years, the cumulative incidence of chronic GVHD was 36%, progression-free survival was 39%, overall survival was 39%, and relapse was 56%. Nonrelapse mortality was 3.7% at dayþ100 and 5.6% at 2 years. We conclude that allogeneic HSCT is a safe and effective option for carefully selected patients age 70 or older.

Ó 2013 American Society for Blood and Marrow Transplantation.

INTRODUCTION

Hematologic malignancies are more common among older patients. This age group has historically had worse outcomes when compared with younger counterparts[1,2]. Allogeneic hematopoietic stem cell transplantation (HSCT) can achieve durable remissions in a number of patients with advanced hematologic malignancies, but its application to the elderly has been traditionally limited by arbitrary age restrictions [1,2], reflecting concerns of high rates of nonrelapse mortality (NRM) and morbidity with traditional myeloablative regi-mens [3-5]. The advent of reduced-intensity conditioning (RIC) regimens has extended HSCT to increasingly older adults[6-8].

Despite the success of RIC, the number of potential patients over the age of 50 that undergo HSCT after remission is low, estimated at only 14% of patients in 1 analysis[9]. In most analyses investigating risk factors to predict NRM after HSCT, if other comorbidities are appropriately taken into account, older age has not been shown to be a significant factor[8,10,11], challenging the concept of an arbitrary upper age limit for consideration of allogeneic transplantation.

Nonetheless, very little data describing the safety and ef fi-cacy of HSCT in patients age 70 or older have been published. The purpose of the current study is to describe our institu-tions’ outcomes for patients age 70 or older undergoing HSCT for advanced hematologic diseases.

METHODS Patients

We identified 54 consecutive patients age 70 or older who underwent allogeneic HSCT at Massachusetts General Hospital (n¼ 14) or the Dana-Farber Cancer Institute (n ¼ 40) between January 1, 2007 and July 11, 2012. Inclusion criteria included all patients who underwent allogeneic HSCT for a hematologic disease as long as patients were age 70 or older on the day of transplantation. This study was approved by the institutional review board of the Dana-Farber/Harvard Cancer Center. Eligibility for transplantation, conditioning regimens, and supportive care were similar in the 2 centers and have been described previously[12,13].

Definitions

Diagnoses were classified according to the World Health Organization system. HCT comorbidity index scores were calculated as described by Sorror et al.[14]. Disease risk index (DRI) scores were calculated as described by Armand et al.[15]. Patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) had cytogenetic risk documented as described by the National Cancer Research Institute Adult Leukemia Working Group[16]. Only RIC regimens were administered, which were consistent with a previously described consensus classification[17].

The primary outcomes were relapse, NRM, overall survival (OS), and progression-free survival (PFS). NRM was defined as any cause of death occurring after transplantation without documented relapse. Relapse was defined as relapse with or without death. PFS was defined as the time from stem cell infusion until the date of relapse or death, whichever occurred Financial disclosure: See Acknowledgments on page 1379.

* Correspondence and reprint requests: Yi-Bin Chen, MD, Massachusetts General Hospital, 100 Blossom St, Cox 106, Boston, MA 02114.

E-mail address:ychen6@partners.org(Y.-B. Chen).

yDr. Ho and Dr. Chen contributed equally to this work.

1083-8791/$e see front matter Ó 2013 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2013.06.008

American Society for Blood

ASBMT

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first. OS was defined as the time from transplantation until the date of death. Patients who were alive at the time of our analysis were censored at the last known alive date.

Neutrophil engraftment was defined as the first day of an absolute neutrophil count >500/mL on 3 consecutive measurements. Platelet recovery was defined as the first day of 2 consecutive measurements of >20,000/mL without transfusion support in the prior 72 hours. All patients received calcineurin inhibitorebased regimens (most commonly tacroli-mus) as graft-versus-host disease (GVHD) prophylaxis. In general, taper of immune suppression was initiated 3 to 4 months after transplantation in the absence of active GVHD, with the goal of immunosuppression cessation by approximately 6 to 8 months after HSCT. No pre-emptive or planned prophylactic donor lymphocyte infusions were given. Acute GVHD (aGVHD)

was graded by consensus grading criteria[18], and chronic GVHD (cGVHD) was defined clinically by treating physicians. Grading of the severity of cGVHD was not included in this analysis given the changes in classification schemes during the period these patients were treated[19,20].

