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.

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.

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.

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.

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.

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.

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.

Blockade of CD300A enhances the ability of human NK cells to lyse hematologic malignancies

Objective: The human cluster of differentiation(CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer(NK) cells targeting hematologic malignancies(HMs).Methods: We implemented a stimulation system involving the CD300A ligand, phosphatidylserine(PS), exposed to the outer surface of malignant cells. Additionally, we utilized CD300A overexpression, a CD300A blocking system, and a xenotransplantation model to evaluate the impact of CD300A on NK cell efficacy against HMs in in vitro and in vivo settings. Furthermore, we explored the association between CD300A and HM progression in patients.Results: Our findings indicated that PS hampers the function of NK cells. Increased CD300A expression inhibited HM lysis by NK cells. CD300A overexpression shortened the survival of HM-xenografted mice by impairing transplanted NK cells. Blocking PS–CD300A signals with antibodies significantly amplified the expression of lysis function-related proteins and effector cytokines in NK cells, thereby augmenting the ability to lyse HMs. Clinically, heightened CD300A expression correlated with shorter survival and an “exhausted” phenotype of intratumoral NK cells in patients with HMs or solid tumors.Conclusions: These results propose CD300A as a potential target for invigorating NK cell-based treatments against HMs.

Prevention of hepatitis B reactivation in patients with hematologic malignancies treated with novel systemic therapies:Who and Why?

The risk of reactivation in patients with chronic or past/resolved hepatitis B virus(HBV)infection receiving chemotherapy or immunosuppressive drugs is a wellknown possibility.The indication of antiviral prophylaxis with nucleo(t)side analogue is given according to the risk of HBV reactivation of the prescribed therapy.Though the advent of new drugs is occurring in all the field of medicine,in the setting of hematologic malignancies the last few years have been characterized by several drug classes and innovative cellular treatment.As novel therapies,there are few data about the rate of HBV reactivation and the decision of starting or not an antiviral prophylaxis could be challenging.Moreover,patients are often treated with a combination of different drugs,so evaluating the actual role of these new therapies in increasing the risk of HBV reactivation is difficult.First results are now available,but further studies are still needed.Patients with chronic HBV infection[hepatitis B surface antigen(HBsAg)positive]are reasonably all treated.Past/resolved HBV patients(HBsAg negative)are the actual area of uncertainty where it could be difficult choosing between prophylaxis and pre-emptive strategy.

Preclinical evaluation of cyclophosphamide and fludarabine combined with CD19 CAR-T in the treatment of B-cell hematologic malignancies in vivo

Background:Chimeric antigen receptor T(CAR-T)cell therapy has achieved marked therapeutic success in ameliorating hematological malignancies.However,there is an extant void in the clinical guidelines concerning the most effective chemotherapy regimen prior to chimeric antigen receptor T(CAR-T)cell therapy,as well as the optimal timing for CAR-T cell infusion post-chemotherapy.Materials and Methods:We employed cell-derived tumor xenograft(CDX)murine models to delineate the optimal pre-conditioning chemotherapy regimen and timing for CAR-T cell treatment.Furthermore,transcriptome sequencing was implemented to identify the therapeutic targets and elucidate the underlying mechanisms governing the treatment regimen.Results:Our preclinical in vivo evaluation determined that a combination of cyclophosphamide and fludarabine,followed by the infusion of CD19 CAR-T cells five days subsequent to the chemotherapy,exerts the most efficacious therapeutic effect in B-cell hematological malignancies.Concurrently,RNA-seq data indicated that the therapeutic efficacy predominantly perturbs tumor cell metabolism,primarily through the inhibition of key mitochondrial targets,such as C-Jun Kinase enzyme(C-JUN).Conclusion:In summary,the present study offers critical clinical guidance and serves as an authoritative reference for the deployment of CD19 CAR-T cell therapy in the treatment of B-cell 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.

