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. Author manuscript; available in PMC: 2015 Feb 7.
Published in final edited form as: Biol Blood Marrow Transplant. 2012 Jul 11;18(12):1835–1844. doi: 10.1016/j.bbmt.2012.07.003

Improved Early Outcomes Using a T Cell Replete Graft Compared with T Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation

Stefan O Ciurea 1, Victor Mulanovich 2, Rima M Saliba 1, Ulas D Bayraktar 1, Ying Jiang 2, Roland Bassett 3, Sa A Wang 4, Marina Konopleva 5, Marcelo Fernandez-Vina 6, Nivia Montes 1, Doyle Bosque 1, Julianne Chen 1, Gabriela Rondon 1, Gheath Alatrash 1, Amin Alousi 1, Qaiser Bashir 1, Martin Korbling 1, Muzaffar Qazilbash 1, Simrit Parmar 1, Elizabeth Shpall 1, Yago Nieto 1, Chitra Hosing 1, Partow Kebriaei 1, Issa Khouri 1, Uday Popat 1, Marcos de Lima 1, Richard E Champlin 1
PMCID: PMC4320643  NIHMSID: NIHMS598754  PMID: 22796535

Abstract

Haploidentical stem cell transplantation (SCT) has been generally performed using a T cell depleted (TCD) graft; however, a high rate of nonrelapse mortality (NRM) has been reported, particularly in adult patients. We hypothesized that using a T cell replete (TCR) graft followed by effective posttransplantation immunosuppressive therapy would reduce NRM and improve outcomes. We analyzed 65 consecutive adult patients with hematologic malignancies who received TCR (N = 32) or TCD (N = 33) haploidentical transplants. All patients received a preparative regimen consisting of melphalan, fludarabine, and thiotepa. The TCR group received posttransplantation treatment with cyclophosphamide (Cy), tacrolimus (Tac), and mycophenolate mofetil (MMF). Patients with TCD received antithymocyte globulin followed by infusion of CD34+ selected cells with no posttransplantation immunosuppression. The majority of patients in each group had active disease at the time of transplantation. Outcomes are reported for the TCR and TCD recipients, respectively. Engraftment was achieved in 94% versus 81% (P = NS). NRM at 1 year was 16% versus 42% (P = .02). Actuarial overall survival (OS) and progression-free survival (PFS) rates at 1 year posttransplantation were 64% versus 30% (P = .02) and 50% versus 21% (P = .02). The cumulative incidence of grade II–IV acute graft-versus-host disease (aGVHD) was 20% versus 11% (P = .20), and chronic GVHD (cGVHD) 7% versus 18% (P = .03). Improved reconstitution of T cell subsets and a lower rate of infection were observed in the TCR group. These results indicate that a TCR graft followed by effective control of GVHD posttransplantation may lower NRM and improve survival after haploidentical SCT.

Keywords: Haploidentical stem cell transplantation, T cell depletion, T cell replete haploidentical graft, GVHD prevention, High-dose posttransplantation cyclophosphamide

INTRODUCTION

Haploidentical hematopoietic transplant is an alternative treatment option for patients without an HLA matched related or unrelated donor [1]. Haploidentical related donors provide a readily available source of stem cells for transplantation [2]. Historically, haploidentical transplants have been associated with intense bidirectional alloreactivity, with higher rates of graft failure and graft-versus-host-disease (GVHD) [3]. T cell depletion (TCD) has been successfully used to reduce the incidence of GVHD [4,5]. However, this approach has been associated with a relatively high risk of nonrelapse mortality (NRM), primarily due to infectious complications and slow immunologic reconstitution posttransplantation, particularly in adults and those with active malignancy at the time of transplantation [6–9].

High-dose posttransplantation cyclophosphamide (Cy) has been shown to attenuate GVHD in mouse models, and early clinical studies with nonmyeloablative conditioning followed by Cy, tacrolimus (Tac), and mycophenolate mofetil (MMF) have reported a low rate of acute GVHD (aGVHD) and chronic GVHD (cGVHD), and treatment-related mortality in less than 20% of patients [10–12].

