Hematological Malignancies in Sickle Cell Disease Patients: Report of Four Cases in Togo and Literature Review

Background: Hemopathies were rarely observed in major sickle cell disease patients some thirty years ago, probably due to the high mortality rate among the latter as a result of progressive complications. Thanks to advances in the management of sickle cell disease, patients' life expectancy has increased considerably, exposing them more frequently to neoplasia, including hematological malignancies. The increased risk of leukemogenesis is multifactorial and linked to the pathophysiological mechanisms of the clinical manifestations of sickle cell disease. Study Setting: The clinical haematology department of campus teaching hospital and the paediatric onco-haematology unit of Sylvanus Olympio teaching hospital in Lomé were used as study settings. Observations: Four hematologic malignancies were collected in a cohort of 5847 major sickle cell syndromes. The median age of the patients was 31.25 years (extremes: 14 and 58 years) and they were predominantly female (sex ratio M/F = 0.25). Two were on background therapy with hydroxyurea. Among the four patients, there were two cases of acute lymphocytic leukemia, including ALL3 in a 58-year-old SS woman and T-ALL2 in a 12-year-old SC. Then, a case of lymphocytic lymphoma in a 20-year-old SS man was reported and finally a case of chronic myelocytic leukemia in a 33-year-old woman of Sβ+ thalassaemia phenotype. Conclusion: To further report this coexistence, it is therefore essential to systematically consider hematological malignancies during major sickle cell syndromes even if there are similarities in the symptomatology of these two serious pathological situations.

Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies treated with anticancer therapy

Hepatitis due to hepatitis B virus(HBV) reactivation can be severe and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy, especially rituximabcontaining therapy for hematological malignancies and those receiving stem cell transplantation. All patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen(HBs Ag) and antibody to hepatitis B core antigen(antiHBc). Patients found to be positive for HBs Ag should be given prophylactic antiviral therapy to prevent HBV reactivation. For patients with resolved HBV infection, no standard strategy has yet been established to prevent HBV reactivation. There are usually two options. One is pre-emptive therapy guided by serial HBV DNA monitoring, whereby antiviral therapy is given as soon as HBV DNA becomes detectable. However, there is little evidence regarding the optimal interval and period of monitoring. An alternative approach is prophylactic antiviral therapy, especially for patients receiving highrisk therapy such as rituximab, newer generation of anti-CD20 monoclonal antibody, obinutuzumab or hematopoietic stem cell transplantation. This strategy may effectively prevent HBV reactivation and avoid the inconvenience of repeated HBV DNA monitoring. Entecavir or tenofovir are preferred over lamivudine as prophylactic therapy. Although there is no well-defined guideline on the optimal duration of prophylactic therapy, there is growing evidence to recommend continuing prophylactic antiviral therapy for at least 12 mo after cessation of chemotherapy, and even longer for those who receive rituximab or who had high serum HBV DNA levels before the start of immunosuppressive therapy. Many novel agents have recently become available for the treatment of hematological malignancies, and these agents may be associated with HBV reactivation. Although there is currently limited evidence to guide the optimal preventive measures, we recommend antiviral prophylaxis in HBs Ag-positive patients receiving novel treatments, especially the Bruton tyrosine kinase inhibitors and the phosphatidylinositol 3-kinase inhibitors, which are B-cell receptor signaling modulators and reduce proliferation of malignant B-cells. Further studies are needed to clarify the risk of HBV reactivation with these agents and the best prophylactic strategy in the era of targeted therapy for hematological malignancies.

