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0Biol Blood Marrow Transplant xxx (2012) 1—6
T Cell—Depleted Stem Cell Transplantation for Adults with High-Risk Acute Lymphoblastic Leukemia: Long-Term Survival for Patients in First Complete Remission with a Decreased Risk of Graft-versus-Host Disease
Jenna D. Goldberg1,3,7,y*, Alex Linker1,Deborah Kuk5, Ravin Ratan7, Joseph Jurcic2,3,7, Juliet N. Barker1,3,7, Hugo Castro-Malaspina1,3,7 Sergio Giralt1,3,7 Katharine Hsu1,3,7, Ann A. Jakubowski1,3, , Robert Jenq1,3,7 Guenther Koehne1,3,7 Esperanza B. Papadopoulos1,3,7 Marcel R.M. van den Brink1,3,7 James W. Young1,3,7 Farid Boulad1,4,7 Nancy A. Kernan1,4,7 Richard J. O'Reilly1,4,7, Susan E. Prockop1,4,7 Joachim Yahalom 6,7 Glenn Heller 5, Miguel-Angel Perales1,3,7
1 Adult Bone Marrow Transplantation Service, New York, New York
2 Leukemia Service, New York, New York
3 Department of Medicine, New York, New York
4 Department of Pediatrics, New York, New York
5 Department of Biostatistics and Epidemiology, New York, New York
6 Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York
7 Weill Cornell Medical College, New York, New York
ASBMTm
American Society for Blood and Marrow Transplantation
Article history: Received 27 June 2012 Accepted 6 September 2012
Key Words:
Acute lymphoblastic leukemia T cell depletion Allogeneic transplantation
ABSTRACT
Consolidation with allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides a survival benefit to patients with acute lymphoblastic leukemia (ALL). We have previously reported comparable survival and relapse rates after T cell—depleted (TCD) allo-HSCT compared with unmodified transplantations for acute myelogenous leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma with significantly decreased graft-versus-host disease (GVHD). We performed a 56-patient retrospective study to evaluate TCD allo-HSCT for the treatment of ALL after myeloablative total body irradiation—based therapy. The 2-year and 5-year overall survival rates for patients with ALL after TCD allo-HSCT were 0.39 (95% confidence interval [CI], 0.26-0.52) and 0.32 (95% CI, 0.19-0.44), respectively, and the 2-year and 5-year disease-free survival rates were 0.38 (95% CI, 0.25-0.50) and 0.32 (95% CI, 0.20-0.44). There was a trend toward improved survival of patients who underwent TCD allo-HSCT in first complete remission compared with those that did so in other remission states. The cumulative incidence of grade II-IV acute GVHD at 1 year was 0.20 (95% CI, 0.10-0.31), and no patients developed grade IV acute GVHD. The cumulative incidence of chronic GVHD in 41 evaluable patients at 2 and 5 years was 0.15 (95% CI, 0.04-0.26), and that of extensive chronic GVHD at 2 and 5 years was 0.05 (95% CI, 0-11.6). We demonstrate OS and DFS rates that compare favorably to unmodified allo-HSCT with lower rates of GVHD.
© 2012 American Society for Blood and Marrow Transplantation.
INTRODUCTION
Approximately one-third of the nearly 4000 cases of acute lymphoblastic leukemia (ALL) occurring annually in the United States affect adults [1]. Although rates of complete remission (CR) after induction and consolidation are nearly equivalent in adults (>78%) and children (>90%), the overall cure rate is only <40% in adults, compared with 80% in children [1]. Patients with relapsed or refractory disease have a dismal prognosis, with a median survival of 6 months [2-4]. Numerous previous studies have demonstrated the benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with ALL in second CR (CR2) or high-risk first CR (CR1) [5-10]. Other studies have not reported a similar benefit, however [11,12]. A recent meta-analysis of
7 published studies of patients with ALL reported a significant advantage for sibling allogeneic transplants in high-risk patients compared with transplants from nonsibling donors [13]. More recent studies also have demonstrated the benefit of allo-HSCT in patients with standard-risk ALL [14,15].