Statistical Analysis

Descriptive statistics were used to summarize patient baseline charac-teristics. Cumulative incidences of GVHD, relapse, and NRM were estimated in the competing risks framework. Cumulative incidence of GVHD was constructed considering death or relapse as competing risks. Cumulative incidences of NRM and relapse were constructed considering relapse for NRM and NRM for relapse as a competing risk. OS and PFS were estimated using the method of Kaplan-Meier, with 95% confidence intervals (CIs) calculated using Greenwood’s formula. Kaplan-Meier curves were compared using the log-rank test, and cumulative incidence curves were compared using the Gray test[21]. Potential prognostic factors for OS, PFS, and relapse were examined using the proportional hazards model for OS and PFS and the Fine and Gray model[22] for cumulative incidence of relapse. All P values are 2-sided with a significance level of .05. All statistical analyses were performed using SAS 9.2 (SAS Institute, Cary, NC) and R version 2.13.2 (R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

Patient Characteristics

Patient characteristics are summarized inTable 1. This was thefirst allogeneic HSCT for all patients except one. The median age at transplantation was 71 years old (range, 70 to 76). The median follow-up for survivors was 21 months (range, 7 to 55). There was a slight male predominance (67%). Prior cytomegalovirus antibodies were detected in 29 of 54 recipients.

Diagnoses varied, with the most common being AML and MDS (Table 2). Among patients with AML, most (84%) were in complete remission (CR) (21 of 25 patients: 17 in CR1, 3 in CR2, 1 in CR3). Of the 12 patients with MDS, 1 was in partial remission, 6 had refractory disease, and 5 were untreated. Of the 37 patients with AML or MDS, 17 (46%) had adverse cytogenetic risk. Six of 10 with adverse risk AML were in CR1, 2 had failed induction, and 2 were untreated. One of 7 with adverse risk MDS was in partial remission, 3 had refractory disease, and 3 were untreated. The 3 patients with acute lymphocytic leukemia were in CR1 (n¼ 2) or CR2 (n ¼ 1). Patients with non-Hodgkin lymphoma consisted of 2 patients with diffuse large B-cell lymphoma (DLBCL) and 2 patients with T cell lymphoma. One patient had blast-phase chronic myeloid leukemia in CR, and 5 patients had chronic lymphocytic leukemia. Patients with myeloproliferative neoplasms consisted of 1 patient who had a myeloprolifera-tive neoplasm/MDS overlap syndrome, 2 patients with chronic myelomonocytic leukemia (CMML), and 1 patient with myelofibrosis.

Table 1

Baseline Characteristics

Characteristic N Percent

Age, y, median (range) 71 (70 to 76) Donor age, y, median (range) 33 (18 to 74) Patient sex

Male 36 66.7

Female 18 33.3

Donor type

Matched related donor (8/8) 8 14.8 Matched unrelated donor (8/8) 44 81.5 Matched unrelated donor (7/8) 2 3.7 Disease AML 25 46.3 MDS 12 22.2 ALL 3 5.6 NHL 4 7.4 CML 1 1.9 CLL 5 9.3 MPN 4 7.4

Cytogenetic risk (of patients with AML or MDS)*

Favorable 1 1.9

Intermediate 19 35.2

Adverse 17 31.5

ECOG performance status

0 10 18.5 1 30 63.0 2 10 18.5 HCT comorbidity index 0 20 37 1 11 20.4 2 6 11.1 3 6 11.1 4 6 11.1 5 5 9.3 Median (range) 1 (0 to 5) Conditioning regimen

Busulfan 3.2 mg/kg andfludarabine 28 51.9 Busulfan 6.4 mg/kg andfludarabine 23 42.6

Fludarabine/melphalan 2 3.7

Clofarabine/ATG/total lymphoid irradiation 1 1.9 DRI score 0 (low) 5 31.5 1 (intermediate) 24 1.9 2 (high) 20 35.2 3 (very high) 5 31.5 Recipient CMV status Positive 29 53.7 Negative/equivocal 25 46.3 GVHD prophylaxis CNIþ MTX 9 16.7 CNIþ sirolimus  MTX 34 63

