Monoclonal antibodies targeting specific cell surface antigens have emerged as a promising therapeutic approach for acute myeloid leukemia (AML), thus widening the treatment landscape of this heinous disease. These antibodies have been designed to selectively target and eliminate leukemic cells while limiting damage to the normal hematopoietic counterpart. Among the potential targets on AML cells, CD33, CD123, and CD47 have shown the major potential in preclinical and clinical trials. Additionally, conjugation of monoclonal antibodies with cytotoxic agents has further enhanced their therapeutic efficacy. Nonetheless, challenges such as antigen heterogeneity, resistance mechanisms, and the immunosuppressive tumor microenvironment remain significant barriers to achieving durable remission in AML patients. This review explores the mechanisms of action, current clinical developments, and ongoing trials into the role of monoclonal antibodies in AML, highlighting their potential to improve clinical outcomes when used alone or in combination with conventional therapies, making them thus able to become, in the near future, a cornerstone in the treatment of AML.

The BCR::ABL1 fusion gene, resulting from the Philadelphia (Ph) chromosome, is the defining feature of Chronic Myeloid Leukemia (CML). The fusion transcript typically results from the juxtaposition of ABL1 exons 2 or 3 and BCR exons 1, 13, 14 or 19, while exons 6 and 8 are less frequently involved. Here, we report the first case of a translocation in a patient with newly diagnosed chronic-phase CML harboring a novel e4a2 BCR::ABL1 fusion gene. This unique fusion includes a 298 bp insertion, derived from a CSE1L gene exons 9 and 10, at the fusion site. The patient showed resistance to first-line dasatinib but achieved a molecular response with the third-generation tyrosine kinase inhibitor ponatinib.

Background: Nucleophosmin-1 (NPM1) mutation accounts for 30% of acute myeloid leukemia (AML) cases and defines either low- or intermediate-risk AML, depending on FLT3-ITD mutation. New combination regimens (NCRs), adding midostaurin and gemtuzumab ozogamicin (GO) to the 3 + 7 scheme, are commonly used, though there are no data that compare NCRs with intensive induction chemotherapy. Methods: To evaluate the efficacy and safety of NCRs and FLAI in NPM1+ AML, we retrospectively analyzed 125 patients treated with FLAI (n = 53) or NCRs (n = 72) at seven Italian Centers. Results: The median age was 61 years and 51/125 (41%) were FLT3-ITD+. The complete remission (CR) rate was 77%, slightly better with NCRs (83% vs. 68%; p = 0.054). NCRs yielded a superior median overall survival (OS) (not reached (NR) vs. 27.3 months; p = 0.002), though the median event-free survival (EFS) was similar (NR vs. 20.5 months; p = 0.07). In low-risk AML, CR was higher in NCRs (94% vs. 72%, p = 0.02), as were median OS (NR vs. 41.6 months; p = 0.0002) and EFS (NR vs. 17.8 months; p = 0.0085). In intermediate-risk AML (FLT3-ITD+), there were no differences in CR (60% vs. 71%; p = 0.5), OS (p = 0.27), or EFS (p = 0.86); only allogeneic transplantation improved OS (NR vs. 13.4 months; p = 0.005), regardless of induction regimen. The safety profile was similar, except for delayed platelet recovery with FLAI (22 vs. 18 days; p = 0.0024) and higher-grade II–IV gastrointestinal toxicity with NCRs (43% vs. 18.8%; p = 0.0066). Conclusions: Our data suggest the superiority of NCRs over FLAI in low-risk patients, while all outcomes were comparable in intermediate-risk patients, a setting in which only transplants positively impacted on survival.

Despite the progress in the knowledge of disease pathogenesis and the identification of many molecular markers as potential targets of new therapies, the cure of acute myeloid leukemia remains challenging. Disease recurrence after an initial response and the development of resistance to old and new therapies account for the poor survival rate and still make allogeneic stem cell transplantation the only curative option. Multidrug resistance (MDR) is a multifactorial phenomenon resulting from host-related characteristics and leukemia factors. Among these, the overexpression of membrane drug transporter proteins belonging to the ABC (ATP-Binding Cassette)-protein superfamily, which diverts drugs from their cellular targets, plays an important role. Moreover, a better understanding of leukemia biology has highlighted that, at least in cancer, ABC protein's role goes beyond simple drug transport and affects many other cell functions. In this paper, we summarized the current knowledge of ABCG2 (formerly Breast Cancer Resistance Protein, BCRP) in acute myeloid leukemia and discuss the potential ways to overcome its efflux function and to revert its ability to confer stemness to leukemia cells, favoring the persistence of leukemia progenitors in the bone marrow niche and justifying relapse also after therapy intensification with allogeneic stem cell transplantation.