We evaluated outcomes of adult patients treated with T cell replete (TCR) haploidentical hematopoietic transplants and compared them with a retrospective cohort of patients previously treated at our institution with TCD haploidentical transplants, using the same preparative regimen, as previously described [13].

METHODS

Patients, Conditioning Regimen, Sources of Stem Cells, and Recovery of T Cell Subsets

Sixty-five consecutive patients, age ≥18 years, received a haploidentical transplant (≥2 HLA-mismatched antigens at HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1) at The University of Texas M.D. Anderson Cancer Center after October 2001 on successive clinical trials: 33 patients received a TCD transplant between October 2001 and February 2009, whereas 32 patients received an unmanipulated TCR graft between February 2009 and March 2011.

The preparative regimen consisted of melphalan 140 mg/m2 on day −8, fludarabine 40 mg/m2/day on days −6, −5, −4, and −3, and thiotepa 10 mg/kg on day −7. For the TCD group, GVHD prophylaxis included rabbit antithymocyte globulin at 1.5 mg/kg/ day on days −6, −5, −4, and −3, followed by infusion of CD34+ selected cells using a CliniMacs system (Miltenyi Biotec, Auburn, CA) [13]. The TCR group received an unmanipulated graft followed by Cy 50 mg/kg/day on days +3 and +4, with Tac and MMF starting on day +5, and continuing at least until 4 months posttransplantation for Tac, and at least until day +35 posttransplantation for MMF. In the last 11 patients, MMF was continued until day 100 due to the development of aGVHD in several of the initial patients. Six patients treated with a TCR haploidentical graft had reduced doses of melphalan (100 mg/m2) and thiotepa (5 mg/kg), due to older age (>55 years) and/or comorbidities.

TCR patients were treated on a clinical trial registered at ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT01010217) (N = 19), or off study because of ineligibility or insurance denial of treatment on study by the patient’s insurance carrier (N = 13). All patients provided written informed consent for their treatment, and the Institutional Review Board of the University of Texas M.D. Anderson Cancer Center approved this retrospective study.

All TCD recipients received peripheral blood progenitor cells, whereas all TCR patients (except one) received bone marrow (BM) as their stem cell source. Patients who developed aGVHD ≥grade 2 were routinely treated with corticosteroids (methylprednisolone 1–2 mg/kg in divided doses).

Reconstitution of T cell subsets, CD4+, CD8+, CD4+CD45RA+ (naive T cells), CD4+CD45RO+ (memory T cells), CD3−CD56+ (natural killer [NK] cells), CD19+ (B cells), was assessed by flow cytometry of peripheral blood samples approximately on days 30, 90, and 180 posttransplantation (N = 18 TCR and N = 7 TCD, respectively).

All patients received similar standard antimicrobial prophylaxis with voriconazole, valacyclovir, and trimethoprim-sulfamethoxazole or pentamidine. Patients received no prophylaxis for cytomegalovirus (CMV) infection and were treated with ganciclovir or foscarnet for CMV antigenemia or disease.

HLA Typing, HLA Ab Testing, and Donor Selection

Patients and donors were typed for alleles at HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 by PCR amplification and oligonucleotide hybridization using commercial kits from Invitrogen (Carlsbad, CA), ELPHA, and/or One Lambda (Canoga Park, CA) that achieved intermediate resolution. The patients were also typed for these loci by high-resolution methods using PCR amplification and nucleotide sequencing (Abbott, Abbott Park, IL). Additional high-resolution tests for selected loci were done in the donors in whom an allele level mismatch could not be ruled out. HLA haplotypes were assigned by the analysis of the segregation of HLA alleles as genetically transmitted units. HLA matching was evaluated from the intermediate and high-resolution results of the patients and the donors.

Donors were selected with consideration of a negative serum sample for donor-specific anti-HLA Abs before transplantation [14], being ABO matched rather than mismatched, male rather than female, and, if feasible, by the presence of killer immunoglobulin-like receptor (KIR)-ligand-mismatch in the graft-versus-host direction [15].