TMTP1, a Novel Tumor-homing Peptide, Specifically Targets Hematological Malignancies and Their Metastases

TMTP1, a 5-amino acid peptide NVVRQ, obtained by using the flagella peptide library screening in our previous studies, can be used for the labeling of malignant in situ and metastatic lesions, and even micro-metastases. In this study, TMTP1 was assessed for its ability to specifically target the malignant hematopoietic cells and metastatic lesions of hematological malignancies. FITC-TMTP1 was chemically synthesized. Immunofluorescence assay and competitive test were carried out to determine the specific binding capacity of TMTPl to hematological malignant cell lines, including HL60, k562, SHI-1, Jurkat, Raji, El-4 and umbilical cord blood mononuclear cells. Mononuclear cells were isolated from the bone marrow of healthy subjects and patients with chronic myeloid leukemia. Then the cells were co-clutured with TMTP1 or scrambled peptides and the binding and affinity of TMTP1 peptide to the primary cells of hematological malignancies were flow cytometrically analyzed. The binding speci-ficity of TMTP1 to target hematological malignancies was measured in vivo by intravenous injection of FITC-conjugated TMTP1 into El-4 lymphoma-bearing mice. The results showed that TMTP1 specifi-cally bound to the cells of a series of hematological malignancies, including HL60, k562, Jurkat, Raji , El-4 and chronic myeloid leukemia primary cells but not to bone marrow mononuclear cells from healthy subjects. By contrast, TMTP1 could bind to the metastatic foci of lymphoma originating from the EL-4 cell line while the scrambled peptide failed to do so. Moreover, the occult metastases could be identified, with high specificity, by detecting FITC-TMTP1. We are led to conclude that TMTP1, as a novel tumor-homing peptide, can serve as a marker for primary malignant and metastatic lesions for the early diagnosis of hematological malignances and a carrier of anticancer drugs for cancer treatment.

CAR T Cell Therapy for Hematological Malignancies

As a rapidly progressing field in oncology,the adoptive transfer of T cells that have been genetically modified with chimeric antigen receptors(CARs)has shown striking efficacy in the management of hematological malignancies and has been reported in a number of clinical trials.of note,CAR T cell therapy has shown extraordinary potential,especially in relapsed/refractory patients.However,there are still challenges regarding the further development of this strategy,spanning from engineering and manufacturing issues,to limited applications,to accompanying toxicities.In this review,we will summarize the general knowledge of this novel method,including receptor composition,applications,adverse events and challenges.Additionally,we will propose several comprehensive recommendations.

Characteristics of escape mutations from occult hepatitis B virus infected patients with hematological malignancies in South Egypt

AIM To investigate the prevalence and virological characteristics of occult hepatitis B virus(HBV) infections in patients with hematological malignancies in South Egypt.METHODS Serum samples were collected from 165 patients with hematological malignancies to monitor titers of HBV DNA, hepatitis B surface antigen(HBs Ag), and antibodies to HBV core(anti-HBc) and surface antigens. Serum samples negative for HBs Ag and positive for anti-HBc were subjected to nucleic acid extraction and HBV DNA detection by real-time polymerase chain reaction. DNA sequences spanning the S region were analyzed in cases with occult HBV infection. In vitro comparative study of constructed 1.24-fold wild type and S protein mutant HBV genotype D clones was further performed. RESULTS HBV DNA was detected in 23(42.6%) of 54 patients with hematological malignancies who were HBsA g negative, but anti-HBc positive, suggesting the presence of occult HBV infection. The complete HBV genome was retrieved from 6 occult HBV patients, and P120 T and S143 L were detected in 3 and 2 cases, respectively. Site directed mutagenesis was done to produce 1.24-fold genotype D clones with amino acid mutations T120 and L143. The in vitro analyses revealed that a lower level of extracellular HBsA g was detected by chemiluminescence enzyme immunoassay(CLEIA) with the clone containing T120 mutation, compared with the wild type or the clone with S143 L mutation despite the similar levels of extracellular and intracellular HBs Ag detected by Western blot. Southern blot experiments showed that the levels of intracellular HBV DNA were not different between these clones. CONCLUSION Occult HBV infection is common in patients with hematological malignancies and associated with P120 T and S143 L mutations. 120 T mutation impairs the detection of HBsA g by CLEIA.

