bims-tremyl 2022-06-26 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2022–06–26
twenty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

CKS1 inhibition depletes leukemic stem cells and protects healthy hematopoietic stem cells in acute myeloid leukemia.
A multiparametric niche-like drug screening platform in acute myeloid leukemia.
Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast percentage AML.
2-Hydroxyglutarate in Acute Myeloid Leukemia: A Journey from Pathogenesis to Therapies.
A Phase II Study of Azacitidine, Venetoclax and Trametinib in Relapsed or Refractory AML Harboring RAS Pathway-Activating Mutations.
Venetoclax in combination with FLAG-IDA-based protocol for patients with acute myeloid leukemia: a real-world analysis.
Splicing factor 3B subunit 1 (SF3B1) mutation in the context of therapy-related myelodysplastic syndromes.
Gilteritinib monotherapy for relapsed/refractory FLT3 mutated acute myeloid leukemia: a real-world, multi-center, matched analysis.
Proposed ECNM-AIM Response Criteria in Advanced Systemic Mastocytosis.
AML, NOS and AML-MRC as defined by multilineage dysplasia share a common mutation pattern which is distinct from AML-MRC as defined by MDS-related cytogenetics.
Impact of FLT3-ITD Insertion Length on Outcomes in Acute Myeloid Leukemia: A Propensity Score-Adjusted Cohort Study.
Azacitidine and donor lymphocytes infusions in acute myeloid leukemia and myelodysplastic syndrome relapsed after allogeneic hematopoietic stem cell transplantation from alternative donors.
Microenvironmental Features Driving Immune Evasion in Myelodysplastic Syndromes and Acute Myeloid Leukemia.
Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC.
Prevalence and Prognostic Role of IDH Mutations in Acute Myeloid Leukemia: Results of the GIMEMA AML1516 Protocol.
Direct targeted therapy for MLL-fusion-driven high-risk acute leukaemias.
The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms.
Hyaluronic acid-GPRC5C signalling promotes dormancy in haematopoietic stem cells.
European LeukemiaNet Response Predicts Disease Progression but Not Thrombosis in Polycythemia Vera.
Clinical outcome of myelodysplastic syndrome progressing on hypomethylating agents with evolving frontline therapies: continued challenges and unmet needs.
Specification of hematopoietic stem cells in mammalian embryos: A rare or frequent event?
Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited.

Sci Transl Med. 2022 Jun 22. 14(650): eabn3248

CKS1 inhibition depletes leukemic stem cells and protects healthy hematopoietic stem cells in acute myeloid leukemia.

William Grey, Ana Rio-Machin, Pedro Casado, Eva Grönroos, Sara Ali, Juho J Miettinen, Findlay Bewicke-Copley, Alun Parsons, Caroline A Heckman, Charles Swanton, Pedro R Cutillas, John Gribben, Jude Fitzgibbon, Dominique Bonnet.

Acute myeloid leukemia (AML) is an aggressive hematological disorder comprising a hierarchy of quiescent leukemic stem cells (LSCs) and proliferating blasts with limited self-renewal ability. AML has a dismal prognosis, with extremely low 2-year survival rates in the poorest cytogenetic risk patients, primarily due to the failure of intensive chemotherapy protocols to deplete LSCs and toxicity of therapy toward healthy hematopoietic cells. We studied the role of cyclin-dependent kinase regulatory subunit 1 (CKS1)-dependent protein degradation in primary human AML and healthy hematopoiesis xenograft models in vivo. Using a small-molecule inhibitor (CKS1i), we demonstrate a dual role for CKS1-dependent protein degradation in reducing patient-derived AML blasts in vivo and, importantly, depleting LSCs, whereas inhibition of CKS1 has the opposite effect on normal hematopoiesis, protecting normal hematopoietic stem cells from chemotherapeutic toxicity. Proteomic analysis of responses to CKS1i in our patient-derived xenograft mouse model demonstrate that inhibition of CKS1 in AML leads to hyperactivation of RAC1 and accumulation of lethal reactive oxygen species, whereas healthy hematopoietic cells enter quiescence in response to CKS1i, protecting hematopoietic stem cells. Together, these findings demonstrate that CKS1-dependent proteostasis is a key vulnerability in malignant stem cell biology.

DOI: https://doi.org/10.1126/scitranslmed.abn3248
Blood Cancer J. 2022 Jun 24. 12(6): 95

A multiparametric niche-like drug screening platform in acute myeloid leukemia.

Reinaldo Dal Bello, Justine Pasanisi, Romane Joudinaud, Matthieu Duchmann, Bryann Pardieu, Paolo Ayaka, Giuseppe Di Feo, Gaetano Sodaro, Clémentine Chauvel, Rathana Kim, Loic Vasseur, Laureen Chat, Frank Ling, Kim Pacchiardi, Camille Vaganay, Jeannig Berrou, Chaima Benaksas, Nicolas Boissel, Thorsten Braun, Claude Preudhomme, Hervé Dombret, Emmanuel Raffoux, Nina Fenouille, Emmanuelle Clappier, Lionel Adès, Alexandre Puissant, Raphael Itzykson.