Comparison of clinical outcomes between unrelated single umbilical cord blood and"ex-vivo"T-cell depleted haploidentical transplantation in children with hematological malignancies

Background Over the last two decades,umbilical cord blood(UCB)and haploidentical transplantation(HaploHSCT)have emerged as alternative sources of hematopoietic stem cell for allogeneic transplantation.There are few retrospective studies and no prospective studies comparing both types of alternative transplantation in pediatric patients.Results We analyzed the data of 134 children with hematological malignancies who received a hematopoietic stem cell transplantation from a single umbilical cord blood(UCB)(n=42)or an"tex-vivo"T-cell depleted transplant from a haploi-dentical-related donor(HaploHSCT)(n=92)between 1996 and 2014.Hematological recovery was faster after HaploHSCT than the UCB transplant group(median times to neutrophil and platelet recovery:13 vs.16 days,10 vs.57 days,respectively)(P<0.001).The HaploHSCT group had a significantly early immune reconstitution based on NK and CD8+T cells compared with the UCB group.However,after the first year post-transplantation.HaploHSCT had a lower number of CD4+ T and B lymphocytes compared with the UCB transplant recipients.The cumulative incidence of TRM was 29±8%in the HaploHSCT group versus 40±5%in the UCB group.Relapse incidence was 21±7%in the HaploHSCT group and 19±8%in the UCB group.Probability of DFS was 58±8%in the HaploHSCT group versus 40±9%in the UCB group(P=0.051).Conclusions TCD haploidentical transplant is associated with advantages in terms of engraftment and early immune reconstitution kinetics.TCD haploidentical transplant was associated with lower incidence of infectious and non-infectious complications,especially in the early phases of the transplant compared with UCB transplant recipients.However,there are no advantages in transplant outcomes compared with UCB transplant.

Centrosome Defects in Hematological Malignancies: Molecular Mechanisms and Therapeutic Insights

Defects in centrosomes are associated with a broad spectrum of hematological malignancies,such as leukemia and lymphoma.Centrosomes in these malignancies display both numerical and structural aberrations,including alterations in the number and size of centrioles,inappropriate post-translational modification of centrosomal proteins,and extra centrosome clustering.There is accumulating evidence that centrosome defects observed in hematological malignancies result from multiple factors,including dysregulation of the centrosome cycle and impairment of centriole biogenesis.In this review,we discuss the plausible mechanisms of centrosome defects and highlight their consequences in hematological malignancies.We also illustrate the latest therapeutic strategies against hematological malignancies by targeting centrosome anomalies.

Epidemiology, resistant pathogens, and causes of early death in cases of bloodstream infection in patients with hematological malignancies from 2012-2019

Purpose:To investigate the epidemiology,causative pathogen antibiotic susceptibility,and mortality risk factors of bloodstream infection(BSI)in patients with hematological malignancies(HMs).Methods:Single-center retrospective analysis of BSI cases in patients with HMs in a Chinese tertiary hospital from 2012-2019.Results:Among 17,796 analyzed admissions,508 BSI episodes(2.9%;95%confidence interval:2.6%-3.2%)were identified.Of 522 resulting isolates,326(62.5%)were Gram-negative,173(33.1%)were Gram-positive.The BSI incidence among patients with different HMs(severe aplastic anemia:6.7%;acute leukemia:6.2%;myelodysplastic syndrome:3.2%;multiple myeloma:1.3%;and lymphoma:1.0%)differed significantly(p<0.001).The BSI incidence was significantly higher in the hematopoietic stem cell transplantation(HSCT)group(10.2%)than in the non-HSCT group(2.5%;p<0.001).Escherichia coli(30.7%,160/522)was the most common pathogen,followed by Coagulase-negative staphylococci(19.4%,101/522)and Klebsiella pneumoniae(10.0%,52/522).,The rates of imipenem resistance for E.coli,K.pneumoniae,Pseudomonas aeruginosa,and Acinetobacter baumannii were 6.4%,15.0%,27.8%,and 79.0%,respectively.All the Gram-positive pathogens were linezolid susceptible.Three vancomycin-resistant Enterococcus species were isolated.The overall 14-day mortality was 9.8%(95%confidence interval:7.2%-12.4%).A multivariate analysis showed that HM subtype severe aplastic anemia,A.baumannii,and malignancy non-remission were independent 14-day mortality risk factors.Conclusions:Gram-negative bacteria were the most common pathogens,with E.coli as the predominant strain,causing BSIs in HM patients.A carbapenem-resistant A.baumanni with a high mortality rate in HM patients made empirical antimicrobial choice a highly challenging issue.