Background:Tyrosine kinase inhibitors (TKIs) have become the preferred drugs for the treatment of chronic phase (CP) chronic myeloid leukemia (CML). This study aims to compare the safety and efficacy of different TKIs as first-line treatments for CML using network meta-analysis (NMA), providing a basis for the precise clinical use of TKIs. Methods:A systematic search was conducted on PubMed, Cochrane Library, Embase, China National knowledge Infrastructure (CNKI), Wanfang, Chinese Science and Technology Periodical Databases (VIP), SinoMed and ClinicalTrials.gov to include RCTs that compared the different TKIs as first line treatment for CML. The search timeline was from inception to 21 July 2023. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the frequentist NMA methods, the efficacy and safety of different TKIs were compared, including the rates of major molecular response (MMR), complete cytogenetic response (CCyR), all grade adverse events, grade 3 or higher hematologic adverse events and liver toxicity. Results:A total of 25 RCTs involving 6,823 patients with CML and 6 types of TKIs were included. In terms of efficacy, second-generation TKIs such as dasatinib, nilotinib, and radotinib showed certain advantages in improving patients' MMR and CCyR compared to imatinib. Additionally, imatinib 800 mg provided better MMRs and CCyRs than imatinib 400 mg. As far as safety was concerned, there was no significant difference in the incidence of all grade adverse events among the different TKIs. All TKIs can cause serious grade 3-4 hematologic adverse events, including anemia, thrombocytopenia, and neutropenia. Dasatinib more likely caused anemia, bosutinib thrombocytopenia, and imatinib neutropenia, whereas nilotinib and flumatinib might have better safety profiles in terms of severe hematologic adverse events. For liver toxicity, radotinib 400 mg and imatinib 800 mg, respectively, had the highest likelihood of ranking first in incidence rates of all grade ALT and AST elevation. Conclusions:In CML, second-generation TKIs are more clinically effective than imatinib even if this last drug has a relatively better safety profile. Thus, as each second-generation TKI has a distinct clinical efficacy and safety, and is associated with different economic factors, its choice should be dictated by the specific patient clinical conditions (patient's specific disease characteristics, comorbid conditions, potential drug interactions, as well as their adherence). Nevertheless, due to the limited number of original research, additional high-quality studies are needed to achieve any firm conclusion on which second-generation TKI is the best choice for that peculiar patient.

Chimeric antigen receptor (CAR) T-cell therapy represents one of the most impressive advances in anticancer therapy of the last decade. While CAR T-cells are gaining ground in various B cell malignancies, their use in acute myeloid leukemia (AML) remains limited, and no CAR-T product has yet received approval for AML. The main limitation of CAR-T therapy in AML is the lack of specific antigens that are expressed in leukemic cells but not in their healthy counterparts, such as hematopoietic stem cells (HSCs), as their targeting would result in an on-target/off-tumor toxicity. Moreover, the heterogeneity of AML and the tendency of blasts to modify surface antigens’ expression in the course of the disease make identification of suitable targets even more challenging. Lastly, AML’s immunosuppressive microenvironment dampens CAR-T therapeutic activities. In this review, we focus on the actual pitfalls of CAR T-cell therapy in AML, and we discuss promising approaches to overcome them.

Despite recent advances, the prognosis of acute myeloid leukemia (AML) remains unsatisfactory due to disease recurrence and the development of resistance to both conventional and novel therapies. Engineered T cells expressing chimeric antigen receptors (CARs) on their cellular surface represent one of the most promising anticancer agents. CAR-T cells are increasingly used in patients with B cell malignancies, with remarkable clinical results despite some immune-related toxicities. However, at present, the role of CAR-T cells in myeloid neoplasms, including AML, is extremely limited, as specific molecular targets for immune cells are generally lacking on AML blasts. Besides the paucity of dispensable targets, as myeloid antigens are often co-expressed on normal hematopoietic stem and progenitor cells with potentially intolerable myeloablation, the AML microenvironment is hostile to T cell proliferation due to inhibitory soluble factors. In addition, the rapidly progressive nature of the disease further complicates the use of CAR-T in AML. This review discusses the current state of CAR-T cell therapy in AML, including the still scanty clinical evidence and the potential approaches to overcome its limitations, including genetic modifications and combinatorial strategies, to make CAR-T cell therapy an effective option for AML patients.

