Comparable Outcome of Alternative Donor and Matched Sibling Donor Hematopoietic Stem Cell Transplant for Children with Acute Lymphoblastic Leukemia in First or Second Remission Using Alemtuzumab in a Myeloablative Conditioning Regimen

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Matched Sibling Donor Hematopoietic Stem Cell

Transplant for Children with Acute Lymphoblastic

Leukemia in First or Second Remission

Using Alemtuzumab in a Myeloablative

Conditioning Regimen

Alana A. Kennedy-Nasser,

1

Catherine M. Bollard,

1

G. Doug Myers,

1

Kathryn S. Leung,

1

Stephen Gottschalk,

1

Yiqun Zhang,

2

Hao Liu,

2

Helen E. Heslop,

1

Malcolm K. Brenner,

1

Robert A. Krance

1

HLA-matched sibling donor (MSD) stem cell transplantation can cure .60% of pediatric patients with acute lymphoblastic leukemia (ALL), but \30% of patients will have a sibling donor. Alternative donor (AD) transplantation can be curative but has a higher risk of graft-versus-host disease (GVHD). The addition of alemtuzumab (Campath 1-H) to AD transplants produces in vivo T cell depletion, which may reduce the risk for GVHD. We now report the outcome for 83 children with ALL (41 MSD, 42 AD) undergoing stem cell transplantation in first or second complete remission. All patients received myeloablative condi-tioning, including cyclophosphamide, cytarabine arabinoside, and total-body irradiation, with alemtuzumab administered to AD recipients. GVHD prophylaxis consisted of a calcineurin inhibitor with either short-course methotrexate or prednisone. Disease-free survival (DFS) for MSD recipients was 72.3% (95% confidence interval [CI], 55.4%-83.6%) versus 62.4% (95% CI, 45.2%-75.4%) for AD recipients. The 100-day mortality was 7.1% in the AD group and 2.4% in the MSD group. Relapse rates were identical (24%). Treatment-related mortality, principally viral infection, explained the difference in survival. For children undergoing stem cell transplantation (SCT) from alternative donors, alemtuzumab with a myeloablative con-ditioning regimen resulted in DFS comparable to MSD.

Biol Blood Marrow Transplant 14: 1245-1252 (2008) Ó 2008 American Society for Blood and Marrow Transplantation

KEY WORDS: Alternative donor stem cell transplantation, Acute lymphoblastic leukemia, GVHD, Leukemia relapse

INTRODUCTION

Approximately 80% of cases of acute lymphoblastic leukemia (ALL) in children are cured using conven-tional chemotherapy [1,2]. However, patients with

high-risk features, such as Philadelphia chromosome, or those who fail to attain remission after induction chemotherapy, may obtain superior disease-free sur-vival (DFS) if they receive matched sibling donor (MSD) hematopoietic stem cell transplantation (SCT) in first complete remission (CR1)[3,4]. Children who relapse and subsequently achieve a second complete re-mission (CR2) are unlikely to be cured with additional chemotherapy alone [5], and matched sibling donor SCT is the treatment of choice, producing 50% long-term survivors in ALL in CR2. Unfortunately, most children needing SCT will lack a suitable sibling donor, and so require alternative donor (AD) transplantation, which historically has been associated with lower overall survival (OS) (36% long-term survival from Na-tional Marrow Donor Program [NMDP] registry data)

[6]. The risk for treatment-related mortality (TRM)

From the1Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and The Methodist Hos-pital, Houston, Texas; and2Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas

Correspondence and reprint requests to: Alana A. Kennedy-Nasser, MD, Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, 6621 Fannin Street, MC3-3320, Houston, TX 77030 (e-mail:aakenned@txccc.org). Received July 11, 2008; accepted August 22, 2008

1083-8791/08/1411-0001$34.00/0 doi:10.1016/j.bbmt.2008.08.010

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and graft-versus-host disease (GVHD) is greater in un-related donor transplants, but relapse rates appear to be lower, perhaps because of an increased graft-versus-leu-kemia (GVL) effect[7,8].

To lower rates of GVHD and facilitate engraft-ment, we included the lymphocyte depleting antibody Campath 1-H (alemtuzumab) in the ablative condition-ing regimens for AD SCT. As a monoclonal antibody targeting the CD52 antigen, alemtuzumab effectively depletes T and B cells in vivo[9-12]. Its long half-life also allows depletion of donor T cells, thereby reducing the risk of GVHD[12]. In this paper, we report our ex-perience with alternative donor transplantation using alemtuzumab in children with acute lymphoblastic leu-kemia in first or second complete remission.

