Allogeneic Hematopoietic Stem Cell Transplantation in Adolescent and Adult Patients with High-Risk T Cell Acute Lymphoblastic Leukemia

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in Adolescent and Adult Patients with High-Risk T Cell

Acute Lymphoblastic Leukemia

Mohammad Bakr,

1

Walid Rasheed,

1

Said Y. Mohamed,

1

Fahad Al-Mohareb,

1

Naeem Chaudhri,

1

Fahad Al-Sharif,

1

Hazza Al-Zahrani,

1

Ghuzayel Al-Dawsari,

1

Abu Jafar Saleh,

1

Amr Nassar,

1

Shad Ahmed,

1

Assem Elghazaly,

1

Syed O. Ahmed,

1

Khalid Ibrahim,

1

Wahiba Chebbo,

1

Ghada M. El Gohary,

1

Muhamad H. Al Mahayni,

1

Fazal Hussain,

1

Zubeir Nurgat,

2

Tusneem Ahmed Elhassan,

3

Claudia U. Walter,

4

Mahmoud Aljurf

1

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is often recommended for patients with T cell acute lymphoblastic leukemia (T-ALL) in second or later complete remission ($CR2) and sometimes in high-risk (HR) patients in first complete remission (CR1). Between January 1995 and July 2009, 53 patients with HR T-ALL underwent allo-SCT at our institution. Median age was 18 years (range, 14-51). Thirty-two patients (60.3%) were in CR1, 18 (34%) were in$CR2, and 3 (5.7%) were in relapse. The cumulative incidence of nonrelapse mortality at 5 years was 22.5%. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 40.2%, and that of chronic GVHD was 43.7%. The majority of relapses (88.9%) occurred within 1 year after SCT. The cumulative incidence of relapse (CIR) at 5 years was 35.6%. CIR was 29.8% in patients in CR1, 35.3% in patients in$CR2 and all patients transplanted in relapse had disease recurrence post-allo-SCT (P5.000). Overall survival (OS) and disease-free survival (DFS) at 5 years were 43.5% and 41.8%, respectively. The 5-year OS was 53.5% (95% CI 34.5%-72.5%) and 5-year DFS was 52% (95% CI 33%-71%) in patients who underwent allo-SCT in CR1, compared with 31.9% (95% CI, 9%-54.8%) and 29.4% (95% CI 7.6%-51.2%) in those who underwent allo-SCT in$CR2. On multivariate analysis, disease status at SCTremained significantly associated with OS (P5.007), DFS (P5.002), and CIR (P5.000). The presence of extramedullary disease at diagnosis had no effect on the different outcomes. Grade II-IV acute GVHD was sig-nificantly associated with a lower OS (P5.006) and DFS (P5.01). Our data indicate that allo-SCTrepresents an effective treatment for HR T-ALL, particularly when performed in CR1.

Biol Blood Marrow Transplant 18: 1897-1904 (2012)Ó2012 American Society for Blood and Marrow Transplantation

KEY WORDS: Acute lymphoblastic leukemia, T cell, Adult, Hematopoietic stem cell transplantation

INTRODUCTION

T cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 20%-25% of cases of acute lymphoblastic leukemia in adults [1]. T-ALL has

clinical, immunologic, cytogenetic, and molecular fea-tures that are distinct from those of B cell acute lym-phoblastic leukemia (B-ALL) [2,3]. In recent study, better outcomes were associated with the use of more intensive treatment, and T-ALL was associated with greater 5-year overall survival (OS) compared with B-ALL (48% versus 41%;P5.001)[4]. Nonetheless, long-term outcomes in adult patients with T-ALL remain unsatisfactory, with a 5-year OS of only 30%-50% [4-6]. Furthermore, outcomes in patients who relapse is very poor, with a 5-year OS of 5%[7]. Although allogeneic hematopoietic stem cell trans-plantation (allo-SCT) is usually recommended for adult patients in second or later complete remission ($CR2), it also has been offered as postremission ther-apy for some patients in first CR (CR1), especially those with high-risk (HR) features [8]. The most From the1Adult Hematology/HSCT;2Pharmacy Services Division;

3Biostatistics Department, Oncology Center; and4Department of Cytogenetics/Molecular Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Financial disclosure:See Acknowledgments on page 1903.