Garenoxacin Prophylaxis for Febrile Neutropenia after Chemotherapy in Hematological Malignancies

Background: Febrile neutropenia is one of the most serious adverse events in patients with hematological malignancies and chemotherapy. The routine use of fluoroquinolone prophylaxis in patients with hematological malignancies is controversial. Therefore, we prospectively evaluated the efficacy and safety of prophylactic use of garenoxacin for febrile neutropenia. Patients and Methods: Consecutive adult patients with hematological malignancies who were at risk for chemotherapy-induced neutropenia lasting more than seven days were eligible for present study. They received oral garenoxacin (400 mg daily) from the neutrophil count decreased to less than 1000/μl and continued until the neutropenia had resolved. The primary endpoint was incidence of febrile neutropenia, and the secondary endpoints were the type and incidence of adverse events. Results: We enrolled 46 consecutive patients (median age, 59 years). The underlying diseases comprised acute myeloid leukemia (n = 17), acute lymphoblastic leukemia (n = 3), malignant lymphoma (n = 23), and multiple myeloma (n = 3). There were 23 febrile neutropenia episodes and 2 episodes of bacteremia. There were no grade 3 or 4 adverse events;however serum creatinine levels were significantly elevated after garenoxacin administration. The overall prophylactic efficacy of garenoxacin was 50%, and there were no infection-related deaths. Conclusions: Prophylactic use of garenoxacin is effective and safe in patients with hematological malignancies. (Clinical trial registration number: UMIN000004979).

Combination of CRISPR/Cas9 System and CAR-T Cell Therapy:A New Era for Refractory and Relapsed Hematological Malignancies

Chimeric antigen receptor T(CAR-T)cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia(ALL),lymphoma and multiple myeloma.However,treatment-related toxicities such as cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)have become significant hurdles to CAR-T treatment.Multiple strategies were established to alter the CAR structure on the genomic level to improve efficacy and reduce toxicities.Recently,the innovative gene-editing technology-clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease9(Cas9)system,which particularly exhibits preponderance in knock-in and knockout at specific sites,is widely utilized to manufacture CAR-T products.The application of CRISPR/Cas9 to CAR-T cell therapy has shown promising clinical results with minimal toxicity.In this review,we summarized the past achievements of CRISPR/Cas9 in CAR-T therapy and focused on the potential CAR-T targets.

Predictive value of co-expression patterns of immune checkpoint molecules for clinical outcomes of hematological malignancies

Co-expression of immune checkpoint(IC)molecules can exacerbate T cell exhaustion in patients with hematological malignancies(HMs)and contribute to the immune escape of tumor cells,which is related to poor clinical outcome.It is worth establishing and optimizing an ideal prediction model based on the co-expression patterns of IC molecules to evaluate the immune status of HM patients and predict their clinical outcome.In this perspective,we summarize the co-expression patterns of IC molecules and their importance as biomarkers that predict the prognosis of patients with different HMs,providing new insights for designing dual IC blockades(ICBs).

Recent progresson nuclear export protein XPO1 inhibitor in the treatment of hematological malignancies

Most tumor suppressor and growth-regulating proteins are transported via the plasmic nuclear transporter exportin 1(XPO1).Many malignancies have excessive XPO1 expression,which is associated with disease progression and resistance to therapy.A novel class of anticancer medication called selective inhibitor of nuclear export(SINE)can down-regulate the levels of a number of antigenic proteins in the cytoplasm,activate tumor suppressor and other growth regulating proteins,and promote the nuclear retention and apoptosis of tumor cells.This article discusses the function of XPO1 in drug resistance and tumor development as well as the advancement of XPO1 inhibitor research for the treatment of hematological cancers.