Functional precision medicine in AML often relies on short-term in vitro drug sensitivity screening (DSS) of primary patient cells in standard culture conditions. We designed a niche-like DSS assay combining physiologic hypoxia (O2 3%) and mesenchymal stromal cell (MSC) co-culture with multiparameter flow cytometry to enumerate lymphocytes and differentiating (CD11/CD14/CD15+) or leukemic stem cell (LSC)-enriched (GPR56+) cells within the leukemic bulk. After functional validation of GPR56 expression as a surrogate for LSC enrichment, the assay identified three patterns of response, including cytotoxicity on blasts sparing LSCs, induction of differentiation, and selective impairment of LSCs. We refined our niche-like culture by including plasma-like amino-acid and cytokine concentrations identified by targeted metabolomics and proteomics of primary AML bone marrow plasma samples. Systematic interrogation revealed distinct contributions of each niche-like component to leukemic outgrowth and drug response. Short-term niche-like culture preserved clonal architecture and transcriptional states of primary leukemic cells. In a cohort of 45 AML samples enriched for NPM1c AML, the niche-like multiparametric assay could predict morphologically (p = 0.02) and molecular (NPM1c MRD, p = 0.04) response to anthracycline-cytarabine induction chemotherapy. In this cohort, a 23-drug screen nominated ruxolitinib as a sensitizer to anthracycline-cytarabine. This finding was validated in an NPM1c PDX model.

DOI: https://doi.org/10.1038/s41408-022-00689-3
Blood Adv. 2022 Jun 21. pii: bloodadvances.2022007334. [Epub ahead of print]

Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast percentage AML.

Lionel Adès, Larisa Girshova, Vadim A Doronin, Maria Díez-Campelo, David Valcárcel, Suman Kambhampati, Nora-Athina Viniou, Dariusz Woszczyk, Raquel De Paz Arias, Argiris Symeonidis, Achilles Anagnostopoulos, Eduardo Ciliao Munhoz, Uwe Platzbecker, Valeria Santini, Robert J Fram, Ying Yuan, Sharon Friedlander, Douglas V Faller, Mikkael A Sekeres.

PANTHER was a global, randomized phase 3 trial of pevonedistat plus azacitidine (n = 227) vs azacitidine monotherapy (n = 227) in patients with newly diagnosed higher-risk myelodysplastic syndromes (MDS) (n = 324), higher-risk chronic myelomonocytic leukemia (n = 27), or acute myeloid leukemia (AML) with 20-30% blasts (n = 103). The primary endpoint was event-free survival (EFS). In the intent-to-treat (ITT) population median EFS was 17.7 months with pevonedistat plus azacitidine vs 15.7 months with azacitidine (hazard ratio [HR], 0.968 [95% confidence interval (CI), 0.757-1.238], P = 0.557) and in the higher-risk MDS cohort median EFS was 19.2 vs 15.6 months (HR, 0.887 [95% CI, 0.659-1.193, P = 0.431). Median overall survival (OS) in the higher-risk MDS cohort was 21.6 vs 17.5 months (HR, 0.785, P = 0.092]), and in patients with AML with 20-30% blasts was 14.5 vs 14.7 months (HR, 1.107, P = 0.664). In a post-hoc analysis, median OS in the higher-risk MDS cohort for patients receiving >3 cycles was 23.8 vs 20.6 months (P = 0.021) and for >6 cycles was 27.1 vs 22.5 months (P = 0.008). No new safety signals were identified, and azacitidine dose intensity was maintained. Common hematologic grade ≥3 treatment emergent adverse events were anemia (33% vs 34%), neutropenia (31% vs 33%), and thrombocytopenia (30% vs 30%). These results underscore the importance of large, randomized controlled trials in these heterogeneous myeloid diseases and the value of remaining on therapy >3 cycles. (ClinicalTrials.gov, NCT03268954).

DOI: https://doi.org/10.1182/bloodadvances.2022007334
Biomedicines. 2022 Jun 09. pii: 1359. [Epub ahead of print]10(6):

2-Hydroxyglutarate in Acute Myeloid Leukemia: A Journey from Pathogenesis to Therapies.

Vittoria Raimondi, Giulia Ciotti, Michele Gottardi, Francesco Ciccarese.

  The oncometabolite 2-hydroxyglutarate (2-HG) plays a key role in differentiation blockade and metabolic reprogramming of cancer cells. Approximatively 20-30% of acute myeloid leukemia (AML) cases carry mutations in the isocitrate dehydrogenase (IDH) enzymes, leading to a reduction in the Krebs cycle intermediate α-ketoglutarate (α-KG) to 2-HG. Relapse and chemoresistance of AML blasts following initial good response to standard therapy account for the very poor outcome of this pathology, which represents a great challenge for hematologists. The decrease of 2-HG levels through pharmacological inhibition of mutated IDH enzymes induces the differentiation of AML blasts and sensitizes leukemic cells to several anticancer drugs. In this review, we provide an overview of the main genetic mutations in AML, with a focus on IDH mutants and the role of 2-HG in AML pathogenesis. Moreover, we discuss the impact of high levels of 2-HG on the response of AML cells to antileukemic therapies and recent evidence for highly efficient combinations of mutant IDH inhibitors with other drugs for the management of relapsed/refractory (R/R) AML.

Keywords:  2-HG; AML; diagnosis; therapy

DOI:  https://doi.org/10.3390/biomedicines10061359
Acta Haematol. 2022 Jun 17.

