All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) have revolutionized the treatment of acute promyelocytic leukemia (APL), offering a cure rate of > 80%. Along with improved survival, the long-term consequences of anti-APL therapy are becoming increasingly apparent, including potential therapy-related myeloid neoplasms (t-MNs). T-MNs are well known to arise after cytotoxic chemotherapy, but the leukemogenic potential of regimens utilizing only ATRA/ATO is not well established. The objective of this study is to examine the incidence, long-term risk, and clinicopathologic features of t-MNs arising after anti-APL therapy and how they correlates with the therapeutic regimen employed. We retrospectively collected treated APL patients between 01/2001 and 02/2021, categorized them into ATRA/ATO + chemo and ATRA/ATO groups based on the regimen used, and evaluated for the development of t-MN. A total of 110 APL patients were identified, including 67 (61%) treated with ATRA/ATO + chemo and 43 (39%) treated with ATRA/ATO only. Overall, 4/110 (3.6%) patients developed t-MNs, with all four emerging in the ATRA/ATO + chemo group. Ultimately, the incidence of t-MN in ATRA/ATO + chemo group was significantly higher compared with ATRA/ATO only group(5.97% vs. 0.0%, respectively; p = 0.0289). Our data spanning over two decades suggests that conventional chemotherapy for APL is associated with a small but significant risk of t-MN, whereas ATR/ATO does not carry this risk. This takes on new significance, considering several recent and ongoing trials have shown that a chemotherapy-free approach might become feasible for all risk APL types in the near future. Consequently, the omission of leukemogenic and arguably unnecessary chemotherapy from APL regimens may reduce the incidence of t-MNs in long-term survivors without sacrificing their cure rates.

The development of numerous drugs is often arrested at clinical testing stages, due to their unfavorable biopharmaceutical characteristics. It is the case of fenretinide (4-HPR), a second-generation retinoid, that demonstrated promising in vitro cytotoxic activity against several cancer cell lines. Unfortunately, response rates in early clinical trials with 4-HPR did not confirm the in vitro findings, mainly due to the low bioavailability of the oral capsular formulation that was initially developed. Capsular 4-HPR provided variable and insufficient drug plasma levels attributable to the high hepatic first-pass effect and poor drug water solubility. To improve 4-HPR bioavailability, several approaches have been put forward and tested in preclinical and early-phase clinical trials, demonstrating generally improved plasma levels and minimal systemic toxicities, but also modest antitumor efficacy. The challenge is thus currently still far from being met. To redirect the diminished interest of pharmaceutical companies toward 4-HPR and promote its further clinical development, this manuscript reviewed the attempts made so far by researchers to enhance 4-HPR bioavailability. A comparison of the available data was performed, and future directions were proposed.

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Plasma membrane proteins with extracellular-exposed domains are responsible for transduction of extracellular signals into intracellular responses, and their accessibility to therapeutic molecules makes them attractive targets for drug development. In this work, using omics technologies and immunochemical methods, we have studied changes in the content of markers of clusters of differentiation (CD markers) of neutrophils (CD33, CD97, CD54, CD38, CD18, CD11b, CD44, and CD71) at the level of transcripts and proteins in NB4, HL-60 and K562 cell lines, induced by the treatment with all-trans-retinoic acid (ATRA). Transcriptomic analysis revealed the induction of CD38, CD54, CD11b, and CD18 markers as early as 3 h after the addition of the inducer in the ATRA-responsive cell lines HL-60 and NB4. After 24 h, a line-specific expression pattern of CD markers could be observed in all cell lines. Studies of changes in the content of CD antigens by means of flow cytometry and targeted mass spectrometry (MS) gave similar results. The proteomic profile of the surface markers (CD38, CD54, CD11b, and CD18), characteristic of the NB4 and HL-60 lines, reflects different molecular pathways for the implementation of ATRA-induced differentiation of leukemic cells into mature neutrophils.