Long non-coding RNA MALAT1 in hematological malignancies and its clinical applications

Metastasis-associated lung adenocarcinoma transcript 1(MALAT1)is a well-established oncogenic long non-coding RNA,the higher expression of which is strongly correlated with cancer events such as tumorigenesis,progression,metastasis,drug resistance,and treatment outcome in solid cancers.Recently,a series of studies has highlighted its potential role in hematological malignancies in terms of these events.Similar to solid cancers,MALAT1 can regulate various target genes via sponging and epigenetic mechanisms,but the miRNAs sponged by MALAT1 differ from those identified in solid cancers.In this review,we systematically describe the role and underlying mechanisms of MALAT1 in multiple types of hematological malignancies,including regulation of cell proliferation,metastasis,stress response,and glycolysis.Clinically,MALAT1 expression is related to poor treatment outcome and drug resistance,therefore exhibiting potential prognostic value in multiple myeloma,lymphoma,and leukemia.Finally,we discuss the evaluation of MALAT1 as a novel therapeutic target against cancer in preclinical studies.

Advances and clinical applications of immune checkpoint inhibitors in hematological malignancies

Immune checkpoints are differentially expressed on various immune cells to regulate immune responses in tumor microenvironment.Tumor cells can activate the immune checkpoint pathway to establish an immunosuppressive tumor microenvironment and inhibit the anti-tumor immune response,which may lead to tumor progression by evading immune surveillance.Interrupting coinhibitory signaling pathways with immune checkpoint inhibitors(ICIs)could reinvigorate the anti-tumor immune response and promote immune-mediated eradication of tumor cells.As a milestone in tumor treatment,ICIs have been firstly used in solid tumors and subsequently expanded to hematological malignancies,which are in their infancy.Currently,immune checkpoints have been investigated as promising biomarkers and therapeutic targets in hematological malignancies,and novel immune checkpoints,such as signal regulatory proteinα(SIRPα)and tumor necrosis factor-alpha-inducible protein 8-like 2(TIPE2),are constantly being discovered.Numerous ICIs have received clinical approval for clinical application in the treatment of hematological malignancies,especially when used in combination with other strategies,including oncolytic viruses(OVs),neoantigen vaccines,bispecific antibodies(bsAb),bio-nanomaterials,tumor vaccines,and cytokine-induced killer(CIK)cells.Moreover,the proportion of individuals with hematological malignancies benefiting from ICIs remains lower than expected due to multiple mechanisms of drug resistance and immune-related adverse events(irAEs).Close monitoring and appropriate intervention are needed to mitigate irAEs while using ICIs.This review provided a comprehensive overview of immune checkpoints on different immune cells,the latest advances of ICIs and highlighted the clinical applications of immune checkpoints in hematological malignancies,including biomarkers,targets,combination of ICIs with other therapies,mechanisms of resistance to ICIs,and irAEs,which can provide novel insight into the future exploration of ICIs in tumor treatment.

Incidence rate and risk factors of second primary neoplasms among older patients with hematological malignancies:Insights from a Chinese single-center experience(1997-2021)

Background:Patients with hematological malignancies face an increased risk of developing second primary neoplasms due to various factors,including immune system compromise and chemotherapy-related effects.However,the incidence and associated risk factors in older patients remain poorly understood.This study aimed to assess the incidence,identify risk factors,and evaluate their impact on survival outcomes among older patients with hematological malignancies.Methods:This retrospective single-center study analyzed data from 163 patients,focusing on the occurrence of second primary neoplasms.Cumulative incidence rates were calculated,and risk factor analysis was conducted using a competing risk model.Results:Among 124 eligible patients with a total follow-up duration of 572.57 person-years,the incidence rate of second primary neoplasms was 15.72/1000 person-years.The standardized incidence ratio(SIR)was 0.81(95%confidence interval[CI][0.39–1.48],P=0.518).History of radiotherapy emerged as a significant risk factor(subdistribution hazard ratio[SHR]=21.61[2.81–166.14],P=0.003),whereas regular natural killer(NK)cell infusion was associated with reduced risk(SHR=3.25 e8[9.81 e9–1.08 e7],P<0.001).Conclusions:These findings underscore the importance of informing older patients with hematological malignancies about the long-term risks of second primary neoplasms.Healthcare providers should carefully weigh risk factors when formulating treatment strategies.The results are valuable for investigating the fundamental principles underlying the occurrence and progression of second primary neoplasms.

