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Chronic Lymphocytic Leukemia

Hematopoietic stem cell transplantation in T-prolymphocytic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation and the Royal Marsden Consortium


T-prolymphocytic leukemia (T-PLL) has a very poor prognosis with conventional immunochemotherapy. Incidental reports suggest that allogeneic hematopoietic stem cell transplantation (allo-HSCT) might have a role in this disease. Therefore, the purpose of the present study was to analyze the outcome of transplants for T-PLL registered with the European Group for Blood and Marrow Transplantation database and the Royal Marsden Consortium. Eligible were 41 patients with a median age of 51 (24–71) years; median time from diagnosis to treatment was 12 months, and in complete remission (CR) (11), partial remission (PR) (12), stable or progressive disease (13) and unknown in 5 patients. A total of 13 patients (31%) received reduced-intensity conditioning. Donors were HLA-identical siblings in 21 patients, matched unrelated donors in 20 patients. With a median follow-up of surviving patients of 36 months, 3-year relapse-free survival (RFS) and OS was 19% (95% CI, 6–31%) and 21% (95% CI, 7–34%), respectively. Multivariate analysis identified TBI and a short interval between diagnosis and HSCT as factors associated with favorable RFS. Three-year non relapse mortality and relapse incidence were each 41% with the majority of relapses occurring within the first year. These data indicate that allo-HSCT may provide effective disease control in selected patients with T-PLL.


T-cell prolymphocytic leukemia (T-PLL) is a rare aggressive disorder of mature T lymphoid cells.1, 2 The disease is associated with frequent chromosome 14 aberrations resulting in juxtaposition of the TCR α/β locus with the oncogenes TCL1 and TCL1b at 14q32.3, 4 However, approximately 20–30% of T-PLL cases have no TCL1 expression.5, 6 Other genetic abnormalities frequently observed in T-PLL include mutations and deletions of the ATM gene at 11q23, and lesions of chromosomes 8 and 17 (involving the TP53 gene).3, 6 T-PLL cells are characterized by a CD2+, CD3+, CD5+, CD7+ phenotype positive for either CD4 or CD8 or both.3 The disease is usually progressive with poor response to chemotherapy, including purine analogs and a median survival of <1 year, but cases with indolent course have been described as well.3 The best response rates were observed with administration of monoclonal anti-CD52 antibody alemtuzumab,5, 7 resulting in >50% of overall response and significant prolongation of survival in responding patients with median disease-free interval of 7 months. This is still far from being satisfactory and more effective treatment approaches are urgently needed.

One of such approaches with potential utility in T-PLL is stem cell transplantation. In the initial alemtuzumab report7 there was already a few patients subjected to either auto- or allo- transplantation. Moreover, there have been also anecdotal reports of cases of T-PLL treated successfully with autologous or allogeneic bone marrow transplantation.8, 9, 10, 11, 12, 13 More recently, small registry analyses suggested that long-term disease control can be observed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in some patients with T-PLL.14, 15 Pooling together patients from the European Group for Blood and Marrow Transplantation (EBMT) database with those from the Royal Marsden series, the present retrospective study analyzes the largest sample of allo-HSCT in T-PLL available to date.

Patients and methods

Data sources and patient eligibility

The EBMT is a voluntary organization comprising 640 transplant centers mainly from Europe. Accreditation as a member center requires submission of minimal essential data (MED-A form) from all consecutive patients to a central registry in which patients may be identified by the diagnosis of underlying disease and type of transplantation. MED-A data is collected by paper forms or an electronic data management system and updated annually. Since 1996, accredited EBMT centers are subject to on-site audits to assess data accuracy and consecutive reporting. Informed consent was obtained locally according to regulations applicable at the time of transplantation. Since 1 January 2003, all transplant centers have been required to obtain written informed consent before data registration following the Helsinki Declaration 1975.

The EBMT database was screened for patients fulfiling the eligibility criteria of this study. Baseline information and transplant characteristics of all patients identified by this procedure were downloaded from the data base. Additional source data required for the purposes of this study, including verification of the diagnosis, was obtained for all patients identified by direct contact with the centers. There was no central review of diagnostic samples.

During data collection for the present study, a preliminary analysis of the Royal Marsden T-PLL transplant registry became available.14 The overlap between the 13 patients of the Royal Marsden study and the EBMT dataset was identified, and updated follow-up information for overlapping and non-overlapping patients was requested from the Royal Marsden consortium, allowing pooling of both series for the purposes of this study.

Study design

The primary objective of this retrospective study was to determine relapse-free survival (RFS) after allo-HSCT for T-PLL. Secondary objectives were to assess overall survival (OS), relapse incidence, as well as non-relapse mortality (NRM) after HSCT, and to define risk factors with a significant impact on these endpoints. Patients were eligible for this study if they had been registered with the EBMT between 1995 and 2006 with a diagnosis of T-PLL and a history of allo-HSCT. Items considered comprised patient age and sex, type of donor, conditioning regimen, T-cell depletion, stem cell source, diagnosis, remission status at time of transplantation, date of transplantation and outcome (survival, relapse and cause of death).