A Phase II Study of Azacitidine, Venetoclax and Trametinib in Relapsed or Refractory AML Harboring RAS Pathway-Activating Mutations.

Sai Prasad Desikan, Farhad Ravandi, Naveen Pemmaraju, Marina Konopleva, Sanam Loghavi, Elias J Jabbour, Naval Daver, Nitin Jain, Kelly S Chien, Abhishek Maiti, Guillermo Montalban-Bravo, Tapan M Kadia, Walid Macaron, Ricardo DeLumpa, Monica Kwari, Gautam Borthakur, Nicholas J Short.

INTRODUCTION: RAS pathway mutations are common mechanisms of resistance to acute myeloid leukemia (AML) therapies. Trametinib, an oral MEK inhibitor, has been shown to have single-agent activity in relapsed/refractory AML and preclinical synergy with venetoclax.
METHODS: We conducted a single-center, open-label, phase 2 trial of the combination of azacitidine, venetoclax, and trametinib in patients with relapsed or refractory AML harboring a RAS pathway-activating mutation.
RESULTS: Sixteen patients were treated. The patients were heavily pretreated with a median number of 4 prior therapies; 13 (81%) had received prior hypomethylating agent (HMA) with venetoclax and 8 (50%) had undergone prior stem cell transplant. Four patients (25%) responded (CR, n=1; CRi, n=1; MLFS, n=2). Two of the 3 patients (67%) who had not previously received HMA plus venetoclax responded; in contrast, only 2 of the 13 patients (15%) who had previously received HMA plus venetoclax responded. The median OS was 2.4 months, and the 6-month OS rate was 31%. Related grade 3-4 adverse events occurred in 50% of patients, and 50% of patients required a dose adjustment of trametinib.
CONCLUSIONS: The combination of azacitidine, venetoclax and trametinib had only modest activity in patients with relapsed/refractory AML, with a response rate that was similar to previous reports of trametinib monotherapy. Substantial toxicity was observed with this combination. Given the established role of RAS pathway mutations in mediating resistance to AML therapies, future studies of better tolerated, more active inhibitors of this pathway are still needed.

DOI: https://doi.org/10.1159/000525566
Ann Hematol. 2022 Jun 23.

Venetoclax in combination with FLAG-IDA-based protocol for patients with acute myeloid leukemia: a real-world analysis.

Ofir Wolach, Avraham Frisch, Liat Shargian, Moshe Yeshurun, Arie Apel, Vladimir Vainstein, Yakir Moshe, Shai Shimony, Odelia Amit, Yael Bar-On, Yishai Ofran, Pia Raanani, Boaz Nachmias, Ron Ram.

  Venetoclax in combination with intensive therapies is explored in both the upfront and relapse/refractory (R/R) setting, and available data suggest that such regimens are effective albeit with added hematological and infectious toxicity. We conducted a multicenter retrospective cohort study of patients with acute myeloid leukemia (AML) treated with venetoclax in combination with FLAG-IDA protocol. Twenty-five patients were included in this analysis (median age 53.4 years). Most patients were treated for R/R AML (n = 24, 96%) with a median of one (range 0-3) previous lines of therapy and 44% of patients (n = 11) having prior allogeneic hematopoietic cell transplantation (HCT). Median follow-up was 10 (range, 4-26) months. Platelet and neutrophil recovery were observed at a median of 31 (95% CI 17.6-38.3) and 23 (95% CI 20-28) days, respectively. The most common adverse events were infectious (blood stream infections, 48% and invasive fungal infections, 32%). Thirty-day mortality was 12%. Composite complete remission (CRc) was 72% for the entire cohort and 91% in patients treated for post-HCT relapse. Incidences of relapse-free and overall survival at 12 months were 67% (95% CI 58-76%) and 50% (95% CI 31-69%), respectively. Real-world data show that the addition of venetoclax to FLAG-IDA protocol is effective in patients with high-risk AML, most notably in the post-HCT relapse setting. Prophylaxis and surveillance for infections are crucial.

Keywords:  High-risk AML; Intensive chemotherapy; Salvage; Venetoclax

DOI:  https://doi.org/10.1007/s00277-022-04883-y
Br J Haematol. 2022 Jun 24.

Splicing factor 3B subunit 1 (SF3B1) mutation in the context of therapy-related myelodysplastic syndromes.

Virginia O Volpe, Najla Al Ali, Onyee Chan, Eric Padron, David A Sallman, Andrew Kuykendall, Kendra Sweet, Jeffrey E Lancet, Rami S Komrokji.

