Published online 31 July 2009
Haematologica, Vol 94, Issue 10, 1399-1406 doi:10.3324/haematol.2009.008649
Copyright © 2009 by Ferrata Storti Foundation
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Acute Lymphoblastic Leukemia

Favorable outcomes with alemtuzumab-conditioned unrelated donor stem cell transplantation in adults with high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in first complete remission

Bella Patel1, Keiren E. Kirkland2, Richard Szydlo3, Rachel M. Pearce2, Richard E. Clark4, Charles Craddock5, Effie Liakopoulou6, Adele K. Fielding1, Stephen Mackinnon1, Eduardo Olavarria3, Mike N. Potter7, Nigel H. Russell8, Bronwen E. Shaw9, Gordon Cook10, Anthony H. Goldstone11, David I. Marks12

1 Department of Haematology, Royal Free and University College London Medical School, London
2 BSBMT Data Registry, Guy’s Hospital, London
3 Department of Haematology, Imperial College London, Hammersmith Hospital Campus, London
4 Department of Haematology, Royal Liverpool University Hospital, Liverpool
5 Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham
6 Haematology and Transplant Unit, The Christie, Manchester, UK, Department of Haematology, Imperial College London, Hammersmith Hospital Campus, London
7 Section of Haemato-oncology, Royal Marsden Hospital NHS Trust, Surrey
8 The Centre for Clinical Haematology, Nottingham University Hospital (City Campus)
9 Section of Haemato-oncology, Royal Marsden Hospital NHS Trust, Surrey, UK and Anthony Nolan Trust, London
10 St James's Institute of Oncology, Leeds Teaching Hospitals Trust
11 Department of Haematology, University College London Hospital, London
12 Adult BMT Unit, United Bristol Healthcare Trust, Bristol, UK

Correspondence: David Marks, Department of Molecular and Cellular Medicine, University Hospitals Bristol Foundation Trust, Bristol BS2 8BJ, UK. E-mail:David.Marks{at}ubht.nhs.uk


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ABSTRACT
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 ABSTRACT
Introduction
 Design and Methods
 Results
 Discussion
 References
 
Background: Approximately 40% of adults with Philadelphia chromosome-negative acute lymphoblastic leukemia achieve long-term survival following unrelated donor hematopoietic stem cell transplantation in first complete remission but severe graft-versus-host disease remains a problem affecting survival. Although T-cell depletion abrogates graft-versus-host disease, the impact on disease-free survival in acute lymphoblastic leukemia is not known.

Design and Methods: We analyzed the outcome of 48 adults (median age 26 years) with high-risk, Philadelphia-chromosome-negative acute lymphoblastic leukemia undergoing T-cell depleted unrelated donor-hematopoietic stem cell transplantation (67% 10 of 10 loci matched) in first complete remission reported to the British Society of Blood and Marrow Transplantation Registry from 1993 to 2005.

Results: T-cell depletion was carried out by in vivo alemtuzumab administration. Additional, ex vivo T-cell depletion was performed in 21% of patients. Overall survival, disease-free survival and non-relapse mortality rates at 5 years were 61% (95% CI 46–75), 59% (95% CI 45–74) and 13% (95% CI 3–25), respectively. The incidences of grades II–IV and III–IV acute graft-versus-host disease were 27% (95% CI 16–44) and 10% (95% CI 4–25), respectively. The actuarial estimate of extensive chronic graft-versus-host disease at 5 years was 22% (95%CI 13–38). High-risk cytogenetics at diagnosis was associated with a lower 5-year overall survival (47% (95% CI 27–71) vs. 68% (95% CI 44–84), p=0.045).

Conclusions: T-cell depleted hematopoietic stem cell transplantation from unrelated donors can result in good overall survival and low non-relapse mortality for adults with high-risk acute lymphoblastic leukemia in first complete remission and merits prospective evaluation.

Key words: adult acute lymphoblastic leukemia, stem cell transplantation, T-cell depletion.


