Voltar
Revisão Acesso aberto Revisado por pares
BIBTEX RIS

Does lineage plasticity enable escape from CAR-T cell therapy? Lessons from MLL-r leukemia

2021; Elsevier BV; Volume: 100; Linguagem: Inglês

10.1016/j.exphem.2021.07.002

ISSN

1873-2399

Autores

Wenjuan Liao, M. Eric Kohler, Terry J. Fry, Patricia Ernst,

Tópico(s)

Semiconductor materials and devices

Resumo

•Increased use of immunotherapy results in unanticipated mechanisms of resistance.•Lineage switching is a mechanism of evasion to CD19-directed immunotherapy.•Multiple cases of lineage switching in MLL-rearranged B-ALL have now been reported. The clinical success of engineered, CD19-directed chimeric antigen receptor (CAR) T cells in relapsed, refractory B-cell acute lymphoblastic leukemia (B-ALL) has generated great enthusiasm for the use of CAR T cells in patients with cytogenetics that portend a poor prognosis with conventional cytotoxic therapies. One such group includes infants and children with mixed lineage leukemia (MLL1, KMT2A) rearrangements (MLL-r), who fare much worse than patients with low- or standard-risk B-ALL. Although early clinical trials using CD19 CAR T cells for MLL-r B-ALL produced complete remission in most patients, relapse with CD19-negative disease was a common mechanism of treatment failure. Whereas CD19neg relapse has been observed across a broad spectrum of B-ALL patients treated with CD19-directed therapy, patients with MLL-r have manifested the emergence of AML, often clonally related to the B-ALL, suggesting that the inherent heterogeneity or lineage plasticity of MLL-r B-ALL may predispose patients to a myeloid relapse. Understanding the factors that enable and drive myeloid relapse may be important to devise strategies to improve durability of remissions. In this review, we summarize clinical observations to date with MLL-r B-ALL and generally discuss lineage plasticity as a mechanism of escape from immunotherapy. The clinical success of engineered, CD19-directed chimeric antigen receptor (CAR) T cells in relapsed, refractory B-cell acute lymphoblastic leukemia (B-ALL) has generated great enthusiasm for the use of CAR T cells in patients with cytogenetics that portend a poor prognosis with conventional cytotoxic therapies. One such group includes infants and children with mixed lineage leukemia (MLL1, KMT2A) rearrangements (MLL-r), who fare much worse than patients with low- or standard-risk B-ALL. Although early clinical trials using CD19 CAR T cells for MLL-r B-ALL produced complete remission in most patients, relapse with CD19-negative disease was a common mechanism of treatment failure. Whereas CD19neg relapse has been observed across a broad spectrum of B-ALL patients treated with CD19-directed therapy, patients with MLL-r have manifested the emergence of AML, often clonally related to the B-ALL, suggesting that the inherent heterogeneity or lineage plasticity of MLL-r B-ALL may predispose patients to a myeloid relapse. Understanding the factors that enable and drive myeloid relapse may be important to devise strategies to improve durability of remissions. In this review, we summarize clinical observations to date with MLL-r B-ALL and generally discuss lineage plasticity as a mechanism of escape from immunotherapy. Relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL) remains a leading cause of cancer mortality in children despite the successful iterative development of risk-adapted, multi-agent chemotherapeutic regimens [1Hunger SP Mullighan CG Acute lymphoblastic leukemia in children.N Engl J Med. 2015; 373: 1541-1552Crossref PubMed Scopus (713) Google Scholar]. Years of sophisticated molecular characterization of childhood ALL [2Mullighan CG Genomic characterization of childhood acute lymphoblastic leukemia.Semin Hematol. 