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Background: Patients with hematologic malignancy (HM) are hypothesized to be at high risk of poor outcomes with coronavirus disease 2019 (COVID-19), due to disease and therapy-related immunosuppression. Despite this, there are minimal reported data describing the outcomes of HM patients with COVID-19. Methods: The COVID-19 and Cancer Consortium (CCC19) (NCT04354701) is an international registry aimed at investigating the clinical course and complications of COVID-19 in patients with cancer. The CCC19 cohort includes patients with active cancer or a history of cancer with presumed or laboratory-confirmed COVID-19. The registry contains de-identified patient demographics, information regarding cancer diagnosis and treatment history, COVID-19 treatments, and clinical outcomes. Patients greater than 18 years of age with laboratory-confirmed, symptomatic COVID-19 and HM diagnoses were included in this study. The primary outcome is a composite of severe COVID-19 illness (composed of mechanical ventilation, severe illness requiring hospitalization, intensive care unit (ICU) requirement, or death); mechanical ventilation, ICU level of care, supplemental oxygen, and 30-day mortality are reported as secondary outcomes. Baseline characteristics are reported for the entire cohort. Reported clinical outcomes are stratified by cancer type, cancer status, line of therapy received (never treated, first, second or later), receipt of cellular therapy or transplant (none, within 12 months, >12 months prior to COVID-19 diagnosis), last receipt of cytotoxic therapy (within 4 weeks, 1-3 months, 3-12 months prior to COVID-19 diagnosis), and receipt of HM therapies under investigation as repurposed treatments for COVID-19 (Bruton tyrosine kinase (BTK) inhibitors, Janus kinase (JAK) inhibitors, Bcr-Abl kinase inhibitors). Results: From March 17, 2020 to July 31, 2020, a total of 757 patients with HM and COVID-19 were enrolled and met inclusion criteria. Median follow-up was 30 days (IQR 17-70 days). Median age was 65 years (IQR 55-75), 62% (470) were over age 60, 57% were men, 45% were non-Hispanic white (22% Black, 18% Hispanic, 5% other), 39% were former or current smokers, 27% were obese, 18% had Eastern Cooperative Oncology Group (ECOG) performance status ≥2, and 51% were on active treatment within 3 months of COVID-19 diagnosis. Among patients with HM, 281 (37%) developed the primary endpoint. Five-hundred and eleven patients (67%) were hospitalized (some with non-severe disease), 188 (25%) required ICU level of care, 133 (18%) required mechanical ventilation, 409 (54%) required supplemental oxygen, and 143 (19%) died within 30 days of COVID-19 diagnosis. Stratified rates of severe outcomes are shown in the Table. The rate of severe COVID-19 was highest in patients with chronic lymphocytic leukemia (53%), and lowest in patients with Hodgkin lymphoma (23%). Patients receiving cytotoxic systemic therapy within 3 months of COVID-19 diagnosis had higher rates of severe COVID-19 (41%) and 30-day mortality (28%) than patients who completed treatment 3-12 months (26% severe COVID-19, 16% 30-day mortality) or more than 12 months (29% severe COVID-19, 13% 30-day mortality) prior to COVID-19 diagnosis. Patients receiving cellular therapy or transplant within a year prior to COVID-19 diagnosis had similar rates of severe COVID-19 (36% v. 38%) and 30-day mortality (23% v. 19%) to patients who had not received such therapies within a year prior to COVID-19 diagnosis. Patients on second-line or later therapy experienced similar rates of poor outcomes (42% severe COVID-19, 20% 30-day mortality) to patients on first-line therapy (39% severe COVID-19, 18% 30-day mortality) and untreated patients (42% severe COVID-19, 20% 30-day mortality). Outcomes for patients receiving therapies under investigation as repurposed COVID-19 treatments were similar to the cohort at large. Conclusions: This is the largest cohort study to date describing COVID-19 outcomes in