We have established the efficacy of T cell—depleted (TCD) allo-HSCT as postremission therapy in patients with acute myelogenous leukemia, myelodysplastic syndrome, or non-Hodgkin lymphoma, including an almost complete elimination of graft-versus-host disease (GVHD) without compromising the antileukemic efficacy of the allograft [16-19]. Here we report the results of a single-center retrospective review of 56 adult patients with ALL who underwent TCD allo-HSCT, which found acceptable overall survival (OS) and disease-free survival (DFS) with a low risk of GVHD.
Financial disclosure: See Acknowledgments on page 5.
* Correspondence and reprint requests: Jenna D. Goldberg, MD, Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. E-mail address: goldbej2@mskcc.org (J.D. Goldberg). y Jenna D. Goldberg and Alex Linker contributed equally to this work.
1083-8791/$ — see front matter © 2012 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2012.09.003
PATIENTS AND METHODS Patients
Fifty-six consecutive adult patients with ALL underwent allogeneic TCD allo-HSCT at Memorial Sloan-Kettering Cancer Center between May 1997 and December 2008. Written informed consent for treatment was obtained
from all patients and donors. Approval for this retrospective review was obtained from the center's Institutional Review and Privacy Board. Eligibility criteria for transplantation included a diagnosis of relapsed or refractory ALL or high-risk ALL in CR1, age <65 years, availability of an HLA-matched or single-allele-mismatched donor, absence of active infection, and lack of coexisting cardiac, pulmonary, hepatic, or renal dysfunction that would preclude administration of the cytoreductive regimen. HLA matching was established by DNA sequence-specific oligonucleotide typing for HLA-A, -B, -C, -DRB1, and -DQB1 loci.
Transplantation Procedure and Supportive Care
All patients received myeloablative cytoreduction comprising hyper-fractionated total body irradiation (HFTBI), followed by thiotepa and highdose cyclophosphamide (18 patients) or thiotepa and fludarabine (38 patients) [16,17,19]. Patients received the fludarabine regimen on a protocol designed to study whether the additional immune suppression from flu-darabine could eliminate the need for antithymocyte globulin (ATG) in TCD allo-HSCT using related donors [17]. Otherwise, patients received a cyclo-phosphamide-based regimen. HFTBI (total dose of 1375 cGy or 1500 cGy, with lung blocking plus chest wall and testicular boosts) was administered as described previously [16]. After HFTBI, thiotepa 5 mg/kg i.v. was administered daily for 2 days. In the 18 patients who received the former regimen, administration of thiotepa was followed by high-dose cyclophosphamide 60 mg/kg i.v. daily for 2 days [16]. In the other 38 patients, fludarabine 25 mg/m2 i.v. was administered daily for 5 days beginning on the first day of thiotepa administration [17].
T cells were removed from bone marrow (BM) grafts by sequential soybean lectin agglutination and sheep RBC rosette depletion [16,20]. T cell depletion of granulocyte colony-stimulating factor-mobilized peripheral blood stem cells (PBSCs) was accomplished by positive selection of CD34+ stem cells using the ISOLEX 300i Magnetic Cell Separator and subsequent sheep RBC rosette depletion [17]. TCD BM or PBSCs were infused within 24-48 hours after completion of chemotherapy. Seventeen patients received BM, and 38 received PBSCs, all of which were TCD. One patient received a combined TCD BM and PBSC allograft.
Recipients of an HLA-matched related donor graft who were treated with HFTBI, thiotepa, and fludarabine (n = 11), and 2 patients aged <20 years did not receive any rejection prophylaxis. Equine (30 mg/kg/dose) or rabbit (5 mg/ kg/dose) ATG before (n = 30) or after (n = 13) stem cell infusion provided graft rejection prophylaxis in all other patients [16,17,21]. Patients who received 2 daily doses of ATG before stem cell infusion were given high-dose methyl-prednisolone (1 mg/kg/day) with each dose. The patients who received 4 doses of ATG after stem cell infusion received methylprednisolone with each dose of ATG, with steroids rapidly tapered. All patients received supportive care and prophylaxis against opportunistic infections in accordance with standard guidelines. No pharmacologic GVHD prophylaxis was given.