Statistical analysis

PFS and OS were calculated using the Kaplan-Meier method. The outcomes of relapse mortality and NRM were each estimated by means of cumulative incidence curves; for relapse, we considered NRM as a competing event and vice versa. We developed proportional hazards Cox models for assessing the impact of several risk factors at transplant on outcome (OS, PFS, NRM, RI). All significant tests are likelihood ratio tests (corresponding to the usual logrank tests for OS and PFS). Backward selection was used to select the most significant predictive factors. The impact of chronic graft-versus-host disease (cGVHD) was analyzed by means of a Cox model in which the occurrence of cGVHD was included as a time-dependent covariate.

All calculations were performed using PASW Statistics 18 (SPSS). Cumulative incidences were calculated by means of SPSS macros developed by the Department of Medical Statistics and Bioinformatics of the LUMC (Leiden, the Netherlands), on the basis of the hazard estimates from the Cox models. The data set for analysis was closed on 31 October 2009.



After verification of diagnosis and source data, 40 patients from 31 EBMT centers (see Appendix) fulfiled the inclusion criteria for this study. The patient with the longest post-transplant survival had an outstandingly long interval of almost 20 years between diagnosis and SCT, suggesting a different biological entity. Therefore, this patient was removed from the data set, resulting in 39 patients eligible for further analysis. Of these, seven overlapped with the Royal Marsden series. Four other Royal Marsden patients were excluded because they had been registered for a prospective non-interventional EBMT study starting in 2007, wheras two additional patients were included in the present analysis making a total of 41 patients.

The characteristics of the 41 eligible patients are summarized in Table 1. Only 10 patients in this series received alemtuzumab as an earlier line of therapy: with a lag time between alemtuzumab administration and transplantation ranging from 4.5 to 15 months. The median interval between diagnosis and HSCT was 12 months. 21 patients were allografted from an HLA-identical sibling; the remainder from matched unrelated donors. In two thirds of the patients (26 of 39) conditioning intensity was considered myeloablative according to the EBMT criteria. Of these, 17 (65%) had received myeloablative doses of TBI, whereas TBI had been administered to only 3 of the 13 patients (23%) who underwent RIC. In 15 patients, grafts were subjected to either in vivo or ex vivo T-cell depletion. Of these, 10 patients received alemtuzumab as part of conditioning (one of these patients has received alemtuzumab also as an earlier line of therapy), 2 patients have been subjected to other in vivo T-cell depletion in the course of conditioning, and 3 patients received ex vivo T-cell-depleted grafts.

Table 1 Patient characteristics at HSCT

Outcome after allo-HSCT

Hematopoietic engraftment was reported for 37 of 39 patients (95%) with information available. Median PFS and OS after HSCT was 10 and 12 months, respectively (Figure 1). With a median follow-up of surviving patients of 36 (18–72) months, ten patients remained alive, eight of them in sustained complete remission, translating into a 3-year RFS and OS of 19 and 21%, respectively. Of note, six of the eight patients who remained relapse-free had undergone conditioning containing myeloablative TBI. The 3-year RFS of this subset was 34% with all five patients beyond the 3-year landmark surviving event-free.

Figure 1

Relapse-free (left) and overall survival (right) after allogeneic HSCT.

Three-year NRM and relapse incidence were each 41%. Altogether, 17 relapses occurred after a median time of 10 months post HSCT. Although 12 of these (71%) were observed within the first year and 16 (94%) within the first 3 years, one patient (who had received RIC) relapsed as late as 6 years after transplant. Regarding the 16 non-relapse deaths, 4 of them had been mainly attributed to graft versus host disease (GVHD), 6 to infection, and 6 to other causes. Crude rates of acute and chronicGVHD appeared to be within the range usually observed for these complications (Table 2).

Table 2 Graft-versus-host disease

Prognostic factor analyses

Univariate prognostic factor analyses for the end points of OS, RFS, relapse and NRM were performed taking into account the variables age, stage of disease at transplantation, stem cell source, utilization of TBI, conditioning intensity, T-cell depletion as part of conditioning, and donor type. The only significant predictor was TBI-based conditioning, which was associated with a lower relapse rate and a trend for better RFS. Moreover, patients in CR or PR1 at the time of transplant tended to have superior RFS because of less disease recurrence (Table 3). This was not limited to the first CR and in fact first remission patients did not perform better than other remission patients (data not shown). Cox modeling adjusting for co-variates potentially affecting RFS (conditioning intensity, age, gender, TBI, T-cell depletion, status at HSCT (CR/PR vs more advanced), interval from diagnosis, and donor) ended up with three factors remaining in the final model, two of them being statistically significant: use of TBI (hazard ratio (HR) 0.44 (95% CI 0.21–0.94), P 0.034) and interval diagnosis—HSCT more than 1 year (HR 2.15 (95% CI 1.00–4.62), P 0.05), and age >50 HR 0.64 (95% CI 0.3–1.37). We didn't find a factor significantly affecting OS.