Correspondence and reprint requests: Mohammad Bakr, MD, Adult Hematology/HSCT, Oncology Center, MBC-64, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11211, Saudi Arabia (e-mail:mmbakr@hotmail.com). Received February 10, 2012; accepted July 10, 2012

Ó2012 American Society for Blood and Marrow Transplantation 1083-8791/$36.00

http://dx.doi.org/10.1016/j.bbmt.2012.07.011

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widely cited HR factors include age, WBC count, im-munophenotype, cytogenetics, time to CR, extrame-dullary disease, and more recently, minimal residual disease (MRD)[9-12].

Data on outcomes of allo-SCT in patients with HR T-ALL are limited. To assess outcomes in this group of patients and to define factors predictive of outcome after allo-SCT, we analyzed our prospec-tively collected data on adult patients with T-ALL who underwent allo-SCT between 1995 and 2009. To our knowledge, this is one of the largest single in-stitutional studies reported to date describing the out-come and predictive factors after allo-SCT in patients with HR T-ALL.

PATIENTS AND METHODS Patient and Disease Characteristics

We analyzed the outcomes of adults (age $14 years) with T-ALL who received a full-intensity condi-tioning regimen and underwent allo-SCT at King Faisal Specialist Hospital and Research Center between January 1995 and July 2009. Treatment pro-tocols were approved by the hospital’s Institutional Review Board, and written informed consent was ob-tained from all patients and donors. Patients eligible for allo-SCT included HR patients in CR1 and any pa-tient in$CR2 or relapse. Patients in CR1 had one or more of the following HR features: age $35 years, WBC count at presentation$100,000/mm3, residual disease in bone marrow (BM) at day 14 postinduction, central nervous system (CNS) involvement at diagno-sis, HR cytogenetic features, and the need for more than one induction regimen to achieve CR1. T cell subtype was determined according to the classification scheme of the European Group for Immunological Classification of Leukemias[13], and myeloid markers were defined as the coexpression of CD13 and/or CD33. Cytogenetic studies were performed on unstimulated BM or peripheral blood (PB) cultures according to standard protocols. Karyotypes were risk-classified as proposed by the Southwest Oncology Group’s 9400 study[14]. (Detailed information about our institutional ALL protocol is available at http:// www.kfshrc.edu.sa/hem_malignancies.)

Transplantation Procedure and Supportive Care Patient and donor characteristics are summarized in Table 1. Full-intensity conditioning regimens were used for all patients. The probability of having an HLA-matched sibling donor in our population is 68% [15]. Although our center protocol dictates the search for a matched unrelated donor (MUD) in patients with acute leukemia who need allo-SCT and do not have a related donor, the likelihood of finding a MUD

from international donor registries is low because of the differences in HLA haplotype frequency in the Mid-dle East region[16]. Fifty-two transplants were from an HLA-matched sibling donors and only 1 transplant was from HLA-matched unrelated cord blood, given that the patient had neither an HLA-matched sibling donor nor a MUD. The majority of patients (94.3%) received cyclophosphamide 60 mg/kg once daily i.v. for 2 con-secutive days (total dose, 120 mg/kg), followed by 12 Gy of fractionated total body irradiation (TBI) given in 6 fractions. Partial lung shielding was established by the patient’s arm. Two patients (3.8%) received

Table 1. Patient Characteristics

Value All patients, n 53

Patient age, years, median (range) 18 (14-51) Age group, years, n (%)

14 to#20 36 (68)

>20 to#35 14 (26.4)

>35 3 (5.6)

Patient sex, male/female, n 46/7

Donor age, years, median (range) 21 (3-54) Donor sex, male/female, n 27/26

Donor–recipient sex match

Male–male 23 (43.4) Male–female 4 (7.5) Female–female 3 (5.7) Female–male 23 (43.4) T cell subtypes Pro-T cell 1 (1.9) Pre-T cell 21 (39.6) Cortical T cell 15 (28.3) Mature T cell 10 (18.9) Unknown 6 (11.3)

WBC109/L at diagnosis, median (range) 97 (0.17-712) Extramedullary disease at diagnosis

CNS 6 (11.3) Mediastinum 19 (35.8) Other 14 (26.4) Cytogenetics Intermediate 22 (41.5) HR/VHR 6 (11.3) ND 25 (47.2)

Disease status at transplantation

CR1 32 (60.3)