  Splicing factor 3B subunit 1 (SF3B1) somatic mutation in the context of therapy-related myelodysplastic syndromes (t-MDS) has not been well defined. In a large cohort of patients with MDS, those with known SF3B1 somatic mutation were compared as de novo MDS (n = 289) and t-MDS with mutant SF3B1 (SF3B1mut ; n = 31). Baseline characteristics, concomitant mutations, and acute myeloid leukaemia (AML) transformation were similar between the two groups. The median overall survival (OS) of de novo MDS SF3B1mut was significantly longer compared to t-MDS SF3B1mut but not significantly different when adjusted for comorbidities. Comparing t-MDS wild-type SF3B1 (SF3B1WT ; n = 241) to t-MDS SF3B1mut (n = 31), complex cytogenetics were seen in 37.4% versus 10.3% (p = 0.009), tumour protein p53 (TP53) mutation was 36.1% versus 10% (p = 0.004), and AML transformation was 34.4% compared to 12.9% (p = 0.016) respectively. OS was significantly shorter in SF3B1WT versus SF3B1mut . When applying the International Working Group for Prognosis of MDS (IWG-PM) proposed SF3B1 criteria, OS was significantly shorter in SF3B1mut t-MDS compared to de novo MDS SF3B1mut with no significance in AML transformation. Survival was compared between t-MDS SF3B1mut who met the new proposed IWG-PM criteria to t-MDS SF3B1mut who did not meet criteria to survival of SF3B1WT t-MDS. OS was 53 versus 22 and 18 months respectively (p = 0.006). AML transformation was 0%, 26.7% and 32.3% (p = 0.021). Leukaemia-free survival was not reached among the three.

Keywords:  International Working Group (IWG); World Health Organization (WHO); acute myeloid leukaemia (AML); splicing factor 3B subunit 1 (SF3B1); survival; therapy-related myelodysplastic syndrome

DOI:  https://doi.org/10.1111/bjh.18319
Ann Hematol. 2022 Jun 24.

Gilteritinib monotherapy for relapsed/refractory FLT3 mutated acute myeloid leukemia: a real-world, multi-center, matched analysis.

Shai Shimony, Jonathan Canaani, Eitan Kugler, Boaz Nachmias, Ron Ram, Avraham Frisch, Chezi Ganzel, Vladimir Vainstein, Yakir Moshe, Shlomzion Aumann, Moshe Yeshurun, Yishai Ofran, Pia Raanani, Ofir Wolach.

  Patients with FLT3-mutated relapsed or refractory (R/R) acute myeloid leukemia (AML) have a dismal prognosis. Gilteritinib is a FLT3 tyrosine kinase inhibitor (TKI) recently approved for patients with R/R AML. We aimed to characterize real-world data regarding gilteritinib treatment in FLT3-mutated R/R AML and to compare outcomes with matched FLT3-mutated R/R AML patients treated with chemotherapy-based salvage regimens. Twenty-five patients from six academic centers were treated with gilteritinib for FLT3-mutated R/R AML. Eighty percent were treated with a prior intensive induction regimen and 40% of them received prior TKI therapy. Twelve patients (48%) achieved complete response (CR) with gilteritinib. The estimated median overall survival (OS) of the entire cohort was eight (CI 95% 0-16.2) months and was significantly higher in patients who achieved CR compared to those who did not (16.3 months, CI 95% 0-36.2 vs. 2.6 months, CI 95% 1.47-3.7; p value = 0.046). In a multivariate cox regression analysis, achievement of CR was the only predictor for longer OS (HR 0.33 95% CI 0.11-0.97, p = 0.044). Prior TKI exposure did not affect OS but was associated with better event-free survival (HR 0.15 95% CI 0.03-0.71, p = 0.016). An age and ELN-risk matched comparison between patients treated with gilteritinib and intensive salvage revealed similar response rates (50% in both groups); median OS was 9.6 months (CI 95% 2.3-16.8) vs. 7 months (CI 95% 5.1-8.9) in gilteritinib and matched controls, respectively (p = 0.869). In conclusion, in the real-world setting, gilteritinib is effective, including in heavily pre-treated, TKI exposed patients.

Keywords:  FLT3; Gilteritinib; Relapsed/refractory AML

DOI:  https://doi.org/10.1007/s00277-022-04895-8
J Allergy Clin Immunol Pract. 2022 Jun 17. pii: S2213-2198(22)00585-2. [Epub ahead of print]

Proposed ECNM-AIM Response Criteria in Advanced Systemic Mastocytosis.

Jason Gotlib, Juliana Schwaab, William Shomali, Tracy I George, Deepti H Radia, Mariana Castells, Melody C Carter, Karin Hartmann, Ivan Alvarez-Twose, Knut Brockow, Patrizia Bonadonna, Olivier Hermine, Marek Niedoszytko, Gregor Hoermann, Wolfgang R Sperr, Hanneke Oude Elberink, Frank Siebenhaar, Joseph H Butterfield, Celalettin Ustun, Roberta Zanotti, Massimo Triggiani, Lawrence B Schwartz, Jonathan J Lyons, Alberto Orfao, Karl Sotlar, Hans-Peter Horny, Michel Arock, Dean D Metcalfe, Cem Akin, Johannes Lübke, Peter Valent, Andreas Reiter.

  Advanced systemic mastocytosis (AdvSM) is characterized by presence of the KIT D816V and other somatic mutations (e.g. in SRSF2, ASXL1, RUNX1) in 95% and 60-70% of patients, respectively. The biologic and clinical consequences of AdvSM include multilineage involvement (e.g. associated hematologic neoplasm, AHN) in 60-80% of patients, variable infiltration and damage (C-findings) of predominantly bone marrow (BM) and visceral organs through affected mast cell (MC) and non-MC (AHN) lineages, and elevated levels of serum tryptase. Recently, the treatment landscape has substantially changed with the introduction of the multikinase/KIT inhibitor midostaurin and the specific KIT D816V inhibitor avapritinib. In this review, we discuss the evolution of AdvSM response criteria that have been developed in order to better capture clinical benefit (e.g. improved responses, progression-free and overall survival). We propose refined response criteria from European Competence Network on Mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM) investigators which utilizes a tiered approach to segregate the effects of histopathologic (e.g., BM MC burden, tryptase), molecular (e.g. KIT D816V variant allele frequency), clinical (e.g. C-findings), and symptom response on long-term outcomes. These response criteria require evaluation in future prospective clinical trials of selective KIT inhibitors and other novel agents.