Myeloid engraftment was defined as an absolute neutrophil count (ANC) >500/mL on 3 consecutive days posttransplantation. Platelet engraftment was defined as an untransfused platelet count >20,000/mL for at least 3 consecutive days. Primary graft failure was defined as the absence of neutrophil recovery (ANC >500/mL) by day 28 and BM biopsy with <5% cellularity. Secondary graft failure was defined as ANC <500/mL after primary engraftment, with BM biopsy showing <5% cellularity [18]. GVHD was diagnosed clinically, confirmed pathologically by biopsy whenever possible, and classified according to standard criteria [22]. Patients who engrafted were evaluable for acute GVHD (aGVHD), and patients surviving at least 100 days were evaluable for chronic GVHD (cGVHD) [23]. Cause of death was determined using a standard algorithm [24].
Data Collection and Statistical Methods
Analyses were performed as of December 31, 2011. OS and DFS probabilities were calculated using the Kaplan-Meier method, and the differences between levels within a covariate were tested using log-rank statistics [25]. The cumulative incidence of relapse (CIR) was calculated using competing-risk methods. The following pretransplantation variables were assessed for theireffects on OS and DFS: disease status, cytogenetic risk stratification (high, standard, or low) [26], presence of extramedullary disease, stem cell source, HLA match, and use of a cyclophosphamide-containing versus a fludarabine-containing preparative regimen. Univariate analyses were performed using the log-rank test. Because only one association between pretransplantation variables and survival endpoints reached statistical significance in the univariate analyses, multivariate analysis was not performed.
RESULTS
Patient Characteristics
Pretransplantation characteristics of the 56 patients are summarized in Table 1. The median age was 36 years, and 11
Table 1
Patient Characteristics
Age, years, median (range) 36(18-63)
Age group, years, n
20-29 16
30-39 7
40-49 15
>50 11
Cytogenetics at diagnosis, n*
Good risk 3
Standard risk 25
Poor risk 24
Not evaluable/unknown 4
Phenotype, n
Multilineage/unknown 2
Extramedullary disease, n
Yes 16
Donor, n
Matched related 22
Mismatched related 6
Matched unrelated 15
Mismatched unrelated 13
Status at HSCT, n
CR1 27
CR2 18
CR3+ 11
Conditioning regimen, n
HFTBI/thiotepa/cyclophosphamide 18
HFTBI/thiotepa/fludarabine 38
* Good risk: hyperdiploidy, del(9p); poor risk: Ph+, t(4;11), t(8;14), complex karyotype (>5 abnormalities), hypodiploidy/near triploidy; standard risk: other [26].
patients were aged >50 years. Twenty-nine patients (52%) underwent transplantation in CR1 or greater, with 11 patients (20%) in third CR (CR3) or greater. Almost half (43%) of the patients had poor-risk cytogenetics. A significant number of patients received an alternative donor graft, with 28 (50%) receiving an unrelated donor graft (13 mismatched) and 6 receiving a mismatched related donor graft (ie, not matched at 10/10 alleles).
Engraftment and GVHD
All 54 patients evaluable for engraftment achieved initial engraftment. However, 2 patients who received a mismatched graft from an unrelated donor experienced secondary graft failure, one at day +35 and the other at day +67. Both patients eventually died with multiorgan failure. The median time to neutrophil engraftment was 13 days for the entire cohort, 15 days for recipients of BM grafts, and 12 days for recipients of PBSC grafts. The median time to platelet engraftment was 14 days for the entire cohort, 25 days for BM recipients, and 13 days for PBSC recipients. Four patients (2 BM recipients and 2 PBSC recipients) did not achieve platelet engraftment. Data on engraftment times were not available for 2 patients (both BM recipients), and 2 patients (both PBSC recipients) were not evaluable for engraftment because of early death.
The cumulative incidence of grade II-IV aGVHD at 1 year in the 54 evaluable patients was 0.20 (95% confidence interval [CI], 0.10-0.31; Figure 1A). No patient developed grade IV aGVHD. The organs involved included skin only in 7 patients, skin and gastrointestinal tract in 2 patients, gastrointestinal tract only in 1 patient, and skin and liver in 1 patient. Two of the patients with aGVHD received a BM or
Figure 1. Cumulative incidences of aGVHD (A) and cGVHD (B).
PBSC graft from a matched related donor, and the other 9 received a BM or PBSC graft from an alternative donor (4 from a matched unrelated donor and 5 from a mismatched related or unrelated donor). The cumulative incidence of cGVHD in 41 evaluable patients at 2 and 5 years was 0.15 (95% CI, 0.04-0.26; Figure 1B), and that of extensive cGVHD at 2 and 5 years was 0.05 (95% CI, 0-11.6).