patients with HM. Rates of severe COVID-19 outcomes including death were high. Unadjusted rates of severe COVID-19 outcomes were higher in patients with previously described risk factors such as advanced age, poor performance status, and progressive disease, as well as those receiving recent cytotoxic therapy. Outcomes varied widely by malignancy but were similar across treatment contexts. Additional data collection and analyses are ongoing. Disclosures Lynch: Bayer: Research Funding; Rhizen Pharmaceuticals: Research Funding; Incyte: Research Funding; TG Therapeutics: Research Funding; Takeda: Research Funding; Juno Therpeutics: Research Funding; Genentech: Research Funding; MorphoSys: Consultancy; Cyteir: Research Funding. Bakouny:BMS: Research Funding; Genentech: Research Funding. Bhutani:Sanofi: Consultancy, Research Funding. Shah:American Cancer Society and the Hope Foundation for Cancer Research: Research Funding; National Cancer Institute: Research Funding. Lyman:Mylan: Consultancy; Beyond Spring: Consultancy; Samsung: Consultancy; Sandoz: Consultancy; Invitae: Consultancy; Spectrum: Consultancy; G1 Therapeutics: Consultancy; Amgen: Research Funding. Kuderer:Janssen: Consultancy; G1 Therapeutics: Consultancy; Beyond Springs: Consultancy; Spectrum Pharmaceuticals: Consultancy; Bayer: Consultancy; Bristol-Myers Squibb: Consultancy; celldex: Consultancy; Total Health: Consultancy; Invitae: Consultancy. Warner:HemOnc.orgLLC: Other: Shareholder/Stockholder/Stock options; National Cancer Institute: Research Funding; IBM Watson Health: Consultancy; Westat: Consultancy. Mesa:Bristol Myers Squibb: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Samus Therapeutics: Research Funding; Genentech: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding; Novartis: Consultancy; Sierra Oncology: Consultancy; LaJolla Pharmaceutical Company: Consultancy. Thompson:AIM Specialty Health, BMS, GlaxoSmithKline, Takeda, Via Oncology: Membership on an entity's Board of Directors or advisory committees; Doximity: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Synapse Precision Medical Council: Other: Travel expenses.

Background While histo- and cytomorphological examinations are central to the diagnosis of myelodysplastic syndromes (MDS), significant inter-observer variability exists. The diagnosis can be challenging in pancytopenic patients (pts) without evidence of dysplasia and is contingent on observer expertise. We developed and externally validated a geno-clinical model that uses mutational data and peripheral blood counts/clinical variables to distinguish MDS from other myeloid malignancies. Methods Clinical and genomic data, including commercially available next-generation sequencing panels, were obtained for patients (pts) treated at the Cleveland Clinic (CC; 652 pts), Munich Leukemia Laboratory (MLL; 1509 pts), and the University of Pavia in Italy (UP, 536 pts). All patients had carried a diagnosis of MDS, chronic myelomonocytic leukemia (CMML), MDS/myeloproliferative neoplasm overlap (MDS/MPN), myeloproliferative neoplasm (MPN; either polycythemia vera, essential thrombocythemia, or myelofibrosis), clonal cytopenia of undetermined significance (CCUS), or idiopathic cytopenia of undetermined significance (ICUS). All diagnoses were established with bone marrow aspiration and according to World Health Organization 2017 criteria. The training cohort included data from CC and UP and randomly divided into learner (80%) and test (20%) cohorts. The final model was independently validated in the MLL cohort. A machine learning algorithm was used to build the model; multiple extraction algorithms were used to extract genomic/clinical variables on both the cohort and individual levels. Performance was evaluated according to the area under the curve of the receiver operating characteristic (ROC-AUC) and accuracy matrices. Results Among the 2697 pts included from all sites, the median age was 70 years [36 - 86]. Median hemoglobin (Hb) was 10.4g/dl [6.9 - 15.7], median platelet count (PLT) was 132 k/dL [14 - 722], median WBC count was 5.3 k/dL [1.4 - 49.9], median ANC was 2.8 k/dL [0.3 - 27.7], median monocyte count was 0.3 k/dL [0 - 9.9], and median lymphocyte count (ALC) was 1.1 k/dL [0.1 - 5.4], and median peripheral blast percentage 0% [0 - 8]. The most commonly mutated genes in all patients were (list top 5 genes) and among pts with MDS were SF3B1 (27%), TET2 (25%), ASXL1 (19%), SRSF2 (16%), and DNMT3A (11%); among patients with MDS-MPN/CMML, the most commonly mutated genes were MDS-MPN/CMML (TET2 46%, ASXL1 34%, SRSF2 29%, RUNX1 13%, CBL 12%) ; among patients with MPNs, the most commonly mutated genes were (JAK2 64%, ASXL1 27%, TET2 14%, DNMT3A 8%, U2AF1 7%); among patients with CCUS the most commonly mutated genes were (TET2 41%, DNMT3A 27%, ASXL1 19%, SRSF2 17%, ZRSR2 10%). The most important features for model predictions (ranked from the most to the least important) included: number of mutations detected/sample, peripheral blast percentage, AMC, JAK2 status, Hb, basophil count, age, eosinophil count, ALC, WBC, EZH2 mutation status, ANC, mutation status of KRAS and SF3B1, platelets, and gender. The final model achieved an average AUROC of 0.95 (95% CI 0.93-0.96) when applied to the test cohort and 0.93 (95% CI 0.91 - 0.94) when it was applied to the MLL cohort. The model also provides individual-level explanations for predictions, providing top differential diagnoses and individual-level explanations of how features influence a putative diagnosis (Figure 1b). Conclusions We developed and externally validated a highly accurate and interpretable model that can distinguish MDS from other myeloid malignancies using clinical and mutational data from a large international cohort. The model can provide personalized interpretations of its outcome and can aid physicians and hematopathologists in recognizing MDS with high accuracy when encountering pts with pancytopenia and with a suspected diagnosis of MDS. Disclosures Sekeres: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mukherjee:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Bristol Myers Squib: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Aplastic Anemia and MDS International Foundation: Honoraria; Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy. Gerds:Sierra Oncology: Research Funding; Imago Biosciences: Research Funding; Apexx Oncology: Consultancy; Celgene: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; AstraZeneca/MedImmune: Consultancy; Gilead Sciences: Research Funding; Pfizer: Research Funding. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Nazha:Jazz: Research Funding; Incyte: Speakers Bureau; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee.

Background: TET-dioxygenases (TET1, TET2, and TET3) are key epigenetic regulators, which require molecular oxygen, αKG, and Fe 2+ to progressively oxidize 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine, leading to the demethylation of mCpGs at promoter and enhancer, a key step for mounting an efficient transcription profile and thereby differentiation. Loss of function TET2 mutation (TET2 MT) is frequently observed in myeloid neoplasms (MN). Despite extensive studies of the biochemical mechanisms underlying distorted myeloid differentiation and neoplastic evolution of TET2 MT HSPCs, targeted therapies are lagging. Here, we report the therapeutic utility of preferential targeting of TET2 mutant and TET-dioxygenase deficient cells either by restoring the lost activity to induce differentiation and death or by inhibiting the residual activity to induce synthetic lethality. Methods: Genetic as well as pharmacologic in vitro and in vivo models of AML were used to validate specific targeting of TET2 mutant cells. Knockout and over-expression in the isogenic background of different cells were used to understand the pro-survival and proliferative mechanism of TET2 loss in myeloid cells. The efficacy of small molecule pharmacophore targeting TET-dioxygenase was evaluated in vitro in cell free and cell culture as