CNIþ mycophenolate mofetil 1 1.9

CNIþ ATG þ MTX 7 13

Other 3 5.6

Number of rehospitalizations, median (range) 1 (0 to 11) ALL indicates acute lymphocytic leukemia; NHL, non-Hodgkin lymphoma; CML, chronic myeloid leukemia; CLL, chronic lymphocytic leukemia; MPN, myeloproliferative neoplasm; CMV, cytomegalovirus; CNI, calcineurin inhibitor; MTX, methotrexate; ATG, antithymocyte globulin.

*Patients with AML or MDS were categorized by favorable risk, inter-mediate risk, or adverse risk cytogenetic profiles using karyotype at diag-nosis[16].

Table 2

Disease Status at Time of Transplantation

Disease n (%) Disease Status at Transplantation (n) AML 25 (46%) CR1 (17), CR2 (3), CR3 (1), induction failure (2),

untreated (2)

MDS 12 (22%) PR (1), refractory (6), untreated (5) ALL 3 (6%) CR1 (2), CR2 (1)

NHL 4 (7%) DLBCL in PR (1), relapsed DLBCL (1), T cell lymphoma (2)

CML 1 (2%) Blastic phase in remission (1)

CLL 5 (9%) PR (2), CR (1), relapse (1), persistent T cell CLL (1) MPN 4 (7%) MPN/MDS overlap, failed chemotherapy (1);

CMML in remission (1) or failed chemotherapy (1); myelofibrosis, failed chemotherapy (1)

ALL indicates acute lymphocytic leukemia; NHL, non-Hodgkin lymphoma; CML, chronic myeloid leukemia; CLL, chronic lymphocytic leukemia; MPN, myeloproliferative neoplasm; PR, partial remission; DLBCL, diffuse large B-cell lymphoma; CMML, chronic myelomonocytic leukemia.

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All patients had an assessment of their pretransplantation risk by calculation of the HCT comorbidity index[14,23]; the median score was 1 (range, 0 to 5). Most had an HCT comorbidity index score of 0 (n ¼ 20) or 1 (n ¼ 11), but a number had higher scores of 2 (n¼ 6), 3 (n ¼ 6), 4 (n ¼ 6), and 5 (n¼ 5). All patients with HCT comorbidity index scores

of 5 had moderate (n ¼ 4) or severe (n ¼ 1) pulmonary

disease, and 3 had a prior solid tumor. Because a number of different hematologic conditions were considered in this analysis, we also calculated the DRI group for each patient [15]. Most patients fell into the intermediate risk (n¼ 24, 44.4%) or high risk (n ¼ 20, 37.0%) DRI groups, although 10 patients (18.6%) were categorized as low (n¼ 5) or very high-risk (n¼ 5) DRI groups.

Transplantation and Donor Characteristics

Most patients received a conditioning regimen containing intravenous busulfan, at a total dose of either 3.2 mg/kg

(n ¼ 28) or 6.4 mg/kg (n ¼ 23) and fludarabine, dosed at

120 mg/m2 total (94% of patients) [12,24]. Two patients

received a combination of melphalan at 140 mg/m2 and

fludarabine. One patient was enrolled in an institutional clinical trial and received a combination of clofarabine, antithymocyte globulin, and total lymphocyte irradiation. The choice of conditioning regimen was based on institution norm, physician choice, and enrollment in specific clinical trials.

All patients received peripheral blood stem cells. Most patients (44/54, or 82%) received stem cells from an 8/8 HLA matched unrelated donor. Eight patients (15%) received an 8/ 8 matched related donor transplantation, whereas 2 patients (4%) received stem cells from a 7/8 matched unrelated donor. The median matched related donor age was 63.5 years.

For GVHD prophylaxis, most patients received a

combi-nation of tacrolimus and sirolimus  mini-methotrexate

(5 mg/m2 per dose) (34/54 patients, 63%) [13]. A small

number of patients received tacrolimus and

mini-methotrexate alone (9/54 patients, 17%) or antithymocyte globulin in combination with tacrolimus and methotrexate (7/54 patients, 13%).