Acute promyelocytic leukemia (APL), a distinct subtype of acute myelogenous leukemia (AML), is commonly associated with a heightened risk of bleeding due to coagulopathy. Thrombotic events, although less frequent, have also been linked to APL. However, the occurrence of ischemic stroke as an initial presentation of APL, particularly concomitant with central nervous system (CNS) bleeding, is exceedingly rare. The combination of these two complications is not reported in APL patients and is anticipated to carry a high mortality rate even with treatment. In this report, we describe the case of a young female patient with no significant medical history, who presented with decreased consciousness and recurrent seizures. Brain magnetic resonance imaging (MRI) revealed the simultaneous occurrence of acute ischemic stroke and acute-on-chronic subdural hematoma. The subsequent bone marrow biopsy confirmed the diagnosis of APL, displaying the characteristic positive promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) t(15;17) translocation. The patient was promptly initiated on a high-risk AML-M3 protocol, coupled with supportive treatment through platelet transfusion. Remarkably, a favorable response to treatment was observed, and a marked improvement in her neurological parameters was observed within 2 weeks duration of treatment. Subsequent assessment through a bone marrow biopsy one month later revealed complete remission, with the PML-RARA fusion gene becoming negative following a single course of consolidation therapy.

Growing evidence demonstrates that cancer-associated fibroblasts (CAF) are responsible for tumor genesis, growth, metastasis, and treatment response. Therefore, targeting these cells may contribute to tumor control. It has been proposed that targeting key molecules and pathways of proliferative functions can be more effective than killing CAFs. In this regard, multicellular aggregates, like spheroids, can be used as human tumor models. Spheroids closely resemble human tumors and mimic many of their features. Microfluidic systems are ideal for cultivation and study of spheroids. These systems can be designed with different biological and synthetic matrices in order to have a more realistic simulation of the tumor microenvironment (TME). In this study, we investigated the effect of all-trans retinoic acid (ATRA) on 3D spheroid invasion of MDA-MB cells exposed to hydrogel matrix derived from CAFs. The number of invasive cells significantly decreased in CAF-ECM hydrogel treated with ATRA (p < 0.05), which indicates that ATRA could be effective for CAFs normalization. This experiment was done using an agarose-alginate microfluidic chip. As compared with common methods, such hydrogel casting is an easier method for chip fabrication and can even reduce costs.
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UNASSIGNED: The online version contains supplementary material available at 10.1007/s10616-023-00578-y.

All-trans-retinoic acid (ATRA)-based differentiation therapy of acute promyelocytic leukemia (APL) represents one of the most clinically effective examples of precision medicine and the first example of targeted oncoprotein degradation. The success of ATRA in APL, however, remains to be translated to non-APL acute myeloid leukemia (AML). We previously showed that aberrant histone modifications, including histone H3 lysine 4 (H3K4) and lysine 27 (H3K27) methylation, were associated with this lack of response and that epigenetic therapy with small molecule inhibitors of the H3K4 demethylase LSD1/KDM1A could reprogram AML cells to respond to ATRA. Serving as the enzymatic component of Polycomb Repressive Complex 2, EZH2/KMT6A methyltransferase plays a critical role in normal hematopoiesis by affecting the balance between self-renewal and differentiation. The canonical function of EZH2 is methylation of H3K27, although important non-canonical roles have recently been described. EZH2 mutation or deregulated expression has been conclusively demonstrated in the pathogenesis of AML and response to treatment, thus making it an attractive therapeutic target. In this study, we therefore investigated whether inhibition of EZH2 might also improve the response of non-APL AML cells to ATRA-based therapy. We focused on GSK-343, a pyridone-containing S-adenosyl-L-methionine cofactor-competitive EZH2 inhibitor that is representative of its class, and HKMTI-1-005, a substrate-competitive dual inhibitor targeting EZH2 and the closely related G9A/GLP H3K9 methyltransferases. We found that treatment with HKMTI-1-005 phenocopied EZH2 knockdown and was more effective in inducing differentiation than GSK-343, despite the efficacy of GSK-343 in terms of abolishing H3K27 trimethylation. Furthermore, transcriptomic analysis revealed that in contrast to treatment with GSK-343, HKMTI-1-005 upregulated the expression of differentiation pathway genes with and without ATRA, while downregulating genes associated with a hematopoietic stem cell phenotype. These results pointed to a non-canonical role for EZH2, which was supported by the finding that EZH2 associates with the master regulator of myeloid differentiation, RARα, in an ATRA-dependent manner that was enhanced by HKMTI-1-005, possibly playing a role in co-regulator complex exchange during transcriptional activation. In summary, our results strongly suggest that addition of HKMTI-1-005 to ATRA is a new therapeutic approach against AML that warrants further investigation.