well as in vivo in a mouse competitive transplant model to demonstrate the proof of therapeutic concept. Result: Ascorbate, used as an activator of αKG/Fe 2+ dependent dioxygenase including TETs, functions via maintaining the redox state of iron (II) in the dioxygenase catalytic site with a half-maximal effective concentration of 13.8 ± 1.3 µM for enhancing TET2activity as measured by an ELISA for 5hmC. However, the reported intracellular cellular concentrations of ascorbate in human remains in the millimolar range, well above the saturating concentration required for TET-dioxygenases activation. Interestingly, ascorbate failed to activate TET in primary mononuclear cells isolated from myeloid neoplasia patients with TET2 mutations. Consistent with the in-vitro observation, we found that ascorbate treatment in physiologically relevant doses has no significant effect in syngeneic murine models (p=0.1). TET-inactivation is a complex phenomenon that is controlled by context-dependent post-translational modifications including lysine acetylation by acetyltransferases and class I and II deacetylases. Therefore, the anti-leukemic effect of the supraphysiological doses of ascorbate in humans and mice leukemia models may not be dependent on TET activation by ascorbate. On the other hand, a comprehensive analysis of the configurations of TET2 MT in myeloid neoplasia (n= 2617) demonstrated a remarkable exclusivity with 2-hydroxyglutarate (2-HG) producing neomorphic IDH1/2 MT. Ectopic inducible expression of IDH1/2 MT induced synthetic lethality of malignant TET2 MT cells. Therefore, themutual exclusivity of TET2 MT and neomorphic IDH1/2 MT is due to synthetic lethality caused by 2-HG production. In addition, we demonstrate that sequential deletion of TET1 and TET3 leads to growth arrest in cellular models, which has never been observed in any myeloid malignancies. Altogether, these observations suggest that malignant TET2 mutant myeloid cells may be vulnerable to inhibition of residual TET-activity coming from TET1 and TET3. Therefore, we synthesized TET-specific inhibitor on 2HG scaffold using iterative computer-aided design, characterized in cell-free as well as cell culture model systems, and selected TETi76 with no cytotoxic effect in normal bone marrow-derived CD34 + cells. TETi76 selectively inhibits TET-dioxygenase activity with IC50 of 1.5, 9.4, and 8.8 μmol/L for TET1/2/3, and it restricts clonal outgrowth of TET2 MT both in vitro and in vivo in malignant and nonmalignant clonal hematopoiesis of indeterminate potential (CHIP). Conclusion: Taken together, here we demonstrated that anti-cancer activity of ascorbate may not come from its role as a TET activator and that a minimum level of TET-dioxygenase activity is required for cell survival, rendering TET2 -mutant malignant cells selectively vulnerable to inhibitors of TET-function. Disclosures Maciejewski: Regeneron: Consultancy; Novartis: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Alexion: Consultancy.

Clinical impact and mechanistic contributions to leukemogenesis are difficult to assign to less common somatic mutations. However, the genetics of inherited syndromes can often be helpful in discerning the biological functions and mechanistic consequences of genes in other diseases. PHF6 (Xq26.2) encodes a protein consisting of two PHD-type zinc finger domains with activity in transcriptional regulation. PHF6 translocations were originally described in T-ALL and its mutations were later observed also in CML and adult AML. Germline (GL) PHF6MT cause Börjeson-Forssman-Lehmann syndrome (BFLS), an X-linked disorder characterized by intellectual disability and, to date, only a few BFLS cases were found to develop lymphoma or T-ALL. While regularly encountered in myeloid neoplasia (MN), the impact and functional meaning of PHF6 are not well established. To determine the incidence, distribution and molecular context of PHF6MT we studied a large cohort of patients with MN (n=8617) collected from our institution and public series. 