2013; 50: 314-324Crossref PubMed Scopus (58) Google Scholar,3Hunger SP Mullighan CG Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine.Blood. 2015; 125: 3977-3987Crossref PubMed Scopus (150) Google Scholar] make it possible to identify subsets of patients with a high likelihood of relapse at diagnosis. Among the poor prognostic groups are those with rearrangements of the mixed lineage leukemia (MLL1, KMT2A) gene at 11q23 [4Andersson AK Ma J Wang J et al.The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.Nat Genet. 2015; 47: 330-337Crossref PubMed Scopus (246) Google Scholar,5Gu Z Churchman ML Roberts KG et al.PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia.Nat Genet. 2019; 51: 296-307Crossref PubMed Scopus (108) Google Scholar]. MLL rearrangements occur as the initial or only genetic lesion in >75% of infants with B-ALL [1Hunger SP Mullighan CG Acute lymphoblastic leukemia in children.N Engl J Med. 2015; 373: 1541-1552Crossref PubMed Scopus (713) Google Scholar]. Because of the elevated risk of relapse and resistance, the development of targeted therapies has been a priority to improve outcomes for this population. Although multiple small molecule inhibitors thought to be selective for MLL fusion oncoproteins have reached clinical trials, immunotherapy has also begun to have an impact in this patient group. Two relatively new immunotherapies use the patient's immune system to target the CD19 cell surface protein, which is coupled to B-cell identity and therefore highly expressed on B-ALL. First, blinatumomab is a CD3/CD19 bispecific T-cell engager (BiTE), or bispecific antibody that redirects a patient's T cells to kill CD19+ cells. Blinatumomab was approved by the U.S. Food and Drug Administration (FDA) for relapsed, refractory, or Philadelphia chromosome–positive B-ALL in 2014, and approval was expanded in 2018 for broader use in B-ALL as a second-line treatment [6Topp MS Gökbuget N Stein AS et al.Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study.Lancet Oncol. 2015; 16: 57-66Abstract Full Text Full Text PDF PubMed Scopus (716) Google Scholar,7Pulte ED Vallejo J Przepiorka D et al.FDA Supplemental Approval: blinatumomab for treatment of relapsed and refractory precursor B-cell acute lymphoblastic leukemia.Oncologist. 2018; 23: 1366-1371Crossref PubMed Scopus (16) Google Scholar]. Second, chimeric antigen receptors (CARs) recognizing CD19 can direct the patient's T cells to kill CD19+ B-ALL. The CAR construct is introduced into patient T cells during ex vivo manufacturing, which endows the T cell with directed specificity using an antibody-derived target binding domain and T-cell receptor signaling domains (Figure 1). Tisagenlecleucel (formerly CTL019) was approved by the FDA in 2017 for the treatment of relapsed or refractory B-ALL in pediatric/young adult patients based on the remarkable success of the phase II trial (NCT02435849) [8Maude SL Laetsch TW Buechner J et al.Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia.N Engl J Med. 2018; 378: 439-448Crossref PubMed Scopus (1576) Google Scholar]. Multiple clinical trials using a variety of CD19-directed CAR T cell products have indicated complete remission rates of 70%–90% in pediatric patients with multiply relapsed and/or highly refractory B-ALL [8Maude SL Laetsch TW Buechner J et al.Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia.N Engl J Med. 2018; 378: 439-448Crossref PubMed Scopus (1576) Google Scholar, 9Gardner RA Finney O Annesley C Brakke H Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults.Blood. 2017; 129: 3322-3331Crossref PubMed Scopus (11) Google Scholar, 10Maude SL Frey N Shaw PA et al.Chimeric antigen receptor T cells for sustained remissions in leukemia.N Engl J Med. 2014; 371: 1507-1517Crossref PubMed Scopus (2821) Google Scholar, 11Lee DW Kochenderfer JN Stetler-Stevenson M et al.T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial.Lancet. 2015; 385: 517-528Abstract Full Text Full Text PDF PubMed Scopus (1623) Google Scholar, 12Mackall CL Merchant MS Fry TJ Immune-based therapies for childhood cancer.Nat Rev Clin Oncol. 2014; 11: 693-703Crossref PubMed Scopus (68) Google Scholar]. Longer follow-up in these trials revealed that patients receiving CD28-containing CAR T cells lost functional CAR T activity within 2 months of infusion. These patients had a high risk of post-CAR relapse without further treatment with a consolidative hematopoietic stem cell transplant [11Lee DW Kochenderfer JN Stetler-Stevenson M et al.T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial.Lancet. 2015; 385: 517-528Abstract Full Text Full Text PDF PubMed Scopus (1623) Google Scholar]. For patients receiving CARs containing the 4-1BB co-stimulatory signaling domain (Figure 1), persistence of CAR T cells could be observed for months to years [8Maude SL Laetsch TW Buechner J et al.Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia.N Engl J Med. 2018; 378: 439-448Crossref PubMed Scopus (1576) Google Scholar, 9Gardner RA Finney O Annesley C Brakke H Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults.Blood. 2017; 129: 3322-3331Crossref PubMed Scopus (11) Google Scholar, 10Maude SL Frey N Shaw PA et al.Chimeric antigen receptor T cells for sustained remissions in leukemia.N Engl J Med. 2014; 371: 1507-1517Crossref PubMed Scopus (2821) Google Scholar]. Follow-up studies of patients who received 4-1BB CAR T cells in clinical trials, as well as in postapproval "real world" studies, have reported that, despite the high initial rate of complete remission, only ~50% of patients remain leukemia-free 1 year after treatment because of post-CAR T cell relapses [9Gardner RA Finney O Annesley C Brakke H Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults.Blood. 2017; 129: 3322-3331Crossref PubMed Scopus (11) Google Scholar,13Maude SL Teachey DT Rheingold SR et al.Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed/refractory ALL.J Clin Oncol. 2016; 34 (3011–3011)Google Scholar, 14Lee III, DW Stetler-Stevenson M Yuan CM et al.Long-term outcomes following CD19 CAR T cell therapy for B-ALL are superior in patients receiving a fludarabine/cyclophosphamide preparative regimen and post-CAR hematopoietic stem cell transplantation.Blood. 2016; 128 (218–218)Google Scholar, 15Pasquini MC Hu ZH Curran K et al.Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma.Blood Adv. 2020; 4: 5414-5424Crossref PubMed Scopus (25) Google Scholar]. For patients receiving either CD28- or 4-1BB-containing CARs, two major patterns of relapse have been observed: antigen-positive (CD19+) relapse occurring in the absence of ongoing CAR T cell activity, and CD19neg relapse in which the loss of the target antigen allows the leukemic cells to survive and expand in the presence of a persistent and functional CAR T cell population [16Shah NN Fry TJ Mechanisms of resistance to CAR T cell therapy.Nat Rev Clin Oncol. 