Transcription
International Journal of Hematology (2021) 117-7PROGRESS IN HEMATOLOGYAiming for the final goalTreatment‑free remission and immunity in chronic myeloid leukemiaHiroshi Ureshino1Received: 11 February 2021 / Revised: 24 February 2021 / Accepted: 25 February 2021 / Published online: 2 March 2021 Japanese Society of Hematology 2021AbstractChronic myeloid leukemia (CML) is caused by the reciprocal translocation t(9;22)(q34;q11), resulting in the BCR-ABL1fusion gene. BCR-ABL1 tyrosine kinase inhibitors (TKIs) improve overall survival in patients with chronic phase CML(CML-CP). Approximately half of the patients who achieve a durable deep molecular response can achieve sustainedtreatment-free remission (TFR) after TKI discontinuation; thus TFR is now a therapeutic goal for most patients with CMLCP. Sensitive BCL-ABL1 transcript detection methods reveal that evidence of residual CML cells remains in patients whoachieve sustained TFR, indicating that the host immune system protects against CML relapse. The human immune systemis composed of innate and adaptive arms. Natural killer cells are major components of the innate immune system, while Tcells are major components of the adaptive immune system. Myeloid-derived suppressor cells and regulatory T cells, bothsuppressors of the immune response, have important roles in the regulation of CML. Here, we review the current understanding of the immune response in CML, especially in TFR.Keywords Chronic myeloid leukemia · Treatment-free remission · Natural killer cells · T lymphocytes · ImmunesurveillanceIntroductionChronic myeloid leukemia (CML) is a clonal hematopoieticstem cell disorder caused by the oncogenic t(9;22)(q34;q11)chromosomal translocation, known as the Philadelphiachromosome. BCR-ABL1 tyrosine kinase inhibitors (TKIs)improve the overall survival of patients with chronic phaseCML (CML-CP) [1]. The measure of treatment success isthe reduction of detectable BCR-ABL1 mRNA levels in theblood to a point 4.0 or 4.5 logs below that found beforetreatment commenced; this is known as a deep molecularresponse (DMR). Approximately half of CML-CP patientswho achieve a durable DMR can maintain molecular remission after TKI discontinuation, and now treatment-freeremission (TFR) is one of the therapeutic goals for patientswith CML-CP [2]. However, why some patients are at higher* Hiroshi [email protected] of Hematology, Respiratory Medicineand Oncology, Department of Internal Medicine,Faculty of Medicine, Saga University, 5‑1‑1 Nabeshima,Saga 849‑8501, Japan13Vol:.(1234567890)risk of molecular relapse which is defined as loss or majormolecular response (MMR) or DMR has not been fully elucidated. Evidence of residual CML cells can still be foundin patients who achieve TFR using sensitive BCL-ABL1DNA-based detection method [3], and, therefore, the hostimmune system could be apparently acting to prevent CMLprogression or relapse after TKI discontinuation. Here, wereview the immunological analyses in studies examining thediscontinuation of TKI treatment for CML-CP.Summary of recent TKI discontinuationstudiesThe pioneer TKI discontinuation study was the STopIMatinib (STIM) study [4], which showed that 41% ofpatients who received imatinib with a durable DMR for atleast 2 years maintained TFR for the next 12 months. Subsequently, the TWISTER study also showed that 42.7% ofpatients maintained TFR after imatinib discontinuation [3].Both of these studies indicated that imatinib could be discontinued safely. Next, several studies on the discontinuation of second-generation TKIs (dasatinib or nilotinib) were