Keywords:  Advanced systemic mastocytosis; IWG-MRT-ECNM; KIT D816V; avapritinib; midostaurin; pure pathologic response

DOI:  https://doi.org/10.1016/j.jaip.2022.05.034
Leukemia. 2022 Jun 20.

AML, NOS and AML-MRC as defined by multilineage dysplasia share a common mutation pattern which is distinct from AML-MRC as defined by MDS-related cytogenetics.

Irene Fuhrmann, Miriam Lenk, Torsten Haferlach, Anna Stengel, Stephan Hutter, Constance Baer, Manja Meggendorfer, Wolfgang Kern, Claudia Haferlach.

DOI: https://doi.org/10.1038/s41375-022-01631-z
Biology (Basel). 2022 Jun 15. pii: 916. [Epub ahead of print]11(6):

Impact of FLT3-ITD Insertion Length on Outcomes in Acute Myeloid Leukemia: A Propensity Score-Adjusted Cohort Study.

Elizabeth M Corley, Moaath K Mustafa Ali, Hanan Alharthy, Kathryn A F Kline, Danielle Sewell, Jennie Y Law, Seung Tae Lee, Sandrine Niyongere, Vu H Duong, Maria R Baer, Ashkan Emadi.

  The prognostic significance of the length of internal tandem duplication (ITD) insertions in mutant FLT3 genes in acute myeloid leukemia (AML) is controversial. We conducted a retrospective study to evaluate the correlation between the ITD base-pair (bp) insertion length and clinical outcomes. The mutational status of the FLT3 gene was evaluated in 402 of 467 consecutive AML patients treated at the University of Maryland Greenebaum Comprehensive Cancer Center between 2013 and 2020; 77 had FLT3-ITD mutations. Patients were divided into three cohorts based on bp insertion length (<30 (0-33rd percentile), 30-53 (34th-66th percentile),and >53 (>66th percentile)). The median overall survival (OS) of patients was 16.5 months (confidence interval (CI) 7.3-NA), 18.5 months (CI 7.3-NA), and 21.9 months (CI 19.1-NA) (p = 0.03) for the <30, 30-53, and >53 bp insertion length cohorts, respectively. The adjusted median event-free survival (EFS) for the ITD insertion lengths >30, 30-53, and >53 bp was 11.1 months (CI 2.8-16.5), 5.2 months (CI 2.9-12.6), and 9.1 months (CI 5.4-NA) (p = 0.5), respectively. Complete remission (CR) rates were 64% (<30 inserted bp), 55% (30-53 inserted bp), and 79% (>53 inserted bp) (p = 0.23). For patients treated with gilteritinib and midostaurin, the unadjusted median OS was not statistically significantly different between cohorts.

Keywords:  FLT3-ITD; acute myeloid leukemia; prognosis4; survival3

DOI:  https://doi.org/10.3390/biology11060916
Ther Adv Hematol. 2022 ;13 20406207221090882

Azacitidine and donor lymphocytes infusions in acute myeloid leukemia and myelodysplastic syndrome relapsed after allogeneic hematopoietic stem cell transplantation from alternative donors.

Carmine Liberatore, Maria Teresa Lupo Stanghellini, Francesca Lorentino, Luca Vago, Matteo Giovanni Carrabba, Raffaella Greco, Sarah Marktel, Andrea Assanelli, Francesca Farina, Consuelo Corti, Massimo Bernardi, Jacopo Peccatori, Katja Sockel, Jan Moritz Middeke, Johannes Schetelig, Anika Bergmann, Christina Rautenberg, Fabio Ciceri, Martin Bornhäuser, Thomas Schroeder, Friedrich Stölzel.

   Introduction: Azacitidine (AZA) either single-agent or with donor lymphocytes infusions (DLI) has been used as a salvage treatment for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) relapsing after allogeneic hematopoietic stem cell transplantation (HSCT). To date, the majority of data come from patients relapsed after HSCT from full-matched donors.
Methods: We report a multicenter, collaborative, retrospective analysis of 71 patients with hematologic (n = 40, 56%) and molecular relapse (n = 31, 44%) of myeloid neoplasms after HSCT from alternative donors (mismatched unrelated, n = 39, 55%; haploidentical, n = 29, 41%) consecutively treated at three European centers with AZA ± DLI.
Results: Median time from HSCT to relapse was 9 months. Additional DLI were given to 33 patients (46%). After a median of four cycles, overall response rate (ORR) was 49% and complete response (CR) rate was 38%. CR lasted for a median of 17 months (range 5-89 months). Median follow-up in the entire cohort was 11 months (range 1-115 months). Event-free survival (EFS) and overall survival (OS) at 1 year were 26% and 53%, respectively. Treatment of molecular relapse granted higher CR rate (65% versus 15%; p = 0.0001), 1-year EFS (43% versus 13%; p = 0.006), and 1-year OS (79% versus 34%; p < 0.001) compared to hematologic relapses. Addition of DLI resulted in significantly higher responses and longer 1-year EFS and OS (Mantel-Byar test, p = 0.004 and p = 0.002, respectively). When applied to our cohort, the APSS-R score confirmed its ability to stratify patients into distinct prognostic groups with significantly different response rates (p = 0.0005) and survival (p < 0.0001). Treatment was well tolerated, with the incidence of late acute and chronic graft-versus-host disease of 27% and 18%, respectively.
Conclusion: AZA ± DLI proved feasible and effective in AML and MDS relapsing after HSCT from alternative donors. Despite modest efficacy among hematologic relapses, pre-emptive treatment with AZA ± DLI fared better in molecular relapse. Additional DLI contributed to improving efficacy and ensuring longer survival.