2019; 16: 372-385Crossref PubMed Scopus (197) Google Scholar]. Multiple studies have now found that patients treated with CD19-directed BiTEs or CD19-directed CAR T cells can relapse with CD19neg disease, which can arise via multiple mechanisms [9Gardner RA Finney O Annesley C Brakke H Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults.Blood. 2017; 129: 3322-3331Crossref PubMed Scopus (11) Google Scholar,16Shah NN Fry TJ Mechanisms of resistance to CAR T cell therapy.Nat Rev Clin Oncol. 2019; 16: 372-385Crossref PubMed Scopus (197) Google Scholar, 17Sotillo E Barrett DM Black KL et al.Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy.Cancer Discov. 2015; 5: 1282-1295Crossref PubMed Scopus (573) Google Scholar, 18Gardner R Wu D Cherian S et al.Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy.Blood. 2016; 127: 2406-2410Crossref PubMed Scopus (335) Google Scholar]. A poorly understood mechanism of CD19neg relapse is "lineage switching," in which leukemia undergoes global changes resulting in the loss of multiple lymphoid markers and the acquisition of a myeloid phenotype (Table 1) 18Gardner R Wu D Cherian S et al.Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy.Blood. 2016; 127: 2406-2410Crossref PubMed Scopus (335) Google Scholar, 19Jabbour E Düll J Yilmaz M et al.Outcome of patients with relapsed/refractory acute lymphoblastic leukemia after blinatumomab failure: no change in the level of CD19 expression.Am J Hematol. 2018; 93: 371-374Crossref PubMed Scopus (9) Google Scholar, 20Haddox CL Mangaonkar AA Chen D et al.Blinatumomab-induced lineage switch of B-ALL with t(4:11)(q21;q23) KMT2A/AFF1 into an aggressive AML: pre- and post-switch phenotypic, cytogenetic and molecular analysis.Blood Cancer J. 2017; 7: e607Crossref PubMed Scopus (18) Google Scholar, 21Wölfl M Rasche M Eyrich M Schmid R Reinhardt D Schlegel PG Spontaneous reversion of a lineage switch following an initial blinatumomab-induced ALL-to-AML switch in MLL-rearranged infant ALL.Blood Adv. 2018; 2: 1382-1385Crossref PubMed Scopus (0) Google Scholar, 22Aldoss I Song JY Extramedullary relapse of KMT2A(MLL)-rearranged acute lymphoblastic leukemia with lineage switch following blinatumomab.Blood. 2018; 131: 2507Crossref PubMed Scopus (10) Google Scholar, 23Fournier E Inchiappa L Delattre C et al.Increased risk of adverse acute myeloid leukemia after anti-CD19-targeted immunotherapies in KMT2A-rearranged acute lymphoblastic leukemia: a case report and review of the literature.Leuk Lymphoma. 2019; 60: 1827-1830Crossref PubMed Scopus (2) Google Scholar, 24Rayes A McMasters RL O'Brien MM Lineage switch in MLL-rearranged infant leukemia following CD19-directed therapy.Pediatr Blood Cancer. 2016; 63: 1113-1115Crossref PubMed Scopus (78) Google Scholar, 25Zoghbi A Zur Stadt U Winkler B Muller I Escherich G Lineage switch under blinatumomab treatment of relapsed common acute lymphoblastic leukemia without MLL rearrangement.Pediatr Blood Cancer. 2017; 64https://doi.org/10.1002/pbc.26594Crossref PubMed Scopus (28) Google Scholar, 26Balducci E Nivaggioni V Boudjarane J et al.Lineage switch from B acute lymphoblastic leukemia to acute monocytic leukemia with persistent t(4;11)(q21;q23) and cytogenetic evolution under CD19-targeted therapy.Ann Hematol. 2017; 96: 1579-1581Crossref PubMed Scopus (16) Google Scholar, 27He RR Nayer Z Hogan M et al.Immunotherapy- (blinatumomab-) related lineage switch of KMT2A/AFF1 rearranged B-lymphoblastic leukemia into acute myeloid leukemia/myeloid sarcoma and subsequently into B/myeloid mixed phenotype acute leukemia.Case Rep Hematol. 2019; 7394619PubMed Google Scholar, 28Park JH Riviére I Gonen M et al.Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia.N Engl J Med. 2018; 378: 449-459Crossref PubMed Scopus (888) Google Scholar, 29Braig F Brandt A Goebeler M et al.Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking.Blood. 2017; 129: 100-104Crossref PubMed Scopus (109) Google Scholar, 30Annesley C Summers C Pulsipher MA et al.Clinical experience of CAR T cell immunotherapy for relapsed and refractory infant ALL demonstrates feasibility and favorable responses.Blood. 2019; 134: 3869Crossref Google Scholar, 31Oberley MJ Gaynon PS Bhojwani D et al.Myeloid lineage switch following chimeric antigen receptor T-cell therapy in a patient with TCF3-ZNF384 fusion-positive B-lymphoblastic leukemia.Pediatr Blood Cancer. 2018; 65: e27265Crossref PubMed Scopus (4) Google Scholar, 32Du J Chisholm KM Tsuchiya K et al.Lineage switch in an infant B-lymphoblastic leukemia with t(1;11)(p32;q23); KMT2A/EPS15, following blinatumomab therapy.Pediatr Dev Pathol. 2021; 24: 378-382Crossref PubMed Scopus (0) Google Scholar, 33Turtle CJ Hanafi LA Berger C CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients.J Clin Invest. 2016; 126: 2123-2138Crossref PubMed Google Scholar Lineage switching relapses have been reported after both CD19-directed BiTE and CAR T-cell therapy and tend to be enriched in MLL rearrangements, although cases harboring other translocations have been reported [18Gardner R Wu D Cherian S et al.Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy.Blood. 2016; 127: 2406-2410Crossref PubMed Scopus (335) Google Scholar,31Oberley MJ Gaynon PS Bhojwani D et al.Myeloid lineage switch following chimeric antigen receptor T-cell therapy in a patient with TCF3-ZNF384 fusion-positive B-lymphoblastic leukemia.Pediatr Blood Cancer. 2018; 65: e27265Crossref PubMed Scopus (4) Google Scholar,33Turtle CJ Hanafi LA Berger C CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients.J Clin Invest. 2016; 126: 2123-2138Crossref PubMed Google Scholar,34Nagel I Bartels M Duell J et al.Hematopoietic stem cell involvement in BCR-ABL1-positive ALL as a potential mechanism of resistance to blinatumomab therapy.Blood. 2017; 130: 2027-2031Crossref PubMed Scopus (45) Google Scholar]. Because of the relatively recent implementation of immunotherapy and the rarity of MLL-r subsets within all B-ALL, it is too early to know whether CD19neg relapse occurs more or less frequently than in other subtypes. However, MLL rearrangements are associated with increased risk of relapse in pediatric ALL patients and occur in most infant ALL patients [35Pieters R De Lorenzo P Ancliffe P et al.Outcome of infants younger than 1 year with acute lymphoblastic leukemia treated with the Interfant-06 Protocol: results from an international phase III randomized study.J Clin Oncol. 2019; 37: 2246-2256Crossref PubMed Scopus (47) Google Scholar]; thus, it is increasingly likely that more children and infants harboring MLL rearrangements will receive immune-based therapies, possibly resulting in an increased number of patients experiencing lineage switch relapses. Interestingly, infants with MLL-r B-ALL and detectable residual disease at the end of induction chemotherapy may have better outcomes if myeloid consolidation regimens are used, suggesting that preventing myeloid relapse would result in an overall benefit [36Kanemitsu Y Shitara K Mizusawa J et al.Primary tumor resection plus chemotherapy versus chemotherapy alone for colorectal cancer patients with asymptomatic, synchronous unresectable metastases (JCOG1007; iPACS): a randomized clinical trial.J Clin Oncol. 