Introduction: Despite recent advances, the only curative approach for most acute myeloid leukemia (AML) patients remains allogeneic hematopoietic cell transplant (HCT). Results of HCT are superior when performed in complete remission (CR), and the prognosis of patients with refractory or relapsed (R/R) AML remains dismal. In recent years venetoclax (VEN)-based combinations emerged as a standard of care in older/unfit patients, but VEN favorable efficacy and safety profile prompted its use also in R/R patients and the inclusion of VEN in induction chemotherapy for younger patients deemed candidate to transplant. However, to date, little is known on the role of VEN-based therapy as first-line or salvage therapy followed by allogeneic HCT in the real-world setting. Aim: The aim of this study is to retrospectively analyze the efficacy of VEN-based therapy as a bridge to transplant either when used as induction therapy or as a salvage option for R/R AML. Methods:We gathered data from 49 AML patients treated at 5 centers in the Triveneto region (Northeastern Italy) from 2020 to 2024, who received VEN in association with hypomethylating agents azacitidine (AZA) or decitabine (DEC), either as first-line treatment (group 1, n=13) or as a salvage therapy (group 2, n=36), followed by allogeneic HCT. Among patients with R/R AML, 24 (66%) received VEN as 2nd line, 10 (28%) as 3rd line and 2 (5%) as 4th line therapy. In group 1, median age at AML diagnosis was 64 years (range: 40-73), ELN 2022 risk was intermediate in 5 patients (38%) and adverse in 8 (62%), with 10 patients (77%) presenting MDS-related changes. VEN was administered for a median of 5 cycles (range: 1-10) at a median dose of 100 mg (due to concomitant posaconazole prophylaxis), in association with AZA or DEC in 9 (69%) and 4 (31%) patients, respectively. Group 2 had a median age at diagnosis of 54 years (range: 21-73), AML risk was favorable in 7 (19%), intermediate in 12 (33%) and adverse in 14 (39%); 13 patients (36%) presented MDS-related changes. In this group VEN was administered for a median of 3 cycles (range: 1-6) at a median dose of 100 mg, combined with AZA in 29 cases (80%), DEC in 6 (17%) and FLAI in 1 (3%). The R/R patients received, prior to VEN, a variety of intensive regimens including 3+7 alone or in combination with midostaurin or GO (10/36, 28%), CPX-351 (10/36, 28%), FLAI (10/36, 28%), MEC (3/36, 8%) or other (3/36, 8%). Regarding allogeneic HCT, among the 13 patients in group 1, median HCT-CI score was 2 (range: 0-4), and donor was HLA-identical sibling in 1 (8%), matched unrelated in 7 (54%), mismatched unrelated in 2 (15%) and haploidentical in 3 (23%). In group 2, median HCT-CI score was 1 (range: 0-6), and donor type was as follows: HLA-identical sibling 7 (19%), matched unrelated in 13 (36%), mismatched unrelated in 1 (3%) and haploidentical in 15 (42%). Results: In group 1, after VEN-based therapy 3/13 patients (23%) attained molecular CR (MR), 6 (46%) cytological CR, 1 (8%) morphological leukemia-free state (MLFS), 2 (15%) partial remission (PR) and 1 (8%) had a primary refractory disease. After HCT, 9 patients (69%) are alive and in molecular or cytological CR, while 4 patients (31%) had died, 2 for transplant related mortality (TRM) while in CR and 2 after AML relapse. Median OS in group 1 is 17.2 months, with a 12-month OS of 81.8% and 36-month OS of 40.9%. In group 2, before VEN-based therapy 23/36 patients (64%) had active AML, 1 (3%) was in PR, 4 (11%) were in molecular relapses and only 8 patients (22%) were in CR (cytological in 7 and molecular in 1). After VEN, 10 patients (28%) attained molecular CR, 17 (47%) cytological CR, 1 (3%) MLFS, 5 (14%) PR while only 3 patients (8%) still had active disease. After HCT, 24 patients (67%) are alive, with 22 in sustained molecular or cytological CR and 2 with relapsed AML, and 12 (33%) had died, 5 for TRM (4 while in CR) and 7 for AML progression. Median OS in this group is 46.2 months, 12-month OS is 88.9%, 36-month OS is 40.9% and 60-month OS is 26.9%.Conclusions: with the limit of a small sample size, our data suggest that VEN-based regimens are an effective strategy to induce response before allogeneic HCT. Of note, VEN therapy as a “bridge to transplant” in R/R AML, even in heavily pre-treated patients, grants high rates of CR, also molecular, thus allowing to perform allogeneic HCT with low leukemia burden.