Keywords:  acute myeloid leukemia; allogeneic hematopoietic stem cell transplantation; alternative donor; azacitidine; myelodysplastic syndrome; post-transplantation relapse

DOI:  https://doi.org/10.1177/20406207221090882
Diseases. 2022 Jun 10. pii: 33. [Epub ahead of print]10(2):

Microenvironmental Features Driving Immune Evasion in Myelodysplastic Syndromes and Acute Myeloid Leukemia.

Georgios Petros Barakos, Eleftheria Hatzimichael.

  Bone marrow, besides the known functions of hematopoiesis, is an active organ of the immune system, functioning as a sanctuary for several mature immune cells. Moreover, evidence suggests that hematopoietic stem cells (the bone marrow's functional unit) are capable of directly sensing and responding to an array of exogenous stimuli. This chronic immune stimulation is harmful to normal hematopoietic stem cells, while essential for the propagation of myeloid diseases, which show a dysregulated immune microenvironment. The bone marrow microenvironment in myelodysplastic syndromes (MDS) is characterized by chronic inflammatory activity and immune dysfunction, that drive excessive cellular death and through immune evasion assist in cancer cell expansion. Acute myeloid leukemia (AML) is another example of immune response failure, with features that augment immune evasion and suppression. In this review, we will outline some of the functions of the bone marrow with immunological significance and describe the alterations in the immune landscape of MDS and AML that drive disease progression.

Keywords:  acute myeloid leukemia; bone marrow microenvironment; immune evasion; myelodysplastic syndromes

DOI:  https://doi.org/10.3390/diseases10020033
ACS Chem Biol. 2022 Jun 24.

Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC.

Jake C Swartzel, Michael J Bond, Andreas P Pintado-Urbanc, Mehana Daftary, Mackenzie W Krone, Todd Douglas, Evan J Carder, Joshua T Zimmer, Takahiro Maeda, Matthew D Simon, Craig M Crews.

The RNA decapping scavenger protein, DcpS, has recently been identified as a dependency in acute myeloid leukemia (AML). The potent DcpS inhibitor RG3039 attenuates AML cell viability, and shRNA knockdown of DcpS is also antiproliferative. Importantly, DcpS was found to be non-essential in normal human hematopoietic cells, which opens a therapeutic window for AML treatment by DcpS modulation. Considering this strong DcpS dependence in AML cell lines, we explored PROTAC-mediated degradation as an alternative strategy to modulate DcpS activity. Herein, we report the development of JCS-1, a PROTAC exhibiting effective degradation of DcpS at nanomolar concentrations. JCS-1 non-covalently binds DcpS with a RG3039-based warhead and recruits the E3 ligase VHL, which induces potent, rapid, and sustained DcpS degradation in several AML cell lines. JCS-1 serves as a chemical biology tool to interrogate DcpS degradation and associated changes in RNA processes in different cellular contexts, which may be an attractive strategy for the treatment of AML and other DcpS-dependent genetic disorders.

DOI: https://doi.org/10.1021/acschembio.2c00145
Cancers (Basel). 2022 Jun 18. pii: 3012. [Epub ahead of print]14(12):

Prevalence and Prognostic Role of IDH Mutations in Acute Myeloid Leukemia: Results of the GIMEMA AML1516 Protocol.

Monica Messina, Alfonso Piciocchi, Tiziana Ottone, Stefania Paolini, Cristina Papayannidis, Federica Lessi, Nicola Stefano Fracchiolla, Fabio Forghieri, Anna Candoni, Andrea Mengarelli, Maria Paola Martelli, Adriano Venditti, Angelo Michele Carella, Francesco Albano, Valentina Mancini, Bernardi Massimo, Valentina Arena, Valeria Sargentini, Mariarita Sciumè, Domenico Pastore, Elisabetta Todisco, Giovanni Roti, Sergio Siragusa, Marco Ladetto, Stefano Pravato, Eleonora De Bellis, Giorgia Simonetti, Giovanni Marconi, Claudio Cerchione, Paola Fazi, Marco Vignetti, Sergio Amadori, Giovanni Martinelli, Maria Teresa Voso.

