In most patients with chronic myeloid leukemia (CML) clonal cells can be kept under control by BCR::ABL1 tyrosine kinase inhibitors (TKI). However, overt resistance or intolerance against these TKI may occur. We identified the epigenetic reader BRD4 and its downstream‐effector MYC as growth regulators and therapeutic targets in CML cells. BRD4 and MYC were found to be expressed in primary CML cells, CD34+/CD38− leukemic stem cells (LSC), and in the CML cell lines KU812, K562, KCL22 and KCL22T315I. The BRD4‐targeting drug JQ1 was found to suppress proliferation in KU812 cells and primary leukemic cells in the majority of patients with chronic phase CML. In the blast phase of CML, JQ1 was less effective. However, the BRD4 degrader dBET6 was found to block proliferation and/or survival of primary CML cells in all patients tested, including blast phase CML and CML cells exhibiting the T315I variant of BCR::ABL1. Moreover, dBET6 was found to block MYC expression and to synergize with BCR::ABL1 TKI in inhibiting the proliferation in the JQ1‐resistant cell line K562. Furthermore, BRD4 degradation was found to overcome osteoblast‐induced TKI resistance of CML LSC in a co‐culture system and to block interferon‐gamma‐induced upregulation of the checkpoint antigen PD‐L1 in LSC. Finally, dBET6 was found to suppress the in vitro survival of CML LSC and their engraftment in NSG mice. Together, targeting of BRD4 and MYC through BET degradation sensitizes CML cells against BCR::ABL1 TKI and is a potent approach to overcome multiple forms of drug resistance in CML LSC. This article is protected by copyright. All rights reserved.
Human endogenous retroviruses (HERVs) represent 8% of the human genome. The expression of HERVs and their immune impact have not been extensively studied in Acute Myeloid Leukemia (AML). In this study, we used a reference of 14,968 HERV functional units to provide a thorough analysis of HERV expression in normal and AML bone marrow cells. We show that the HERV retrotranscriptome accurately characterizes normal and leukemic cell subpopulations, including leukemia stem cells, in line with different epigenetic profiles. We then show that HERV expression delineates AML subtypes with different prognoses. We finally propose a method to select and prioritize CD8+ T cell epitopes derived from AML‐specific HERVs and we show that lymphocytes infiltrating patient bone marrow at diagnosis contain naturally occurring CD8+ T cells against these HERV epitopes. We also provide in vitro data supporting the functionality of HERV‐specific CD8+ T‐cells against AML cells. These results show that HERVs represent an important source of genetic information that can help enhancing disease stratification or biomarker identification and an important reservoir of alternative tumor‐specific T cell epitopes relevant for cancer immunotherapy. This article is protected by copyright. All rights reserved.
Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100,000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults DIAGNOSIS: CML is characterized by a balanced genetic translocation, t (9;22) (q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR::ABL1 fusion oncogene, which in turn translates into a BCR::ABL1 oncoprotein.
Four tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, bosutinib, and nilotinib are approved by the United States Food and Drug Administration for first-line treatment of newly diagnosed CML in chronic phase (CML-CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses but had no impact on survival prolongation, likely because of the availability of effective TKIs salvage therapies for patients who have a cytogenetic relapse with frontline TKI therapy.
For CML post failure on frontline therapy, second-line options include second and third generation TKIs. Although potent and selective, these TKIs exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities, disease stage, and BCR::ABL1 mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib, asciminib, and olverembatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP and failure (due to resistance) of at least 2 TKIs, and for all patients in advanced phase disease. Older patients who have a cytogenetic relapse post failure on all TKIs can maintain long-term survival if they continue a daily most effective/least toxic TKI, with or without the addition of non-TKI anti-CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, busulfan, others). This article is protected by copyright. All rights reserved.
Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open‐label, clinical trials in dialysis‐dependent and non–dialysis‐dependent patients with CKD and anemia, the hypoxia‐inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis‐stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron‐binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.