Engraftment

Of the 54 patients in this study, 2 patients died before engraftment: 1 patient with CMML from graft failure and 1 patient with AML from disease progression. One patient relapsed before engraftment. All other patients achieved neutrophil and platelet engraftment. Of the 43 patients who experienced a neutrophil nadir<500/

m

L, the median time to neutrophil engraftment was 13 days (range, 2 to 31 days). The median time to platelet engraftment was 17 days (range,

3 to 83 days) among the 40 patients whose absolute platelet count dropped to<20,000/

m

L.

Chimerism was measured by standard short tandem repeat (STR) genotyping analysis, and the median all-cell donor chimerism among 51 patients who engrafted was 94% (range, 36% to 100%) at day 30; 84% (43/51) achieved 80% all-cell donor chimerism by 1 month after HSCT. Median all-cell donor chimerism was 94% among 39 patients who had a measurement at a subsequent time point near day 100 (range, 0% to 100%). Sustained chimerism (defined as

day-30 total leukocyte chimerism80% and day 100 80%)

Table 3

Summary of Survival and GVHD Outcomes (n¼ 54)

Day 100 (95% CI) 6 Mo (95% CI) 1 Yr (95% CI) 2 Yrs (95% CI)

OS, % 49 (36 to 62) 39 (25 to 53)

PFS, % 39 (26 to 51) 39 (26 to 51)

Cumulative incidence of NRM, % 3.7 (.7 to 11.4) 5.6 (1.4 to 14.0) 5.6 (1.4 to 14.0) 5.6 (1.4 to 14.0)

Cumulative incidence of relapse, % 55.6 (41 to 68) 55.6 (41 to 68)

Grades II-IV aGVHD 13 (5.6 to 23)

Grades III-IV aGVHD 9.3 (3.4 to 19)

All cGVHD 34 (22 to 47) 36 (23 to 49)

Extensive cGVHD 22 (12 to 34) 24 (14 to 37)

OS and PFS were calculated by the method of Kaplan and Meier. The cumulative incidence of NRM, relapse, and GVHD were calculated using the competing risks method. Both aGVHD and cGVHD were assessed using consensus criteria.

Figure 1. Cumulative incidence of (A) acute and (B) chronic GVHD. (A) The cumulative incidence of grades II to IV aGVHD is shown in red, whereas grades III to IV acute GVHD are in blue. (B) The cumulative incidence of all cGVHD is shown as a red line; extensive cGVHD is in blue. These analyses were per-formed using death and relapse as competing risks. (A color version of this figure can be seen atwww.bbmt.org.)

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was seen in 28 of 39 patients and was associated with improved OS (mortality hazard ratio [HR], .34; 95% CI, .14 to .83, P¼ .018), PFS (HR, .21; 95% CI, .09 to .49, P ¼ .0003), and lower risk of relapse (HR, .19; 95% CI, .07 to .51, P¼ .001). Graft versus Host Disease

The cumulative incidence of grades II to IV aGVHD was 13% at 200 days (Table 3,Figure 1A), whereas the cumulative incidence of grades III to IV aGVHD was 9.3%. The cumulative incidence of cGVHD was 34% at 1 year and 36% at 2 years after transplantation (Table 3, Figure 1B). The cumulative incidence of extensive cGVHD was 22% at 1 year and 24% at 2 years.

Survival Outcomes

The cumulative incidence of relapse at 2 years was 55.6%. NRM was 3.7% at 100 days and 5.6% at 2 years (Table 3, Figure 2). There were 4 patient deaths without relapse of disease: 1 patient with CMML failed to engraft and died from complications of graft failure on dayþ29; 1 patient with AML died from sepsis on dayþ64; 1 patient with MDS died from complications of dementia, believed to be age-related and not due to the transplantation, on dayþ1163; and 1 patient with MDS died from complications from aGVHD on

day þ158. OS and PFS rates at 1 year were 49% and 39%,

respectively, and at 2 years were 39% and 39%, respectively (Table 3,Figure 3).