Donor Leukocyte Infusion
Four patients received unselected donor lymphocyte infusion (DLI) after their initial transplantation, and 1 patient received Epstein-Barr virus (EBV) cytotoxic T lymphocytes. DLI was administered for infection in 2 patients, for minimal residual disease in 1 patient, and for mixed BM chimerism in 1 patient who later developed cGVHD and died.
Reactivation of Cytomegalovirus and EBV
Thirty patients had documented to have cytomegalovirus (CMV)-positive serology. Of the 28 patients evaluable for viral reactivation (minus 2 premature deaths), 9 (32%) had CMV reactivation. One of these patients died from CMV pulmonary disease. Of 40 patients who were surveilled with EBV PCR, 7 (18%) had evidence of EBV reactivation. Four of these patients required therapy with rituximab. One other patient, who underwent transplantation before routine EBV PCR surveillance testing, had an EBV lymphoproliferative disorder detected on lung biopsy analysis and received DLI and rituximab.
Nonrelapse Mortality
Causes of death in our cohort included infection in 10 patients, GVHD in 8 patients, organ failure in 5 patients, and nonengraftment in 2 patients, both of whom had evidence of reemergent host cells on BM evaluation. Of the 10 patients who died of infection, 5 had a documented bacterial infection (4 with vancomycin-resistant enteroccocci [VRE] and 1 with Clostridium difficile colitis), and 3 had a documented viral infection (1 patient each with CMV, EBV, and adeno-virus). Three of the 4 patients who died with VRE infection were noted to have VRE colonization before transplantation, and the fourth patient underwent transplantation before institution of routine VRE surveillance. We previously described the virulence of VRE in unmodified and TCD allo-HSCT [27]. One patient each was diagnosed with a fungal infection (Aspergillus flavus) and toxoplasmosis. Of the 5 patients with fatal organ failure, 4 died from pulmonary toxicity and 1 died from veno-occlusive disease. All 4 patients who died from pulmonary toxicity suffered progressive pulmonary failure that culminated in acute respiratory distress syndrome. Seven of the 8 patients with fatal GVHD died from infection in the setting of immuno-suppressive treatment (1 with bacterial infection, 3 with fungal infection, 2 with viral infection, and 1 with toxoplasmosis). The eighth patient had biopsy-proven GVHD and died of concurrent demyelination; however, he was classified as dying from GVHD based on the algorithm of Copelan et al. [24].
The nonrelapse mortality (NRM) at 2 years was significantly higher for patients who underwent allo-HSCT in CR3+ compared with those who did so in CR1 or CR2 (0.63 versus 0.33; P = .030). Eight of the 11 patients undergoing transplantation in CR3+ died from a transplantation-related cause, resulting in an 2-year NRM rate of 0.39 for the entire cohort. Because the mortality rate from GVHD-related causes differed from our previous data onTCD allo-HSCT [16-19], we evaluated GVHD-related mortality and NRM not related to GVHD by disease status. We found that the 2-year NRM without GVHD was related to disease status (CR1, 0.19; CR2, 0.28; CR3+, 0.55; P = .089), whereas GVHD-related mortality was not (P = .569).
CIR, DFS, and OS
The CIR for the entire cohort was 0.23, and was not affected by disease status (P = .522) or cytogenetic risk group (P = .408). With a median follow-up of 6.1 years, the entire cohort had a 2-year DFS of 0.38 (95% CI, 0.25-0.50), a 5-year DFS of 0.32 (95% CI, 0.20-0.44) (Figure 2A), a 2-year of 0.39 (95% CI, 0.26-0.52), and a 5-year OS of 0.32 (95% CI, 0.19-0.44) (Figure 2B). Data on 2-year and 5-year DFS and OS by disease status are presented in Table 2. Patients in CR1 had a higher DFS (P = .062; Figure 2C) and OS (P = .056; Figure 2D) than those in CR2+. Analysis of pre-transplantation prognostic factors revealed a higher median OS (P = .041) and a trend toward improved DFS (P = .051) in patients with a matched related donor compared with those with other donors. No differences in either DFS or OS were seen based on cytogenetic risk group, presence of extra-medullary disease, or age at transplantation. In addition, no differences in DFS or OS were found based on cytoreduction regimen (HFTBI-thiotepa-cyclophosphamide versus HFTBI-thiotepa-fludarabine) or graft source, as reported previously in patients with non-Hodgkin lymphoma treated with the same approach [19].