The incremental impact of autologous hematopoietic cell transplantation (AHCT) on disease burden with quadruplet induction in newly diagnosed multiple myeloma (NDDM) can be reappraised with the serial assessment of minimal residual disease (MRD). We describe the impact of AHCT on MM burden assessed by next‐generation sequencing (NGS) for patients enrolled in a clinical trial utilising quadruplet induction, AHCT, followed by MRD‐adapted consolidation. We describe quantitative changes in MRD burden with AHCT and explore patient and disease features influencing the magnitude of MRD reduction with AHCT. Among 123 included patients, 109 underwent AHCT and had MRD assessment pre and post AHCT. Forty per cent achieved MRD<10‐5 post‐induction, increasing to 70% after AHCT. Of the 65 patients (60%) who remained MRD positive post‐induction, 54 (83%) had a reduction in MRD burden with AHCT. The median reduction in MRD with AHCT was 1.10 log10 (range ‐1.26 to 3.41). Patients with high‐risk cytogenetic abnormalities (HRCA) had greater reduction in MRD burden (P=0.02) after AHCT. Median relative reduction was 0.91 log10 (range ‐0.75 to 2.14), 1.26 log10 (range ‐0.21to 3.26) and 1.34 log10 (range ‐1.28 to 3.41) for patients with 0, 1 and 2+ HRCA, respectively. The presence of HRCA was the only factor associated with greater than 1 log10 reduction in MRD burden with AHCT. Serial NGS MRD demonstrates the incremental effect of AHCT in MM marrow burden in the context of quadruplet induction, particularly in high risk MM. This article is protected by copyright. All rights reserved.
Numerical abnormalities of chromosome 1q (+1q21) are common in patients with newly diagnosed multiple myeloma (MM) but their prognostic impact remains a matter of debate. In addition, the impact of the number of copies of 1q21 is not known. We analyzed 912 consecutive patients with symptomatic MM to evaluate the prognostic implications of +1q21 and of their copy number variations, as assessed by FISH. At the time of initial diagnosis 249 (27.3%) patients had +1q21, of which 150 (16.4%) had 3 copies and 99 (10.9%) had 4 or more copies. Presence of +1q21 was associated with advanced ISS stage (p=0.003), concurrent presence of other cytogenetics aberrations and advanced R‐ISS stage (p<0.001). Patients with +1q21 had inferior PFS (median 34 vs 20 months, p<0.001) and OS (median 75 vs 44 months, p<0.001) but the copy number of 1q21 had no additional prognostic impact. In multivariate analysis, adjusting for R‐ISS, age, treatment and HDM, +1q21 remained an independent prognostic factor both for PFS (p<0.001) and OS (p=0.008). The detrimental prognostic effect of +1q21 was more profound in R‐ISS‐3 patients, identifying a subgroup with OS of just 16 months (vs 46 for R‐ISS‐3 without +1q21, p<0.001). We further validated our findings in an independent cohort of 272 patients. In conclusion, presence of +1q21 is associated with more advanced disease, inferior PFS and OS but especially patients with R‐ISS‐3 disease and +1q21 have a very poor outcome comprising an ultra‐high‐risk group. This article is protected by copyright. All rights reserved.
High‐dose melphalan and stem cell transplantation (HDM/SCT) is an effective treatment for selected patients with AL amyloidosis. We report the long‐term outcomes of 648 patients with AL amyloidosis treated with HDM/SCT over 25 years. Hematologic CR was achieved by 39% of patients. The median duration of hematologic CR was 12.3 years, and 45% of patients with a hematologic CR had no evidence of a recurrent plasma cell dyscrasia at 15 years after HDM/SCT. With a median follow‐up interval of 8 years, the median event‐free survival (EFS) and overall survival (OS) were 3.3 and 7.6 years, respectively. Patients with a hematologic CR had a median OS of 15 years, and 30% of these patients survived >20 years. On multivariable analysis, dFLC >180 mg/L and BM plasma cells >10% were independently associated with shorter EFS, whereas BNP >81 pg/mL, troponin I >0.1 ng/mL, and serum creatinine >2.0 mg/dL were independently associated with shorter OS. We developed a prognostic score for EFS, which incorporated dFLC >180 mg/L and BMPC% >10% as adverse risk factors. Patients with low‐risk (0 factors), intermediate‐risk (1 factor), and high‐risk (2 factors) disease had median EFS estimates of 5.3, 2.8, and 1.0 years, respectively (p<0.001). The 100‐day treatment‐related mortality rate was 3% in the latest treatment period (2012‐2021), and the 25‐year risk of t‐MDS/AML was 3%. We conclude that HDM/SCT induces durable hematologic responses and prolonged survival with improved safety in selected patients with AL amyloidosis. This article is protected by copyright. All rights reserved.
