Lineage swap in leukemia, characterised by a whole cell-fate conversion from one lineage to a different, is related to a dismal prognosis. The period of immunotherapy has witnessed a notable enhance in its incidence, approaching 8% of B-ALL following anti-CD19 chimeric antigen receptor T-cell (CAR-T) remedy [1]. This important problem underscores the urgent want for a deeper understanding of lineage swap. The prevailing literature, primarily comprising case reviews and small case sequence, fails to supply a complete portrayal of the clinicopathological options of this phenomenon [1,2,3,4,5]. Moreover, knowledge on its genetic and molecular foundation are scant, with the understanding largely restricted to its affiliation with KMT2A fusions and BCR::ABL1 [6, 7]. Thus, we undertook a multi-institutional investigation into lineage swap in acute leukemias, with a two-fold goal: primarily, to realize an in-depth understanding of its clinicopathologic options, an important step for figuring out at-risk sufferers and shaping prevention and administration methods in inclined populations; and secondly, to establish potential genetic drivers and achieve insights into clonal evolution pathways of those leukemias, in the end paving the best way towards focused therapies.
This examine included 33 instances of acute leukemia, which underwent lineage swap, identified from 2003 to 2022. To exclude instances the place the second leukemia is likely to be therapy-related, inclusion was restricted to sufferers demonstrating cytogenetic or molecular proof for clonal-relatedness between their first and second leukemias, as decided by karyotype, fluorescence in-situ hybridization (FISH), and next-generation sequencing (NGS). In two instances (#6 and 18), the clonal relatedness was additional substantiated by equivalent IGH gene rearrangements. Moreover, sufferers identified with mixed-phenotype acute leukemia for the primary acute leukemia, whether or not bilineal or biphenotypic, have been excluded. Nonetheless, we included instances of bilineal leukemia identified because the second leukemia, supplied one inhabitants represented residual illness of the primary leukemia.
The cohort comprised 22 males and 11 females, with a median age of 34.6 years (vary, 0.1–83.2). The primary leukemia underwent a lineage swap after a median interval of seven.8 months (vary, 0.9–38.2). On the swap level, 79% (26/33) of sufferers have been in full remission (CR) of the primary leukemia, as confirmed by circulate cytometry. The swap concerned a conversion from ALL to acute myeloid leukemia (AML) in 28 sufferers (25 with B-ALL and three with T-ALL), from lymphoid blast part (LyBP) to myeloid blast part (MyBP) of CML in a single, and from AML (together with one case of myeloid sarcoma) to B-ALL in 4 (Desk 1). Kids appeared extra prone to current with T-ALL or AML as an preliminary prognosis in comparison with adults and skilled a modestly longer period between the preliminary prognosis and lineage swap (Desk S1). Previous to lineage swap, all 33 sufferers acquired chemotherapy and 6 underwent allogeneic hematopoietic stem cell transplantation (HSCT). As well as, 15 of the B-ALL sufferers additionally acquired focused immunotherapies, together with anti-CD19 monoclonal antibodies in ten sufferers, anti-CD20 in 5, and anti-CD22 in 5, in addition to CAR-T remedy in two (Desk 1 and Desk S2). In these eventualities, lineage swap is believed to be pushed by the immunologic strain exerted by the focused remedy, the place a phenotypic swap might enable immune escape of leukemic cells. The discharge of inflammatory cytokine can also be thought to contribute to the method [8].
Morphologically, AML, both presenting as the primary or the second leukemia, predominantly displayed monocytic or myelomonocytic differentiation (21/33, 64%) (Desk 1 and Fig. S1). The illness within the remaining sufferers was categorised as AML with minimal differentiation (5/33, 15.2%), AML with maturation (3/33, 9.1%), pure erythroid leukemia (2/33, 6.1%), AML with out maturation (1/33, 3.0%), and MyBP-CML (1/33, 3.0%). The immunophenotype of those instances, as detailed in Desk S3, usually aligns with that of their respective typical leukemia sorts.