J.D. Goldberg et al. / Biol Blood Marrow Transplant xxx (2012) 1-6
Years Years
Figure 2. DFS (A) and OS (B) for the entire cohort and DFS (C) and OS (D) by disease status.
DISCUSSION
Our results represent the first published report of ex vivo TCD allo-HSCT for the treatment of ALL in adults without posttransplantation pharmacologic GVHD prophylaxis. Recognizing the limitations of a retrospective study that encompasses many years, we nevertheless have demonstrated acceptable OS, DFS, and relapse rate with low rates of GVHD in the context of the historical experience with T cell-replete allo-HSCT [5-10]. Notably, our results for patients in CR1 are promising, with a plateau in the OS and DFS curves for these patients at approximately 2 years.
Fifty-six adult patients underwent TCD allo-HSCT for the treatment of ALL. This patient population was particularly high risk, with only 7 patients aged <20 years and 24
Table 2
OS and DFS by Disease Status
2-Year 5-Year
OS 0.48 (0.29-0.67) 0.48 (0.29-0.67)
DFS 0.48 (0.29-0.67) 0.48 (0.29-0.67)
OS 0.39 (0.16-0.61) 0.22 (0.03-0.41)
DFS 0.33 (0.12-0.55) 0.22 (0.03-0.41)
OS 0.18 (0-0.41) 0.09 (0-0.26)
DFS 0.18 (0-0.41) 0.09 (0-0.26)
patients with poor-risk cytogenetic classification (43%). Slightly more than half of the patients (29; 52%) underwent transplantation in >CR1. Sixteen patients (29%) had extra-medullary disease at presentation. For the entire cohort, the 2-year OS of 0.39 and 2-year DFS of 0.38 were comparable to previous data on T cell-replete transplantation in this high-risk patient population. For patients in CR1, OS and DFS were 0.48 at both 2 years and 5 years. In the absence of posttransplantation pharmacologic GVHD prophylaxis, the cumulative incidence of aGVHD at 1 year was only 0.20 (with no incidence of grade IV aGVHD), consistent with our previous data on TCD allo-HSCT, despite the fact that 34% of the patients received a mismatched donor graft. The incidence of cGVHD was only 15% at 2 years posttransplantation.
The 2-year NRM of 0.39 for the entire cohort is higher than our previous findings for TCD allo-HSCT in other diseases [16-18], with infection the most prevalent non-relapse-related cause of death. Five of the 10 deaths attributed to infection resulted from early bacterial infections (range, day +5 to day +66), 4 of which due to VRE bacteremia; thus, it is difficult to attribute these deaths to TCD of the graft. Furthermore, we have previously demonstrated that the risk of VRE bloodstream infections is not increased by TCD [27]. The increased NRM associated with disease status at allo-HSCT suggests that heavy pretreatment of patients, especially those with advanced disease, was a likely contributor to NRM. In addition, although OS and DFS
were associated with remission status, the CIR was not, further suggesting that the degree of pretreatment may contribute to post-HSCT outcomes in these patients. Another striking finding is the 8 deaths due to GVHD in the context of a low overall prevalence of GVHD, an expected distribution of involved organs, and no incidence of grade IV GVHD. This high mortality attributable to GVHD also contrasts with our previous experiences with TCD [16-18]. It is possible that the significant treatment before transplantation in our cohort (and in patients with ALL in general), including extensive exposure to glucocorticoids, led to increased susceptibility to complications of GVHD and its immunosuppressive treatments. Of note, GVHD-related mortality was apparently not related to disease status. This finding may be related to the small number of patients who experienced GVHD after TCD allo-HSCT, or may imply that the common use of steroids or some other pretransplantation characteristic other than the amount of pretreatment increases the risk of complications associated with GVHD and its therapy for patients with ALL.
Certain interventions that could potentially decrease the NRM for patients with ALL undergoing TCD allo-HSCT. First, acknowledging the small size of our CR3+ group, a reduced-intensity conditioning approach could be offered to patients with ALL in >CR2, given the high rate of NRM in these patients with the intense regimens required for TCD. In addition, preemptive use of antibiotics active against VRE for colonized patients could be considered. Alternative nontransplantation options also may be explored for patients in >CR2.