Treatment‑free remission and immunity in chronic myeloid leukemia reported. The DAsatinib DIscontinuation trial (DADI) trialenrolled CML-CP patients receiving second-line dasatinib[5] and the Stop Tasigna Trial (STAT2) enrolled patientsreceiving second-line nilotinib [6]. TFR was achieved in49% (DADI) and 67.9% (STAT2) of patients at 12 months.These results suggested that discontinuation of second-linesecond-generation TKIs was feasible, and first-line secondgeneration TKI discontinuation trials were also instigated.The first-line DADI trial enrolled CML-CP patients whoachieved a DMR with first-line dasatinib treatment for atleast 24 months [7], and the ENESTfreedom trial enrolledpatients who achieved a DMR with first-line nilotinib treatment for at least 24 months [8]. After 1 year as consolidation treatment, the dasatinib or nilotinib was discontinuedand 55.2% (first-line DADI) and 51.6% (ENESTfreedom) ofpatients were in TFR. The largest European Stop TyrosineKinase Inhibitor (EURO-SKI) trial enrolled 758 CMP-CPpatients with a DMR maintained for 1 year during treatmentwith any TKI, and the TFR rate was 56% at 12 months aftertreatment ceased [9]. These studies suggested that discontinuation was a safe procedure with imatinib, dasatinib, and643nilotinib (Fig. 1). Detailed results of TKI discontinuationtrials are summarized in Table 1.Innate and adaptive immunity in humansThe human immune system consists of innate and adaptive arms, characterized by their functional diversities.Natural killer (NK) cells, a subset of large lymphocytes,play important roles in innate immunity against viruses ortumors by secreting cytotoxic granules [10] and elicitingantibody-dependent cellular cytotoxicity by releasing cytotoxic cytokines, which activate macrophages to kill targetcells. Meanwhile, the proliferating, antigen-specific T lymphocytes [11].On primary exposure to an antigen from a pathogen, naïveT cells receive signals via the T-cell receptor (TCR), stimulating their clonal expansion and leading to the proliferationof effector T cells. Through this process, T cells gain appropriate effector function such as lytic activity against virusinfected or tumor target cells [12]. The majority of effectorFig. 1 Kaplan–Meier curves for treatment-free remission. The results of four TKI discontinuation studies (STIM a; DOMEST b; ENESTfreedom c; first-line DADI d) were similar, nevertheless the study design and patient characteristics were different13
644Table 1 Details of tyrosinekinase inhibitor discontinuationstudiesH. UreshinoStudy nameTKIs before discontinuationNMedian TKI treatment duration(months)Criteria ofmolecularrelapseTFR %STIMTWISTERA-STIMISAVDADIKIDENESTfreedomSTOP 2G IM2NILstFirst-line asatinibImatinibNilotinibDasatinib, nilotinibDasatinibNilotinibImatinibImatinib, dasatinib, 710074.8107.140.433.269DMR lossDMR lossMMR lossDMR lossDMR lossMMR lossMMR lossMMR lossDMR lossMMR lossMMR lossMMR lossMMR lossDMR lossMMR lossDMR lossDMR lossDMR lossMMR 60.955.238.548DMR deep molecular response, MMR major molecular response, TFR treatment free remissionT cells die via apoptosis on completing their action (targetcell death). The small minority that survives is defined asmemory T cells, which contribute to adaptive immunity.T‑cell immunity in CMLDasatinib induces large granular lymphocyte expansionassociated with favorable outcomes in patients with CMLCP, suggesting that the cytotoxic T cells ( CD8 CD57 )may be performing specific anti-CML immune responses.CML-CP patients with increased numbers of peripheralblood CD8 T cells reportedly have better rates of TFR.The first-line DADI trial showed that a lower proportion of CD4 T cells at the time of dasatinib discontinuation wasassociated with a higher rate of TFR [7], and the DADI trial(be careful, first-line DADI and DADI trial were differenttrials) also showed that patients with a lower CD4/CD8 ratiotended to achieve a higher rate of TFR [5]. Meanwhile, theD-STOP study showed that