Allogeneic stem cell transplantation (alloSCT) is used for treating patients with T-prolymphocytic leukemia (T-PLL). However, direct evidence of GvL activity in T-PLL is lacking. We correlated minimal residual disease (MRD) kinetics with immune interventions and T-cell receptor (TCR) repertoire diversity alterations in patients after alloSCT for T-PLL. Longitudinal quantitative MRD monitoring was performed by clone-specific real-time PCR of TCR rearrangements (n=7), and TCR repertoire diversity assessment by next-generation sequencing (NGS; n=3) Although post-transplant immunomodulation (immunosuppression tapering or donor lymphocyte infusions) resulted in significant reduction (>1 log) of MRD levels in 7 of 10 occasions, durable MRD clearance was observed in only two patients. In all three patients analyzed by TCR-NGS, MRD responses were reproducibly associated with a shift from a clonal, T-PLL-driven profile to a polyclonal signature. Novel clonotypes that could explain a clonal GvL effect did not emerge. In conclusion, TCR-based MRD quantification appears to be a suitable tool for monitoring and guiding treatment interventions in T-PLL. The MRD responses to immune modulation observed here provide first molecular evidence for GvL activity in T-PLL which, however, may be often only transient and reliant on a poly-/oligoclonal rather than a monoclonal T-cell response.
T-prolymphocytic leukemia (T-PLL) is a rare T-cell malignancy. It has an aggressive clinical course resistant to chemotherapy. Preliminary clinical data suggest that cellular immunotherapy conferred with allogeneic stem cell transplantation (alloSCT) may provide long-term disease control in a proportion of patients.1, 2, 3, 4, 5 However, direct evidence that GvL activity is indeed effective in T-PLL is lacking.6
While circumstantial evidence for GvL in hematological malignancies could be derived from the correlation with immune-modulating events such as chronic GvHD (cGvHD), donor lymphocyte infusion, immunosuppression withdrawal, and higher relapse rates with T-cell-depleted alloSCT, the most compelling evidence for GvL may be provided by investigating the effects of immune modulation on minimal residual disease (MRD) kinetics as demonstrated in CLL.7, 8, 9, 10, 11
Clone-specific rearrangements of the T-cell receptor (TCR) genes are present in virtually all T-PLL cases. Therefore, identification and quantification of clonal T cells by PCR can be a valuable tool to monitor MRD in T-PLL and other T-cell malignancies after alloSCT.12 In addition to measuring MRD kinetics, comprehensive longitudinal TCR repertoire analysis by next-generation sequencing (NGS) may help to dissect the anatomy of GvL activity in T-PLL by delineating TCR diversity in relation to GvL responses.13, 14, 15
In this study we sought to investigate MRD kinetics and TCR repertoire diversity alterations after alloSCT as tools for proving and modulating GvL activity in T-PLL. The results suggest that TCR-based MRD quantification is possible. GvL is effective in T-PLL but often only limited or transient, and is driven by poly- or oligoclonal T-cell responses rather than single dominant T-cell clones.
The study sample consisted of consecutive 10 patients diagnosed with T-PLL who received alloSCT at the University of Heidelberg between August 2007 and March 2015. The median age at alloSCT was 59 years (range 43–72) with the majority of patients (80%) being male. Eight patients proceeded to transplant in first CR (7) or PR (1) after first-line alemtuzumab monotherapy, one patient was in CR subsequent to salvage chemotherapy upon alemtuzumab failure, and one patient was in PR subsequent to salvage alemtuzumab after chemotherapy failure. A minimum wash-out time of 6 weeks (median 12 weeks, range 6–22 weeks) between the last alemtuzumab dose and alloSCT had been observed in all patients. Five patients were transplanted with an unrelated donor, four patients with a related donor and one patient received haploidentical alloSCT. Conditioning was fludarabine with cyclophosphamide and/or TBI-based, with all regimens to be considered as reduced-intensity (4) or non-myeloablative (6). Patient and transplant characteristics are detailed in Table 1. Informed consent for transplantation, data collection and scientific evaluation of blood and marrow samples was obtained from every patient in accordance with the Declaration of Helsinki. The research was approved by the Ethics Committee of the University of Heidelberg (S-120/2002).