Of the 32 patients who relapsed, 4 developed cGVHD during their follow-up period; this occurred after relapse in 3 of these 4 patients. One patient with AML relapsed on

dayþ105; he developed cGVHD during immunosuppression

taper and recovered donor chimerism to 98% but subse-quently died from Serratia marcescens septicemia on

day þ268. The second patient had AML and relapsed on

dayþ142; he developed cGVHD during immunosuppression

taper with count recovery. He maintained remission until

day þ637 when he relapsed again; immunosuppression

taper and a donor lymphocyte infusion were attempted but were unsuccessful, and he subsequently died from AML on dayþ680. The third patient had MDS, relapsed on day þ162, and developed cGVHD in the setting of immunosuppression taper; a donor lymphocyte infusion was performed but was unsuccessful, and the patient died on dayþ258. Eighteen

patients are alive and relapse-free, of whom 15 developed cGVHD. Four patients died from NRM as described previ-ously; the patient who died from complications of dementia had developed cGVHD before death.

Figure 2. Cumulative incidence of NRM (red) and relapse (blue). Each was treated as a competing risk in this analysis. (A color version of thisfigure can be seen atwww.bbmt.org.)

Figure 3. Kaplan-Meier estimates of OS and PFS. (A) Survival curves for all patients. OS is shown in red, whereas PFS is shown in blue. Hash marks indicate times at which patients are censored from the analysis. (B and C) Patients with AML or MDS that had either favorable or intermediate risk cytogenetics (red line) had improved OS (P¼ .045) and PFS (P ¼ .016) compared with patients with adverse risk cytogenetics (blue line) or other disease (green line). (A color version of thisfigure can be seen atwww.bbmt.org.)

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Prognostic Factors

We performed a univariable analysis to identify prog-nostic factors for OS, PFS, and relapse. Because the rate of NRM was very low, we did not evaluate predictors for NRM. For patients with MDS and AML, the OS and PFS rates were significantly longer for patients with favorable/intermediate cytogenetics compared with patients with unfavorable cytogenetics or with other disease (2-year OS: 53% versus

30%, respectively, P ¼ .045; 1-year PFS: 60% versus 26%,

respectively, P¼ .016) (Table 4,Figure 3B, C). Univariable Cox regression analysis showed that patients with favorable/ intermediate cytogenetic risk AML/MDS had a decreased HR for mortality (HR, .47; 95% CI, .22 to 1.002, P¼ .051) and for disease progression (HR, .41; 95% CI, .19 to .87, P¼ .02). The cumulative incidence of relapse for AML/MDS patients with favorable/intermediate cytogenetics was significantly lower compared with patients with unfavorable cytogenetics or other diseases (2-year cumulative incidence of relapse: 35% versus 68%, P¼ .02 using Gray test; HR, .4; 95% CI, .19 to .85, P¼ .017 from the Fine and Gray model).

For all patients, busulfan dose (3.2 versus 6.4 mg/kg) did not appear to be associated with differences in OS (HR, .96; 95% CI, .48 to 1.90, P¼ .90), PFS (HR, 1.15; 95% CI, .59 to 2.27, P¼ .68), or relapse (HR, 1.16; 95% CI, .58 to 2.32, P ¼ .67). Age, gender, donor type (matched unrelated donor versus matched related donor), GVHD prophylaxis, cytomegalovirus positivity, and HCT comorbidity index score were not significant predictors for OS, PFS, or relapse in the uni-variable analysis (data not shown). Very high DRI score was significant for predicting poor OS (HR, 5.84; P ¼ .04) but not relapse (HR, 3.02; P¼ .29) due largely to the small sample

size in this group (n ¼ 5). An ECOG (Eastern Cooperative

Oncology Group) score of 2 was associated with an HR of 2.98 for mortality compared with an ECOG score of 0 (95% CI, 1.02 to 8.75; P¼ .046) but was not associated with worse PFS (HR, 2.13; 95% CI, .77 to 5.90, P¼ .15) or relapse (HR, 1.24; 95% CI, .42 to 3.63, P¼ .70). There was no significant difference in outcomes between patients with an ECOG score of 1 and an ECOG score of 0. A multivariable model could not befit to the data given the number of variables.