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Introduction
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 ABSTRACT
 Introduction
Design and Methods
 Results
 Discussion
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In adult acute lymphoblastic leukemia despite high initial rates of complete remission the majority of adult patients relapse.1 Hematopoietic stem cell transplantation (HSCT) from a sibling donor, carried out while the recipient is in first complete remission, extends disease-free survival in certain populations of patients. In high-risk acute lymphoblastic leukemia, sibling allografting results in a 22–35% survival advantage over alternative therapies.2–6 A donor versus no donor analysis in the UKALL/XII/ECOG2993 collaborative study of 1929 participants showed significantly prolonged overall survival with sibling allografting compared to chemotherapy in standard risk ALL in first complete remission.1 In high-risk patients, although relapse was significantly reduced, a high non-relapse mortality resulted in no overall survival advantage, a finding which was largely attributed to the inclusion of older (>35 years) patients within the high-risk group.

The greater curative potential of allogeneic HSCT and a better understanding of risk factors for treatment failure with chemotherapy7 have inevitably led to the investigation of alternative sources of donor stem cells for HSCT in poor-risk ALL. For patients with Philadelphia chromosome (Ph)-positive disease, unrelated donor (URD) HSCT in first complete remission is an accepted strategy resulting in superior outcomes to those achieved with chemotherapy.8 Comparative studies previously9,10 found equivalent transplant-related mortality and disease-free survival rates between adults undergoing matched URD or sibling HSCT for high-risk ALL. A detailed analysis of URD-HSCT for Ph-negative ALL in first complete remission was recently presented by Marks et al.11 This CIBMTR registry study of largely T-cell replete URD HSCT reported a 5-year overall survival rate of 39% in 169 patients. However, procedural-related mortality was a major cause of treatment failure, occurring in 42% of patients, with graft-versus-host disease (GVHD) reported as the second most common cause of death.

T-cell depletion is the most effective method of preventing GVHD after allogeneic HSCT, a substantial cause of transplant-associated morbidity and mortality.12,13 However, this can be at the cost of impaired immune reconstitution14 and a reduced graft-versus- vs. leukemia effect15 due to a loss of antigen- and tumor-specific T cells. Whether there is a role for T-cell depletion in the setting of transplants from URD for poor-risk Ph-negative ALL is not known.

In the UK, most URD grafts are T-cell depleted (TCD). We, therefore, used the British Society of Blood and Marrow Transplantation (BSBMT) data registry to identify adult recipients of URD transplants for Ph-negative ALL. Here we report the outcome of 48 consecutive patients undergoing TCD URD transplantation for high-risk Ph-negative ALL in first complete remission.


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Design and Methods
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 ABSTRACT
 Introduction
 Design and Methods
Results
 Discussion
 References
 
Study patients were identified through the BSBMT registry database. All transplant centers in the United Kingdom and Republic of Ireland are required to report outcomes of consecutive transplants to the BSBMT registry. Search criteria included: (i) age between 15 and 55 years old, inclusive, (ii) a diagnosis of de novo ALL between 1993–2005, (iii) a TCD-URD transplant performed in first complete remission. One hundred and seven patients fulfilled these criteria in 21 transplant centers. Ph status was checked with all the centers and Ph-positive patients excluded. Forty-eight patients from 16 transplant centres were finally confirmed as having high-risk Ph-negative ALL and constituted the study population.

Definition of high risk
Patients were defined as having high-risk ALL if they were over 35 years old, had a high white blood cell count (>30x109/L in B- cell disease/immunophenotype unknown, >100x109/L in T-cell disease), had adverse cytogenetics including t(4;11) with or without other abnormalities, a complex karyotype (≥5 abnormalities) or low hypodiploidy/near triploidy at diagnosis and took more than 8 weeks to achieve first complete remission. Two further patients were considered to have high-risk ALL because of persistent extramedullary disease in first complete remission.

Typing of human leukocyte antigens
Matching status of human leukocyte antigens (HLA) was assigned based on the data available. In all but three cases, matching status was entered for five HLA loci (HLA-A,-B,-C,-DRB1,-DQB1). In three cases the matching status for HLA-C was unknown. When possible, actual HLA types were obtained and verified (51% of cases).

In 18 cases the HLA matching status was defined as definite, i.e. the actual tissue types had been reviewed and the result obtained with high resolution typing. The matching status of the remaining pairs was designated as either probable (tissue typing reviewed and of medium resolution or transplantation after 01/01/2000 when HLA class I and II typing was routinely performed by molecular techniques, n = 21) or possible (tissue typing reviewed and serological typing or transplant performed before 2000, n=9).