The transformation of acute promyelocytic leukemia (APL) from an often fatal to highly curable cancer with long-term survival exceeding 90% is one of the greatest and most inspiring successes in oncology. A deeper understanding of the pathogenesis of APL heralded the introduction of highly effective therapies targeting the mutant protein that drives the disease, leading to the chemotherapy-free approach to cure almost all patients. In this review, we discuss the paradigm of treatment of APL in 2023, reinforce the high risk of early death without prompt initiation of treatment at first clinical suspicion, and dedicate a special focus to novel agents and future directions to improve cure rates and quality of life in patients affected by APL.

Primary effusion lymphoma (PEL), an aggressive non-Hodgkin lymphoma caused by Kaposi sarcoma-associated herpesvirus (KSHV), lacks standard therapy and has a median survival of 10-22 months with combination chemotherapy. PEL is a tumor of plasmablast-like B cells generally expressing CD38, the target of daratumumab (Dara). Initially, we assessed PEL cells from eight patients and established that each expressed high levels of CD38 by flow cytometry. PEL cell lines were also evaluated and most had high CD38 expression. We then assessed Dara\'s effects on complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) of PEL cell lines as well as its clinical benefits on two patients with PEL. Despite high CD38 expression, Dara did not induce CDC of PEL cell lines, due in part to high levels of the complement-inhibitory proteins, CD55 and CD59. However, Dara induced significant and dose-dependent increases in ADCC, particularly in those lines with high CD38 levels. Two FDA-approved drugs, all trans-retinoic acid (ATRA) and pomalidomide (Pom), significantly increased surface CD38 levels in low-CD38 expressing PEL cell lines, resulting in increased Dara-induced ADCC. Two patients with refractory PEL were treated with Dara alone or in combination with Pom. One patient with leptomeningeal PEL had a complete response to Dara and Pom combination treatment. Others had improvement in performance status and resolution of malignant ascites with Dara alone. Together, these data support the use of Dara monotherapy or in combination with ATRA or Pom as a potential therapeutic option for PEL.

Acute promyelocytic leukemia (APML) is defined as a balanced chromosomal translocation between chromosomes 15 and 17 t(15;17)(q24;q21), which results in the formation of promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARA) fusion protein. A widespread recommendation for APML treatment is combined all-trans retinoic acid (ATRA)/arsenic trioxide (ATO) therapy. Differentiation syndrome (DS), or retinoic acid syndrome, is one of the well-known complications of APML treated with ATRA or ATO. The presenting symptoms of APML-induced DS are diverse, and rare symptoms are easily misdiagnosed. However, unexplained fever, dyspnea, weight gain > 5 kg, leukocytosis, acute renal failure, and a chest radiograph demonstrating pleural or pericardial effusion are the most common manifestations of DS. Early recognition and prompt initiation of corticosteroids are key factors in the management of DS. As soon as ATRA/ATO therapy is started, prophylactic treatment with steroids has been recommended to minimize the severity of DS. It is proposed that ATRA/ATO should be stopped or held once the signs and symptoms of DS develop. This case report describes a 45-year-old male who was diagnosed with APML after he developed episodes of hematuria and nose bleeding at home. The patient was also given an empiric steroid along with ATRA/ATO to lessen the intensity of DS. Our study suggests that early initiation of prophylactic steroid treatment can improve the prognosis and mortality of patients with APML-induced DS.