Table 3 Univariate prognostic factor analysis (2-year estimates of proportions based on Kaplan-Meier curves for OS and EFS, and on cumulative incidence curves for Rel and NRM; all P-values stem from likelihood ratio tests based on Cox models testing for overall differences)

The impact of cGVHD on relapse, RFS and OS was analyzed in a time-dependent Cox model in which no confounders were included. Although cGVHD was associated with less relapse and better survival, none of these effects was statistically significant (relapse HR 0.53, P 0.35; RFS HR 0.71, P 0.49; OS HR 0.78, P 0.60).


Given the dismal prognosis of T-PLL with chemotherapy, the feasibility and efficacy of allogeneic HSCT approaches are of considerable interest. However, apart from anecdotal case reports, there have been only two retrospective studies addressing this issue. The series from Krishnan et al.14 included 28 patients who had received an alemtuzumab-based therapy, reached either CR (majority) or good partial response and were consolidated with allogeneic (n=13) or autologous (n=15) HSCT. The median OS of all transplanted patients compared favorably with that of 23 control patients who achieved CR after alemtuzumab without subsequent HSCT and survived at least 6 months thereafter (48 vs 20 months).14 A CIBMTR registry analysis15 identified 47 patients with prolymphocytic leukemia who had undergone allogeneic HSCT. One-year survival was 33%; however, the follow-up in this study was only 13 months, and survival times were not specifically reported for those 21 patients who indeed had T-PLL (the remainder had B-PLL or PLL unspecified).15

The present study is the first investigating a larger number of allotransplantations for T-PLL with a reasonable follow-up. However, only one-fourth of the included patients were in CR at HSCT, whereas for other patients allo-HSCT apparently was used as rescue procedure and therefore, the preselection for patients with very poor prognosis has to be taken into consideration. Thus, this series of patients is different from the patients described by Krishnan et al.,14 who predominantly included patients in CR. Nevertheless, although the estimated long-term RFS was about 20% in the study population, the results are somewhat disappointing. This is because clear-cut evidence for effective graft-versus-leukemia activity was not found, and sustained disease control seemed to be largely restricted to those patients who were conditioned with myeloablative doses of TBI.

Principally, allo-HSCT could be effective by two different therapeutic mechanisms: High-dose cytotoxic therapy with or without TBI, and graft-versus-leukemia activity. An argument in favour of the efficacy of the high-dose principle would be the superiority of myeloablative over-reduced intensity conditioning. Myeloablative conditioning did not emerge as a significant predictor for RFS in multivariate analysis, but was, however, strongly correlated with TBI usage, which remained as significant favorable factor in the final Cox model for RFS. However, it has to be kept in mind that due to the small number of patients in the analysis, the predictive value of these models is limited and the estimates are not very precise. Especially the resulting subset of—significant—predictors should be interpreted with caution in the absence of sufficient power to build a comprehensive model. Nevertheless, the fact that six of the eight patients in our dataset who remained relapse-free had undergone conditioning containing myeloablative TBI may suggest that this modality may have a potential for long-term disease control in T-PLL. This is an important information for planning future treatment approaches in T-PLL. On the other hand, only two of the eight patients who had undergone myeloablative TBI for auto-HSCT from the autologous part of the Royal Marsden series enjoyed long-term RFS.14

In contrast, we were unable to deduce clear-cut evidence for the efficacy of graft-versus-leukemia in T-PLL from our analysis. Although only few late relapses were observed and there was some favorable (albeit not statistically significant with the small numbers studied here) effect of cGVHD on disease control in time-dependent Cox models, we failed to show any efficacy of RIC allo-HSCT. However, other circumstantial evidence by individual clinical observations13 and minimal residual disease studies suggests that graft-versus-leukemia can be effective in T-PLL.16

The other variable that was predicting a favorable RFS in multivariate Cox modeling was a short interval from diagnosis to HSCT. The problem is that large proportions of patients never achieve CR, which in the absence of acceptable therapeutic alternatives may suggest that such patients may benefit from allotransplantation performed as early as possible. However, we were unable in our series of patients to confirm that allo-HSCT may be best performed in first remission,14 rather our data suggest that transplantation in any remission may be beneficial for the outcome.

In conclusion, this study suggests that a small proportion of patients with T-PLL achieve long-term disease survival after allogeneic HSCT. Although our investigation leaves many questions unanswered, no other analysis of T-PLL patients comparable in size and baseline information exists and, thus, this analysis may help to optimize transplantation outcome and could serve as a platform for designing future studies on allo-HSCT in this rare disease.


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We acknowledge all collaborating EBMT Investigators and Institutions that contributed cases to this study listed in the Appendix. Moreover, we also acknowledge Investigators and Centers that were consulted and whose cases were disqualified from the analysis.

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Correspondence to W Wiktor-Jedrzejczak.

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The authors declare no conflict of interest.



Table A1

Table a1 List of participating investigators

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Wiktor-Jedrzejczak, W., Dearden, C., de Wreede, L. et al. Hematopoietic stem cell transplantation in T-prolymphocytic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation and the Royal Marsden Consortium. Leukemia 26, 972–976 (2012).

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  • prolymphocytic leukemia
  • bone marrow transplantation
  • graft versus leukemia

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