$CR2 18 (34)

Relapse 3 (5.7)

Time from diagnosis to transplantation, months, median (range)

CR1 3.9 (3-10) >CR1 14 (5-50) Conditioning regimen Cyclophosphamide/TBI 50 (94.3) Busulfan/cyclophosphamide 2 (3.8) Fludarabine/TBI 1 (1.9) GVHD prophylaxis MTX/CSA 51 (96.2) MTX/CSA/steroid 1 (1.9) CSA/Mycophenolate mofetil 1 (1.9) CD 34+stem cells infused,106/kg body

weight, median (range)

PB 4.6 (2.6-7.9)

BM 3.7 (1.6-7.9)

Stem cell source

PB 15 (28.3)

BM 37 (69.8)

Cord blood 1 (1.9)

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busulfan 16 mg/kg (1 mg/kg per dose orally every 6 hours over 4 consecutive days) and cyclophosphamide 60 mg/kg once daily i.v. for 2 consecutive days (total dose, 120 mg/kg). One patient (1.9%) received fludara-bine 30 mg/m2of body surface area/day i.v. for 5 days and 12 Gy fractionated TBI given in 6 fractions. Che-motherapy doses of conditioning regimens were based on adjusted body weight.

Short-course methotrexate plus cyclosporine (MTX/CSA) was the most common GVHD prophy-laxis regimen used, given to 51 patients (96.2%). MTX was given in a dose of 15 mg/m2body surface area i.v. on day 1 and 10 mg/m2on days 3 and 6. All patients received 3 doses of MTX. CSA was started on the day before transplantation and was given i.v. at a dose of 1.5 mg/kg every 12 hours up to day 21. Thereafter, the patients received oral cyclosporine 5 mg/kg every 12 hours. The full dose of cyclosporine was given up to day 50 posttransplantation, with a tar-get level of 200-400 ug/L. CSA was tapered in accor-dance with our institutional protocol.

All patients received irradiated and filtered blood products. RBC transfusions were given to patients with a hemoglobin level\80 mg/dL. Platelet transfu-sions were given to patients with a platelet count\10 109/L, or\15109/L in those with fever or clinical signs of bleeding. Granulocyte colony-stimulating factor was not administered routinely but was given to selected neutropenic patients with infective compli-cations at the discretion of the treating physician; overall 14 patients (26.4%) received granulocyte colony-stimulating factor. All patients underwent cy-tomegalovirus (CMV) surveillance with weekly pe-ripheral blood PP65 antigenemia testing during hospitalization. CMV antigenemia monitoring con-tinued at every clinic visit up to day 120 posttransplan-tation in all patients and sometimes longer for patients who continued with immunosuppressive therapy for GVHD. Antimicrobial prophylaxis against viral her-pes and Pneumocystis jiroveci infections continued for 6 months after discontinuation of immunosuppressive therapy. Antifungal prophylaxis was used up to day 30, and longer in patients with GVHD receiving immuno-suppressive therapy. Detailed information on our in-stitutional SCT protocol is available at http:// www.kfshrc.edu.sa/HSCT.

Engraftment and Toxicities

The time to neutrophil engraftment was defined as the first of 3 consecutive days with an absolute neutro-phil count (ANC) of$0.5109/L. The time of platelet engraftment was defined as the first day of 3 consecutive days with a sustained untransfused platelet count of

$20 109/L. Toxicity after SCT was graded acc-ording to the National Cancer Institute’s Common Toxicity Criteria (NCI, Bethesda, MD, USA).

Acute and Chronic GVHD

Acute GVHD (aGVHD) was diagnosed and scored as grade 0-IV in accordance with standard mor-phologic, clinical, and biochemical criteria [17]. Chronic GVHD (cGVHD) was assessed in patients surviving more than 100 days after allo-SCT.

Statistical Analysis

The probabilities of OS and DFS were estimated using the Kaplan-Meier method [18], and survival curves were compared using the log-rank test. Relapse, nonrelapse mortality (NRM), aGVHD, and cGVHD were determined with cumulative incidence estimates, with death in remission, relapse, and death without GVHD as competing risk events [19]. The Fine-Gray method[20]was used for group comparisons.