2021; 39: 1098-1107Crossref PubMed Scopus (6) Google Scholar]. Understanding the factors contributing to relapse from this otherwise effective therapy will be critical to improving on the initial success of this approach. Below, we address the clinical observations and potential underlying mechanisms of relapse. Specifically, we focus on the concept of lineage plasticity in generating CD19neg relapse in a poor-prognosis patient group in which this phenomenon has been documented.Table 1Published cases of CD19neg relapse with myeloid phenotype after CD19-directed immunotherapies, both CAR T and BiTEsImmunotherapyTotal relapse casesCD19-negative relapse casesNo. of myeloid switch casesPhenotype after CD19-directed immunotherapyIgH clonal relationshipTime between immunotherapy and lineage switchCytogeneticsAge/SexRef.CD19 CAR-T222Case 1CD19–, CD13 (dim)+, CD64+, HLA-DR (dim)+, CD15+, CD33+, CD71, MPO+Yes22 dt(4;11)(q21;q23) MLL/AF452 y/F18Gardner R Wu D Cherian S et al.Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy.Blood. 2016; 127: 2406-2410Crossref PubMed Scopus (335) Google ScholarCase 2CD19-, CD4+, CD56+, CD64+, CD13+, CD33+, CD38+, HLA-DR+, CD34+, CD45+,CD71+No21 dins(11;10)(q23;p12p1?1.2) MLL/ MLLT1018 mo/F421CD19 negative myeloid phenotype switchYesNo data reportedt(4;11)(q21;q23) MLL/AF452 y/not reported33Turtle CJ Hanafi LA Berger C CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients.J Clin Invest. 2016; 126: 2123-2138Crossref PubMed Google Scholar111CD13+, CD34+. CD117+, CD123+, CD11b+, CD38(mod), CD7+, CD19–, CD10–, CD22–, TdT–, CD24–, CD20–, MPO–No data reported8 moTCF3(Ex11)-ZNF384(Ex2) fusion13 mo/M31Oberley MJ Gaynon PS Bhojwani D et al.Myeloid lineage switch following chimeric antigen receptor T-cell therapy in a patient with TCF3-ZNF384 fusion-positive B-lymphoblastic leukemia.Pediatr Blood Cancer. 2018; 65: e27265Crossref PubMed Scopus (4) Google Scholar111CD19–, CD34–, CD10–, CD3–, CD16–, CD117–, HLADR–, nTdT–, CD2–, CD7–, CD38–, cCD22–, cCD79a–, cCD3–, CD45+, CD13+, CD15+, CD33+, CD56+, CD36+, CD64 (partial)+, cMPO+No data reported9 dt(4;11)(q21;q23) MLL/AF440 y/F20Haddox CL Mangaonkar AA Chen D et al.Blinatumomab-induced lineage switch of B-ALL with t(4:11)(q21;q23) KMT2A/AFF1 into an aggressive AML: pre- and post-switch phenotypic, cytogenetic and molecular analysis.Blood Cancer J. 2017; 7: e607Crossref PubMed Scopus (18) Google Scholar111sCD19low, CD33+;CD34−, CD14++, CD15++, CD11b++, CD64+No data reported9 dt(4;11)(q21;q23) MLL/AF45 mo/F21Wölfl M Rasche M Eyrich M Schmid R Reinhardt D Schlegel PG Spontaneous reversion of a lineage switch following an initial blinatumomab-induced ALL-to-AML switch in MLL-rearranged infant ALL.Blood Adv. 2018; 2: 1382-1385Crossref PubMed Scopus (0) Google Scholar111CD19–, PAX5–, CD33+, CD43+, lysozyme+No data reported8 mot(4;11)(q21;q23) MLL/AF477 y/M22Aldoss I Song JY Extramedullary relapse of KMT2A(MLL)-rearranged acute lymphoblastic leukemia with lineage switch following blinatumomab.Blood. 2018; 131: 2507Crossref PubMed Scopus (10) Google Scholar111CD19–, CD34–, CD10–, CD38+, cMPO+, CD33+, CD13(low)+, CD64 +, CD65+, cCD79+Yes53 dt(4;11)(q21;q23) MLL/AF446 y/F23Fournier E Inchiappa L Delattre C et al.Increased risk of adverse acute myeloid leukemia after anti-CD19-targeted immunotherapies in KMT2A-rearranged acute lymphoblastic leukemia: a case report and review of the literature.Leuk Lymphoma. 2019; 60: 1827-1830Crossref PubMed Scopus (2) Google Scholar111CD19–, CD34–, CD79a–, TdT–,CD33+ CD11b+, CD14 (subset/dim)+, CD64+, MPO+;CD13(dim)+, CD22(dim),+ CD33(dim),+ CD38+, HLA-DR+No data reported15 dt(4;11)(q21;q23) MLL/AF43 mo/not reported24Rayes A McMasters RL O'Brien MM Lineage switch in MLL-rearranged infant leukemia following CD19-directed therapy.Pediatr Blood Cancer. 