  IDH1/2 mutations are common in acute myeloid leukemia (AML) and represent a therapeutic target. The GIMEMA AML1516 observational protocol was designed to study the prevalence of IDH1/2 mutations and associations with clinico-biological parameters in a cohort of Italian AML patients. We analyzed a cohort of 284 AML consecutive patients at diagnosis, 139 females and 145 males, of a median age of 65 years (range: 19-86). Of these, 38 (14%) harbored IDH1 and 51 (18%) IDH2 mutations. IDH1/2 mutations were significantly associated with WHO PS >2 (p < 0.001) and non-complex karyotype (p = 0.021) when compared to IDH1/2-WT. Furthermore, patients with IDH1 mutations were more frequently NPM1-mutated (p = 0.007) and had a higher platelet count (p = 0.036). At relapse, IDH1/2 mutations were detected in 6 (25%) patients. As per the outcome, 60.5% of IDH1/2-mutated patients achieved complete remission; overall survival and event-free survival at 2 years were 44.5% and 36.1%, respectively: these rates were similar to IDH1/2-WT. In IDH1/2-mutated patients, high WBC proved to be an independent prognostic factor for survival. In conclusion, the GIMEMA AML1516 confirms that IDH1/2 mutations are frequently detected at diagnosis and underlines the importance of recognizing IDH1/2-mutated cases up-front to offer the most appropriate therapeutic strategy, given the availability of IDH1/2 inhibitors.

Keywords:  AML; DH1; IDH2; prevalence; prognosis

DOI:  https://doi.org/10.3390/cancers14123012
Clin Transl Med. 2022 Jun;12(6): e933

Direct targeted therapy for MLL-fusion-driven high-risk acute leukaemias.

Sandra Cantilena, Luca Gasparoli, Deepali Pal, Olaf Heidenreich, Jan-Henning Klusmann, Joost H A Martens, Alexandre Faille, Alan J Warren, Mawar Karsa, Ruby Pandher, Klaartje Somers, Owen Williams, Jasper de Boer.

   BACKGROUND: Improving the poor prognosis of infant leukaemias remains an unmet clinical need. This disease is a prototypical fusion oncoprotein-driven paediatric cancer, with MLL (KMT2A)-fusions present in most cases. Direct targeting of these driving oncoproteins represents a unique therapeutic opportunity. This rationale led us to initiate a drug screening with the aim of discovering drugs that can block MLL-fusion oncoproteins.
METHODS: A screen for inhibition of MLL-fusion proteins was developed that overcomes the traditional limitations of targeting transcription factors. This luciferase reporter-based screen, together with a secondary western blot screen, was used to prioritize compounds. We characterized the lead compound, disulfiram (DSF), based on its efficient ablation of MLL-fusion proteins. The consequences of drug-induced MLL-fusion inhibition were confirmed by cell proliferation, colony formation, apoptosis assays, RT-qPCR, in vivo assays, RNA-seq and ChIP-qPCR and ChIP-seq analysis. All statistical tests were two-sided.
RESULTS: Drug-induced inhibition of MLL-fusion proteins by DSF resulted in a specific block of colony formation in MLL-rearranged cells in vitro, induced differentiation and impeded leukaemia progression in vivo. Mechanistically, DSF abrogates MLL-fusion protein binding to DNA, resulting in epigenetic changes and down-regulation of leukaemic programmes setup by the MLL-fusion protein.
CONCLUSION: DSF can directly inhibit MLL-fusion proteins and demonstrate antitumour activity both in vitro and in vivo, providing, to our knowledge, the first evidence for a therapy that directly targets the initiating oncogenic MLL-fusion protein.

Keywords:  MLL-fusion; leukaemia; mouse models; precision medicine; targeted therapy

DOI:  https://doi.org/10.1002/ctm2.933
Leukemia. 2022 Jun 22.

The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms.

Joseph D Khoury, Eric Solary, Oussama Abla, Yassmine Akkari, Rita Alaggio, Jane F Apperley, Rafael Bejar, Emilio Berti, Lambert Busque, John K C Chan, Weina Chen, Xueyan Chen, Wee-Joo Chng, John K Choi, Isabel Colmenero, Sarah E Coupland, Nicholas C P Cross, Daphne De Jong, M Tarek Elghetany, Emiko Takahashi, Jean-Francois Emile, Judith Ferry, Linda Fogelstrand, Michaela Fontenay, Ulrich Germing, Sumeet Gujral, Torsten Haferlach, Claire Harrison, Jennelle C Hodge, Shimin Hu, Joop H Jansen, Rashmi Kanagal-Shamanna, Hagop M Kantarjian, Christian P Kratz, Xiao-Qiu Li, Megan S Lim, Keith Loeb, Sanam Loghavi, Andrea Marcogliese, Soheil Meshinchi, Phillip Michaels, Kikkeri N Naresh, Yasodha Natkunam, Reza Nejati, German Ott, Eric Padron, Keyur P Patel, Nikhil Patkar, Jennifer Picarsic, Uwe Platzbecker, Irene Roberts, Anna Schuh, William Sewell, Reiner Siebert, Prashant Tembhare, Jeffrey Tyner, Srdan Verstovsek, Wei Wang, Brent Wood, Wenbin Xiao, Cecilia Yeung, Andreas Hochhaus.

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

DOI: https://doi.org/10.1038/s41375-022-01613-1
Nat Cell Biol. 2022 Jun 20.

Hyaluronic acid-GPRC5C signalling promotes dormancy in haematopoietic stem cells.