Outcomes evaluated in univariate analysis included death, NRM, relapse, and DFS. Factors evaluated for association with these outcomes are listed in Table S1(available athttp://dx.doi.org/10.1016/j.bbmt. 2012.07.011). Cox regression models were used to ex-amine the association of various factors with OS and DFS[21]. The impact of aGVHD or cGVHD on out-come was evaluated by introducing GVHD as a time-dependent covariate. Cox regression models were also used to evaluate the association of various factors with NRM and cumulative incidence of relapse (CIR). This was done with proper censoring, with relapse censored in the NRM and death in remission censored in the CIR. Potential prognostic factors were considered for multivariate analysis if thePvalue in univariate analysis was#.20. Multivariate regression models were fit using stepwise regression, with entry and exitPvalues of .10. Statistical analyses were performed using SPSS version 17.0 (SPSS, Inc., Chicago, IL) and R version 2.10.0 with software packages survival version 2.35-7 and cmprsk version 2.2-1 (http://www.r-project.org).

RESULTS Patient Features

Patient characteristics are summarized inTable 1. Between January 1995 and July 2009, 118 of the 463 patients with newly diagnosed ALL referred to our center were diagnosed with T-ALL. Fifty-three pa-tients underwent allo-SCT and were included in this study; some of them were referred in CR for allo-SCT after undergoing induction chemotherapy out-side our institution. The median patient age was 18 years (range, 14-51 years). At the time of allo-SCT, 32 patients (60.3%) were in CR1, 18 (34%) were in$CR2, and 3 (5.7%) were in relapse. T cell subtypes are shown inTable 1. Nine patients (17%) had myeloid marker coexpression. Twenty-eight pa-tients (52.8%) had successful metaphase karyotyping,

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18 of whom also underwent fluorescence in situ hybridization analysis. Karyotype data were not avail-able for 25 patients (47.2%); some patients demon-strated insufficient metaphases, whereas others were referred for allo-SCT in CR without sufficient cytoge-netic data at diagnosis. Twenty-two patients (41.5%) had intermediate-risk cytogenetic features (13 in CR1, 8 in$CR2, and 1 in relapse), including 10 pa-tients (19%) with normal karyotype. Six papa-tients (11.3%) had HR or very HR (VHR) cytogenetic fea-tures (3 in CR1 and 3 in$CR2), including 4 patients with complex cytogenetics, 1 patient with MLL gene rearrangement, and 1 patient with t(4;11). None of our patients exhibited Philadelphia chromosome or BCR-ABL1 fusion (Table S2) available at http:// dx.doi.org/10.1016/j.bbmt.2012.07.011.

Engraftment

Engraftment data were available for 48 of the 53 patients. One patient died on day 65 posttransplan-tation without achieving engraftment, and data are missing for 4 patients. All the patients survived for more than 21 days posttransplantation. ANC and platelet engraftment data are presented in Table 2. The median time to neutrophil recovery was 18 days in the PB group (range, 12-32 days) and 22 days in the BM group (range, 11-47 days) (P5.10), and the median time to platelet recovery was 14 days in the PB group (range, 9-28 days) and 19 days in the BM group (range, 11-125 days) (P5.07).

Transplantation-Related Toxicity

The cumulative incidence of NRM for all 53 pa-tients was 11.6% (95% CI, 10.4%-12.8%) at day 100 post-SCT and 22.5% (95% CI, 20.9%-24.1%) at 5 years post-SCT. Nonrelapse causes of death are sum-marized in Table 2. NRM at 5 years was not signifi-cantly different between patients in CR1 and those in

$CR2 (17% [95% CI, 16.8%-17.2%] versus 31.8% [95% CI, 29.1%-34.5%];P5 .20). Transplantation-related toxicities are summarized inTable 2.

aGVHD and cGVHD

The cumulative incidence of grade II-IV aGVHD was 40.2% (95% CI, 38.3%-42.1%), and that of cGVHD (both limited and extensive) was 43.7% (95% CI, 41.1%-46.3%). The median time to onset of cGVHD was 166 days (range, 100-778 days). Relapse

Eighteen patients relapsed, at a median time of 167 days (range, 49-426 days) after SCT. The CIR at 5 years was 35.6% (95% CI, 34%-38%). Sixteen patients (88.9%) relapsed less than 1 year post-SCT, with the latest relapse occurring at 1.2 years. The CIR at 5 years was significantly associated with disease status

at the time of transplantation. The CIR was 29.8% (95% CI, 28.4%-31.2%) in patients who underwent allo-SCT in CR1 and 35.3% (95% CI, 33%.3-37.3%) in those who underwent allo-SCT in $CR2; all patients who underwent allo-SCT while in relapse experienced dis-ease recurrence less than 3 months posttransplantation (P5 .000). CIR was 83.3% (95% CI, 77.8%-88.7%) in patients with HR/VHR cytogenetic features, com-pared with 27.3% (95% CI, 24.7%-29.9%) in patients with intermediate-risk cytogenetic features (P 5 .03) (Figure 1).