Quantitative MRD monitoring
Quantitative MRD monitoring was performed using clone-specific real-time quantitative PCR (RQ-PCR) of clonal TCR beta (TRB) and/or gamma gene rearrangements.12, 16, 17 Data interpretation followed EuroMRD guidelines.18
Next-generation sequencing of the TCR repertoire
TCR repertoire diversity was analyzed longitudinally by NGS. TRBV-TRBD-TRBJ gene rearrangements were amplified according to BIOMED2 protocol on genomic DNA.19 Paired-end libraries with individual barcoded samples were prepared and sequenced on Illumina’s MiSeq platform. Raw NGS data were processed, annotated with germline sequences from IMGT20 and analyzed through an R-based (www.R-project.org) purpose-built bioinformatics immunoprofiling platform (ARResT/Interrogate, bat.infspire.org; manuscript in preparation). First, pairs of raw paired-end reads were joined into one longer sequence using a sensitive iterative approach: overlapping regions of at least 10 nucleotides with up to 2 and then 4 mismatches were allowed. Consequently, short (<60 nucleotides) and low quality (>5 expected errors, based on Phred quality scores) sequences were filtered out. Next, TRBV and TRBJ genes were identified and the position of the junctional region was determined. An iterative sequence curation approach was employed to correct low-frequency base calls in strict junction-aware clusters of sequences. Finally, sequences without the junctional region identified were filtered out. The quality of sequences in all the analyzed samples was high, with the average number of reads passing all the filters over 90% (Supplementary Table 1). Unique clonotypes were defined as clusters of sequences having at least 96% similarity of the junctional nucleotide sequence and identical TRBV and TRBJ genes. For repertoire analyses, the abundances of features (for example, TRBV) were counted in clonotypes rather than in reads in order to alleviate the effects of technical and biological biases.
Kaplan–Meier product-limit estimates were used for calculating survival. Events for overall survival were defined as death from any cause. Events for PFS were defined as relapse, progression or death from any cause, whatever came first. Survival time calculations were performed using GraphPad Prism software (release 5.0; San Diego, CA, USA). Data were analyzed as of 31 July 2016.
In ARResT/Interrogate, Jensen–Shannon divergence was used to compute repertoire similarity between pairs of samples visualized within heatmaps; principal component analysis was conducted to evaluate the effect of repertoire components on sample relationships; Shannon entropy was used to estimate the alpha diversity of rearrangements of individual samples.
Correlation of MRD kinetics with immune events and the clinical course
All patients were in clinical CR immediately after hematological reconstitution from alloSCT. Patients #3 and #9 died early (day +93 and +211 post transplant) because of severe acute GvHD, and for patient #5 no MRD marker could be established, leaving seven patients for whom at least one clone-specific MRD marker was available; these MRD markers and their sensitivity levels are shown in Table 2. Of the seven patients with MRD markers, two (patients #7 and #10) were MRD negative immediately (<50 days) after alloSCT. Whereas patient #10 died early (day +241 post transplant) from severe acute GvHD without measurable MRD, patient #7 subsequently showed increasing MRD levels, which responded to immunosuppressant tapering but—in the absence of cGvHD—re-appeared from month +16 onwards, followed by fatal clinical relapse. Five patients (#1, #2, #4, #6, #8) were MRD positive early (<100 days) after alloSCT. In all of these five patients, immunosuppressant tapering (four out of five) and/or DLI (three out of four) resulted in significant reduction of MRD levels (>1 log) and was accompanied by cGvHD in three patients. However, durable MRD negativity was obtained in only two patients (#4, #8; alive and free of disease 92+ and 24+ months after alloSCT). MRD re-increased in the remaining three patients after 5–28 months despite ongoing cGvHD in one of them. Table 3 shows MRD kinetics of all patients by certain clinical landmarks. In addition, Figure 1a and c delineates the MRD kinetics of three patients with the longest follow-up in correlation to immune interventions and the clinical course.