Definitions

Engraftment was defined as achieving an absolute neutrophil count (ANC) ≥5 × 109/L for 3 consecutive days before day 28, with donor-derived cells detected by microsatellite analysis [16]. Platelet recovery was defined as achieving a platelet count ≥20 × 109/L unsupported by platelet transfusions for 7 days. Primary graft failure was defined as failure to achieve an ANC ≥5 × 109/L before day 28. Acute and cGVHD were defined and graded according to previously described criteria [17,18]. Toxicity was scored using the National Cancer Institute criteria (available at http://ctep.info.nih.gov/reporting/ctc.html).

Infectious episodes were clinically documented if fever or other signs and symptoms of infection were present, along with laboratory and/or radiographic features consistent with pulmonary, sinus, brain, gastrointestinal, skin and soft tissue, or other organ infection, but no pathogen was identified. An infection was considered microbiologically documented if, in addition to the above findings, a disease-causing organism was identified from a body fluid or tissue sample by microbiologic or molecular testing or pathology. Polymicrobial infection was defined as more than 1 microorganism detected in the same body fluid or tissue sample. Fever with or without neutropenia, or without clinical or microbiological documentation, was excluded from reporting. Mild infections 1/M those not causing significant symptoms, not requiring therapy or hospitalization 1/M were excluded. All temporally related positive blood cultures for the same organism were considered a single episode of bacteremia. For coagulase-negative Staphylococcus, more than 1 positive culture was needed to diagnose bacteremia in a symptomatic patient [19].

CMV infection and disease were diagnosed using standard guidelines [20]. The presence of an invasive fungal infection was determined based on the revised definitions of the European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus group [21]. Death associated with a documented infection was defined as death of a patient with findings consistent with infection, or as detection of the pathogen at autopsy [22]. Patients were censored for graft failure, death, or relapse.

Statistical Analysis

The primary objectives were to compare the NRM, engraftment, incidence of GVHD, immune reconstitution, and infectious complications between TCR and TCD haploidentical transplants. Other endpoints included overall survival (OS), progression-free survival (PFS), and disease progression. Actuarial OS and PFS were estimated based on the Kaplan-Meier method. The cumulative incidence of progression, NRM, and GVHD was estimated, accounting for competing risks for each outcome. Death in remission was considered a competing risk for progression, disease progression a competing risk for NRM, and disease progression or death before GVHD as competing risks for GVHD. Outcomes were compared between the TCR and TCD groups on univariate analysis using the Cox proportional hazards regression analysis. Patient and transplantation characteristics were compared between the 2 groups using chi-square and the Fisher exact tests for categorical variables and the Wilcoxon rank sum test for continuous variables. Statistical significance was defined at the 5% level. Analysis was performed using STATA 9.0 (StataCorp 2005, College Station, TX). For assessment of infections, descriptive statistics, including frequency (percentages) for categorical variables and median (range) for quantitative variables, were used to summarize infections and mortality data. The effects of transplantation source on infections were investigated by survival analysis. Patients were followed up for 180 days from stem cell transplantation (SCT) to observe infections. Because some patients had multiple infection episodes during the follow-up time period, survival analysis of recurrent events data was performed. All statistical analyses were performed using SAS 9.1 (SAS Institute Inc., Cary, NC) [23–25].

RESULTS

Patient characteristics are summarized in Table 1. Patients in the TCR group tended to be older (median age 45 versus 36 years; P = .06), and 28% versus 6% were older than 50 years (P = .02). All patients had hematologic malignancies; the most common diagnoses were acute myeloid leukemia/myelodysplastic syndrome (Table 1). Most of the patients were not in remission from their malignancies in both groups. Twelve of 20 patients (60%) with acute leukemia in the TCR group had poor-risk cytogenetics versus 14 of 30 patients (47%) in the TCD group (P = .30). The donors were 5/10 allele match for the majority of patients in both groups. Fifty-six percent and 42% of patients received transplantation from a sibling donor in the TCR and TCD groups, respectively. There were no significant differences in number of HLA allele mismatches or sex mismatch between the donor and the recipient in the 2 groups (Table 1). Stem cell source was primarily BM in the TCR group and peripheral blood CD34+ selected progenitor cells in the TCD group (Table 1). As a result, the number of CD34+ cells (median 2.5 versus 10.1 × 106/kg) and number of CD3+ cells infused (17 versus 0.01 × 106/kg) differed significantly (P< .0001) between the TCR and TCD groups.