Rehospitalizations

We evaluated the number of rehospitalizations after HSCT for each patient based on discharge summary information collected from the medical record, which includes hospitals affiliated with Partners HealthCare, Boston, Massachusetts. This does not account for hospitalizations outside of the Partners network and did not include emergency depart-ment or clinic visits. The median number of all-cause rehospitalizations (including for disease relapse) was 1 rehospitalization during the follow-up period (range, 0 to 11). Nineteen of 53 patients (36%) who survived beyond the

initial transplantation admission never required rehospital-ization. The median number of rehospitalizations for all patients within 6 months was 0 (range, 0 to 2), and the median number of rehospitalizations for all patients within 1 year was 1 (range, 0 to 7).

DISCUSSION

The burden of hematologic malignancies is highest among elderly patients, who, for multiple reasons, also have worse

outcomes [1,2]. Allogeneic HSCT using RIC regimens may

offer improved survival and lower rates of relapse compared with other therapies[4,6,10,12,25-27]. In this retrospective analysis, we report our experience with HSCT for 54 consecutive patients over the age of 70 from 2007 to 2012. Based on our results, we conclude that HSCT appears to be an effective and tolerable option for carefully selected adults over the age of 70, with an encouragingly low cumulative incidence of NRM of 5.6% at 1 year, as well as a 2-year PFS of 39% and 2-year OS of 39%. Among patients in this cohort who underwent transplantation for MDS or AML (68% of this cohort), we found that the presence of favorable/interme-diate risk cytogenetics was associated with superior outcomes, specifically 1-year PFS of 75% and 1-year OS of 60%. Increasingly, it appears that RIC HSCT is successful in carefully selected elderly cohorts with a variety of hemato-logic malignancies. A large study performed by the Center for International Blood & Marrow Transplant Research (CIBMTR) studied patients older than age 40 undergoing RIC HSCT, which included 63 patients with AML and 55 patients with MDS older than age 65[11]. In that study, which included patients up to age 79, age did not appear to adversely affect NRM, relapse, disease-free survival, or OS. This was also described in a prior series of patients older than age 60 treated with RIC regimens at the Dana-Farber Cancer Insti-tute [12]. Patients older than age 65 (range, 65 to 71) at transplantation did no worse than those age 60 to 65 in

terms of NRM, relapse, OS, or PFS, afinding confirmed in

a similar retrospective study of 600 patients from France [28]. Previously, the largest reported series of HSCT over age 70 consisted of 33 patients treated at the Fred Hutchinson Cancer Research Center[29]. That study included patients treated between 1998 and 2008 and reported that, for this age group, the 5-year cumulative incidence of NRM was 31%, and relapse was 42%; 5-year OS was 25% and PFS was 27%.

This current study adds to the literature by reporting survival outcomes in the largest series of patients older than age 70 that underwent transplantation with current regi-mens. Our results are similar to those previously reported for patients older than age 60, treated at the same institution between 2002 and 2008 with similar conditioning regimens and GVHD prophylaxis[12]. In that study, the cumulative incidence of relapse and NRM at 2 years was 54.6% and 10%,

Table 4

Summary of Survival Outcomes by Risk Group

OS PFS Cumulative Incidence of Relapse

Risk Group 1 Yr (95% CI) 2 Yrs (95% CI) 1 Yr (95% CI) 2 Yrs (95% CI) 1 Yr (95% CI) 2 Yrs (95% CI) AML/MDS with favorable/intermediate

cytogenetics

75 (50 to 89) 53 (25 to 75) 60 (36 to 78) 60 (36 to 78) 35 (15 to 56) 35 (15 to 56) AML/MDS with adverse cytogenetics or

other disease

34 (19 to 50) 30 (16 to 46) 26 (13 to 42) 26 (13 to 42) 68 (49 to 81) 68 (49 to 81)

P Value .045 .016 .02

Patients with AML or MDS who had favorable or intermediate cytogenetic risk had an improved OS, PFS, and lower cumulative incidence of relapse at both 1 and 2 years after transplantation compared with patients who had either adverse cytogenetics or other diseases. Because the outcomes of patients with adverse risk AML/MDS were similar compared with patients with other disease, these 2 categories are collapsed for the interest of power.