Yu Wei Zhang, Julian Mess, Nadim Aizarani, Pankaj Mishra, Carys Johnson, Mari Carmen Romero-Mulero, Jasmin Rettkowski, Katharina Schönberger, Nadine Obier, Karin Jäcklein, Nadine M Woessner, Maria-Eleni Lalioti, Talia Velasco-Hernandez, Katarzyna Sikora, Ralph Wäsch, Bernhard Lehnertz, Guy Sauvageau, Thomas Manke, Pablo Menendez, Sebastian Gottfried Walter, Susana Minguet, Elisa Laurenti, Stefan Günther, Dominic Grün, Nina Cabezas-Wallscheid.

Bone marrow haematopoietic stem cells (HSCs) are vital for lifelong maintenance of healthy haematopoiesis. In inbred mice housed in gnotobiotic facilities, the top of the haematopoietic hierarchy is occupied by dormant HSCs, which reversibly exit quiescence during stress. Whether HSC dormancy exists in humans remains debatable. Here, using single-cell RNA sequencing, we show a continuous landscape of highly purified human bone marrow HSCs displaying varying degrees of dormancy. We identify the orphan receptor GPRC5C, which enriches for dormant human HSCs. GPRC5C is also essential for HSC function, as demonstrated by genetic loss- and gain-of-function analyses. Through structural modelling and biochemical assays, we show that hyaluronic acid, a bone marrow extracellular matrix component, preserves dormancy through GPRC5C. We identify the hyaluronic acid-GPRC5C signalling axis controlling the state of dormancy in mouse and human HSCs.

DOI: https://doi.org/10.1038/s41556-022-00931-x
Hemasphere. 2022 Jun;6(6): e721

European LeukemiaNet Response Predicts Disease Progression but Not Thrombosis in Polycythemia Vera.

Douglas Tremblay, Andrew Srisuwananukorn, Lukas Ronner, Nikolai Podoltsev, Jason Gotlib, Mark L Heaney, Andrew Kuykendall, Casey L O'Connell, Jamile M Shammo, Angela Fleischman, Ruben Mesa, Abdulraheem Yacoub, Ronald Hoffman, Erin Moshier, Nicole Zubizarreta, John Mascarenhas.

DOI: https://doi.org/10.1097/HS9.0000000000000721
Blood Cancer J. 2022 Jun 24. 12(6): 93

Clinical outcome of myelodysplastic syndrome progressing on hypomethylating agents with evolving frontline therapies: continued challenges and unmet needs.

Ahmad Ghorab, Aref Al-Kali, Michelle Elliot, Naseema Gangat, Hasan Alkhateeb, Mithun Shah, Yuanhang Liu, Cecilia Arana Yi, Hemant Murthy, Mohamed Kharfan-Dabaja, Ayalew Tefferi, Mrinal Patnaik, Mark Litzow, Talha Badar.

DOI: https://doi.org/10.1038/s41408-022-00691-9
Blood. 2021 Dec 17. pii: blood.2020009839. [Epub ahead of print]

Specification of hematopoietic stem cells in mammalian embryos: A rare or frequent event?

Miguel Ganuza, Wilson Kendrick Clements, Shannon L McKinney Freeman.

Hematopoietic stem cells (HSCs) are the blood forming stem cells thought to be responsible for supporting the blood system throughout life. Transplantability has long been the flagship assay used to define and characterize HSCs throughout ontogeny. However, it has recently become clear that many cells emerge during ontogeny that lack transplantability, yet nevertheless are fated to ultimately contribute to the adult HSC pool. Here, we explore recent advances in understanding the numbers and kinetics of cells that emerge during development to support lifelong hematopoiesis-advances that are made possible by new technologies allowing interrogation of lifelong blood potential without embryo perturbation or transplantation. Illuminating the dynamics of these cells during normal development informs efforts to better understand the origins of hematologic disease and engineer HSCs from differentiating pluripotent stem cells.

DOI: https://doi.org/10.1182/blood.2020009839
Nat Metab. 2022 Jun 23.

Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited.

Zhaoqi Li, Brian W Ji, Purushottam D Dixit, Konstantine Tchourine, Evan C Lien, Aaron M Hosios, Keene L Abbott, Justine C Rutter, Anna M Westermark, Elizabeth F Gorodetsky, Lucas B Sullivan, Matthew G Vander Heiden, Dennis Vitkup.

Production of oxidized biomass, which requires regeneration of the cofactor NAD+, can be a proliferation bottleneck that is influenced by environmental conditions. However, a comprehensive quantitative understanding of metabolic processes that may be affected by NAD+ deficiency is currently missing. Here, we show that de novo lipid biosynthesis can impose a substantial NAD+ consumption cost in proliferating cancer cells. When electron acceptors are limited, environmental lipids become crucial for proliferation because NAD+ is required to generate precursors for fatty acid biosynthesis. We find that both oxidative and even net reductive pathways for lipogenic citrate synthesis are gated by reactions that depend on NAD+ availability. We also show that access to acetate can relieve lipid auxotrophy by bypassing the NAD+ consuming reactions. Gene expression analysis demonstrates that lipid biosynthesis strongly anti-correlates with expression of hypoxia markers across tumor types. Overall, our results define a requirement for oxidative metabolism to support biosynthetic reactions and provide a mechanistic explanation for cancer cell dependence on lipid uptake in electron acceptor-limited conditions, such as hypoxia.

DOI: https://doi.org/10.1038/s42255-022-00588-8