Correlation of TCR repertoire diversity with immune interventions and clinical course
The TRB repertoire of the three patients with the longest follow-up was interrogated longitudinally before and after alloSCT using NGS. In total, 104 samples (patient blood (n=91) and bone marrow (n=10) plus donor blood samples (n=3)) were analyzed (Figure 2a). Overall, 10 697 556 reads were obtained (median 78 659; range 1114–236 806 reads/sample). Sequence numbers were remarkably low in samples after alemtuzumab treatment (pre-alloSCT; Supplementary Table 1). The diagnostic sample in all three analyzed patients predominantly showed one or two major clonotypes (Figure 2b). Kinetics of these leukemic clonotypes closely followed kinetics of RQ-PCR-quantified MRD (Figure 1a and c and Table 2b). In all three patients, MRD decline was reproducibly associated with a shift from a clonal, T-PLL-driven profile to a polyclonal signature that largely corresponded to the donor TCR repertoire and receded with increasing MRD levels. Immediately after alemtuzumab treatment and alloSCT, the TRB repertoire was heavily skewed in all three patients but recovered over time (Figures 2c and 3). In each of the samples after alloSCT, several expanded non-leukemic clonotypes were observed at a maximum frequency of 3% to 54% of total TRB sequences. Notably, there was no obvious correlation of GvL-induced MRD decline with emergence of particular dominant T-cell clonotypes that could explain a clonal GvL effect. Expanded clonotypes were most dominant in one patient who received a transplant of his brother, who in turn already exhibited the same clonotypes with a frequency of up to 15%. There were no CMV reactivations in the analyzed patients. Therefore, it was not possible to correlate known viral reactivations with clonal expansions following diminution of the viral load. There was no obvious correlation of GvL-induced MRD decline or GvHD with emergence of dominant T-cell clonotypes. Clonal expansions were observed only in the context of T-PLL relapse, reflecting the malignant clone.
T-PLL is an aggressive disease with poor outcome. In the absence of effective chemotherapeutic or targeted treatment options, alloSCT may be a potent therapeutic tool. However, it is still uncertain to what extent GvL is indeed active in this lymphoproliferative disorder. To this end, delineation of MRD kinetics in relation to immune events might help to characterize potential GvL activity in T-PLL, and how it might be exploited to optimize treatment of the disease.
TCR-based RQ-PCR is an established tool for monitoring MRD kinetics in certain lymphoid malignancies. For example, in ALL, MRD levels at different time points not only predict outcome but also indicate the need for salvage therapy as well as direct the type of optimal treatment such as alloSCT.21, 22, 23, 24, 25 So far, MRD monitoring is not established in T-PLL. This study shows for the first time that in T-PLL immunomodulation can decrease the MRD load up to complete MRD clearance. This finding is the clearest evidence to date that GvL is indeed effective in this entity. However, unlike similar observations in CLL7, 8, 9, 10, 11 the GvL effect in T-PLL appears to be often only limited or transient, failing to provide long-term disease control (although only a single patient had severe cGvHD, indicating a strong anti-host immune effect). Nevertheless, MRD assessment by clone-specific TCR-based RQ-PCR is a useful tool for monitoring MRD kinetics in T-PLL after alloSCT. Therefore, regular monitoring of MRD in T-PLL after alloSCT to identify early the need for immune interventions seems to be recommendable. Although basically mixed chimerism would also have been a trigger for immunomodulation as per institutional routine, we never observed mixed chimerism in the absence of detectable MRD in any of these seven patients.