It is now well known that the bone marrow (BM) cell niche contributes to leukemogenesis, but emerging data support the role of the complex crosstalk between AML cells and the BM microenvironment to induce a permissive immune setting that protects leukemic stem cells (LSCs) from therapy-induced death, thus favoring disease persistence and eventual relapse. The identification of potential immune targets on AML cells and the modulation of the BM environment could lead to enhanced anti-leukemic effects of drugs, immune system reactivation, and the restoration of AML surveillance. Potential targets and effectors of this immune-based therapy could be monoclonal antibodies directed against LSC antigens such as CD33, CD123, and CLL-1 (either as direct targets or via several bispecific T-cell engagers), immune checkpoint inhibitors acting on different co-inhibitory axes (alone or in combination with conventional AML drugs), and novel cellular therapies such as chimeric antigen receptor (CAR) T-cells designed against AML-specific antigens. Though dozens of clinical trials, mostly in phases I and II, are ongoing worldwide, results have still been negatively affected by difficulties in the identification of the optimal targets on LSCs.

Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by an increased risk of thrombotic and hemorrhagic events, that represent the leading causes of mortality and morbidity. Currently, while thrombotic risk is assessed through the IPSET-t and r-IPSET scores, there is no specific prognostic tool used to predict hemorrhagic risk in ET. The aim of the study was to define incidence and risk factors connected to hemorrhagic events by retrospectively analyzing 308 ET patients diagnosed between 1996 and 2022 at the Division of Hematology of Udine and treated according to the current international guidelines. According to molecular status, 193 patients (62.7%) were JAK2 mutated, 66 (21.4%) had a CALR mutation, 14 (4.5%) had a MPL mutation, 21 patients (6.8%) were "triple negative," and 14 patients (4.5%) were not evaluable. According to IPSET-t score, 49.7% patients were at high, 24.3% at intermediate, and 26.0% at low-risk, respectively. Twelve (3.9%) patients experienced bleeding at ET diagnosis, while 24 (7.8%) had at least one hemorrhagic event during follow-up at a median time of 103 months (range: 1-309). Forty hemorrhagic events were totally recorded and defined as minor in 22 cases, moderate in 11 cases, and severe in 7 cases. Cumulative incidence (CI) of hemorrhage at 10 and 20 years was 6.0% and 12.0%, respectively. A statistically significant correlation between hemorrhagic risk and IPSET-t score emerged: 10 years hemorrhage CI was 3.2% for low-risk, 2.9% for intermediate-risk, and 9.8% for high-risk patients, respectively (p=0.002). We found no correlation between hemorrhagic risk and gender or mutational status. Results of our study highlight the validity of IPSET-t score in predicting individual hemorrhagic risk among ET patients, suggesting a possible role of IPSET-t scoring system as a global evaluator for vascular events in ET patients.

Background: B-cell prolymphocytic leukemia (B-PLL) is a rare mature B-cell tumor with an aggressive clinical course and poor prognosis. It is characterized by prominent splenomegaly and prolymphocytes exceeding 55% of the lymphoid cells in the blood. Purine analog-based chemo-immunotherapy is the first-line therapy for B-PLL. Owing to its rarity, there are few reports on the efficacy of bendamustine and rituximab (BR) regimen. Our study presents three cases of BR being effective in the treatment of B-PLL and provides experience for clinical treatment. Case Description: This report describes the cases of three male patients (median age: 66 years old) who initially presented with abdominal discomfort. Physical examinations and imaging revealed splenomegaly, while a peripheral blood (PB) smear revealed a prolymphocyte count exceeding 70% of the lymphoid cells. Therefore, the three patients were diagnosed with B-PLL. Further molecular detection showed that they harbored P53 abnormalities (17p deletion/TP53 mutation) associated with resistance to conventional chemotherapies. In addition, one of the patients had a highly complex karyotype and multiple gene mutations. All patients underwent four cycles of BR, and two of them received two further cycles of rituximab monotherapy. Ultimately, the patients achieved a complete response (CR) that lasted for 25, 33, and 34 months, respectively, with a median follow-up time of 34 months. The adverse events of the BR mainly included a grade 3 haematological toxicities. Also, the treatment was well-tolerated. Conclusions: This case series suggests that BR regimen is promising for bringing deep remission to patients with B-PLL. Prospective trials are still required for further elucidation.