With lowering costs of sequencing and genetic profiling techniques, genetic drivers can now be detected readily in tumors but current prognostic models for Natural‐killer/T cell lymphoma (NKTCL) have yet to fully leverage on them for prognosticating patients. Here, we used next‐generation sequencing to sequence 260 NKTCL tumors, and trained a genomic prognostic model (GPM) with the genomic mutations and survival data from this retrospective cohort of patients using LASSO Cox regression. The GPM is defined by the mutational status of 13 prognostic genes and is weakly correlated with the risk‐features in International Prognostic Index (IPI), Prognostic Index for Natural‐Killer cell lymphoma (PINK) and PINK‐Epstein‐Barr virus (PINK‐E). Cox‐proportional hazard multivariate regression also showed that the new GPM is independent and significant for both progression‐free survival (PFS, HR: 3.73, 95% CI 2.07‐6.73; P<0.001) and overall survival (OS, HR: 5.23, 95% CI 2.57‐10.65; P=0.001) with known risk‐features of these indices. When we assign an additional risk‐score to samples, which are mutant for the GPM, the Harrell's C‐indices of GPM‐augmented IPI, PINK and PINK‐E improved significantly (P<0.001, χ2 test) for both PFS and OS. Thus, we report on how genomic mutational information could steer towards better prognostication of NKTCL patients. This article is protected by copyright. All rights reserved.
The presence of measurable residual disease (MRD) is the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). We conducted a prospective, single‐arm, phase II study in adults with B‐cell ALL with MRD ≥1x10‐4 after ≥3 months from the start of frontline therapy or one month from any salvage therapy. Blinatumomab was administered at a standard dosing of 28 micrograms daily as a continuous infusion for up to five cycles and up to 4 additional maintenance cycles. Thirty‐seven patients with a median age of 43 years (range, 22‐84 years) were treated. Twenty‐seven patients (73%) were treated in first complete remission (CR) and 10 patients (27%) in second CR and beyond. Eighteen patients (49%) had Philadelphia‐chromosome positive ALL and received concomitant tyrosine kinase inhibitor therapy. Twenty‐three patients (62%) had a baseline MRD ≥10−3. A median of three cycles (range, 1‐9 cycles) were administered. Overall, 27 patients (73%) achieved MRD‐negative remission. With a median follow‐up of 31 months (range, 5‐70 months), the estimated 3‐year relapse‐free survival (RFS) rate was 63% (95% confidence interval [CI], 43%‐77%) and overall survival (OS) rate 67% (95% CI, 46%‐81%). These rates were 51% (95% CI, 27%‐70%) and 61% (95% CI, 36%‐78%) in patients with baseline MRD ≥1x10‐3, and 83% (95% CI, 45%‐95%) and 77% (95% CI, 32%‐95%) in patients with baseline MRD <10−3, respectively. The rates of adverse events were consistent with previous studies of blinatumomab. In summary, blinatumomab induced MRD negativity in most patients and resulted in high rates of RFS and OS. This study is registered at www.clinicaltrials.gov as #NCT02458014. Funding provided by Amgen Inc. This article is protected by copyright. All rights reserved.
Intravascular lymphoma (IVL) is a rare extranodal non‐Hodgkin lymphoma. We performed a retrospective analysis of 55 IVL patients who were treated at our institution 2003–2018. Median age at diagnosis was 68 years, and 64% were males. The most frequent presenting symptoms were skin rash 43% and weight loss 30%. MRI brain on IVL patients with CNS involvement (CNS‐IVL) showed multifocal involvement in 76% (13/17). 89% (17/19) of non‐CNS‐IVL patients with abnormal FDG‐PET had biopsy of an avid lesion resulting in definitive diagnosis. The top diagnostic biopsy site was the bone marrow (45%). 56% had multiorgan involvement. Based on CNS involvement, 36.5% (20/55) had CNS‐IVL and 63.5% (35/55) had non‐CNS‐IVL. CNS‐IVL group consists of clinically isolated CNS involvement (CNS‐only IVL) (22%;12/55) and mixed clinical CNS and peripheral site involvement (M‐IVL) (14.5%; 8/55). Non‐CNS‐IVL group consists of clinically isolated skin involvement (skin‐only IVL) (9%; 5/55) and peripheral IVL with or without skin involvement (P‐IVL); (54.5%; 30/55). Skin involvement was predominantly in the lower extremities. Pathologically, 89% (48/54) were B‐cell IVL. Rituximab + high‐dose methotrexate‐based regimen were used in 62% (10/16) of CNS‐IVL patients and RCHOP in 60% (17/28) of non‐CNS‐IVL patients. Estimated 5‐year progression free survival (PFS) and overall survival (OS) for the entire cohort were 38.6% and 52% respectively. Skin‐only IVL was associated with excellent survival. Platelet count <150x109/L, age > 60Y, and treatment without Rituximab were poor prognostic factors. Further research is necessary to identify novel therapies. This article is protected by copyright. All rights reserved.