Statistical analysis
Probabilities of overall survival and disease-free survival were calculated by the Kaplan-Meier method. Comparisons between groups were made using the log-rank test. Probabilities of non-relapse mortality, relapse, acute and chronic GVHD disease were calculated as cumulative incidences using competing risks analysis with group comparisons made using Gray’s test.16 The competing risks considered were relapse for non-relapse mortality, non-relapse death for relapse and death from any cause for chronic GVHD.


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Results
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 ABSTRACT
 Introduction
 Design and Methods
 Results
Discussion
 References
 
Patient-related, disease and transplant characteristics
Patient-related, disease and transplant characteristics of the 48 patients are shown in Table 1. The median age of the patients at diagnosis was 26.2 years (range, 16 – 50), and the median follow-up of surviving patients was 56 months (range, 18–160). Adverse karyotype was present in 17/48 (35%) of patients, 22/40 (55%) of evaluable patients had a high presenting white blood cell count and 14/48 (29%) were aged over 35 years. Multiple poor prognostic features were present in 40% (19/48) of the patients. Of these 12/48 (25%) had two adverse risk factors present at diagnosis and 7/48 (15%) had three. Forty-seven of the 48 (98%) patients received conditiong regimes containing total body irradiation. All patients received a TCD transplant with in vivo administration of alemtuzumab. In ten patients additional T-cell depletion was performed using alemtuzumab in vitro. Details of in vivo alemtuzumab treatment were available for 41 of the 48 recipients of a TCD transplant. Alemtuzumab -1G (60–100 mg) was used in nine patients, alemtuzumab -1H (50–100 mg) in 31 patients and alemtuzumab -1M, at an unknown dose, in one case. Donor lymphocyte infusions were given to four patients following transplantation.


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  		Table 1. Patient, disease and transplant characteristics.

Engraftment
Neutrophil engraftment to a level of 0.5x109/L occurred in all patients at a median of 16.5 days (range, 11–35) after transplantation with 46/48 (96%) evaluable patients engrafting before day 28. The median time to engraftment was 18 days in patients receiving bone marrow grafts and 16 days in patients receiving peripheral blood stem cells grafts (p=0.16). Platelet engraftment occurred in 41 evaluable patients at a median of 21 days (range, 11–209), and was achieved by day 28 in 28 (66%) of these patients.

Overall survival and disease-free survival
With a median follow-up of 56 months (range 18–160) 30 of 48 patients were alive and of these 27 were free of leukemia. The Kaplan-Meier estimates for overall survival of all patients at 3 and 5 years were 64% (95% CI 48–76) and 61% (95% CI 45–74), respectively (Figure 1). The disease-free survival rate was 59% at 3 years and unchanged at 5 years. Factors influencing disease-free survival and overall survival were examined by univariate analysis and are shown in Table 2. The only factor that had a significant effect on overall survival was adverse cytogenetics which was associated with a significantly shorter survival (p=0.045).


Figure 10941399
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  		Figure 1. Primary outcomes of 48 high-risk ALL patients who underwent TCD URD-HSCT.


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  		Table 2. Univariate analysis of overall survival and disease-free survival.

Relapse
Recurrent leukemia occurred in 13 (27%) patients at a median time of 8 months (0.8–30) following transplantation. The median survival after relapse was 2.5 months with only two patients surviving at 6 months. The 3-and 5- year cumulative relapse rates were 28% (95% CI 20–42) for all patients (Figure 1). Four of the 13 relapsed patients had received donor lymphocyte infusions, one was reported to be in complete remission at last follow-up and three subsequently died in continued relapse. Various factors were investigated for their effect on relapse risk and are shown in Table 3. Delayed achievement of complete remission or development of acute GVHD did not significantly affect relapse rate following URD transplantation.


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  		Table 3. Univariate analysis of relapse.

Graft-versus-host disease
Acute GVHD occurred in 65% of patients and was grade I in 18 patients (39%), grade II in eight (17%), and grades III–IV in four (9%). Cumulative incidences of grades II–IV and grades III–IV acute GVHD were 27% (95%CI 16–44) and 10% (95% CI 4–25), respectively (Figure 2A). The probability of limited or extensive chronic GVHD was 44% (95% CI 30–61) at 5 years (22 of 45 evaluable patients) while that of extensive disease was 22% (95% CI 13–38) (Figure 2B). Ten patients had extensive chronic GVHD and 12 limited involvement. The incidence of chronic GVHD was significantly higher in recipients of peripheral blood stem cell grafts than in recipients of bone marrow grafts (78% vs. 24%; at 5 years p=0.001). Additional ex vivo T-cell depletion did not affect the incidence of acute or chronic GVHD.