Table 1.

Characteristics of 65 Patients Treated with TCR and TCD Haploidentical SCT at M.D. Anderson Cancer Center

TCR, N = 32 TCD, N = 33 P Value
Median follow-up survivors (months) 11 (6–28) 48 (11–76)
Disease status*
  Active disease at transplantation 19 (59%) 21 (64%) .70
Age at transplantation
Median (range) 45 (20–63) 36 (18–56) .06
  >50 years 9 (28%) 2 (6%) .02
Sex, female 13 (41%) 17 (52%) .40
Diagnosis
  AML/MDS 16 (50%) 26 (79%)
  ALL 4 (13%) 4 (12%)
  CML 5 (16%) 2 (6%)
  NHL/CLL 3 (9%) 1 (3%)
  HD 2 (6%) 0 (0%)
  Other 2 (6%) 0 (0%)
Cytogenetics†
  Poor-risk 12/20 (60%) 14/30 (47%) .30
  Intermediate/good-risk 8/20 (40%) 16/30 (53%)
Conditioning
  Ablative 26 (81%) 33 (100%)
  Reduced-intensity 6 (19%) 0 (0%)
Donors
  Siblings 18 (56%) 14 (42%) .20
  Parent/child 13 (41%) 19 (58%)
  Other 1 (3%) 0 (0%)
Number of mismatches
  5 20 (63%) 17 (52%) .30
  4 5 (16%) 5 (15%)
  3 4 (13%) 6 (18%)
  2 3 (9%) 3 (9%)
  4 of 8† 0 (0%) 2 (6%)
Sex mismatch 16 (50%) 17 (52%) .90
Cell type
  BM 31 (97%) 0
  Peripheral blood 1 (3%) 33 (100%)
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TCR indicates T cell replete; TCD, T cell depleted; SCT, stem cell transplantation; AML, acute myeloid leukemia; MDS, myelodysplastic syndromes; ALL, acute lymphoblastic leukemia; CML, chronic myeloid leukemia; NHL, non-Hodgkin’s lymphoma; CLL, chronic lymphocytic leukemia; HD, Hodgkin disease; BM, bone marrow.

*

Patients with CML in chronic phase were considered in remission at transplantation.

†

For patients with ALL and MDS, cytogenetics were categorized as high-risk if del5, del7, +8, del7q, abnormalities involving 3q, 9q, 11q, 20q, 21q, 17, or more than 3 abnormalities were present; good-risk cytogenetics included t(8;21), inv(16), or t(16;16); intermediate-risk included diploid cytogenetics or other chromosomal abnormalities.

Transplant Outcomes

As of September 2011, the median follow-up among surviving patients was 11 months (range, 6–28 months) for the TCR group and 48 months (range, 11–76 months) for the TCD group. One patient in each group died within the first month posttransplantation. The primary cause of death was attributed to sepsis/pneumonia for the patient in the TCD group (day +27) and respiratory syncytial virus infection for the patient in the TCR group (day +8). The latter patient had upper respiratory symptoms before transplantation, which progressed to pneumonia immediately posttransplantation.