PATIENTS, MATERIALS, AND METHODS Patients

We obtained institutional review board approval to conduct this retrospective analysis. Beginning in Janu-ary 1998, children \21 years of age with ALL in CR1 or CR2 with an HLA-matched sibling donor received a uniform myeloablative conditioning regimen. Since January 2001, children with ALL in CR1 or CR2 with-out a matched sibling donor (up to 1-antigen mis-matched related or unrelated donor) received a uniform myeloablative conditioning regimen that in-cluded alemtuzumab. From January 1998 to Decem-ber 2000, 17 children with ALL in CR1 or CR2 received an AD graft without alemtuzumab in the con-ditioning regimen and were excluded from the analysis. The diagnosis of ALL was confirmed by review of diagnostic bone marrow samples. Most children re-ceived ALL therapy according to POG- or COG-ap-proved studies. Patients must have achieved at least 1 CR to be included in this analysis. Remission status was determined within 2 weeks of transplantation by histopathological and cytogenetic analysis of marrow and cerebrospinal fluid.

Patient Characteristics

Forty-one patients meeting the above criteria re-ceived MSD transplants from January 1998 to August 2007. Forty-two patients received AD transplants that included alemtuzumab in the preparative regimen from January 2001 to August 2007. Forty-nine chil-dren were male and 34 were female. Age range was 0.8 to 19.7 years (median 5 8.5 years). Seventy-one pa-tients had B cell phenotype and 12 had T cell pheno-type ALL. Table 1 lists patient characteristics prior to transplant. There was no significant difference in clinical variables between the patient groups. Of the AD cohort, 31 received matched unrelated donor grafts, 9 mismatched unrelated donor grafts, and 2

mismatched related donor grafts. A total of 19 patients were transplanted in CR1, of whom 9 received MSD and 10 received AD grafts for initial induction failure (with subsequent remission prior to SCT), presence of Philadelphia chromosome or hypodiploid karyo-type. Sixty-four patients were in CR2 at the time of SCT, with equal numbers receiving MSD and AD grafts (32 in each group). Patients in CR2 were strati-fied based on duration of CR1, with ‘‘early relapse’’ de-fined as duration of CR1 less than or equal to 18 months, while ‘‘late relapse’’ was defined as duration of CR1 greater than 18 months. Twenty-five patients suffered early relapse, while 39 suffered late relapse. Conditioning Regimen

The myeloablative conditioning regimen for MSD recipients consisted of cytarabine arabinoside 3 g/m2

Table 1. Baseline Patient Characteristics

Characteristic MSD (n 5 41) AD (n 5 42) P

Age at SCT .887*

Median 9.1 years 7.8 years

Range (1.5 to 19.7 years) (0.8 to 19.0 years)

Sex .423† Male (%) 26 (63%) 23 (55%) Female (%) 15 (37%) 19 (45%) ALL phenotype .503‡ B lineage (%) 34 (83%) 37 (88%) T lineage (%) 7 (17%) 5 (12%) Presence of CNS disease at diagnosis (%) 8 (20%) 5 (12%) .340‡

Infant ALL, MLL gene rearrangement (%)

2 (5%) 2 (4%)

Remission status at SCT .840†

CR1 (%) 9 (22%) 10 (24%)

CR2 (%) 32 (78%) 32 (76%)

Time to first relapse in CR2 patients, months (range)

24.4 (4.8 to 81.1) 32.9 (3.1 to 65.4) .747§

#18 months 15 (47%) 10 (31%) .200†

>18 months 17 (53%) 22 (69%)

Time from first relapse to BMT in CR2 patients, days .011* Median 103 122 Range (46 to 474) (86 to 268) Indications of SCT in CR1 .102‡ BCR/ABL 3 (33%) 7 (70%) Induction failure 3 (33%) 3 (30%) Hypodiploid 3 (33%) 0 (0%)

Sites of first relapse prior to SCT .302‡ BM relapse (without CNS involvement) 11 (34%) 16 (50%) Combined BM/CNS relapse 7 (22%) 10 (32%) Isolated CNS relapse 11 (34%) 5 (12%) Other isolated extramedullary relapse 1 (3%) 1 (3%)

MSD indicates matched sibling donor; AD, alternative donor; SCT, stem cell transplantation; ALL, acute lymphoblastic leukemia; CNS, central nervous system; MLL, multiple lineage leukemia; CR1, first complete re-mission; CR2, second complete rere-mission; BCR/ABL, breakpoint cluster region/abelson; BM, bone marrow; NS, not statistically significant. *Wilcoxon test.