Figure 20941399
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  		Figure 2. Cumulative incidences of GVHD after TCD URD-HSCT for high-risk ALL. (A) Acute grades II–IV and III–IV. (B) Chronic extensive.

Non-relapse mortality
Death occurred for reasons other than relapse in six patients at a median of 117 days (range, 60–1033) following transplantation. The causes of death were infection (n=2), graft failure (n=1), neurological toxicity (n=1), secondary malignancy (n=1) and unknown (n=1). Importantly, GVHD-related deaths were not reported. Late non-relapse mortality occurred in one patient at 34 months due to adenocarcinoma of the lung.

The estimated cumulative incidence of non-relapse deaths in first complete remission at 3 years, in plateau, was 13% (95% CI 3–25) (Figure 1). The probabilities of non-relapse mortality at day 100 and day 365 were 4.2% (95% CI 3–16) and 10.4 % (95% CI 4–24), respectively. Various factors were investigated for an association with a significantly increased non-relapse mortality but none was found to be statistically significant by univariate analysis (Table 4).


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  		Table 4. Univariate analysis of non-relapse mortality.


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Discussion
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 Design and Methods
 Results
 Discussion
References
 
This study is the first to report the longer term outcome of TCD URD transplantation for adults with poor risk Ph-negative ALL in first complete remission. With this approach the multicenter non-relapse mortality rate was 13% (95% CI 3–25) and the disease-free survival rate an encouraging 59% (95% CI 45–74) at 5 years. There is considerable evidence for a potent graft-versus-leukemia effect in allografting for ALL, with nearly all randomized studies demonstrating a significantly lower incidence of relapse with this therapy.1,17 The finding of durable leukemia-free remissions in more than 50% of patients undergoing TCD allografting for high-risk ALL in this study suggests that a graft-versus-ALL effect might be preserved with this treatment approach. Such an interpretation lends support to the rationale for partial T-cell depletion, which is to reduce severe (grade III–IV) GVHD whilst still allowing for some graft-versus-leukemia effect and mild acute or chronic GVHD. Indeed, nearly 40% of patients experienced grade I acute GVHD and this could also have been protective against relapse.

Notably, the probability of relapse in this series of patients with poor-risk ALL undergoing TCD URD-HSCT compares favorably with that reported for T-cell replete sibling allografting in high-risk patients on the MRC/ECOG study1 (28% vs. 39% at 5 years, respectively). Furthermore, the predicted 5-year survival in high-risk subgroups (high WBC: 68%, >8 weeks to first complete remission: 57%) in this analysis contrasts well with an approximately 30% 5-year overall survival in comparable groups receiving mostly T-replete URD transplants reported by the CIBMTR study.11 Thus, the finding of higher rates of disease relapse with TCD allotransplantation reported by some authors18 does not appear to be recapitulated in this series of high-risk ALL. Reports in childhood ALL19 showing comparable disease-free survival rates in patients undergoing HLA-matched sibling donor transplants and in those undergoing T-cell-modified URD-HSCT for ALL in first or subsequent complete remission provide further support for retention of a graft-versus-leukemia effect with a TCD approach.

Patients with adverse cytogenetics had a significantly worse overall survival (47 vs. 68%, p=0.045) and a trend towards a lower disease-free survival (47% vs. 65%, p=0.065) in this study. Their outcomes are, however, similar to those reported by the CIBMTR11 for patients with ALL with adverse karyotype using a T-replete transplantation approach (overall survival: 38% at 5 years). The optimal conditioning approach in this ALL subgroup is, therefore, yet to be determined and further study is clearly warranted.

CD52 is expressed on 66–78% of ALL cells.20 We, therefore, recognize the possibility that alemtuzumab may have contributed to an antileukemic effect which may have partly offset a reduced graft-versus-leukemia effect. However, since all patients were in first complete remission and information on minimal residual disease at transplant is lacking, the magnitude of such a contribution is impossible to assess. Whether TCD URD transplantation is effective in those entering transplant with detectable minimal residual disease requires specific study, a matter which is likely to be addressed in the next UK-US ALL trial.