The current study was approached with the assumption that response to induction chemotherapy, in acute myeloid leukemia (AML), overshadows pre‐treatment risk variables in predicting survival and therefore be used as an anchor for a simplified risk model. We considered 759 intensively‐treated patients with AML, not promyelocytic: median age 60 years; primary 66%, secondary 25%, and therapy‐related 9%; European LeukemiaNet cytogenetic risk category favorable 8%, intermediate 61%, and adverse 31%. Complete remission with (CR) or without (CRi) count recovery was achieved in 608 (80%) patients. After a median follow‐up of 22 months, 503 deaths, 272 relapses, and 257 allogeneic hematopoietic stem cell transplants (AHSCTs) were recorded. Multivariable analysis identified failure to achieve CR/CRi (HR 3.8, 95% CI 3.1‐4.8), adverse karyotype (2.2, 1.8‐2.8), and age >55 years (2.1, 1.6‐2.7) as main risk factors for survival. HR‐weighted scoring resulted in four‐tiered risk stratification: low (0 points; N=183), intermediate‐1 (1 point; N=331), intermediate‐2 (2 points; N=117), and high (≥3 points; N=128), with respective median survival (5‐year rate) not reached (68%), 34 (37%), 13 (20%), and 5 (5%) months (p <0.001). FLT3‐ITD mutation was associated with inferior survival in intermediate‐1 (p=0.004) and TP53 in intermediate‐2 (p=0.06) and high (p=0.02) risk disease; the latter was fully accounted for by the close association between TP53 mutation and complex/monosomal karyotype while the observations regarding FLT3‐ITD were not affected by treatment with midostaurin. AHSCT had a favorable impact on survival, most apparent in intermediate‐1 (p<0.001), intermediate‐2 (p=0.03), and high (p=0.01) risk disease. The proposed 3‐factor survival model offers a novel prototype that is amenable to further enhancement by molecular information and was validated in an external cohort of 1,032 intensively‐treated AML patients. This article is protected by copyright. All rights reserved.
CRISPR/Cas genome engineering has emerged as a powerful tool to modify precise genomic sequences with unparalleled accuracy and efficiency. Major advances in CRISPR technologies over the last five years have fueled the development of novel techniques in hematopoiesis research to interrogate the complexities of hematopoietic stem cell (HSC) biology. In particular, high throughput CRISPR based screens using various “flavors” of Cas coupled with sequencing and/or functional outputs are becoming increasingly efficient and accessible. In this review, we discuss recent achievements in CRISPR‐mediated genomic engineering and how these new tools have advanced the understanding of HSC heterogeneity and function throughout life. Additionally, we highlight how these techniques can be used to answer previously inaccessible questions and the challenges to implement them. Finally, we focus on their translational potential to both model and treat hematological diseases in the clinic. This article is protected by copyright. All rights reserved.
Low‐dose dasatinib is safe and effective in patients with chronic myeloid leukemia in chronic phase (CML‐CP). No randomized trials have compared the outcome with standard‐dose dasatinib. This study aims to compare the outcome of patients with CML‐CP treated with frontline dasatinib 50 mg/day versus 100 mg/day. We analyzed 233 patients with newly diagnosed CML‐CP treated with low‐dose dasatinib (N=83) or standard‐dose dasatinib (N=150). Propensity score analysis with 1:1 matching was performed and identified 77 patients in each cohort without significant baseline differences. Response rates were reported as the cumulative incidences of complete cytogenetic response, major molecular response (MMR), molecular response (MR)4 and MR4.5. Failure‐free survival (FFS), event‐free survival (EFS), transformation‐free survival (TFS), and overall survival (OS) were also compared. Patients on low‐dose dasatinib with suboptimal response by ELN 2013 criteria had the option to increase the dose to 100 mg/day. The overall median follow‐up time was 60 months. The 3‐year MMR rates were 92% and 84% for low‐dose and standard‐dose dasatinib, respectively (P=0.23). Dasatinib 50 mg/day induced higher cumulative incidence of MR4 (77% versus 66%; P=0.04) and MR4.5 (77% versus 62%; P=0.02) at 3 years. The 4‐year FFS, EFS and OS rates were 89% versus 77% (P=0.04), 95% versus 92% (P=0.06), and 97% versus 96% (P=0.78) with low‐dose and standard‐dose dasatinib, respectively. The rate of any grade pleural effusion was 5% with dasatinib 50 mg/day compared to 21% with 100 mg/day. Dasatinib 50 mg/day is at least as effective as 100 mg/day with a better safety profile and drug exposure. This article is protected by copyright. All rights reserved.