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similar to our reported incidence at 2 years of 55.6% and 5.6%, respectively. In addition, in that study, OS and PFS at 2 years were 46% and 35%, respectively; in the current analysis, we report 2-year OS and PFS rates of 39% and 39%. Of note, 2 patients in the current study were included in that prior analysis but, given this small number, are unlikely to signif-icantly influence our conclusions.

Inherent in this type of analysis is the selection of fit patients deemed eligible for HSCT by practicing physicians. Most of our cohort had HCT comorbidity index scores of 2 or less, although 17 patients (31%) had scores of 3 or above. Although the HCT comorbidity index score did not seem to correlate with OS in our analysis, the rate of NRM was so low (5.6% at 1 year) that it is difficult to make firm conclusions. What appears to be clear is that transplantation physicians can safely select candidate patients who arefit for HSCT, even among patients over 70 years of age.

Given the retrospective nature of the analysis, the heterogeneous patient population selected for trans-plantation, and the referral patterns at our institutions, there is no control arm of comparably age patients who either were deemed notfit for HSCT or were treated with alterna-tive therapies. Thus, we are unable to assess whether HSCT improved the prognosis of such patients. Insight into which elderly patients are most likely to benefit from HSCT is limited by the heterogeneity of underlying hematologic diseases we included. More patients in this cohort had AML or MDS, relative to other hematologic malignancies, likely because of the lack of suitable alternative therapies for these diseases particularly in this elderly patient population. Nevertheless, most of our patients were in advanced risk

categories as classified by the DRI and thus would have

generally poor outcomes with conventional treatment. Previous comparisons suggest a benefit for HSCT in elderly patients with MDS and AML[30-32]. For instance, 1 study compared RIC HSCT with azacitidine treatment in patients with MDS; those who underwent transplantation had an improvement in survival after 2 years[25]. Another study compared the results of HSCT from the CIBMTR with consecutive cohorts of AML patients age 60 or older receiving chemotherapy-based treatment on CALGB (Cancer and Leukemia Group B) protocols and found reduced relapse rates and increased leukemia-free survival with HSCT[32]. Most recently, a multicenter study coordinated by the CALGB and Bone Marrow Transplant Clinical Trials Network (BMT CTN) illustrated the impressive results of RIC HSCT for patients age 60 or older (range, 60 to 74) with AML in CR1 treated with uniform conditioning and GVHD prophylaxis regimens. Results showed a 2-year OS rate of 46% along with relatively low rates of TRM and GVHD[33].

It is most notable that the incidence of both NRM and aGVHD were low in our cohort of patients. The observed rate of grades II to IV and III to IV aGVHD is comparable with our previously described RIC cohorts[12,13,33,34]. Our observed low incidence of NRM and aGVHD in this elderly group likely reflects effective patient selection. As seen with most RIC cohorts, disease relapse and associated subsequent mortality remain the most common cause for failure and the biggest challenge for successful long-term disease management. cGVHD was more common among patients who were alive and relapse-free; only one patient relapsed after developing cGVHD.

Further follow-up is needed in larger patient cohorts to determine if physicians can accurately predict which patients truly benefit from allogeneic transplantation and

which are at the highest risk for NRM. Patients with AML or MDS who had favorable or intermediate cytogenetics appeared to have better outcomes in our study; however, further interpretations are limited by heterogeneity both of this subgroup and of the entire cohort. The poorer outcomes seen within those patients with adverse risk cytogenetics is an area for further study; this group may benefit from more intensive pre and posttransplantation interventions, such as alternative therapies before HSCT and prophylactic donor lymphocyte infusions or other interventions after HSCT, to try to harness an effective graft-versus-leukemia effect. Additionally, most transplantations were matched unrelated donors, which was likely because many in our cohort did not have eligible siblings or their treating physician chose not to use a sibling donor due to the sibling’s age. A study is currently in progress through the CIBMTR registry to simi-larly describe the characteristics and outcomes of patients over the age of 70 undergoing HSCT that will provide a larger cohort from which to learn. Finally, future studies will also have to focus on other more qualitative outcomes such as cost-effectiveness and quality of life, because various complications may be much more expensive and difficult to treat in older patients relative to younger counterparts.