Natural products against hematological malignancies and identification of their targets

Naturally occurring molecules derived from higher plants, animals, microorganisms and minerals play an important role in the discovery and development of novel therapeutic agents. The identification of molecular targets is of interest to elucidate the mode of action of these compounds, and it may be employed to set up target-based assays and allow structure-activity relationship studies to guide medicinal chemistry efforts toward lead optimization. In recent years, plant-derived natural compounds possessing potential anti-tumor activities have been garnering much interest and efforts are underway to identify their molecular targets. Here, we attempt to summarize the discoveries of several natural compounds with activities against hematological malignancies, such as adenanthin, oridonin, gambogic acid and wogonoside, the identification of their targets, and their modes of actions.

Adoptive therapy with CAR redirected T cells for hematological malignancies

The survival of patients with hematological malignancies has been significantly improved due to the development of new therapeutic agents. However, relapse remains a major matter for concern. Recently, T cells engineered with chimeric antigen receptor(CAR) were reported to show unprecedented responses in a range of hematological malignancies. The persistence of the CAR-T cell can last for years and tends toward long-term antitumor memory by which relapses can be effectively prevented. The primary side effects that appear in most clinical trials are cytokine release syndrome and neurotoxicity. However, these symptoms can be treated and reversed. In this review, we describe CAR structure and function and summarize recent advances in CAR-T cell therapy in hematological malignancies.

Research Progress on Artemisinin and Its Derivatives against Hematological Malignancies

Although current therapeutic methods against hematological malignancies are effective in the early stage,they usually lose their effectiveness because of the development of drug resistances.Seeking new drugs with significant therapeutic effects is one of the current research hotspots.Artemisinin,an extract from the plant Artemisia annua Linne,and its derivatives have excellent antimalarial effects in clinical applications as well as excellent safety.Recent studies have documented that artemisinin and its derivatives(ARTs)also have significant effects against multiple types of tumours,including hematological malignancies.This review focuses on the latest research achievements of ARTs in the treatment of hematological malignancies as well as its mechanisms and future applications.The mechanisms of ARTs against different types of hematological malignancies mainly include cell cycle arrest,induction autophagy and apoptosis,inhibition of angiogenesis,production of reactive oxygen species,and induction of differentiation.Additionally,the review also summarizes the anticancer effects of ARTs in many drug-resistant hematological malignancies and its synergistic effects with other drugs.

Weathering the storm:COVID-19 infection in patients with hematological malignancies

The coronavirus disease 2019(COVID-19)is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Within a matter of months,this highly contagious novel virus has led to a global outbreak and is still spreading rapidly across continents.In patients with COVID-19,underlying chronic diseases and comorbidities are associated with dismal treatment outcomes.Owing to their immunosuppressive status,patients with hematological malignancies(HMs)are at an increased risk of infection and have a worse prognosis than patients without HMs.Accordingly,intensive attention should be paid to this cohort.In this review,we summarize and analyze specific clinical manifestations for patients with coexisting COVID-19 and HMs.Furthermore,we briefly de-scribe customized management strategies and interventions for this susceptible cohort.This review is intended to guide clinical practice.