†c2test.

‡Fisher’s exact test. §Log-rank test.

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i.v. every 12 hours for 6 doses on days 28 to 25; cyclo-phosphamide 45 mg/kg i.v. daily on days 27 and 26 with MESNA for bladder protection; total-body irradiation (TBI) 12.0 Gy delivered in 8 fractions of 1.5 Gy on days 24 to 21. AD recipients received the same conditioning regimen except the TBI dose was 14.0 Gy delivered in fractions of 1.75 Gy on days 24 to 21, and we included alemtuzumab (3 mg for pa-tients 5 through 15 kg; 5 mg for papa-tients 16 to 30 kg; 10 mg for patients greater than 30 kg) i.v. daily on days 24 to 21. All male patients received an additional 4.0 Gy of irradiation to the testes. Patients with com-bined central nervous system (CNS)/hematologic re-lapse or isolated CNS rere-lapse received 10.8 Gy additional irradiation to the cranial midplane, given in 6 fractions of 1.8 Gy daily prior to beginning the conditioning regimen.

Stem Cell and Bone Marrow Collection

Unrelated donors were recruited through the NMDP. DNA-based allele typing for class II DR has been performed since 1997. Class I A and B typing was antigen-specific until March 2005, when allele typing was instituted. All patients received unmanipu-lated bone marrow cells, except 2 AD recipients who received granulocyte-colony stimulating factor (G-CSF) mobilized CD341-selected peripheral blood

stem cells, collected according to established methods and infused via a central venous catheter on day 0 within 24 hours of the last dose of irradiation.

GVHD Prophylaxis

Intravenous cyclosporine A was initiated at day 22 and adjusted to maintain trough levels of 150-200 ng/ mL in MSD recipients; while AD recipients received tacrolimus to maintain trough levels of 5-10 ng/mL. All SCT recipients received short-course methotrex-ate, except for 2 MSD and 2 AD recipients, who re-ceived prednisone for clinical reasons. Intravenous cyclosporine or tacrolimus was converted to oral when the patient could tolerate medications by mouth and was weaned off between 2 to 3 months in the absence of GVHD. Acute and chronic GVHD (aGVHD, cGVHD) were diagnosed according to conventional criteria and treated according to institu-tional guidelines. Patients were not considered evalu-able for aGVHD if they died before engraftment or for cGVHD if they died before day 100 after trans-plantation.

Supportive Care and Infection Prophylaxis All patients received bacterial, fungal, and Pneumo-cystis jiroveci pneumonia prophylaxis during the peri-transplant period. Monitoring of viral and fungal infections was carried out as per our institutional stan-dard of care. Cytomegalovirus (CMV)-seropositive

patients or those with seropositive donors received CMV prophylaxis, most often with ganciclovir, through day 100.

Study Endpoints

Major study endpoints were DFS, engraftment, TRM, relapse, and frequency of aGVHD and cGVHD. CMV infection was defined as 2 consecutive peripheral blood polymerase chain reaction (PCR)-positive results or antigenemia $2 leukocytes/ 100,000 cells. Adenovirus infection was defined as adenovirus PCR positivity from any source. Epstein-Barr virus lymphoproliferative disease (EBV-LPD) was defined as EBV viral load .4000 copies/mg in the presence of lymphadenopathy or other clinical manifestations[13]. Data were analyzed as of July 1, 2008.

Neutrophil engraftment was defined as the first of 3 consecutive days with an absolute neutrophil count .500 cells/mL. Platelet engraftment was defined as unsupported platelet count .20,000 cells/mL. Patients were not considered evaluable for engraftment if they died before day 30. Donor engraftment was determined on blood and/or bone marrow using fluo-rescence in situ hybridization probes for sex chromo-somes (sex-mismatched transplants) or PCR amplification of specific polymorphic DNA sequences (short tandem repeats).