Engraftment of neutrophils occurred in 94% versus 81% for patients in the TCR and TCD groups, respectively (P = .10). Three and 2 patients had mixed chimerism in the TCR and TCD groups, respectively; the rest had complete donor chimerism for both myeloid and T cells. Follow-up chimerism and outcomes for patients with mixed chimerism was as follows: (1) for the TCD group, of the 2 patients with mixed chimerism on day 30, 1 patient with acute myelogenous leukemia (AML) developed graft failure in the presence of donor-specific anti-HLA Abs, underwent a retransplantation, and died of disease progression, whereas the other patient lost T cell chimerism on day 60 and died of disease relapse. (2) For the TCR group, all 3 patients with mixed chimerism had reduced-intensity conditioning and 2 of them had chronic lymphocytic leukemia (CLL). One patient with CLL lost the graft at day 60 and underwent a retransplantation with nonmyeloablative conditioning including fludarabine/Cy/total body irradiation [12], and is alive and in remission at last follow-up; 1 patient with CLL had mixed chimerism on day 30, lost the graft on day 60 in the presence of very high HHV-6 viremia, and later died of disease relapse; the third patient with AML had high mixed chimerism at day 60 (98% T and 82% M cells) and remains in molecular complete remission at more than 1 year posttransplantation. Most recent chimerism for this patient was 96% T and 83% M cells.

Recovery of neutrophils occurred after a median of 18 days (range, 5–24 days) and 13 days (range, 9–26 days; P = 4.8), and platelets after a median of 26 days (range, 11–307 days) versus 12 days (range, 7–48 days; P=.03) in the TCR versus the TCD group, respectively (Table 2).

Table 2.

Outcomes for Patients Treated with a TCR versus a TCD Haploidentical Graft Using the Same Conditioning Regimen

TCR
N = 32		 TCD
N = 33		 HR 95% CI P Value
Primary engraftment 94% (29/31) 81% (26/32) .10
ANC 500/µL (days), median (range) 18 (5–24) 13 (9–26) 4.8
N = 29 N = 27
PLT 20,000/µL (days), median (range) 26 (11–307) 12 (5–24) .03
N = 25 N = 24
ALC 1000/µL (days), median (range) 127 (44–423) 65 (27–273) .10
N = 15* N = 13
CI grade II–V aGVHD† (day 100) 20% (10–41) 11% (4–32) 1.6 0.4–6.4 .20
N = 30 N = 27
cGVHD (at 1 year) 7% (2–28) 18% (8–41) 0.2 0.03–0.98 .03
N = 30 N = 27
Day 100 outcomes
  Overall N = 32 N = 33
    OS 84% (66–93) 76% (57–87) 0.6 0.2–1.9 .40
    PFS 81% (63–91) 61% (42–75) 0.4 0.2–1.1 .08
    Progression 6% (2–24) 18% (9–37) 0.3 0.1–1.5 .10
    NRM 12% (5–31) 21% (11–41) 0.5 0.2–1.8 .30
Day 100 outcomes
  No active disease at transplantation N = 13 N = 12
    OS 100% 58% (27–80) N/A .01
    PFS 100% 58% (27–80) N/A .01
    Progression 0% 0% N/A N/A
    NRM 0% 42% (21–81) N/A .01
Outcomes at 1 year
  Overall
    OS 64% (44–78) 30% (15–46) 0.4 0.2–0.85 .02
    PFS 50% (31–67) 21% (9–36) 0.5 0.2–0.9 .02
    Progression 34% (20–57) 36% (23–57) 0.6 0.3–1.5 .30
    NRM 16% (7–35) 42% (28–63) 0.3 0.1–0.8 .02
Outcomes at 1 year
  No active disease
    OS 92% (57–99) 33% (10–59) 0.1 0.01–0.7 .02
    PFS 82% (44–95) 25% (6–50) 0.1 0.03–0.7 .01
    Progression 18% (5–64) 8% (1–54) 1.03 0.1–11 .90
    NRM 0% 67% (45–99) N/A .001
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TCR indicates T cell replete; TCD, T cell depleted; HR, hazard ratio; CI, confidence interval; ANC, absolute neutrophil count; PLT, platelet count; ALC, absolute lymphocyte count; aGVHD, acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease; OS, overall survival; PFS, progression-free survival; NRM, nonrelapse mortality; N/A, not applicable.

*

Three patients could still recover ALC to 1000/µL at the time of evaluation.

†

aGVHD within 100 days.