Targeting SAMHD1: To overcome multiple anti-cancer drugs resistance in hematological malignancies

Sterile α motif and histidine/aspartic acid domain containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate (dNTPs) triphosphohydrolase that can hydrolyze dNTPs into deoxynucleosides and triphosphates to keep the balance of the intracellular dNTPs pool. Moreover, it has been reported that SAMHD1 plays a role in regulating cell proliferation and the cell cycle, maintaining genome stability and inhibiting innate immune responses. SAMHD1 activity is regulated by phosphorylation, oxidation, SUMOylation, and O-GlcNAcylation. SAMHD1 mutations have been reported to cause diseases, including chronic lymphocytic leukemia and mantle cell lymphoma. SAMHD1 expression in acute myeloid leukemia predicts inferior prognosis. Recently, it has been revealed that SAMHD1 mediates the resistance to anti-cancer drugs. This review will focus on SAMHD1 function and regulation, the association between SAMHD1 and hematological malignancies and will provide updated information on SAMHD1 mediating resistance to nucleoside analogue antimetabolites, topoisomerase inhibitors, platinum-derived agents and DNA hypomethylating agents. Furthermore, histone deacetylase inhibitors and tyrosine kinase inhibitors indirectly increase anti-cancer drug resistance by increasing SAMDH1 activity. We herein highlight the importance of the development of novel agents targeting SAMHD1 to overcome treatment resistance of hematological malignancies, which would be an opportunity to improve the outcome of patients with refractory hematological malignancies.

SURVIVAL TRENDS IN CHILDHOOD HEMATOLOGICAL MALIGNANCIES

Survival of patients with childhood hematological malignancies has increased markedly in the past decades. To examine the finescale details of how this progress has occurred, we carried out KaplanMeier causespecific survival analysis using the Surveillance Epi demiology and End Results （SEER） dataset for patients with childhood hematologi cal malignancies Hodgkin＇s Lymphoma, NonHodgkin＇s Lymphoma, Lymphoblastic Leukemia and Myeloid Leukemia diagnosed in five eras： 1983-1987; 1988-1992; 1993-1997; 1998-2002 and 2003-2007. We generated KaplanMeier estimates of survival for each of the first 24 years after diagnosis. These figures agree with previously reported five and tenyear values and attest to the remarkable increase in survival that has occurred over the past three decades of medical progress. The trend towards progres sively increasing survival shows no sign of slowing, suggesting that we may expect further increases in survival in the years ahead. Most of the increase in survival for childhood hematological malignancies has occurred by reducing the risk of death in the first two years after diagnosis. This may be largely explained by the fact that this is the time period when patients are at highest risk of death.

Challenges and optimal strategies of CAR T therapy for hematological malignancies

Remarkable improvement relative to traditional approaches in the treatment of hematological malignancies by chimeric antigen receptor (CAR) T-cell therapy has promoted sequential approvals of eight commercial CAR T products within last 5 years. Although CAR T cells’ productization is now rapidly boosting their extensive clinical application in real-world patients, the limitation of their clinical efficacy and related toxicities inspire further optimization of CAR structure and substantial development of innovative trials in various scenarios. Herein, we first summarized the current status and major progress in CAR T therapy for hematological malignancies, then described crucial factors which possibly compromise the clinical efficacies of CAR T cells, such as CAR T cell exhaustion and loss of antigen, and finally, we discussed the potential optimization strategies to tackle the challenges in the field of CAR T therapy.

Clinical development of chimeric antigen receptor-T cell therapy for hematological malignancies

Cellular therapies have revolutionized the treatment of hematological malignancies since their conception and rapid development.Chimeric antigen receptor(CAR)-T cell therapy is the most widely applied cellular therapy.Since the Food and Drug Administration approved two CD19-CAR-T products for clinical treatment of relapsed/refractory acute lymphoblastic leukemia and diffuse large B cell lymphoma in 2017,five more CAR-T cell products were subsequently approved for treating multiple myeloma or B cell malignancies.Moreover,clinical trials of CAR-T cell therapy for treating other hematological malignancies are ongoing.Both China and the United States have contributed significantly to the development of clinical trials.However,CAR-T cell therapy has many limitations such as a high relapse rate,adverse side effects,and restricted availability.Various methods are being implemented in clinical trials to address these issues,some of which have demonstrated promising breakthroughs.This review summarizes developments in CAR-T cell trials and advances in CAR-T cell therapy.