Continuous renal replacement therapy with oXiris®in patients with hematologically malignant septic shock:A retrospective study

BACKGROUND The mortality rate from septic shock in patients with hematological malignancies(HMs)remains significantly higher than that in patients without HMs.A longer resuscitation time would definitely be harmful because of the irreversibly immunocompromised status of the patients.Shortening the resuscitation time through continuous renal replacement therapy(CRRT)with oXiris^(■)would be an attractive strategy in managing such patients.AIM To explore the effects of CRRT and oXiris^(■)in shortening the resuscitation time and modifying the host response by reducing inflammation mediator levels.METHODS Forty-five patients with HM were diagnosed with septic shock and underwent CRRT between 2018 and 2022.Patients were divided into two groups based on the hemofilter used for CRRT(oXiris^(■)group,n=26;M150 group,n=19).We compared the number of days of negative and total fluid balance after 7 d of CRRT between the groups.The heart rate,norepinephrine dose,Sequential Organ Failure Assessment(SOFA)score,and blood lactic acid levels at different time points in the two groups were also compared.Blood levels of inflammatory mediators in the 26 patients in the oXiris^(■)group were measured to further infer the possible mechanism.RESULTS The average total fluid balance after 7 d of CRRT in the oXiris^(■)group was significantly lower than that of patients in the M150 hemofilter group.The SOFA scores of patients after CRRT with oXiris^(■)therapy were significantly lower than those before treatment on day 1(d1),d3 and d7 after CRRT;these parameters were also significantly lower than those of the control group on d7.The lac level after oXiris^(■)therapy was significantly lower than that before treatment on d3 and d7 after CRRT.There were no significant differences in the above parameters between the two groups at the other time points.In the oXiris^(■)group,procalcitonin levels decreased on d7,whereas interleukin-6 and tumor necrosis factor levels decreased significantly on d3 and d7 after treatment.CONCLUSION CRRT with oXiris^(■)hemofilter may improve hemodynamics by reducing inflammatory mediators and playing a role in shortening the resuscitation period and decreasing total fluid balance in the resuscitation phases.

Efficacy and Safety Assessment of Antifungal Sequential Therapy from Micafungin to Liposomal Amphotericin B for Antibiotics-Refractory Febrile Neutropenia in Patients with Hematologic Malignancies

Invasive fungal infections are a major challenging problem in the management of febrile neutropenia (FN) in patients with hematologic malignancies. Liposomal amphotericin B (L-AmB) or micafungin (MCFG) has been widely used as a first-line empirical antifungal therapy for suspected fungal infection in such patients. However, there are several issues in patients receiving these agents: drug related toxicities for L-AmB and breakthrough fungal infections for MCFG. In order to make the best use of these 2 agents, we conducted a prospective study of sequential therapy from MCFG to L-AmB, and evaluated the efficacy and safety of this strategy in FN patients with hematologic malignancies. A total of 18 patients were enrolled, and 11 patients who fulfilled the protocol defined criteria were evaluated. Underlying diseases consisted of acute leukemia (n = 9), non-Hodgkin lymphoma (n = 1), and myelodysplastic syndrome (n = 1). Treatment success was achieved in 8 patients (72.7%). Drug-related adverse events occurred in 8 patients (72.7%). All of those adverse events except one case were below grade 2. Three patients required discontinuation of L-AmB. Although our empirical antifungal sequential therapy seems to be encouraging for antibiotics-refractory FN in patients with hematologic malignancies, further investigation in large-scale studies is warranted.