In agreement with results of previous studies we found TCD allotransplantation effective in preventing GVHD and graft rejection after URD-HSCT.21–24 The very low (10%) overall incidence of grade III to IV acute GVHD in our study population, together with only a single case of secondary graft failure, is consistent with this. However, chronic GVHD did occur in approximately half of the patients. The interpretation of this finding is confounded by the variation in alemtuzumab antibody, dosing and scheduling in our series which may have resulted in suboptimal prophylaxis of chronic GVHD in some cases. However, the finding of a reduction in acute GVHD but not always chronic GVHD after TCD URD-HSCT is well described24–27 and may reflect differing pathogenic mechanisms between these GVHD syndromes.28

A major drawback of T-cell depletion is slow immune reconstitution and post-transplant infection but only a third of transplant-related deaths in this series were due to infection. Pharmacokinetic studies have shown clinically significant differences in the type of CD52 antibody with rat antibodies, alemtuzumab -1G, having a shorter half-life (12–13 hours) than that of the humanized form, alemtuzumab-IH (15–21days), resulting in persistent lympholytic concentrations with the latter and a higher incidence of infections.14 A formal comparison between these agents and non-relapse mortality did not reveal any significant association.

There are very few studies addressing the utility of URD transplantation in Ph-negative ALL and none specifically examining the impact of T-cell depletion in this setting. Significant heterogeneity in selection of patients and transplant characteristics between studies limits an adequate comparison. Nonetheless, the finding of a higher rate of non-relapse mortality (RR 2.67; CI 1.42–4.99) in 16 patients who had received a TCD transplant by a variety of methods reported in the CIBMTR study is not corroborated in this larger series of TCD transplants. Importantly, the lack of GVHD-attributable deaths in this BSBMT series contrasts sharply with the findings of CIBMTR study in which GVHD was the second commonest cause of death.11 The cautions applicable to analysis of all retrospective registry data are also relevant here: in particular, the selection bias for surviving patients, which may result in improved outcomes being reported. For this reason considerable caution should be applied in comparing the overall survival rate of 60% with the 30–40% survival of adult ALL patients undergoing URD-HSCT reported by other studies. However, prospective randomized studies in this area are difficult to perform. Hence, retrospective data analysis is a pragmatic basis for initial investigation in this setting. Increasing age confers the highest risk of treatment-related mortality. The median age of our population was lower (26 years) than that of other published series (23–33 years), which might have contributed to the low observed non-relapse mortality although it is of note that older age did not increase non-relapse mortality or negatively influence overall outcome in the series reported. It is also recognized that the adolescent population (15–20 years) included in the study are now treated according to pediatric protocols, although it is important to note that randomized controlled evidence supporting the efficacy of this approach is still awaited.

The grim outlook of relapsed ALL in adults is indicated by the report by Fielding et al. which described a 5-year survival rate of 7% in 609 patients following initial recurrence.29 Prevention of relapse through primary application of the most effective therapies is, therefore, vital. In this study we demonstrate the potential efficacy of TCD URD transplantation for high-risk ALL and show that durable leukemia- free remissions can be achieved with this approach. These results support the prospective study of TCD URD transplantation in Ph-negative ALL to further define the role of this strategy.


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Acknowledgments
 
this work was performed on behalf of the Clinical Trials Committee of the BSBMT. The authors thank all of the data managers and transplantation physicians at the following participating centers for providing data and responding to additional requests: Manchester Royal Infirmary, Manchester; St Bartholomew's Hospital, London; Royal Hallamshire Hospital, Sheffield; Glasgow Royal Infirmary, Glasgow; University Hospital Wales, Cardiff; Leicester Royal Infirmary, Leicester.


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Footnotes
 
Authorship and Disclosures

BP and DIM designed the study; RP and RS performed the statistical analysis; KK, collected data; BP prepared the manuscript; BES collected and analyzed HLA typing data; all authors participated in the interpretation of data and approved the final version of the manuscript.

The authors reported no potential conflicts of interest.

Received for publication March 13, 2009. Revision received May 11, 2009. Accepted for publication May 28, 2009.


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 ABSTRACT
 Introduction
 Design and Methods
 Results
 Discussion
 References
 
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