1 Overall, 73% of patients were AML (pAML 69%; sAML 4%), MDS (22%) and MDS/MPN (5%) with a median age at diagnosis of 67 ys (18-100). We detected 149 patients (2%) carrying at least 1 PHF6MT with 11 harboring more than 1 hit. Four patients carried -X in addition to PHF6MT (2 males; 2 females). Majority of patients (68%) carried frameshift del/ins and nonsense. Mutations were scattered across all coding region with a slightly enrichment (47%) in the second PHD domain (239-330 aa) including the frequent R274Q/X (n=17). Common hits mainly affected arginine residues essential for DNA binding capacity (R129X n=9, R116X=7, R319X=5, R225X=3) followed by other hits (I314T=6, Y301X and C20fs=4 each). Of note, R116X, R225X, R274X, C280Y, H329R and Y303* lesions overlapped with the T-ALL PHF6MT spectrum while no overlap was found with GL mutations found in BFLS. Overall, 75% of all PHF6MT carriers were males and carried mostly (80%) truncating lesions. Compared to mutational frequencies observed in other X-linked genes, truncating PHF6MT behaved similarly to those in ZRSR2 (78%), STAG2 (73%) and BCOR (62%). Conversely, BCORL1MT, KDM6AMT and PIGAMT were evenly distributed between genders. When evaluating mutational characteristics in males and females, no differences were found in sex-adjusted median variant allelic burden of PHF6MT (54.8 vs 51%) nor its mRNA expression levels suggesting locus inactivation. PHF6MT tended to be older than PHF6WT patients (72 vs 68 ys; P= .05) and had mostly (63%) AML followed by MDS (23%) and MDS/MPN (14%). OS was similar between PHF6MT and PHF6WT patients (P= .16). Expression analyses showed that PHF6 loss leads to deregulation of chromatin and transcriptional factor genes. Indeed, in our cohort the most comutated genes were transcriptional factors and chromatin modifiers genes such as RUNX1 (26/149, 17%), ASXL1 (23/149, 15%) and TET2 (17/149, 11%). Of note, this group characterized by the triple ASXL1, RUNX1, TET2 mutational configuration clustered in one of the genomic groups previously identified (GC-3) 1 but the presence of these lesions did not worsen the OS as compared to PHF6MT without this mutational constellation. A low frequency of SF3B1MT (4%) was also noted confirming the enrichment of PHF6MT in AML rather than in low risk MDS. Further, 12% (14 males; 4 females) of PHF6MT patients had X-mutation mosaicism as shown by concomitant hits in BCOR (n=8), ZRSR2 (4), STAG2 (5), KDM6A (1). PHF6MT were equally founder lesions (30%; 44/149) and subclonal (34%; 50/149) whereas the rest was indistinguishable by VAF discrimination (co-dominant). The most common subclonal mutations were U2AF1 (14%, 6/44), IDH1/2 (9%, 4/44) and RUNX1 (7%, 3/44). When PHF6MT were subclonal, the founder hits were in TET2 (14%, 7/50), DNMT3A and RUNX1 (12%, each 6/50) genes. Given the high frequency of RUNX1MT in PHF6MT we investigated whether RUNX1 and PHF6 might be correlated. Transcriptomic analysis of 6246 patients (from 9 public studies) 2 showed a direct linear correlation (AdjR2= .03, P=5.55e-05) between the expression of the two genes. Our study is the largest to date to investigate the genetic landscape of PHF6MT in MN and highlights a strong connection of PHF6 with transcriptional regulation and chromatin genes. Ongoing scDNA-seq will clarify whether these mutations were acquired in distinct clones helping in dissecting the clonal hierarchy of PHF6MT cases. Disclosures Carraway: Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Other: Independent review committee; Takeda: Other: Independent review committee; Astex: Other: Independent review committee; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Advani: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Glycomimetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Research Funding; Immunogen: Research Funding; OBI: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding. Maciejewski: Regeneron: Consultancy; Novartis: Consultancy; Alexion: Consultancy; Bristol Myers Squibb/Celgene: Consultancy.