We compared our experience with TCD allo-HSCT with other published experiences with T cell—replete allo-HSCT for ALL. Goldstone et al. [14] recently published the largest randomized study of adult ALL in the MRC UKALL XII/ECOG E2993 trial. A donor versus no donor analysis of Philadelphia chromosome (Ph)-negative patients in CR1 revealed a 5-year OS of 53% in patients with a donor. Thomas et al. [8] studied the optimal postinduction therapy for patients in CR1 in the LALA-94 trial. High-risk patients were assigned to undergo allo-HSCT when an HLA-identical sibling was identified. High-risk Ph- patients who underwent allo-HSCT (without central nervous system disease) had a 5-year DFS of 44% and a 5-year OS of 51%, and Ph+ patients had a 3-year DFS of 34% and a 3-year OS of 36%. Our 5-year OS of 48% in the present study compares quite favorably with these findings, especially given that 16 (59%) of our patients in CR1 were Ph+.
Outcome data for patients who underwent allo-HSCT in >CR1 are more limited. However, it appears that survival outcomes are comparable in TCD allo-HSCT and T cell— replete strategies in this patient population. In an analysis of allo-HSCT recipients who relapsed after their initial therapy in the MRC UKALL XII/ECOG E2993 trial, Fielding et al. [2] found a 5-year OS of 23% in recipients of matched related donor transplants and 16% in recipients of matched unrelated donor transplants.
We previously reported that certain patient populations can have favorable survival after TCD allo-HSCT with a decreased risk of GVHD in the absence of posttransplantation pharmacologic prophylaxis [16-19]. A recent cooperative group-led multicenter trial of ex vivo TCD allo-HSCT in patients with acute myelogenous leukemia in CR1 or CR2 supports our center's experience [28]. The risk of grade II-IV aGVHD in the multicenter trial was comparable at 22.7%, with only a 6.8% incidence of extensive cGVHD at 24 months posttransplantation. Thus, TCD allo-HSCT offers appropriate patients comparable survival along with the decreased morbidity associated with GVHD.
Our findings should be confirmed prospectively, given that this study has some limitations common to retrospective studies. We cannot rule out a selection bias. The study encompasses many years, during which many clinical changes have occurred. In addition, our small sample size limits our conclusions.
In summary, this first published experience of adult patients who underwent TCD allo-HSCT for ALL demonstrates survival and relapse rates that compare favorably with those for T cell—replete transplants but, importantly, with a lower rate of GVHD. The survival outcomes for patients in CR1 are promising, with a plateau noted at approximately 2 years posttransplantation. Further studies are needed to identify subpopulations of patients with ALL who would benefit most from a TCD strategy as opposed to a T cell—replete strategy. Patients with an advanced disease status might have improved outcomes with a reduced-intensity strategy. In addition, studies are needed to assess whether the addition of posttransplantation maintenance therapy might improve outcomes after TCD allo-HSCT in certain patient populations. Finally, minimal residual disease monitoring should be incorporated into future studies to assess whether minimal residual disease affects clinical outcomes after TCD allo-HSCT.
ACKNOWLEDGMENTS
We gratefully acknowledge the expert care provided to our patients by the fellows, housestaff, and nurses of Memorial Sloan-Kettering Cancer Center.
Financial disclosure: Supported in part by National Institutes of Health grant P01 CA23766. Additional support was also received from When Everyone Survives, Cycle for Survival, the New York Community Trust, and the Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center, funded by William H. and Alice Goodwin and the Commonwealth Foundation for Cancer Research (M.P.).
REFERENCES
1. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006;354:166-178.
2. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL): an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944-950.
3. Tavernier E, Boiron JM, Huguet F, et al. Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. Leukemia. 2007;21:1907-1914.
4. Camera A, Annino L, Chiurazzi F, et al. GIMEMA ALL-Rescue 97: a salvage strategy for primary refractory or relapsed adult acute lymphoblastic leukemia. Haematologica. 2004;89:145-153.
5. Sebban C, Lepage E, Vernant JP, et al. French Group of Therapy of Adult Acute Lymphoblastic Leukemia. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. J Clin Oncol. 1994;12:2580-2587.
6. Thiebaut A, Vernant JP, Degos L, et al. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation: a follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am. 2000;14:1353-1366.