The cumulative incidence of grade II–IV aGVHD within 100 days was 20% versus 11% (P = .20) and grade III–IV was 5% versus 9% (P = .59) for TCR and TCD recipients, respectively. The rate of cGVHD at 1 year was low in both groups, with a cumulative incidence of 7% versus 18% (P = .03) in the TCR and TCD group, respectively (Table 2, Figure 1). No patient developed extensive cGVHD in the TCR group.

Figure 1.

Figure 1

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Outcomes of T cell replete (TCR) and T cell depleted (TCD) haploidentical transplant patients treated with fludarabine, melphalan, and thiotepa conditioning. (A) Progression-free survival for all patients. (B) Progression-free survival for patients in remission at transplantation. (C) Non-relapse mortality for all patients. (D) Non-relapse mortality for patients in remission at transplantation. (E) Cumulative incidence of chronic graft-versus-host disease (cGVHD). (F) Cumulative incidence of grade II–IV acute graft-versus-host disease (aGVHD).

OS and PFS were superior in the TCR group when compared at day 100 and at 1 year after transplantation (Table 2, Figure 1). Actuarial OS and PFS rates at 1 year posttransplantation were 64% versus 30% (P = .02) and 50% versus 21% (P =.02) for the TCR versus TCD groups, respectively. OS (92% versus 33%; P = .02) and PFS (82% versus 25%; P = .01) remained significantly superior in the TCR group when analysis was restricted to patients who were in remission at transplantation.

Better survival was related to a significantly lower rate of NRM in the TCR group; the rate of relapse or progression of malignancy was not different between the 2 groups (Table 2, Figure 1). The day 100 cumulative incidence of NRM was 12% for the TCR group versus 21% for the TCD group (P = .30). The difference became more pronounced at 1 year posttransplantation, showing a significantly lower incidence of NRM in the TCR group (16% versus 42%; P = .02). For patients in remission, NRM was significantly lower in the TCR group both at day 100 (0% versus 42%; P = .01) and 1 year posttransplantation (0% versus 67%; P = .001).

Reconstitution of T Cell Subsets after Transplantation

Improved NRM in the TCR group was accompanied by a better immune reconstitution of T cell subsets in the first 6 months posttransplantation (Figure 2). On day 30 posttransplantation, a 20-fold greater number of CD4+ and CD8+ T cells were observed among evaluable patients in the TCR group (N = 18) compared to the TCD group (N = 7). The median number of absolute CD4+ cells in the TCR group was 26 versus 1/µL (P = .00084; N = 25), and the median number of absolute CD8+cells was 22 versus 1/µL (P = .006; N = 25), respectively. The CD4+ T cells remained significantly lower in the TCD group until after day 180, when the median absolute CD4+ count was 194/µL in the TCR compared with 69/µL in the TCD group (P = .04). The absolute CD8+ counts also seemed to be higher at day 180 in the TCR group (median 167 versus 54/µL); however, it did not reach statistical significance (P = .40) (Figure 2).

Figure 2.

Figure 2

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Recovery of T cell subsets after transplant in T cell replete (TCR) and T cell depleted (TCD) haploidentical stem cell transplantations. **P < .002 (with Bonferroni correction); *P > .002 < .05. (A) Recovery of absolute CD8+ cell numbers (median). (B) Recovery of absolute CD4+ cell numbers (median). (C) Recovery of absolute CD4+CD45RA+ cell numbers (naive T cells) (median). (D) Recovery of absolute CD4+CD45RO+ cell numbers (memory T cells) (median). (E) Recovery of absolute CD56+ cell numbers (natural killer [NK] cells) (median). (F) Recovery of absolute CD19+ cell numbers (B cells) (median).

Improved immune reconstitution was also noted for naive and memory T cells in the TCR group. The median absolute numbers of CD4+CD45RA+ (naive T cells) and CD4+CD45RO+ (memory T cells) were higher at day 30 and at day 90 posttransplantation, 3.4 versus 0.7/µL and 7.3 versus 0.55/µL for the naive T cells, and 24 versus 2.6/µL and 97 versus 16/µL for the memory T cells between the TCR and the TCD groups, respectively (Figure 2). Interestingly, there was a higher proportion of CD3−CD56+ NK cells at all time points in the TCD group, although these differences were not statistically significant. The number of CD19+ B cells was similar between the 2 groups during the first 6 months posttransplantation (Figure 2). After day 180, there were no significant differences in any lymphocyte subsets.