Survival and Causes of Death

At the time of this report, 26 of our 53 patients were still alive, 2 with relapse. Causes of death are sum-marized in Table 2. For all 53 patients, the 5-year OS was 43.5% (95% CI, 30%-57%), and the 5-year DFS was 41.8% (95% CI, 29%-56%). Both OS and DFS were significantly related to disease status at the time of allo-SCT. Five-year OS was 53.5% (95% CI, 34.5%-72.5%) and DFS was 52% (95% CI, 33%-71%) in patients who underwent allo-SCT in CR1, compared with 31.9% (95% CI, 9%-54.8%) and 29.4% (95% CI, 7.6%-51.2%) for those who

Table 2. Results

Value

All patients 53

ANC recovery, days, median (range)* 21 (11-47) Platelet recovery, days, median (range)* 16 (9-125) aGVHD grade, n (%)

Grade 0-I 32 (60.4)

Grade II 6 (11.3)

Grade III-IV 15 (28.3)

Day of aGVHD onset, median (range) 31 (4-100)

cGVHD, n (%) 15 (28.3) Infection, n (%) Febrile neutropenia 48 (90.6) Fungal infection 4 (7.5) CMV infection 22 (41.5) Herpes zoster 12 (22.6) Hepatic sinusoidal obstruction syndrome 7 (13.2) Hemorrhagic cystitis 3 (5.7) Pulmonary complications, n (%) IPS 8 (15.1) BOOP 5 (9.4) Hemorrhage 1 (1.9) Relapse (n518)

Day of relapse, median (range) 167 (49-426) Survival, n (%) Alive 26 (49.1) Dead 27 (50.9) NRM at day l00 6 (11.3) Causes of death (n527), n (%) Relapse 16 (59.3) IPS/ARDS 3 (11.1) Lung fibrosis/BOOP 3 (11.1) aGVHD 1 (3.7) Infection 2 (7.4) Other 2 (7.4)

ARDS indicates adult respiratory distress syndrome; BOOP, bronchioli-tis obliterans with organizing pneumonia; HZ, herpes zoster; IPS, idio-pathic pneumonia syndrome.

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underwent allo-SCT in $CR2 (P value 5 .000 for both) (Figures 2 and 3).

Five-year OS was 59.5% (95% CI, 34%-85%) in CD1a1 patients versus 38.9% (95% CI, 20%-57%) in CD1a2 patients (P 5 .416). Five-year DFS was 53.3% (95% CI, 28%-78%) versus 37.8% (95% CI, 20%-56%) (P5.648).

There were no significant differences in OS or DFS between patients with intermediate-risk cytoge-netic features and those with HR/VHR cytogecytoge-netic features (OS, 45% versus 16.7%, P 5 .32; DFS, 39.8% versus 16.7%,P5.26).

Prognostic Factors Univariate analysis

Results of the univariate analysis are shown in Table S1 available at (http://dx.doi.org/10.1016/ j.bbmt.2012.07.011). All outcome endpoints were

sig-nificantly related to disease status at allo-SCT. OS and DFS were lower in patients who underwent allo-SCT in $CR2 compared with those who underwent allo-SCT in CR1. In addition, patients who underwent allo-SCT in $CR2 had a higher relapse rate and a trend toward higher NRM. Female-to-female trans-plantation was associated with a lower DFS and a higher relapse rate compared with male-to-male transplantation. The relapse rate was higher in patients with HR/VHR cytogenetic features at the time of di-agnosis compared with those with intermediate-risk features. Extramedullary disease or CNS involvement at diagnosis had no effect on OS, DFS, relapse rate, or NRM. Grade II-IV aGVHD was significantly associ-ated with lower OS, lower DFS, and a 5.6-fold increase in NRM compared with grade 0-I aGVHD. aGVHD was not associated with lower relapse rate. Although cGVHD was numerically associated with a lower relapse rate, this association was not statistically signif-icant (HR, .38; 95% CI, .09-1.59;P5.19).