a lower proportion of CD4 Tcells was associated with molecular relapse after TKI discontinuation [13].Human leukocyte antigen (HLA)-restricted cytotoxicT cells (CTLs) induced by leukemia-associated antigens (e.g., BCR-ABL1, PR1, BMI-1, PRAME, WT1, orCXorf48) are detected in patients with CML, and patientswith CXorf48-specific CTLs are more likely to achieve13TFR following imatinib discontinuation than those without [14]. We previously showed that certain HLA alleles,which induce antigen-specific CTLs, are associated withthe successful achievement of TFR in patients with CMLCP [15]. Increased numbers of the memory CD8 T-cell (CD8 CD27 CD45RA ) fraction in patients with CML-CPis associated with successfully maintaining TFR [16], whilepatients with increased PD-1-expression on C D8 CTLs (asignature of immune cell exhaustion) are at increased riskof relapse [17]. These results suggested that a specific T-cellpopulation acted in cancer immunosurveillance, contributing to the regulation of leukemic cells in CML, and theirexhaustion contributed to leukemia relapse. While the specific constitution of the T-cell population targeting CMLcells is likely to play a pivotal role in eliciting a durable TFRin CML, the magnitude of the T-cell proportion required forits maintenance is controversial.Regulatory T cells in CMLVarious immunological self-tolerance systems exist to prevent autoimmune reactions. Regulatory T cells (Tregs) havea pivotal role in preventing excessive autoimmune responses[18]. The differentiation and function of Tregs is regulatedby the transcription factor, forkhead box protein 3 (Foxp3).The number of Tregs is significantly increased in patients
Treatment‑free remission and immunity in chronic myeloid leukemia with CML-CP at diagnosis, indicating that aberrant immuneconditions can exist in patients with CML [19]. Myeloidderived suppressor cells (MDSCs), a heterogeneous population with immunosuppressive activity, mediate the recruitment and expansion of Treg [20]. Imatinib and dasatinib candecrease the number of Tregs and MDSCs in patients withCML, and successful maintenance of TFR is associated withreduced numbers of these populations at the time of TKIdiscontinuation [20].NK‑cell immunity in CMLNK cells are components of the innate immune responseagainst pathogens or tumors. Patients with newly diagnosedCML generally suffer from NK-cell dysfunction, whereastreatment with TKIs can restore NK-cell function and thiscorresponds with molecular remission [21]. Patients withearly recovery of the NK-cell population after allogeneicstem cell transplantation have favorable survival outcomes,thus NK cells have a pivotal role in CML regulating leukemic cells.Surface expression of CD56 divides human NK cellsinto functionally immature CD56bright and mature CD56dimsubsets. CD56bright NK cells can enhance their proliferation and cytokine production, and C D56dim NK cells havemore potent cytotoxic functions. In the IMMUNOSTIM andEURO-SKI studies [9, 22, 23], higher numbers of matureNK cells before discontinuation of imatinib were shown toplay an important role in the successful maintenance of TFR.By contrast, the D-STOP study showed that patients with alower number of NK cells at dasatinib discontinuation hada highly durable TFR and the authors propose that smallchanges in the number of NK cells during the consolidationphase treatment with dasatinib may contribute to TFR [13].However, the STAT2 and first-line DADI studies reportedthat increased numbers of NK cells did not affect the successful achievement of TFR [5, 6]. The clinical impact ofNK cells in patients who have discontinued TKIs remainscontroversial.NK cells are regulated by the balance between activatingand inhibitory signals via interactions of their surface receptor molecules