The biggest challenge of performing HSCT in the elderly population may, in fact, be the hesitance or reluctance of oncologists to refer older patients for consideration for HSCT. One study from the M.D. Anderson Cancer Center showed that even after instituting an “automatic transplantation consultation” program for patients over age 50 with AML or high-risk MDS, few patients eventually underwent plantation: only 53 of 99 eligible patients had a trans-plantation evaluation, and only 14 of those patients eventually proceeded to transplantation[9]. Clearly, despite increasing data suggesting safety and benefit of RIC trans-plantation regimens in elderly patients, HSCT remains an underused treatment in this population. Studies like ours, which demonstrate encouraging tolerability and effective-ness in highly selected elderly patients, will hopefully increase awareness of, and thus access to, HSCT for this patient population. When treating patients age 70 and over with a reasonable performance status and comorbidity profile, age alone should not preclude referral for trans-plantation consultation and consideration for allogeneic HSCT.

ACKNOWLEDGMENT

This study was presented in abstract form at the annual meeting of the American Society of Blood and Marrow Transplantation, Salt Lake City, Utah, February 13 to 17, 2013. Financial disclosure: This research was performed with departmental support; there are no funding sources to disclose.

Conflict of interest statement: There are no conflicts of interest to report.

Authorship statement: V.T.H. and Y.-B.C. contributed equally to this manuscript.

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Figure

Updating...

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  6. Klingemann HG, Storb R, Fefer A, et al. Bone marrow transplantation inpatients aged 45 years and older. Blood. 1986;67:770-776
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  13. Kröger N. Allogeneic stem cell transplantation for elderly patients withmyelodysplastic syndrome. Blood. 2012;119:5632-5639
  14. McClune BL, Weisdorf DJ, Pedersen TL, et al. Effect of age on outcome ofreduced-intensity hematopoietic cell transplantation for older patients
  15. Koreth J, Aldridge J, Kim HT, et al. Reduced-intensity conditioninghematopoietic stem cell transplantation in patients over 60 years:
  16. Ho VT, Aldridge J, Kim HT, et al. Comparison of tacrolimus and siroli-mus (Tac/Sir) versus tacrolisiroli-mus, sirolisiroli-mus, and mini-methotrexate
  17. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation(HCT)-specific comorbidity index: a new tool for risk assessment
  18. Armand P, Gibson CJ, Cutler C, et al. A disease risk index for patientsundergoing allogeneic stem cell transplantation. Blood. 2012;120:905-913
  19. Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogeneticclassification in acute myeloid leukemia: determination of prognostic
  20. 2009;15:1628-1633.
  21. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conferenceon Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825-828
  22. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Healthconsensus development project on criteria for clinical trials in chronic
  23. Vigorito AC, Campregher PV, Storer BE, et al. Evaluation of NIHconsensus criteria for classification of late acute and chronic GVHD.
  24. Gray RJ. A class of K-sample tests for comparing the cumulative inci-dence of a competing risk. Ann Stat. 1988;16:1141-1154
  25. Fine JP, Gray RJ. A proportional hazards model for the subdistributionof a competing risk. J Am Stat Assoc. 1999;94:496-509
  26. Sorror ML, Logan BR, Zhu X, et al. Prospective validation of thepredictive power of the hematopoietic cell transplantation comorbidity
  27. Chen Y-B, Coughlin E, Kennedy KF, et al. Busulfan dose intensity andoutcomes in reduced intensity allogeneic peripheral blood stem cell
  28. Platzbecker U, Schetelig J, Finke J, et al. Allogeneic hematopoietic celltransplantation in patients age 60-70 years with de novo high-risk
  29. Murphy WJ, Artz AS, Champlin RE, et al. Blood stem cell transplantationin older patients. Biol Blood Marrow Transplant. 2009;15:1638-1639
  30. Appelbaum FR. What is the impact of hematopoietic cell trans-plantation (HCT) for older adults with acute myeloid leukemia (AML)?
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