Multivariate analysis

Table 3shows the results of the multivariate anal-ysis. Disease status at allo-SCT remained statistically significantly associated with OS, DFS, and CIR. OS and DFS were lower in patients who underwent allo-SCT while in relapse compared with those who under-went allo-SCT in CR1 (OS: HR, 15.4; 95% CI, 2.8-85.3; P 5 .002; DFS: HR, 27.7; 95% CI, 4.3-179.7;P5.000).

Grade II-IV aGVHD modeled as a time-dependent covariate was significantly associated with lower OS and DFS compared with grade 0-I aGVHD. There was no significant difference in relapse rate be-tween patients who developed cGVHD and those without cGVHD (HR, 0.87; 95% CI, 0.74-1.03; Figure 1. CIR by cytogenetics.

Figure 2. OS by disease status at transplantation.

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P5.10). Patients with HR/VHR cytogenetic features at the time of diagnosis had an 8.8-fold higher relapse rate compared with those with intermediate-risk fea-tures (HR, 8.8; 95% CI, 2.2-34;P5.02).

DISCUSSION

Survival appears to be similar or possibly more fa-vorable in patients with T-ALL compared with those with B-ALL [6]; however, the literature is deficient on prospective studies focusing on T-ALL, owing to the disorder’s relative rarity. Many previous prospec-tive ALL trials have reported the outcomes of T cell subtypes as part of subgroup analysis. This makes pre-cise comparison of outcomes in different studies quite difficult, because of differences in patient characteris-tics and treatment protocols. Allo-SCT is usually rec-ommended for patients with HR ALL in CR1 and those who relapse and achieve CR2 [22]. According to our institutional protocol, allo-SCT is offered to adults (age$14 years) with T-ALL at HR of relapse; thus, our uniformly treated patients represent HR group, including those with allo-SCT in CR1.

In general, a 5-year OS of 30%-50% has been re-ported in adult patients with T-ALL[6]. In our series, the OS for these HR patients was 43.5% for the whole group and 53.5% for those who underwent allo-SCT in CR1. One of the largest series of adult ALL to date is the UKALLXII/ECOG 2993 trial. Marks et al.[23]reported descriptions and outcomes of a large cohort of adults with T-ALL treated in this prospec-tive trial with ‘‘biological assignment.’’ Of note, the

donor group in this study included patients with and without HR features, with a median age of 29 years, compared with 18 years in our study. Five-year OS was 61% for the donor group, compared with 46% for those without an available donor (P5.02). For pa-tients with ALL in CR1, allo-SCT incurred a survival advantage compared with autologous SCT or chemo-therapy[24]. The benefit was greater in the standard-risk patients compared with the HR patients. This result was clearly seen in the UKALLXII/ECOG 2993 trial[25], as well as in a recent meta-analysis of 11 donor/no-donor studies[26]. However, this obser-vation is limited by the donor versus no-donor assign-ment in these studies. This lack of survival difference between the donor and no-donor patients in the HR group was related to the high NRM in these HR pa-tients. The assumption that all patients with ALL in CR1 are candidates for allo-SCT is not yet supported by the results of prospective randomized trials.

Relapse rates after allo-SCT are much lower than those after chemotherapy or autologous SCT, but allo-SCT is associated with higher NRM[25]. In our study, the relapse rate at 5 years was 35.6%, compared with 25% for patients with T-ALL with donors in the UKALLXII/ECOG 2993 study. This difference might be explained by the fact that all of our patients were HR, including those in CR1. Our 5-year NRM of 22.5% is comparable to the 22% NRM in the T-ALL donor

group in the UKALLXII/ECOG 2993 study.

Although our patients were all HR and thus would be expected to have a higher NRM, this similar rate might be explained by the fact that most of our patients are young, with a median age of 18 years.

Cytogenetics is considered probably the single most important prognostic factor in adult patients with ALL. Patients with T-ALL with a complex karyotype have poor survival (19% at 5 years)[23]. In our study, OS in patients with HR/VHR cytogenetic features was similar to that reported in the UKALLXII/ECOG 2993 trial. There were no statistically significant differences in OS and DFS between patients with intermediate-risk cytogenics and those with HR/VHR cytogenetics, pos-sibly because of the relatively small size of our cohort. Furthermore, all of our patients with intermediate-risk cytogenetics had other HR features.