Co‐occurrence of mutations in two different genes has distinctive outcomes on cell viability ranging from no effect to enhancing viability, but can also reduce viability or fitness. The latter interaction type may explain mutual exclusivity of certain somatic mutations in cancer. Myeloproliferative neoplasms (MPN) are driven by oncogenic mutation in the JAK2, CALR or MPL gene, which were described as mutually exclusive in the past. Although co‐occurrence of two driver mutations was reported in rare patients, some reports showed that mutations were acquired in two independent clones, thereby raising the question, whether the co‐occurrence of both mutations in a hematopoietic stem cell (HSC) reduces cellular fitness. In this study, we examined the effect of Jak2‐V617F and Calr‐del52 co‐expression on HSC fitness with the aim to confirm or rule out their synthetic lethal interaction. We crossed mice expressing single mutations and analyzed the hematopoietic phenotype of double mutants. To assess stem cell fitness, we performed primary and secondary bone marrow transplantation assays. Double mutant mice had a more severe MPN phenotype and reduced survival compared to single mutants. Moreover, HSCs expressing both mutations outcompeted non‐mutated HSCs and maintained competitive fitness in primary and secondary transplants. This article is protected by copyright. All rights reserved.
Azacitidine and decitabine are hypomethylating agents that have dose‐dependent epigenetic and cytotoxic effects and are widely used in the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). In this review, we discuss the path to regulatory approval of azacitidine and decitabine, highlighting the substantial efforts that have been made to optimize the dosing schedule and administration of these drugs, including the development of new, oral formulations of both agents. We also review novel combination strategies that are being investigated in ongoing clinical trials for patients with MDS and AML, as well as efforts to expand the current indications of these agents. This article is protected by copyright. All rights reserved.
Coronavirus Disease (COVID‐19) can be considered as a human pathological model of inflammation combined with hypoxia. In this setting, both erythropoiesis and iron metabolism appear to be profoundly affected by inflammatory and hypoxic stimuli, which act in the opposite direction on hepcidin regulation. The impact of low blood oxygen levels on erythropoiesis and iron metabolism in the context of human hypoxic disease (e.g., pneumonia) has not been fully elucidated. This multicentric observational study was aimed at investigating the prevalence of anemia, the alterations of iron homeostasis, and the relationship between inflammation, hypoxia and erythropoietic parameters in a cohort of 481 COVID‐19 patients admitted both to medical wards and intensive care unit (ICU). Data were collected on admission and after seven days of hospitalization. On admission, nearly half of the patients were anemic, displaying mild‐to‐moderate anemia. We found that hepcidin levels were increased during the whole period of observation. The patients with a higher burden of disease (i.e., those who needed intensive care treatment or had a more severe degree of hypoxia) showed lower hepcidin levels, despite having a more marked inflammatory pattern. EPO levels were also lower in the ICU group on admission. After seven days, EPO levels rose in the ICU group while they remained stable in the non‐ICU group, reflecting that the initial hypoxic stimulus was stronger in the first group. These findings strengthen the hypothesis that, at least in the early phases, hypoxia‐driven stimuli prevail on inflammation in the regulation of hepcidin and, finally, of erythropoiesis. This article is protected by copyright. All rights reserved.