Statistical Methods

For statistical comparison between the MSD and AD cohorts, the chi-squared test and Fisher’s exact test were used for categorical variables and the Wilcoxon 2-sample test for continuous variables. Kaplan-Meier estimates and the log-rank test were employed for the comparison of time-to-event out-comes, including DFS following SCT, time to relapse, and time to TRM following SCT. The analysis time was censored administratively at 1000 days following SCT. For the endpoint of relapse, death without re-lapse was considered an independent competing risk. TRM was determined from the date of transplantation until death related to transplantation. All P-values are 2-sided, with P \ .05 considered statistically signifi-cant. All statistical analyses were performed using the STATA 9.0 and SAS 9.2 software packages.

RESULTS

Table 2outlines the post-SCT characteristics of these transplants.

Toxicity

All patients were evaluable for toxicity. Ten pa-tients died of treatment-related causes (nonrelapse deaths). Although the most frequent cause of death

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in the MSD cohort was relapse (78% of MSD deaths attributable to relapse), TRM was greater in the AD cohort (19.5% in AD versus 4.9% in MSD recipients; P 5 .045). The most common cause of TRM was pul-monary failure or multiorgan failure attributable to viral infections, and was limited to the AD cohort: CMV pneumonitis (n 5 2); disseminated adenovirus (n 5 1); herpes simplex virus pneumonitis (n52) and human herpesvirus 6 pneumonitis (n51). Other causes of nonrelapse death in AD recipients were idiopathic pneumonitis (n 5 1) and sepsis (n 5 1). Only 2 MSD recipients died of treatment-related causes, and both failed to initially engraft: fungal disease (n 5 1) and id-iopathic pneumonitis (n 5 1).

Engraftment

Of the 83 patients, 82 were evaluable for engraft-ment (1 AD recipient died 5 days post SCT of sepsis) and 95% achieved neutrophil engraftment at a median of 18 days in both cohorts (range: 12-26 in MSD and

14-24 in AD). Two MSD recipients experienced initial graft failures, with subsequent engraftment after infu-sion of additional CD341 cells; however, both later died of treatment-related causes as described above. Median time to transfusion-independent platelet recovery was 19 days (range: 8-46) for MSD and 26 days (range: 11-130) for AD recipients (P 5 .009). One patient failed to achieve platelet recovery before death. No episodes of late graft failure occurred. GVHD

The incidence and severity of aGVHD and cGVHD was low in both cohorts. Of 40 evaluable MSD recipients, 5 (12.5%) developed grade II to III aGVHD, compared to 3 of 41 (7.3%) evaluable AD recipients. No patient in either cohort developed grade IV aGVHD. The incidence of cGVHD was low: 8 of 40 (20%) MSD recipients and 6 of 39 (15.4%) AD re-cipients developed limited, cGVHD. Extensive, cGVHD did not occur.

Table 2. Post-SCT Characteristics

Variable MSD (n 5 41) AD (n 5 42) P

Days to engraftment, median (range)

ANC greater than or equal to 500 cells/mL 3 days 18 (12 to 26) 18 (14 to 24) .720*

Unsupported platelets greater than 20,000 cells/mL 20 (8 to 46) 26 (11 to 130) .009*

Infections, n (%)

CMV reactivation 2 (5%) 12 (29%) .004‡

EBV-LPD 0 1 (2%)

Adenovirus reactivation 2 (5%) 14 (33%) .002‡

Invasive fungal infection 1 (2%) 3 (7%)

Bacterial sepsis 3 (7%) 3 (7%)

Acute GvHD in evaluable patients .482‡

Grade II to III 5/40 (12.5%) 3/41 (7.3%)

Grade IV 0 0

Chronic GvHD in evaluable patients .770†

Limited 8/40 (20%) 6/39 (15.4%)

Extensive 0 0

Deaths, n (%) 9 (22%) 13 (31%) .353†

Deaths due to bacterial sepsis 0 1

Deaths due to fungal disease 1 0

Deaths due to viral infection 0 6

CMV 0 2

Adenovirus 0 1

HSV 0 2

HHV6 0 1

Pulmonary toxicity/pneumonitis 1 2

Deaths due to relapse 7 5

Median time to death post transplant, days (range) 268 (54 to 3646) 147 (5 to 2187) .204§