Infectious Complications in TCR and TCD Haploidentical Transplants

The incidence of viral and fungal infections was significantly lower when compared to the TCD group (Table 3). There was a trend for a lower probability of developing any infection in the first 6 months posttransplantation in the TCR group (P = .06).

Table 3.

Infectious Complications in the First 180 Days Posttransplantation by Causative Agent in the TCR and TCD Haploidentical Transplant Groups

Type of Transplant
 TCD Haploidentical (N = 33)
 TCR Haploidentical (N = 32)
 Survival Analysis
Type of Infection No. of
Episodes		 No. of Infected
Patients		 No. of Episodes/
1000 pt-days		 No. of
Episodes		 No. of Infected
Patients		 No. of Episodes/
1000 pt-days		 P Value
Viral 82 24 22.2 50 27 10.8 .035
Bacterial 38 21 10.3 32 19 6.9 .66
Fungal 12 11 3.2 3 3 0.6 .008
Parasite 2 2 0.5 0 0 0 .17
Total infection episodes* 146 30 39.4 91 31 19.7 .06
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TCD indicates T cell depleted; TCR, T cell replete; pt, patient.

*

Includes viral, bacterial, fungal infections, and all others such as clinically documented and parasitic infections.

Viruses were the most common cause of infection in both groups. During the first 180 days posttransplantation, there were 22 episodes per 1000 patient-days in the TCD group and 11 episodes per 1000 patient-days in the TCR group during the first 180 days posttransplantation. Patients in the TCD group were 1.5 times (95% confidence interval [CI]: 1.03–2.1) more likely to develop a viral infection (P = .035) during this time period (Table 3). Among the viral infections, CMV reactivation and human polyomavirus BK cystitis were the most frequent. Fourteen of 33 patients (42.2%) had CMV reactivation with a total of 30 episodes in the TCD group compared with 15 of 32 patients (46.8%) with 24 episodes in TCR group. For human polyomavirus BK cystitis, 15 of 33 cases (45.4%) were found in the TCD group versus 11 of 32 (34.4%) in the TCR group.

There was no significant difference in the incidence of bacterial infections between the 2 groups. Thirty-two bacterial infections occurred in the TCR group compared with 38 episodes in the TCD group. On average, 7 and 10 episodes occurred per 1000 patient-days for the TCR and TCD group, respectively.

Invasive fungal infections were third in frequency, with 12 episodes in 11 of 33 patients (33%) in the TCD group, and only 3 episodes in 3 of 32 patients (9%) in the TCR group. The TCR group had a significantly lower probability of having a fungal infection (P = .008). Patients in the TCD group were 5.6 times (95% CI: 1.6–20.2) more likely to have an invasive fungal infection within 6 months posttransplantation than those in the TCR group (Table 3).

Survival analysis revealed a significantly lower probability of death from an infection in the TCR group. The NRM attributed to infections was 24% in the TCD group and 9% in the TCR group (P = .01).

DISCUSSION

No direct comparison between T cell depleted and TCR haploidentical transplants has been reported to date. Some centers reported success with TCD haploidentical transplants, particularly in children and young adults and patients in remission [26,27]. Our center and others have experienced a relatively high rate of treatment-related mortality in adult patients using a similar approach [13]. Our results seem similar to other large series involving adult patients, most with active disease at the time of transplantation [28].

We analyzed the early results of haploidentical transplants in adult recipients treated on 2 successive studies, and report improved outcomes with TCR transplants, using posttransplantation Cy, Tac, and MMF for GVHD prevention. The study evaluated patients on sequential protocols; the majority of patients had active malignancy at the time of transplantation. Uniform policies for supportive care were used for both cohorts of patients. We have found a lower rate of treatment-related mortality and associated improved immune reconstitution of T cell subsets in the TCR group. The rate of aGVHD was relatively low in both groups. Although depletion of mature T cells from the graft was an effective method of controlling GVHD in the TCD group, the T cell recovery posttransplantation was significantly delayed; this was associated with higher incidence of infectious complications and NRM. We have also observed a 5-fold lower incidence of fungal infections and almost 2-fold lower incidence of viral infections in patients receiving a TCR haploidentical transplant.