The incidence of grade III-IV aGVHD in our study cohort was 28%, compared with the roughly 20% reported in the literature[27]. We have no clear explanation for this difference, but our sample size is too small to allow a ready comparison with other stud-ies reporting aGVHD incidence. Allo-SCT in this group of patients was mainly from female to male, which may be a factor in this increased incidence.

Although in the present study cGVHD appeared to be associated with a relative reduction in relapse rate, this was not statistically significant. In contrast, aGVHD was not associated with a lower relapse rate,

Table 3. Multivariate Analysis

Endpoint/Covariate Hazard Ratio 95% CI PValue

Death

aGVHD II-IV* 1.19 1.05-1.35 .006 Disease status at transplantation .007

CR1 1.00 $CR2 1.3 0.47-4.10 .60 Relapse 15.40 2.80-85.30 .002 NRM aGVHD II-IV* 1.68 0.77-3.65 .18 Relapse

Disease status at transplantation .00

CR1 1.00 $CR2 1.90 0.60-5.40 .20 Relapse 111.70 10.60-1170.50 .00 Cytogenetics .001 Intermediate 1.00 ND 0.75 0.20-2.40 .60 HR/VHR 8.80 2.20-34.00 .02 cGVHD* 0.87 0.74-1.03 .10 Disease-free survival aGVHD II-IV* 1.20 1.04-1.40 .01 Disease status at transplantation .002

CR1 1.00

$CR2 1.60 0.61-4.12 .33 Relapse 27.70 4.30-179.70 .00 ND indicates no data.

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probably owing to its association with increased risk of early death. The efficacy of allo-SCT in ALL is medi-ated in part by the graft-versus-leukemia effect [28]. The suggested GVHD-associated graft-versus-leuke-mia effect of allo-SCT in ALL is indicated by the lower relapse rate in patients with aGVHD and/or cGVHD. The magnitude of this antileukemic effect of GVHD was similar in T-ALL and B-ALL[29].

Interestingly, in our study cohort, patients with CNS or other extramedullary disease at diagnosis had better OS and DFS. All of these patients under-went allo-SCT in CR1, which turned out to be the most important predictive factor for outcome after allo-SCT. In the UKALLXII/ECOG 2993 trial, CNS disease at diagnosis did not affect outcomes in patients with T-ALL, although it did affect outcomes in the complete patient cohort [23]. Lazarus et al. [30] reported that allo-SCT can confer long-term DFS in patients with ALL and CNS involvement at diagnosis. In a study from the Fred Hutchinson Cancer Center, extramedullary disease at time of di-agnosis was found to have no effect on outcome after allo-SCT [31].

Many previous studies have shown that allo-SCT is beneficial for adults with HR ALL in CR1 [26]. Recent advances in molecular genetics and genomics allow better identification of HR patients [32,33]. The recent incorporation of molecular MRD analysis in clinical studies has clear implications for redefining the prognosis of ALL[34].

Several novel purine analogs, including clofara-bine [35]and nelarabine, have shown promise in the treatment of ALL. Nelarabine has demonstrated re-markable activity in relapsed/refractory T-ALL and currently is being evaluated in first-line studies by at least 3 groups (M.D. Anderson Cancer Center,

GMALL, and MRC-ECOG) [36]. Other novel

agents also have been investigated and proposed for integration in the management of ALL, including mammalian target of rapamycin inhibitors, sonic hedgehog antagonists, and gamma-secretase inhibi-tors [37-39].

In summary, allo-SCT can provide effective treat-ment for HR patients with T-ALL, particularly if per-formed in CR1. Outcomes of allo-SCT in patients beyond CR1 appear to be significantly less favorable. Future clinical studies should focus on better risk strat-ification using recent molecular MRD applications, along with standard clinical and cytogenetic predictors of outcome, to identify more patients in CR1 status who might benefit from allo-SCT.

ACKNOWLEDGMENTS

Financial disclosure:The authors have no conflicts of interest to disclose.

SUPPLEMENTARY DATA

Supplementary data related to this article can be found athttp://dx.doi.org/10.1016/j.bbmt.2012.07.011

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