Following lineage swap, 28 sufferers underwent chemotherapy, with eight of them additionally acquired HSCT (Desk 1); three died shortly with out receiving therapy; and therapy specifics have been unknown for 2. On the final follow-up, 25 sufferers died and eight have been alive. 5 of the eight surviving sufferers achieved CR of each leukemias and three had persistent second leukemia. The median survival for the entire cohort was 12.3 months from the prognosis of the primary leukemia and a pair of.9 months after lineage swap. Notably, among the many eight sufferers who acquired HSCT after lineage swap, all seven with accessible info achieved CR though two subsequently relapsed with the second leukemia. In distinction, solely certainly one of 19 affected person who didn’t obtain HSCT after lineage swap was in CR ultimately follow-up (p < 0.001). HSCT was additionally related to an extended total survival (OS) from the second leukemia (93.7 vs 1.9 months; p < 0.001). Moreover, the univariate Cox evaluation confirmed that HSCT, pediatric standing, and the presence of 11q23/KMT2A fusions have been all correlated with OS (p < 0.2), whereas a multivariate evaluation recognized HSCT as the only real impartial prognostic issue (p < 0.001).
A pivotal contribution of our examine is the improved understanding of the genetic and molecular options of leukemic lineage swap (Fig. 1, Tables S4 and S5). The commonest chromosomal alterations shared between the primary and second leukemias have been 11q23/KMT2A fusions (18/33, 54.5%). These rearrangements predominantly arose from t(4;11) (n = 11), adopted by t(9;11) and t(11;19) (n = 2 every), in addition to extra particular person instances involving t(2;11), t(10;11), and inv(11). Different shared alterations included 5q- in a posh karyotype (n = 4), −7/7q- (n = 2), +8 in a posh karyotype (n = 2), and -9p-/CDKN2A deletion (n = 2), together with t(12;19)/TCF3::ZNF384, t(5;14)/TCLX3::BCL11b, t(9;22)/BCR::ABL1, 17p11.2 aberrations, and +13, every noticed in a single case. Notably, the second leukemia exhibited a extra advanced karyotype in comparison with the primary leukemia, with extra instances carrying three or extra chromosomal aberrations (17/29 vs 10/30, p = 0.05), indicating an evolving genetic panorama.
A Key medical, cytogenetic, and molecular findings in sufferers with leukemic lineage swap. B Clonal structure of particular person sufferers primarily based on the outcomes of NGS carried out on paired specimens of the primary and second leukemias. VAF for particular mutations are indicated in parentheses. Dashed circles and dashed traces: inferred clones or pathways with out direct molecular proof. In affected person 24, the VAF of JAK2 V617F in each the primary and second leukemias was notably decrease in comparison with different mutations, suggesting a lack of JAK2 mutation throughout leukemic transformation of PV, a phenomenon beforehand reported. Affected person 29 was present process steroid therapy on the time of NGS for T-ALL, which was performed one week after the preliminary prognosis, with a bone marrow blast rely of 49.5% and peripheral blood blasts at 21% by differential rely. MDS myelodysplastic syndrome, NGS next-generation sequencing, Pt affected person, PV polycythemia vera, VAF variant allele frequency.