There are numerous reports of cancers in Gaucher disease from mostly small single‐center studies; however, precise risk estimates and cancer types involved have not been delineated. We conducted a study involving 2123 patients with Gaucher disease type 1 (GD1) to assess the incidence of hematological malignancies, gammopathies, and solid tumors in an international observational study, the International Cooperative Gaucher Group Gaucher Registry (Clinicaltrials.gov: NCT00358943). Risk for cancer overall and for each type of malignancy was compared to the United States (US) population using the Surveillance, Epidemiology, and End Results database. Natural history of gammopathy was determined through assessing the progression from a diagnosis of monoclonal gammopathy of unknown significance (MGUS) to multiple myeloma (MM). Risk for hematological malignancies was more than 4 times higher than expected compared to the general population: non‐Hodgkin lymphoma was approximately 3 times higher; MM was approximately 9 times higher. Age‐specific incidence rates of MGUS were unexpectedly high among younger patients. The 10‐year cumulative incidence of MM after diagnosis of MGUS was 7.9%, comparable to the general population. Compared to the general US population, GD1 patients were at higher risk for solid malignancies of liver (2.9 times), kidney (2.8 times), melanoma (2.5 times), and breast (1.4 times). Colorectal, prostate, and lung cancer risks were lower than expected. These findings help advance care of patients with GD1 by supporting recommendations for individualized monitoring for malignancies and antecedents such as MGUS for MM and provoke important questions of the role of glucosylceramide and related sphingolipids in cancer biology. This article is protected by copyright. All rights reserved.
Patients with B‐cell malignancies have suboptimal immune responses to SARS‐CoV‐2 vaccination and are a high‐risk population for severe COVID19 disease. We evaluated the effect of a third booster BNT162b2 vaccine on the kinetics of anti‐ SARS‐CoV‐2 neutralizing antibody (NAbs) titres in patients with B‐cell malignancies. Patients with NHL (n=54) Waldenström's macroglobulinemia (n=90) and chronic lymphocytic leukemia (n=49) enrolled in the ongoing NCT04743388 study and compared against matched healthy controls. All patient groups had significantly lower NAbs compared to controls at all time points. One month post the third dose (M1P3D) NAbs increased significantly compared to previous time points (median NAbs 77.9%, p <0.05 for all comparisons) in all patients. NAbs≥50% were seen in 59.1% of patients, 34.5% of patients with suboptimal responses post‐second dose, elicited a protective NAb titre ≥50%. Active treatment, rituximab and BTKi treatment were the most important prognostic factors for a poor NAb response at 1MP3D; only 25.8% of patients on active treatment had NAbs ≥50%. No significant between group differences were observed. Patients with B‐cell malignancies have inferior humoral responses against SARS‐CoV‐2 and booster dose enhances the NAb response in a proportion of these patients. This article is protected by copyright. All rights reserved.
Ponatinib, the only third‐generation pan‐BCR::ABL1 inhibitor with activity against all known BCR::ABL1 mutations including T315I, has demonstrated deep and durable responses in patients with chronic‐phase chronic myeloid leukemia (CP‐CML) resistant to prior second‐generation (2G) TKI treatment. We present efficacy and safety outcomes from the Ponatinib Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) and CML Evaluation (PACE) and Optimizing Ponatinib Treatment in CP‐CML (OPTIC) trials for this patient population. PACE (NCT01207440) evaluated ponatinib 45 mg/day in CML patients with resistance to prior TKI or T315I. In OPTIC (NCT02467270), patients with CP‐CML and resistance to ≥2 prior TKIs or T315I receiving 45 or 30 mg/day reduced their doses to 15 mg/day upon achieving ≤1% BCR::ABL1IS or received 15 mg/day continuously. Efficacy and safety outcomes from patients with CP‐CML treated with ≥1 2G TKI (PACE, n=257) and OPTIC (n=93), 45‐mg starting dose cohort, were analyzed for BCR::ABL1IS response rates, overall survival (OS), progression‐free survival (PFS), and safety. By 24 months, the percentages of patients with ≤1% BCR::ABL1IS response, PFS, and OS were 46%, 68%, and 85%, respectively, in PACE and 57%, 80% and 91%, respectively, in OPTIC. Serious treatment‐emergent adverse event and serious treatment‐emergent arterial occlusive event rates were 63% and 18% in PACE and 34% and 4% in OPTIC. Ponatinib shows high response rates and robust survival outcomes in patients whose disease failed prior 2G TKIs, including patients with T315I mutation. The response‐based dosing in OPTIC led to improved safety and similar efficacy outcomes compared with PACE. This article is protected by copyright. All rights reserved.