To the Editor We read with interest the manuscript by Haddad et al. “Treatment-free remission in patients with chronic myeloid leukemia following the discontinuation of tyrosine kinase inhibitors.” After reporting the outcome of 284 chronic myeloid leukemia (CML) patients discontinuing tyrosine kinase inhibitors (TKIs) therapy, the Authors tested the impact of the frequency of molecular monitoring after TKIs stop; they found that outcome in patients followed with a polymerase chain reaction (PCR) testing performed monthly in the first 6 months then every 2 months until the end of first year (group 1) was similar for patients in which molecular monitoring was done every 6–8 weeks in the first 6 months and every 3 months thereafter (group 2). These data seem to suggest the safety of a more “relaxed”molecular monitoring after TKI discontinuation. We have recently reported on our experience in 168 CML patients that stopped TKIs while in sustained deep molecular response (DMR) and that were monitored after discontinuation like patients in group 1 at MD Anderson. We found that 123 patients (73.2%) maintained major molecular response while 45 (24.8%) lost MMR; while being similar in the two cohorts at time of TKI stop, mean BCR::ABL1 RNA level was significantly higher in patients subsequently loosing MMR already at 1 month after discontinuation (0.0060 ± 0.0107 vs. 0.0010 ± 0.0026; p = 0.0005), and the difference was even greater at 2 months (0.1354 ± 0.4259 vs. 0.0020 ± 0.0076; p < 0.0001). More, a ROC analysis defined a BCR::ABL1 transcript value <0.0051% at 1 month as the most powerful to predict a successful treatment-free remission (TFR), with a specificity of 92%. Considering than most recurrences occur within the first 6–8 months after TKI stop, the last ELN recommendations emphasize the need for a frequent molecular monitoring after discontinuation, that is, monthly for the first 6 months, every 2 months until month 12, and every 3 months thereafter. However, the efforts and costs required by such a frequent molecular monitoring should not be underestimated, as well as the need for an increased frequency of clinical controls for patients attempting TKI discontinuation, that could be a burden particularly for patients referring to a tertiary hospitals. A few years ago, Shanmuganathan and colleagues retrospectively applied on a cohort of 107 CML patients discontinuing TKIs 4 algorithms of molecular monitoring, to find the safe minimum frequency of BCR::ABL1 testing. They found that a monitoring frequency of every 2 months in the first 6 months and every 3 months until month 12 was associated with a 52% reduction of testing with a minimal delay in relapse detection and TKI restarting. However, the authors suggested re-initiation of monthly testing at loss of MR4.5, so well below the currently defined trigger for treatment recommencement (MR3) or even for TKI discontinuation (MR4). A recent paper from a Canadian group showed that a shorter BCR::ABL1 doubling time (DT), defined as 12.75 days at 2 months (DT at 1 month was not statistically significative) was associated with higher rate of TFR failure in a cohort of 131 CML patients treated with imatinib. This data seems to reflect a faster kinetic of CML relapse after TKI discontinuation, as has been found already in 2012 by Branford et al. in patients losing response during imatinib therapy, and is in line with our finding of a significant raise in BCR::ABL1 transcript a 1 and 2 months after TKI stop. While waiting for identification of reliable predictors of a successful TFR, an accurate molecular follow-up after discontinuation is needed. Taking into account the dynamics of CML recurrence and the recent data on BCR::ABL1 transcript after TKI stop, as well as costs and impact of a stringent molecular testing, we feel that an individualization of monitoring should be pursued. A reasonable proposal could be to test monthly for the first 1 or 2 months and then according to Received: 23 September 2022 Revised: 24 November 2022 Accepted: 28 November 2022