Relapses post SCT, n (%) 9 (22%) 8 (14%) .743†

Median time to relapse, months (range) 8.8 (3.0 to 24.4) 7.4 (3.4 to 13.7) Relapse rate

Entire cohort 23.9% (95% CI, 13.2-41.1%) 24.3% (95% CI, 12.8-43.1%) .842†

CR2 patients 27.5% (95% CI, 14.7-47.6%) 22.2% (95%CI, 10.5-43.2%) .813†

3-year disease-free survival

Entire cohort 72.3% (95%CI, 55.4-83.6%) 62.4% (95%CI, 45.2-75.4%) .232†

CR2 patients 67.9% (95%CI, 48.4-81.3%) 67.0% (95%CI, 46.9-80.7%) .777†

Early relapse (CR1 less than or equal to 18 months) 46.7% (95%CI, 21.2-68.7%) 40.0% (95%CI, 12.3-67.0%) .664†

Late relapse (CR1 greater than 18 months) 86.7% (95%CI, 56.4-96.5%) 79.5% (95%CI, 54.2-91.9%) .395†

MSD indicates matched sibling donor; AD, alternative donor; SCT, stem cell transplantation; ANC, absolute neutrophil count; CMV, cytomegalovirus; EBV-LPD, Epstein-Barr virus lymphoproliferative disorder; BM, bone marrow; HSV, herpes simplex virus; HHV6, human herpesvirus 6; CI, confidence interval.

*Wilcoxon test. †c2test.

‡Fisher’s exact test. §Log-rank test.

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Infectious Complications

CMV infection was more prominent in AD recipients compared to MSD recipients (29% versus 5%; P 5 .004), an observation that is consistent with other published reports [14,15]. Despite ganciclovir prophylaxis, 2 patients died of CMV pneumonitis in the AD cohort. Adenovirus infection occurred in 33% of AD recipients, including 1 death, but only 5% of MSD recipients (P 5 .002). EBV-LPD devel-oped in 1 AD recipient and responded to treatment with EBV-specific cytotoxic T lymphocytes generated in our laboratory[16,17]. Respiratory viral infections (respiratory syncytial virus and influenza A or B), herpes simplex virus, and herpes zoster were similar in both cohorts (data not shown). Invasive fungal infec-tions occurred in 3 AD recipients and 1 MSD recipient (who subsequently died from fungal pneumonia). Seri-ous bacterial sepsis occurred in 3 MSD and 3 AD re-cipients, including 1 AD recipient with grade 4 mucositis who died at day 15 from sepsis.

Survival Analysis

Median follow-up time of all patients is 52.2 months (range: 10.6-127.2) for all patients; 77.8 months (range: 11.3-127.2) for MSD recipients, and 33.5 months (range: 10.6-78.5) for AD recipients. Be-cause of the disparity in follow-up among MSD and AD cohorts, patients in the MSD cohort were cen-sored at 1000 days for Kaplan-Meier analysis. How-ever, no patient in either cohort relapsed or died because of a cause other than relapse beyond day 1000 post-SCT. A total of 22 patients died (9 MSD, 13 AD) at a median time of 169 days post-SCT (range: 5-1097) (Table 2). The 3-year DFS in all patients was 67.1% and comparable in both MSD and AD recipi-ents (72.3% versus 62.4%; P 5 .232) (Figure 1). The 100-day mortality was low: 7.1% in AD recipients and 2.4% in MSD recipients.

Patients who underwent SCT in CR2 fared identi-cally regardless of their donor, with 3-year DFS 67.9% for MSD and 67.0% AD (P 5 .777) (Figure 2). How-ever, patients in CR1 trended toward improved survival with MSD grafts: the 3-year DFS after MSD transplant compared to AD was 87.5% and 50.0%, respectively (P 5 .071). Of the 9 MSD recipients in CR1, 1 patient died from relapse; of the 10 AD recipients, 3 patients died of treatment-related causes and 2 relapsed.

Of the 64 patients in CR2, when stratified based on time to first relapse, patients with ‘‘early relapse’’ (first remission lasting less than 18 months) fared signifi-cantly worse than patients whose relapse occurred greater than 18 months after initial diagnosis (DFS 82.0% versus 44.8%, respectively; P \ .001) primarily because of a high rate of relapse post-SCT in the ‘‘early relapse’’ patients (Figure 3). This disparity in outcome was seen regardless of donor source (Table 2).