Regardless of the substantial genetic heterogeneity, instances will be simplistically divided into two distinct medical subgroups primarily based on the presence or absence of 11q23/KMT2A fusions (Fig. 1A, Desk S1). Essentially the most pronounced distinction between the 2 teams lies within the excessive prevalence of an antecedent power myeloid malignancy (CMN) in sufferers missing 11q23/KMT2A fusions (6/15, 40.0%), with a median interval of three.5 years (vary, 0.2–8 years) previous the prognosis of the primary acute leukemia. Particularly, the illnesses included myelodysplastic syndrome (n = 3), polycythemia vera, major myelofibrosis, and CML (n = 1 every). One other three sufferers probably had both a “subclinical” CMN or clonal hematopoiesis, inferred from the sustained stem-line cytogenetic abnormalities throughout the interval between the 2 acute leukemias. Apparently, regardless of the presence of antecedent or “subclinical” CMN, B-ALL sometimes emerged because the preliminary leukemia (8/9, 88.9%), which, unexpectedly, displayed cytogenetic abnormalities characteristically related to myeloid neoplasms (7/8, 87.5), together with t(8;9)(p22;p24.1) recognized to contain PCM1::JAK2, 5q-, -7/7q-, and +8. Remarkably, no sufferers with 11q23/KMT2A had CMN previous to the primary leukemia. Moreover, in comparison with sufferers with KMT2A fusions, these with out the fusions have been older (46.1 vs 25.2 years, p = 0.03) with much less frequent monocytic differentiation of AML (5/15 vs 16/18, p < 0.001). Notably, two sufferers within the latter group skilled a lineage swap to pure erythroid leukemia, a novel discovering not beforehand reported. Lastly, sufferers with out 11q23/KMT2A fusions tended to have a extra advanced karyotype and extra detected mutations, presumably reflecting the founder impact of 11q23/KMT2A fusions obviating the necessity for added leukemogenic occasions. Focused sequencing in 19 sufferers recognized TP53, NRAS, and WT1 as probably the most ceaselessly mutated genes. But, their mutation frequencies in our cohort aligned with these normally leukemias of the identical lineage, casting doubt on their driver function in lineage swap [9, 10]. In distinction, mutations of EZH2 and RUNX1 occurred at a considerably increased fee (20%) in our B-ALL sufferers with out 11q23/KMT2A fusions, in sharp distinction to lower than 1% within the normal B-ALL inhabitants [11, 12]. The discovering, regardless of the small pattern dimension, suggests the significance of monitoring for lineage swap in B-ALL with these mutations. As well as, recurrent alterations in EZH2 and KMT2A trace on the function of epigenic dysfunction in leukemic lineage swap [13]. In help, in vitro analysis has demonstrated that modifications in DNA methylation can set off a lineage swap in leukemic cells [14]. Different mutated genes broadly fell into 4 teams: tumor suppressors, signaling and kinase pathways, epigenetic regulators, and transcription elements (Fig. 1A).
In 10 sufferers, sequencing knowledge have been accessible in each their first and second leukemias (Fig. 1B), which shed essential lights on the mobile origin and evolution pathway of lineage swap. In 5 instances, findings supported divergent clonal evolution: except for shared genetic alterations, distinct extra mutations have been noticed between the 2 leukemias. Hypothetically, in such instances, each leukemias are derived from the identical leukemia-initiating cell, which retains the potential to distinguish into both a lymphoid or myeloid lineage. In distinction, the opposite 5 sufferers confirmed no clear branching in clonal structure: they maintained the entire set of authentic mutations, with or with out buying extra mutations within the second leukemia. Maybe, in these eventualities, lineage swap originates from the majority of leukemic blasts by means of both direct reprogramming or dedifferentiation to a multipotent state adopted by dedication to a brand new lineage. This complexity means that a number of tumor evolutionary mechanisms might exist. The excellence between totally different pathways in particular person instances might information the choice of tailor-made focused therapies. Two pivotal questions come up: (1) In tumors following divergent clonal evolution, might simultaneous focusing on of each lineages forestall tumor escape? And if that’s the case, how can we establish sufferers for whom the advantages outweigh the unwanted side effects of extra therapy? (2) For tumors aligned with the reprogramming or dedifferentiation pathways, would possibly the discount of extrinsic inducible elements function a preventive technique [15]? It’s our hope that this examine prompts additional inquiries into these important areas.
In conclusion, the current examine supplies a complete clinicopathological, genetic, and molecular characterization of this dismal occasion. Potential threat elements embrace pediatric sufferers, 11q23/KMT2A fusions, B-ALL with EZH2 or RUNX1 mutations, B-ALL rising after a clonally associated CMN part, or B-ALL carrying genetic abnormalities sometimes related to myeloid neoplasms. The presence of those threat elements warrants a radical immunophenotypic analysis of a number of cell lineages, significantly following remedy or at relapse, to promptly detect a lineage swap. At present, even handed consolidation with early allogeneic HSCT could possibly be thought of on this subset of sufferers. Enhanced genomic understanding and insights into clonal evolution can pave the best way for modern preventive and therapeutic methods towards this difficult illness.