2016; 63: 1113-1115Crossref PubMed Scopus (78) Google Scholar111CD19–, CD20–, CD22–, CD24+;cyIGM–, cyCD79a–, CD2–, CD3–, CD7–, CD8–, cyCD3–, CD13+, CD33+, CD15+, cyMPO+, CD117–, CD66c+, CD10+, CD34–, CD45+, TdT–, Cd38+, CD52–No data reported3 wkNo8 y/F25Zoghbi A Zur Stadt U Winkler B Muller I Escherich G Lineage switch under blinatumomab treatment of relapsed common acute lymphoblastic leukemia without MLL rearrangement.Pediatr Blood Cancer. 2017; 64https://doi.org/10.1002/pbc.26594Crossref PubMed Scopus (28) Google Scholar111CD19–, cCD79a–, CD22–, CD34-, CD33(low)+, CD65+, CD15+Yes28 dt(4;11)(q21;q23) MLL/AF415 y/M26Balducci E Nivaggioni V Boudjarane J et al.Lineage switch from B acute lymphoblastic leukemia to acute monocytic leukemia with persistent t(4;11)(q21;q23) and cytogenetic evolution under CD19-targeted therapy.Ann Hematol. 2017; 96: 1579-1581Crossref PubMed Scopus (16) Google Scholar111CD19–, PAX5–, CD34–, lysozyme+, CD33+, CD64(dim)+, CD13+, myeloperoxidase+, cytoCD79a-No data reported1 mot(4;11)(q21;q23) MLL/AF440 y/F27He RR Nayer Z Hogan M et al.Immunotherapy- (blinatumomab-) related lineage switch of KMT2A/AFF1 rearranged B-lymphoblastic leukemia into acute myeloid leukemia/myeloid sarcoma and subsequently into B/myeloid mixed phenotype acute leukemia.Case Rep Hematol. 2019; 7394619PubMed Google Scholar111CD19–,CD33+, CD11b+, CD14+, CD64+, HLA-DR+, CD38+, CD56+, CD4+, minor clone CD19+, CD22+, CD24+, CD38+Yes15 dt(1;11)(p32;q23) MLL/EPS156 m/F32Du J Chisholm KM Tsuchiya K et al.Lineage switch in an infant B-lymphoblastic leukemia with t(1;11)(p32;q23); KMT2A/EPS15, following blinatumomab therapy.Pediatr Dev Pathol. 2021; 24: 378-382Crossref PubMed Scopus (0) Google ScholarF=Female; M=Male; y=year; mo=month; d=day Open table in a new tab F=Female; M=Male; y=year; mo=month; d=day Rearrangements of the MLL1 gene, including internal tandem duplications, occur in adults and children, producing leukemia with mixed myeloid, B-lymphoid, or T-lymphoid characteristics, hence the original designation of "mixed lineage" or "bi-phenotypic" leukemia. Whereas about half of older adults present with acute myelogenous leukemia (AML), the ratio of ALL to AML in infants with MLL-r leukemia is nearly 6 to 1 [37Marschalek R Systematic classification of mixed-lineage leukemia fusion partners predicts additional cancer pathways.Ann Lab Med. 2016; 36: 85-100Crossref PubMed Google Scholar]. In infants, approximately 90% of MLL-r ALL is arrested at a CD19+ pro-B/pre-B stage [37Marschalek R Systematic classification of mixed-lineage leukemia fusion partners predicts additional cancer pathways.Ann Lab Med. 2016; 36: 85-100Crossref PubMed Google Scholar]. Coexpression of myeloid genes and stage of B-cell differentiation (pro-B/pre-B cells) varies as a function of age of the patient [38Jansen MWJC Corral L van der Velden VHJ et al.Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement.Leukemia. 2007; 21: 633-641Crossref PubMed Scopus (87) Google Scholar]. As early as 1986, undifferentiated, mixed lineage features of MLL-r leukemia were appreciated and interpreted to reflect transformation of a multipotent progenitor [39Mirro J Kitchingman G Williams D et al.Clinical and laboratory characteristics of acute leukemia with the 4;11 translocation.Blood. 1986; 67: 689-697Crossref PubMed Google Scholar]. The first transcriptional signatures illustrated the distinct identity of pediatric MLL-r B-ALL overall, which occupied a position in principal component space (cell identity) between lymphoid and myeloid leukemia [40Armstrong SA Staunton JE Silverman LB et al.MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.Nat Genet. 