7. Cornelissen JJ, Carston M, Kollman C, et al. Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome. Blood. 2001;97:1572-1577.
8. Thomas X, Boiron JM, Huguet F, et al. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004;22:4075-4086.
9. Hunault M, Harousseau JL, Delain M, et al. Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial. Blood. 2004;104:3028-3037.
10. Fielding AK, Rowe JM, Richards SM, et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome—positive acute lymphoblastic leukemia confirms superiority of allogeneic
transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009;113:4489-4496.
11. Labar B, Suciu S, Zittoun R, et al. Allogeneic stem cell transplantation in acute lymphoblastic leukemia and non-Hodgkin's lymphoma for patients <50 years old in first complete remission: results of the EORTC ALL-3 trial. Haematologica. 2004;89:809-817.
12. Ribera JM, Oriol A, Bethencourt C, et al. Comparison of intensive chemotherapy, allogeneic or autologous stem cell transplantation as post-remission treatment for adult patients with high-risk acute lymphoblastic leukemia: results of the PETHEMA ALL-93 trial. Haematologica. 2005;90:1346-1356.
13. Yanada M, Matsuo K, Suzuki T, et al. Allogeneic hematopoietic stem cell transplantation as part of postremission therapy improves survival for adult patients with high-risk acute lymphoblastic leukemia: a meta-analysis. Cancer. 2006;106:2657-2663.
14. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008;111:1827-1833.
15. Cornelissen JJ, van der Holt B, Verhoef GE, et al. Myeloablative alloge-neic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison. Blood. 2009;113:1375-1382.
16. Papadopoulos EB, Carabasi Mh, Castro-Malaspina H, et al. T-cell—de-pleted allogeneic bone marrow transplantation as postremission therapy for acute myelogenous leukemia: freedom from relapse in the absence of graft-versus-host disease. Blood. 1998;91:1083-1090.
17. Jakubowski AA, Small TN, Young JW, et al. T cell—depleted stem-cell transplantation for adults with hematologic malignancies: sustained engraftment of HLA-matched related donor grafts without the use of antithymocyte globulin. Blood. 2007;110:4552-4559.
18. Castro-Malaspina H, Jabubowski AA, Papadopoulos EB, et al. Transplantation in remission improves the disease-free survival of patients with advanced myelodysplastic syndromes treated with myeloablative
T cell—depleted stem cell transplants from HLA-identical siblings. Biol Blood Marrow Transplant. 2008;14:458-468.
19. Perales MA, Jenq R, Goldberg JD, et al. Second-line age-adjusted International Prognostic Index in patients with advanced non-Hodgkin lymphoma after T-cell—depleted allogeneic hematopoietic SCT. Bone Marrow Transplant. 2010;45:1408-1416.
20. Kernan NA, Flomenberg N, Collins NH, et al. Quantitation of T lymphocytes in human bone marrow by a limiting dilution assay. Transplantation. 1985;40:317-322.
21. Kernan NA, Bordignon C, Heller G, et al. Graft failure after T-cell— depleted human leukocyte antigen—identical marrow transplants for leukemia, I: analysis of risk factors and results of secondary transplants. Blood. 1989;74:2227-2236.
22. Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol. 1997;97:855-864.
23. Sullivan KM. Chronic graft-versus-host disease. Cancer Treat Res. 1990; 50:79-98.
24. Copelan E, Casper JT, Carter SL, et al. A scheme for defining cause of death and its application in the T cell depletion trial. Biol Blood Marrow Transplant. 2007;13:1469-1476.
25. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966;50:163-170.
26. Moorman AV, Harrison CJ, Buck GA, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood. 2007;109:3189-3197.
27. Weinstock DM, Conlon M, Iovino C, et al. Colonization, bloodstream infection, and mortality caused by vancomycin-resistant enterococcus early after allogeneic hematopoietic stem cell transplant. Biol Blood Marrow Transplant. 2007;13:615-621.
28. Devine SM, Carter S, Soiffer RJ, et al. Low risk of chronic graft-versus-host disease and relapse associated with T cell—depleted peripheral blood stem cell transplantation for acute myelogenous leukemia in first remission: results of the Blood and Marrow Transplant Clinical Trials Network Protocol 0303. Biol Blood Marrow Transplant. 2011;17: 1343-1351.