Nine MSD and 8 AD recipients relapsed post SCT at a median of 265 days in MSD (range: 89-731) and 221 days in AD (range: 102-441) recipients. The inci-dence of relapse was identical (23.9% MSD versus 24.3% AD; P 5 .842). The cumulative incidence of re-lapse for MSD and AD recipients in CR2 at the time of SCT was 27.5% and 22.2%, respectively (P 5 .813).

DFS MSD (n=41) AD (n=42) P=0.232 AD (n=42) MSD (n=41) P=0.842 0.0 0.2 0.4 0.6 0.8 1.0

Days after Transplantation

Probability

0 200 400 600 800 1000

Relapse

Figure 1. Disease-free survival (DFS) and cumulative incidence of re-lapse by donor source in all patients. Comparable DFS (top lines) and incidence of relapse (bottom lines) observed in matched sibling donor (MSD) and alternative donor (AD) recipients. The 3-year DFS for MSD and AD recipients was 72.3% and 62.4%, respectively (P 5 .232). The cumulative incidence of relapse for MSD and AD recipients was 23.9% and 24.3%, respectively (P 5 .842). P=0.777 AD (n=32) 0.0 0.2 0.4 0.6 0.8 1.0

Days after Transplantation

Probability 0 200 400 600 800 1000 DFS Relapse MSD (n=32) AD (n=32) MSD (n=32) P=0.813

Figure 2. DFS and incidence of relapse in patients in second complete remission (CR2) at the time of transplant. Sixty-four children underwent SCT in CR2, with comparable DFS (top lines) and incidence of relapse (bottom lines) observed regardless of donor source. The 3-year DFS for MSD and AD recipients in CR2 was 67.9% and 67.0%, respectively (P 5 .777). The cumulative incidence of relapse for MSD and AD recip-ients in CR2 was 27.5% and 22.2%, respectively (P 5 .813).

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Quality of life among disease-free survivors as termined by either Karnofsky or Lansky score, de-pending on age, was equivalent in both cohorts (mean performance score, 98.1%; range: 60%-100% for AD and 40%-100% for MSD).

DISCUSSION

Our study illustrates that low rates of GVHD can be achieved using alemtuzumab in alternative donor SCT for children with ALL in first or second remis-sion without hindering the GVL effect. Except for TRM, the endpoints of our study, including DFS, relapse rates, engraftment, and frequency of aGVHD or cGVHD, were all unaffected by donor source.

Historically, high rates of GVHD and infections following alternative donor SCT resulted in disap-pointing outcomes for children with leukemia. How-ever, T cell depletion has been shown to be crucial in preventing significant GVHD following allogeneic SCT. When the graft is not depleted of T cells, the incidence of grades III and IV aGVHD may exceed 40% and clinically significant cGVHD may exceed 30%[18]. Although T cell depletion substantially re-duces the incidence of aGVHD, the effect on overall DFS is less striking, because it is also associated with a higher ALL relapse rate. The NMDP recently re-ported 36% 5-year DFS for 363 children with ALL in CR2 transplanted from AD (in this case, unrelated HLA-matched donors) [6]. Those patients receiving T cell-depleted grafts had a significantly lower inci-dence of aGVHD compared to recipients of non-T cell-depleted grafts (21% versus 34%; P 5 .006) in

univariate analysis [6]. However, T cells in the AD graft also appear to protect against relapse [19]. Patients without aGVHD had lower 3-year DFS than those with even mild (grades I-II) aGVHD (32.7% versus 61.2%), and the 3-year cumulative re-lapse rate was 55.6% versus 22% (P 5 .03) for MSD and MUD SCT, respectively [19]. Thus, improved DFS for MUD transplants was attributable to a GVL effect at the expense of unwanted GVHD.

In our study, the relapse rates of MSD and AD co-horts were identical. The low incidence of GVHD with apparent sparing of the GVL effect in AD recip-ients is likely attributable to in vivo T cell depletion from alemtuzumab. Multiple studies have reported a reduced incidence of GVHD [20-22] without rise in relapse rates in alemtuzumab recipients [12,23]. Shah et al. [12] recently reported the effects of in vivo alemtuzumab compared to antithymocyte globu-lin (ATG) in unrelated donor transplants in pediatric patients with hematologic malignancies. Rates of GVHD were significantly reduced in the alemtuzumab cohort (0 of 14 compared to 6 of 13 ATG recipients; P 5 .006) without increased relapse rates. As the ma-jority of precursor B-ALL blasts express CD52 [24], alemtuzumab given during the conditioning regimen may contribute to the eradication of minimal residual disease; thus, offering further protection against relapse in AD SCT recipients.