Erythroferrone (ERFE) is an erythroblast‐secreted regulator of iron metabolism. The production of ERFE increases during stress erythropoiesis, leading to decreased hepcidin expression and mobilization of iron. Pregnancy requires a substantial increase in iron availability to sustain maternal erythropoietic expansion and fetal development and is commonly affected by iron deficiency. To define the role of ERFE during iron‐replete or iron‐deficient pregnancy, we utilized mouse models expressing a range of ERFE levels: transgenic mice overexpressing ERFE (TG), wild‐type (WT) and ERFE knockout (KO) mice. We altered maternal iron status using diets with low or standard iron content and performed analysis at E18.5. Iron deficiency increased maternal ERFE in WT pregnancy. Comparing different maternal genotypes, ERFE TG dams had lower hepcidin relative to their liver iron load but similar hematological parameters to WT dams on either diet. In ERFE KO dams, most hematologic and iron parameters were comparable to WT, but MCV was decreased under both iron conditions. Similar to dams, TG embryos had lower hepcidin on both diets, but their hematologic parameters did not differ from those of WT embryos. ERFE KO embryos had lower MCV than WT embryos on both diets. The effect was exacerbated under iron‐deficient conditions where ERFE KO embryos had higher hepcidin, lower Hb and Hct and lower brain iron concentration compared to WT embryos, indicative of iron restriction. Thus, under iron‐deficient conditions, maternal and embryo ERFE facilitate iron mobilization for embryonic erythropoiesis. This article is protected by copyright. All rights reserved.
β‐thalassemia is a genetic disorder caused by mutations in the β‐globin gene, and characterized by anemia, ineffective erythropoiesis and iron overload. Patients affected by the most severe transfusion‐dependent form of the disease (TDT) require lifelong blood transfusions and iron chelation therapy, a symptomatic treatment associated with several complications. Other therapeutic opportunities are available, but none is fully effective and/or applicable to all patients, calling for the identification of novel strategies. Transferrin receptor 2 (TFR2) balances red blood cells production according to iron availability, being an activator of the iron‐regulatory hormone hepcidin in the liver and a modulator of Erythropoietin signalling in erythroid cells. Selective Tfr2 deletion in the BM improves anemia and iron‐overload in non‐TDT mice, both as a monotherapy and, even more strikingly, in combination with iron‐restricting approaches. However, whether Tfr2 targeting might represent a therapeutic option for TDT has never been investigated so far. Here we prove that BM Tfr2 deletion improves anemia, erythrocytes morphology and ineffective erythropoiesis in the Hbbth1/th2 murine model of TDT. This effect is associated with a decrease in the expression of α‐globin, which partially corrects the unbalance with β‐globin chains and limits the precipitation of misfolded hemoglobin, and with a decrease in the activation of unfolded protein response. Remarkably, BM Tfr2 deletion is also sufficient to avoid long‐term blood transfusions required for survival of Hbbth1/th2 animals, preventing mortality due to chronic anemia and reducing transfusion‐associated complications, such as progressive iron‐loading. Altogether, TFR2 targeting might represent a promising therapeutic option also for TDT. This article is protected by copyright. All rights reserved.
The best stem cell source for T‐cell replete HLA‐haploidentical transplantation with post‐transplant cyclophosphamide (PTCy) remains to be determined. In this EBMT retrospective study we analyzed the impact of stem cell source on leukemia‐free survival (LFS) in adult patients with primary refractory or relapsed acute myeloid leukemia (AML) given grafts from HLA‐haploidentical donors with PTCy as graft‐versus‐host disease (GVHD) prophylaxis. A total of 668 patients (249 bone marrow (BM) and 419 peripheral blood stem cells (PBSC) recipients) met the inclusion criteria. The use of PBSC was associated with a higher incidence of grade II‐IV (HR = 1.59, P = 0.029) and grade III‐IV (HR = 2.08, P = 0.013) acute GVHD. There was a statistical interaction between patient age and the impact of stem cell source for LFS (P < 0.01). In multivariate Cox models, among patients <55 years, the use of PBSC versus BM resulted in comparable LFS (HR = 0.82, P = 0.2). In contrast, in patients ≥55 years of age, the use of PBSC versus BM was associated with higher non‐relapse mortality (NRM) (HR = 1.7, P = 0.01), lower LFS (HR = 1.37, P = 0.026) and lower overall survival (OS) (HR = 1.33, P = 0.044). In conclusions, our data suggest that in patients ≥55 years of age with active AML at HLA‐haploidentical transplantation, the use of BM instead of PBSC as stem cell source results in lower NRM and better LFS. In contrast among younger patients, the use of PBSC results in at least a comparable LFS. This article is protected by copyright. All rights reserved.