Determination of MRD levels by NGS has been successfully used to efficiently predict the risk of relapse in different hematological malignancies such as adult and childhood ALL,26, 27 CLL28, 29 as well as cutaneous T-cell lymphoma.15 Multiplexed PCR followed by NGS has the benefit of being applicable to all patients without prior allele-specific customization necessary in RQ-PCR-based techniques, whereas having the potential to offer higher sensitivity. In our study, NGS-based MRD assessment in T-PLL was feasible and reflected MRD kinetics determined by RQ-PCR, despite not being designed specifically for MRD sensitivity (input DNA amount only 100 ng, limited number of readings obtained per sample, conservative definition of MRD positivity). Another point is that TRB-based NGS analysis quantifies MRD in relation to all T cells because these are the only cells harboring TRB rearrangements. In contrast, RQ-PCR quantifies MRD in relation to total DNA. In general, results from the two techniques are highly correlated, but in case of T-cell lymphopenia NGS-based MRD levels can be markedly overestimated, as seen in patient 2. This however might be overcome by additional sequencing-based calibrations. Our study clearly demonstrates the feasibility of NGS-based MRD analysis in T-PLL. Standardization, quality control and validation of this technology in a multicenter, scientifically controlled and independent setting is warranted and currently the focus of an European network, the EuroClonality-NGS Consortium (coordinated by AW Langerak).
Besides MRD monitoring, TCR repertoire analysis by NGS provides high-resolution information on immune reconstitution and emergence of dominant clones after alloSCT, for example, in response to infection, GvHD or GvL. It has been shown that the physiological hierarchy of the TCR repertoire is heavily skewed after alloSCT.30 In addition, limited TCR diversity after alloSCT has been linked to higher susceptibility to leukemic relapse,31, 32 infection31 and the development of GvHD.32 However, to the best of our knowledge, there are currently no comprehensive longitudinal studies available investigating the composition of the T-cell repertoire after immune interventions in the alloSCT context. Here, we show for the first time that GvL activity in a hematological malignancy is rather relying on a polyclonal T-cell response than on the emergence of novel dominant T-cell clones with antileukemic activity. Further studies are necessary to prove if this pattern also accounts for other neoplastic alloSCT indications, such as acute leukemia and lymphoma.
In this context it has to be considered that all patients received alemtuzumab for induction therapy. Although a minimum wash-out time of 6 weeks between the last alemtuzumab dose and alloSCT had been observed, it cannot be excluded that effective alemtuzumab serum levels were present at the day of allograft infusion with implications for the integrity of the transplanted cell product. However, it is unlikely that this has interfered with donor lymphocyte infusion effects during longer follow-up or with the overall TCR repertoire pattern during GvHD/GvL episodes.
A limitation of this study is its small sample size. However, as the purpose of this analysis is not to investigate the impact of alloSCT on the clinical outcome of T-PLL, but to provide proof-of-principle evidence both for GvL and for the suitability of MRD quantification by RQ-PCR and NGS, the sample numbers investigated appear to be clearly informative.
In conclusion, this study provides the clearest evidence to date for GvL activity in T-PLL, even though it appears to be often only limited or transient. Moreover, GvL in T-PLL does not seem to be driven by the emergence of novel dominant T-cell clones but is rather relying on poly- or oligoclonal T-cell responses. Nonetheless, further evaluation of MRD monitoring might help to optimize alloSCT-based immunotherapeutic strategies in T-PLL. To this end, TRB-based NGS could not only serve as an effective tool for dissecting post-transplant immune reconstitution and GvL activity, but also emerge as an interesting alternative for MRD quantification in T-cell malignancies.
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We thank all our patients for their kind willingness to contribute clinical data and biological samples to make this study possible. TR, AK, VB, ND funded by CEITEC MU (CZ.1.05/1.1.00/02.0068) and EuroClonality, with computational resources provided by MetaCentrum under program LM2010005, and CERIT-SC under program Centre CERIT Scientific Cloud, part of the Operational Program Research and Development for Innovations, CZ.1.05/3.2.00/08.0144.
The authors declare no conflict of interest.
Presented in part in abstract form at the 57th Annual Meeting of the American Society of Hematology (ASH; December 5–8, 2015, Orlando, FL, USA) and the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT; April 3–6, 2016, Valencia, Spain).
Supplementary Information accompanies this paper on Bone Marrow Transplantation website
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Sellner, L., Brüggemann, M., Schlitt, M. et al. GvL effects in T-prolymphocytic leukemia: evidence from MRD kinetics and TCR repertoire analyses. Bone Marrow Transplant 52, 544–551 (2017) doi:10.1038/bmt.2016.305
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