Previous studies have reported on prolonged immune deficiency and higher risk of infectious complications in TCD haploidentical transplant recipients [29–33]. Pirsch et al. [29] initially showed that recipients of HLA-matched TCD transplants had significantly higher incidence of fungal infections, whereas the highest risk of such infections was noted in mismatched TCD transplants. Overall, 83% of the mismatched TCD transplants and 55% of the matched TCD transplants died of infection [29]. T cell depletion was a strong independent predictor of invasive fungal infection in multivariate analysis [29]. Among patients who developed a deep fungal infection, the highest risk was found among mismatched transplantations with TCD, followed by matched transplantations with TCD and matched without TCD [29]. Slow reconstitution of CD4+ cells was previously recognized in TCD marrow transplants, with low-normal levels being reached approximately 6 months posttransplantation [30]. Daley et al. [31] have shown that regeneration of the T cell compartment was more severely impaired during the first 180 days post-TCD transplant than in those who received untreated marrow, and these patients had a greater rate of infections and disease recurrence. Recipients of TCD marrow grafts had lower proportions of cytotoxic and proliferative T cells in the first 6 months posttransplantation [31]. These studies are consistent with our finding of a higher rate of infections and treatment-related mortality early posttransplantation.

There are several limitations to our study, primarily related to a relatively small number of patients analyzed and the treatment of patients on sequential studies. Because of that, no multivariate analysis could be performed. The follow-up period for the TCR group is shorter than for TCD recipients; however, we ensured that all patients had at least 6 months’ follow-up in order to directly compare the outcomes between the 2 groups during the early posttransplantation period. Patient characteristics in each group were similar. When the analysis was restricted to patients with AML only, the same pattern and differences were found (data not shown).

In conclusion, this analysis demonstrates the feasibility of myeloablative TCR haploidentical transplants using fludarabine, melphalan, and thiotepa conditioning, and that this type of transplantation can be performed with a low rate of aGVHD and cGVHD using posttransplantation Cy, Tac, and MMF as posttransplantation immunosuppressive therapy. Better immune reconstitution could have contributed to improved early NRM. This approach for haploidentical transplant is an effective treatment option for patients lacking an HLA-identical related or unrelated donor.

ACKNOWLEDGMENTS

Funding: This study was supported in part by an M.D. Anderson Cancer Center Institutional Research Grant to Stefan O. Ciurea.

Footnotes

Financial disclosure: The authors have no conflict of interest to declare.

This paper was presented in part at the 2011 American Society of Hematology Meeting, San Diego, California.

Authorship Statement: Stefan O. Ciurea contributed to study design, collected and analyzed the data, and prepared the manuscript; Victor Mulanovich contributed with data collection and interpretation, and reviewed and approved the manuscript; Rima M. Saliba, Ying Jiang, and Roland Bassett contributed with statistical analysis, and reviewed and approved the manuscript; Ulas D. Bayraktar, Nivia Montes, Doyle Bosque, Julianne Chen, and Gabriela Rondon contributed with data collection, and reviewed and approved the manuscript; Sa A. Wang contributed with flow cytometric analysis and interpretation of the flow cytometry data, and reviewed and approved the manuscript; Marcelo Fernandez-Vina contributed with HLA typing, and reviewed and approved the manuscript; Gheath Alatrash, Marina Konopleva, Qaiser Bashir, Muzaffar Qazilbash, Simrit Parmar, Elizabeth Shpall, Yago Nieto, Amin Alousi, Chitra Hosing, Partow Kebriaei, Issa Khouri, Uday Popat, and Marcos de Lima contributed with patient accrual, and reviewed and approved the manuscript. Richard E. Champlin contributed to study design, patient accrual, data interpretation, and co-authored the manuscript.

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