The pathogenesis of idiopathic aplastic anemia (IAA) involves a human leukocyte antigen (HLA)-restricted T-cell autoreactivity against unknown antigens preferentially distributed on early hematopoietic stem and progenitor cells (HSPCs). Genetically acquired GPI-anchor and HLA deficiency have been both linked to clonal immune evasion from T-cell pressure. We hypothesized that, in analogy to anti-tumor adaptive immune evasion, pathophysiology of immune escape in IAA originates together with a broader dysfunction of antigen presentation/processing machinery and immune regulatory proteins, beyond HLA molecules, as an effect of immune pressure under T-cell attack. This initial immune reaction would produce up-modulation of these pathways, ultimately promoting the acquisition of mutations and expansion of immune resistant clones. To test this hypothesis, we first performed single-cell RNAseq analysis in HSPCs in IAA patients at disease manifestation, 1 which showed signatures of dysfunction of antigen presentation machinery, with up-regulation of most of the HLA molecules, proteasome subunits and endoplasmic reticulum related organelle transporters. Strikingly, DRB1 was among the top 3 genes upregulated in IAA patients compared to controls (q-values 1.23E-35; Fig.1A), underscoring the etiological impact that antigen presentation via this locus has in the initiation of autoimmune process. Mild upregulation was also seen in DQB1 and B loci (q-values 4.7E-07 and 2.1E-10, respectively). We then studied molecular escape mechanisms by genotyping 204 IAA and PNH patients, with either a targeted or whole genome sequencing (WGS) platform. By application of a newly in-house developed bioinformatic pipeline, we detected somatic aberrations in HLA region involving both class I and II alleles in 36% of IAA patients including point mutations, frameshift insertions or deletions and copy number variations inducing allelic loss. B*14:02 and A*02:01 emerged as the most commonly mutated class I alleles with a few hotspot mutations identified, particularly in exon 1 (c.19C>T, p.R7X, Fig.1B,C), confirming previous reports. 2,3 In class II, DQB1 and DPA1 loci were frequently targeted by fine mutational events, while more complex allelic loss phenomena interested prevalently DRB1 and DQB1 loci. Those aberrations were identified at diagnosis (35%), during disease follow-up (33%) or at the time of malignant evolution (27%), with higher clonal size in specimens collected during the course of the disease (median VAF 3% [2-27%] at diagnosis, 8% [2-98%] at follow-up, and 2.2% [2.0-6.1%] at evolution). Of 41 patients with at least one HLA aberration and characterized with an extended genotypic study, only 6 harbored also >1 somatic myeloid mutation (14%), versus 30/90 (33%) not affected by somatic hits in HLA (p=.026; Fig.1D). HLA aberrant cases also showed lower number of somatic myeloid mutations (OR=0.44; p=.0262) with driver hits rarely present (Fig.1E). In terms of PIGA mutations, an increased PIGA mosaicism was observed in the HLA mutant group, underlying that both processes have similar pathophysiologic origin as a product of the immune selection pressure (OR: 1.55 [95%CI 1.1-4.2], p=.0201). We then investigated, through WGS of 53 patients, the presence of somatic mutations in other immune genes which could be triggered by immune pressure. Hence, in 47% of the cases we were able to find pathogenic or likely pathogenic hits in genes encompassing proteasome complex, vesicle trafficking, transactivators and interferon regulatory factors, including CREBBP, TAP1, CIITA, PSMC5, PSMB4 and IRF9 (Fig.1F), whose pathogenicity was computationally assessed through recently implemented somatic classifiers. 4 Those hits were not mutually exclusive neither with HLA nor with PIGA mutations, however their VAF was significantly lower compared to concurrent HLA and PIGA lesions, underscoring their lower driver potential within the immune escape environment compared to PNH and HLA-lacking clones. Altogether our results describe the diversity of molecular and immune events taking place in IAA and PNH. Our study suggests that following initial immune insult, clonal architecture of residual hematopoiesis can be dominated by multiple modes of immune escape, agonistically participating to a mechanism of "adaptive" clonal recovery, likely in opposition to the "maladaptive" malignant progression. Figure 1 Figure 1. Disclosures Maciejewski: Alexion: Consultancy; Regeneron: Consultancy; Novartis: Consultancy; Bristol Myers Squibb/Celgene: Consultancy.