Another potential explanation for GVL sparing by alemtuzumab is the expansion of regulatory T cells (Tregs) after transplant. Transplant recipients with GVHD may have lower absolute numbers of donor Tregs in the graft[25], and murine models have shown that infusion of donor Tregs with the transplant prod-uct or post-SCT prevents GVHD while maintaining GVL activity[26]. Bloom et al.[27]recently reported an increased percentage of Tregs within the CD41T cell population in patients receiving alemtuzumab following renal transplant, and this increase was inde-pendent of maintenance immunosuppression. Cur-rently, our group is prospectively investigating the role of alemtuzumab in promoting Treg expansion as a mechanism for minimizing clinically significant GVHD while sparing the GVL effect.

Although controversy has surrounded the optimal treatment for children with recurrent ALL, duration of CR1 has remained an important predictor of outcome in many studies [5,6,28]. However, interpreting and comparing these studies has proved challenging be-cause of lack of uniformity regarding the definition of ‘‘early relapse.’’ In our cohort of patients, early re-lapse was defined as CR1 lasting # 18 months. Al-though DFS was significantly lower in patients with early relapse, it was statistically similar regardless of donor source (ie, patients with early relapse with MSD grafts did equally as poor as those with AD grafts, and conversely, those with late relapse had

P<0.001 0.0 0.2 0.4 0.6 0.8 1.0

Days after Transplantation

Cumulative incidence rate

0 200 400 600 800 1000

Relapse

CR1 >18 months (n=25) CR1 ≤ 18 months (n=39)

Figure 3. The cumulative hazard rate of relapse based on duration of first complete remission (CR1) — ‘‘early’’ versus ‘‘late’’ relapse. Of the 64 patients in CR2 at the time of SCT, when stratified based on ‘‘early’’ (CR1 #18 months) and ‘‘late’’ (CR1 .18 months) relapse, the cumula-tive hazard rate of relapse post-SCT for patients with late relapse and early relapse prior to SCTwas 11.3% and 67.1%, respectively (P \.001).

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similarly good outcomes after MSD or AD transplan-tation). As pediatric ALL patients transplanted in CR2 are typically considered standard-risk patients, given the disparity in outcomes in our study, those patients with early relapse should probably be considered high risk for transplant, regardless of donor source. Thus, we contend that comparison of outcomes fol-lowing SCT should factor the additional risk for chil-dren with ALL and initial remission \18 months.

Two limitations of our study should be noted. First, although the sample size of patients in each cohort is very good, it is likely underpowered to detect all but ex-treme differences in outcome. The second limitation is the median follow-up time of the 2 cohorts. We recog-nize the shorter median follow-up time in AD recipi-ents (33 months) compared to MSD recipirecipi-ents (77 months); however, there were no treatment-related deaths or relapses beyond 25 months in either cohort. The only significant difference in outcome between MSD and AD recipients was TRM, which was higher in the AD cohort, likely because of the profound and prolonged immune suppression that follows alemtuzu-mab treatment as previously shown by our group and others [14,15]. Compared to MSD, the AD cohort experienced higher rates of viral reactivations and in-fections, notably CMV and adenovirus. Six AD recipi-ents died of viral-related infections, despite aggressive antiviral management, prophylaxis and preemptive treatment. Hence, better antiviral therapies are needed to eradicate viral infections post-SCT. To this end, we have developed methods to produce viral-specific cytotoxic T lymphocytes against CMV, EBV, and ade-novirus to administer following transplant[29]. As an-tiviral treatments improve, TRM in alemtuzumab recipients may accordingly improve; thus, greater DFS may be achieved in alternative donor transplants for pediatric ALL.

Our experience transplanting children with ALL in CR1 and CR2 with alternative donors using alemtu-zumab suggests that durable engraftment with low rates of GVHD can be achieved, with DFS similar to those receiving a matched sibling donor.

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