2002; 30: 41-47Crossref PubMed Scopus (1499) Google Scholar]. Both immunophenotypic and genomic features of childhood MLL-r ALL have been interpreted to indicate that the cell of origin is a primitive fetal progenitor rather than a committed B-cell progenitor, given the association of MLL rearrangements with young age [41Ford AM Ridge SA Cabrera ME et al.In utero rearrangements in the trithorax-related oncogene in infant leukaemias.Nature. 1993; 363: 358-360Crossref PubMed Scopus (356) Google Scholar,42Greaves MF Maia AT Wiemels JL Ford AM Leukemia in twins: lessons in natural history.Blood. 2003; 102: 2321-2333Crossref PubMed Scopus (357) Google Scholar]. It is thus not surprising that MLL-r leukemia is common among cases of relapse-related lineage switching [43Dorantes-Acosta E Pelayo R Lineage switching in acute leukemias: a consequence of stem cell plasticity?.Bone Marrow Res. 2012; 2012406796Crossref PubMed Google Scholar]. Reviewing pediatric cases from the 1980s to the 2010s, two groups carefully documented lineage switching after chemotherapy and found frequencies of 1%–6% of any lineage switch posttreatment, which was predominantly from pro-/pre-B-ALL to AML [44Stass S Mirro J Melvin S Pui CH Murphy SB Williams D Lineage switch in acute leukemia.Blood. 1984; 64: 701-706Crossref PubMed Google Scholar,45Rossi JG Bernasconi AR Alonso CN et al.Lineage switch in childhood acute leukemia: an unusual event with poor outcome.Am J Hematol. 2012; 87: 890-897Crossref PubMed Scopus (68) Google Scholar]. MLL-r leukemia accounted for 78% of the cases that switched lineages posttherapy in the latter study [45Rossi JG Bernasconi AR Alonso CN et al.Lineage switch in childhood acute leukemia: an unusual event with poor outcome.Am J Hematol. 2012; 87: 890-897Crossref PubMed Scopus (68) Google Scholar]. These clinical observations suggest an underlying heterogeneity or lineage plasticity inherent in cells transformed by MLL-fusion oncoproteins. The current designation of mixed phenotype acute leukemia (MPAL) includes a specific category for MLL-r, as well as BCR-ABL+ leukemia, because of their prevalence in this mixed lineage group [46Weinberg OK Arber DA Mixed-phenotype acute leukemia: historical overview and a new definition.Leukemia. 2010; 24: 1844-1851Crossref PubMed Scopus (103) Google Scholar,47Arber DA Orazi A Hasserjian R et al.The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.Blood. 2016; 127: 2391-2405Crossref PubMed Google Scholar]. Consistent with this concept of high lineage plasticity in MLL-r leukemia, evasion of CD19-targeted immunotherapy through relapse with myeloid markers has been reported under treatment with blinatumimab [20Haddox CL Mangaonkar AA Chen D et al.Blinatumomab-induced lineage switch of B-ALL with t(4:11)(q21;q23) KMT2A/AFF1 into an aggressive AML: pre- and post-switch phenotypic, cytogenetic and molecular analysis.Blood Cancer J. 2017; 7: e607Crossref PubMed Scopus (18) Google Scholar, 21Wölfl M Rasche M Eyrich M Schmid R Reinhardt D Schlegel PG Spontaneous reversion of a lineage switch following an initial blinatumomab-induced ALL-to-AML switch in MLL-rearranged infant ALL.Blood Adv. 2018; 2: 1382-1385Crossref PubMed Scopus (0) Google Scholar, 22Aldoss I Song JY Extramedullary relapse of KMT2A(MLL)-rearranged acute lymphoblastic leukemia with lineage switch following blinatumomab.Blood. 2018; 131: 2507Crossref PubMed Scopus (10) Goog

Referência(s)