with their ligands. Killer immunoglobulin-likereceptors (KIR), common NK-cell surface receptors, haveabundant structural and functional polymorphisms, whichalter NK-cell functions. The KIR2DL5B genotype [24] orthe strong avidity between KIR3DL1 and the HLA-Bw allotype of its HLA class I ligand correlate with a lower probability of DMR [25] in patients receiving TKI treatment,and thereby also with a lower chance of achieving TFR.Patients who have haplotype A KIR genotype or KIR3DL1but not the most avid ligand (HLA-Bw4) maintain higher645rates of TFR than patients with haplotype B KIR genotypeor KIR3DL1 in the context of an HLA-Bw4 [26].Immunomodulatory agents in CML for TFROnly up to 80% of patients with newly diagnosed CMLCP achieve a M R4.5 by TKI monotherapy [27], and TKItreatment is unable to eliminate quiescent leukemic stemcells because their survival is not dependent on BCR-ABL1tyrosine kinase activity [28]. Therefore, the combinationof TKIs with other types of drug is required to achieve a MR4.5 in more patients (more patients enable to attempt TKIdiscontinuation) and discontinuation TKI safely. Interferonα (IFNα) stimulates CTLs for the elimination of leukemic cells; it works synergistically with imatinib resultingin higher rates of molecular remission [29]. Furthermore,treatment with IFNα enables discontinuation of imatinibin patients who received prior combination of IFNα andimatinib, and the TWISTER trial showed that patients whoreceive IFNα treatment achieve a higher rate of TFR, whichalso correlates with a longer duration of IFN treatment( 12 months). The EURO-SKI trial, the largest TKI discontinuation study (758 patients), also showed that patientswho receive IFNα prior to TKI maintain TFR. Although nowrarely used, physicians may consider IFNα for patients identified at high risk of molecular relapse. The immunomodulatory drug lenalidomide is routinely used to treat multiplemyeloma and myelodysplastic syndrome, and stimulatesimmune effector cells (T cells and NK cells) and blocksMDSCs and Tregs, leading to anti-tumor effects. A smallstudy has shown that lenalidomide potentially contributesto achievement of TFR in patients with CML-CP. Furtherinvestigation is warranted to clarify these findings [30].Immunomodulatory effects of TKIsTKIs have well-known off-target immunomodulatory effects.Dasatinib strongly induces expansion of large granularlymphocyte subsets, which have strong cytotoxic functions, yielding favorable clinical outcomes in patients withCML-CP [31]. The proportion of NK-cell subsets with cytotoxic potential increases during imatinib treatment, whileno significant immunological changes were observed withbosutinib [32]. Furthermore, treatment with imatinib, dasatinib, or nilotinib reduces immunosuppressive cell fractions,including Tregs and MDSCs [33]. These results suggest thatTKIs have immunomodulatory functions, but the associationbetween these off-target effects and TFR has not been fullyelucidated.13
646H. UreshinoFuture outlookThe immune response in CML have not been fully elucidated comprehensively. We previously reported HLApolymorphisms associated with TFR, while NK cell activation status and KIR polymorphisms contributed to deepmolecular DMR [15, 25], thus we hypothesized DMRdepends on NK cell activation status and T-cell–mediatedimmunity contributes to TFR in CML-CP patients.8.9.10.ConclusionSeveral clinical studies show that TKI discontinuation isa safe procedure. The establishment of the optimal treatment strategy before TKI discontinuation is needed forpatients who are defined as being at higher risk of molecular relapse.11.12.13.Funding This work was supported by research grants from JSPS KAKENHI (19K17860, HU) and Okinaka Memorial Institute for MedicalResearch (HU).14.Declarations15.Conflict of interest Nothing to declare.16.References1. Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S,Hughes TP, et al. Long-term outcomes of imatinib treatment forchronic myeloid leukemia. N Engl J Med. 2017;376:917–27.2. Ureshino H, Kamachi K, Kimura S. Surrogate markers for treatment-free remission in patients with chronic myeloid leukemia.Clin Lymphoma Myeloma Leuk. 2020;20:785–90.3. Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C,Yeung DT, et al. Safety and efficacy of imatinib cessation forCML patients with stable undetectable minimal residual disease:results from the TWISTER study. Blood. 2013;122:515–22.4. Mahon F-X, Réa D, Guilhot J, Guilhot F, Huguet F, Nicolini F,et al. Discontinuation of imatinib in patients with chronic myeloidleukaemia who have maintained complete molecular remission forat least 2 years: the prospective, multicentre Stop Imatinib (STIM)trial. Lancet Oncol. 2010;11:1029–35.5. Imagawa J, Tanaka H, Okada M, Nakamae H, Hino M, Murai K,et al. Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response forlonger than 1 year (DADI trial): a multicentre phase 2 trial. LancetHaematol. 2015;2:e528–35.6. Takahashi N, Nishiwaki K, Nakaseko C, Aotsuka N, Sano K,Ohwada C, et al. Treatment-free remission after two-year consolidation therapy with nilotinib in patients with chronic myeloid leukemia: STAT2 trial in Japan. Haematologica. 2018;103:1835–42.7. Kimura S, Imagawa J, Murai K, Hino M, Kitawaki T, Okada M,et al. Treatment-free remission after first-line dasatinib discontinuation in patients with chronic myeloid leukaemia (first-line1317.18.19.20.21.22.23.DADI trial): a single-arm, multicentre, phase 2 trial. LancetHaematol. 2020;7:e218–25.Hochhaus A, Masszi T, Giles FJ, Radich JP, Ross DM, GómezCasares MT, et al. Treatment-free remission following frontlinenilotinib in patients with chronic myeloid leukemia in chronicphase: results from the ENESTfreedom study. Leukemia.2017;31:1525–31.Saussele S, Richter J, Guilhot J, Gruber FX, Hjorth-HansenH, Almeida A, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, nonrandomised, trial. Lancet Oncol. 2018;19:747–57.Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L,Lanier LL, et al. Innate or adaptive immunity? The example ofnatural killer cells. Science. 2011;331:44–9.Sourdive DJD, Murali-Krishna K, Altman JD, Zajac AJ, Whitmire JK, Pannetier C, et al. Conserved T cell receptor repertoirein primary and memory CD8 T cell responses to an acute viralinfection. J Exp Med. 1998;188:71–82.Zehn D, King C, Bevan MJ, Palmer E. TCR signaling requirements for activating T cells and for generating memory. CellMol Life Sci. 2012;69:1565–75.Kumagai T, Nakaseko C, Nishiwaki K, Yoshida C, Ohashi K,Takezako N, et al. Dasatinib cessation after deep molecularresponse exceeding 2 years and natural killer cell transitionduring dasatinib consolidation. Cancer Sci. 2018;109:182–92.Matsushita M, Ozawa K, Suzuki T, Nakamura M, Nakano N,Kanchi S, et al. CXorf48 is a potential therapeutic target forachieving treatment-free remission in CML patients. BloodCancer J. 2017;7:e601–7.Ureshino H, Shindo T, Tanaka H, Saji H, Kimura S. HLA polymorphisms are associated with treatment-free remission following discontinuation of tyrosine kinase inhibitors in chronicmyeloid leukemia. Mol Cancer Ther. 2021;20:142–9.Jo T, Noguchi K, Hayashi S, Irie S, Hayase R, Shioya H, et al.Long-lasting memory of cellular immunity in a chronic myeloidleukemia patient maintains molecular response 5 after cessationof dasatinib. Oncol Lett. 2018;15:2935–8.Schütz C, Inselmann S, Sausslele S, Dietz CT, Müller MC,Eigendorff E, et al. Expression of the CTLA-4 ligand CD86on plasmacytoid dendritic cells (pDC) predicts risk of diseaserecurrence after treatment discontinuation in CML. Leukemia.2017;31:829–36.Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010;127:759–67.Hughes A, Clarson J, Tang C, Vidovic L, White DL, Hughes TP,et al. CML patients with deep molecular responses to TKI haverestored immune effectors and decreased PD-1 and immune suppressors. Blood. 2017;129:1166–76.Irani YD, Hughes A, Clarson J, Kok CH, Shanmuganathan N,White DL, et al. Successful treatment-free remission in chronicmyeloid leukaemia and its association with reduced immunesuppressors and increased natural killer cells. Br J Haematol.2020;191:433–41.Savani BN, Rezvani K, Mielke S, Montero A, Kurlander R,Carter CS, et al. Factors associated with early molecular remission after T cell-depleted allogeneic stem cell transplantationfor chronic myelogenous leukemia. Blood. 2006;107:1688–95.Rea D, Henry G, Khaznadar Z, Etienne G, Guilhot F, NicoliniF, et al. Natural killer-cell counts are associated with molecularrelapse-free survival after imatinib discontinuation in chronicmyeloid leukemia: the IMMUNOSTIM study. Haematologica.2017;102:1368–77.Ilander M, Olsson-Strömberg U, Schlums H, Guilhot J, BrückO, Lähteenmäki H, et al. Increased proportion of mature NK
Treatment‑free remission and immunity in chronic myeloid leukemia 24.25.26.27.28.29.cells is associated with successful imatinib discontinuation inchronic myeloid leukemia. Leukemia. 2017;31:1108–16.Yeung DT, Tang C, Vidovic L, White DL, Branford S, HughesTP, et al. KIR2DL5B genotype predicts outcomes in CML patientstreated with response directed sequential imatinib/nilotinib strategy. Blood. 2015;126:2720–3.Ureshino H, Shindo T, Kojima H, Kusunoki Y, Miyazaki Y, Tanaka H, et al. Allelic polymorphisms of KIRs and HLAs predictfavorable responses to tyrosine kinase inhibitors in CML. CancerImmunol Res. 2018;6:745–54.Caocci G, Martino B, Greco M, Abruzzese E, Trawinska MM,Lai S, et al. Killer immunoglobulin-like receptors can predict TKItreatment-free remission in chronic myeloid leukemia patients.Exp Hematol. 2015;43:1015–8.Kantarjian HM, Hughes TP, Larson RA, Kim D-W, IssaragrisilS, le Coutre P, et al. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia.2021;35:440–53.Copland M, Hamilton A, Elrick LJ, Baird JW, Allan EK, Jordanides N, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does noteliminate the quiescent fraction. Blood. 2006;107:4532–9.Simonsson B, Gedde-Dahl T, Markevärn B, Remes K, StentoftJ, Almqvist A, et al. Combination of pegylated IFN-α2b with64730.31.32.33.imatinib increases molecular response rates in patients withlow- or intermediate-risk chronic myeloid leukemia. Blood.2011;118:3228–35.Ross DM, Pagani IS, Irani YD, Clarson J, Leclercq T, Dang P,et al. Lenalidomide maintenance treatment after imatinib discontinuation: results of a phase 1 clinical trial in chronic myeloidleukaemia. Br J Haematol. 2019;186:e56-60.Kreutzman A, Juvonen V, Kairisto V, Ekblom M, Stenke L,Seggewiss R, et al. Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at diagnosis and expandduring dasatinib therapy. Blood. 2010;116:772–82.Kreutzman A, Yadav B, Brummendorf TH, Gjertsen BT, Lee HeeM, Janssen J, et al. Immunological monitoring of newly diagnosedCML patients treated with bosutinib or imatinib first-line. OncoImmunol. 2019;8:1–13.Fei F, Yu Y, Schmitt A, Rojewski MT, Chen B, Greiner J, et al.Effects of nilotinib on regulatory T cells: the dose matters. MolCancer. 2010;9:1–10.Publisher’s Note Springer Nature remains neutral with regard tojurisdictional claims in published maps and institutional affiliations.13
TWISTER Imatinib 40 71 DMR loss 47.1 A-STIM Imatinib 80 79 MMR loss 65 ISAV Imatinib 108 103.1 DMR loss 48 DADI Dasatinib 63 82 DMR loss 48 KID Imatinib 90 80.8 MMR loss 62.2 ENESTfreedom Nilotinib 190 43.5 MMR loss 51.6 STOP 2G TKI Dasatinib, nilotinib 60 76 MMR loss 65 D-stop Dasatini
