Clofarabine Preconditioning followed by Allogeneic Transplant Using TBI and Post-Transplant Cyclophosphamide for Relapsed Refractory Leukemia.

Acute myeloid leukemia patients with induction failure or relapsed refractory disease have minimal chance of achieving remission with subsequent treatments. Several trials have shown the feasibility of clofarabine-based conditioning in allogeneic stem cell transplants (allo-HSCT) for non-remission AML patients. Pre-transplant conditioning with clofarabine followed by reduced-intensity allo-HSCT has also demonstrated a potential benefit in those patients with human leukocyte antigen (HLA)-identical donors, but it is not commonly used in haploidentical and mismatched transplants. In this case report, we describe our experience of seven cases of non-remission AML who received clofarabine preconditioning followed by an allo-HSCT with PTCy. The 2-year overall survival and disease-free survival was 83.3% (95% confidence interval (CI): 27.3-97.9%) and 85.7% (95% CI: 33.4-97.9%). Median days of neutrophil and platelet recovery were 16 (range of 13-23) and 28 (range of 17-75), respectively. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) at day 100 and chronic GVHD at 1-year showed 28.6% (95% CI: 8-74.2%) and 28.6% (95% CI: 3-63.9%), respectively. The two-year relapse rate was 14.3% (95% CI: 2.14-66.6%). One-year GVHD-free relapse-free survival (GFRS) at 1-year was 71.4% (95% CI: 25.8-92%). Our patients showed successful outcomes with clofarabine preconditioning to reduce the leukemic burden at the pre-transplant period followed by PTCy to reduce GVHD resulting in lower relapsed rate and better GFRS in these patients.

Treatment patterns and comparative analysis of non-intensive regimens in elderly acute myeloid leukemia patients-a real-world experience from India.

Elderly patients with acute myeloid leukemia have a poor prognosis. Data from developing countries is sparse in the literature. In this retrospective study, 402 patients aged ≥ 60 years, diagnosed between Jan 2013 and Dec 2017, were analyzed for treatment patterns and survival. Median age of the whole cohort was 68 years (range 61-84). A total of 213 patients (53.3%) refused care; 188 patients (46.7%) received either BSC, LDAC, or HMA. Survival (in months) was 3.9, 6.4, and 1.2 with LDAC, HMA, and BSC, respectively. One-year survival was 17.2% and 6% with HMA and LDAC, respectively (P = 0.02). Overall response rate (ORR) did not differ between HMA and LDAC group (p = 0.12). HMA cohort had higher complete responses (20.6% vs 7.4%, p = 0.02), stable disease (32.7% vs 13.5%, p = 0.02), and transfusion independence (TI) (46.5% vs 22.2%, p = 0.01). Survival did not differ between the groups if the patients achieved ORR (12.3 vs 9.8 p = 0.2) or TI (11.6 vs 6.4 p = 0.2). Stable disease with HMA led to longer survival (8.1 vs 5.3 p = 0.01). HMAs were more effective than LDAC irrespective of cytogenetic risk category and blasts, of note HMAs improved survival of poor risk patients (5.6 vs 2.9 p = 0.004). HMA treatment (HR = 0.48; 95% 0.29-0.79, p = 0.004) and transfusion independence (HR = 0.2; 95% 0.1-0.3, p = 0.0001) predicted survival in multivariate analysis. Neutropenia and febrile neutropenia were frequent in HMA. Thrombocytopenia was the common adverse event with LDAC. Novel and cost-effective drugs are essential to improve the prognosis of these patients.

Identification of post-transcriptional regulatory networks during myeloblast-to-monocyte differentiation transition.

Treatment of leukemia cells with 1,25-dihydroxyvitamin D3 may overcome their differentiation block and lead to the transition from myeloblasts to monocytes. To identify microRNA-mRNA networks relevant for myeloid differentiation, we profiled the expression of mRNAs and microRNAs associated to the low- and high-density ribosomal fractions in leukemic cells and in their differentiated monocytic counterpart. Intersection between mRNAs shifted across the fractions after treatment with putative target genes of modulated microRNAs showed a series of molecular networks relevant for the monocyte cell fate determination, as for example the post-transcriptional regulation of the Polo-like kinase 1 (PLK1) by miR-22-3p and let-7e-5p.

Advancing the understanding of venetoclax in t(11;14)-positive multiple myeloma: a comprehensive review of clinical evidence and future prospects.

Venetoclax is a selective inhibitor of the anti-apoptotic protein B-cell lymphoma 2 (BCL2), as a targeted therapy for multiple myeloma (MM) patients. It was initially approved by the United States Food and Drug Administration for the treatment of chronic lymphocytic leukemia in April 2016 and later for acute myeloid leukemia in October 2020. However, venetoclax is used as an off-label in a subset group of relapsed and refractory multiple myeloma (RRMM) patients with the presence of translocation t(11;14). Preclinical and clinical studies have highlighted the potential of venetoclax in the management of MM patients, with a specific focus on t(11;14) as a predictive biomarker for initiating venetoclax-based treatment. Later, several studies in RRMM patients that used venetoclax in combination with dexamethasone or/and proteasome inhibitors have shown promising results, in which management guidelines have included venetoclax as one of the options to treat MM patients. Hence, this review focuses on the use of venetoclax in RRMM, clinical efficacy, safety, dosing strategies, and predictive biomarkers for initiating venetoclax. Additionally, we discuss ongoing studies that are investigating different combination of venetoclax regimens in MM patients.

Vitamin D levels in patients of acute leukemia before and after remission-induction therapy.

OBJECTIVES: To determine the levels of 25-hydroxyvitamin [25(OH)D3] in patients with acute leukemia and the effect of remission-induction chemotherapy. METHODOLOGY: This study was case control, all newly diagnosed patients of acute leukemia between the age of one to sixty years and residents of Pakistan were enrolled and evaluated. Those who were unwilling or unable to provide written informed consent were excluded. All selected patients (n=86) were grouped in to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). AML was further categorized as A1 before remission-induction (n=17) and B1 after remission induction (n=13), ALL was further categorized as A2 before remission-induction (n=31) and B2 after remission induction (n=25). The 25-hydroxyvitamin [25(OH)D3] levels were measured in the sera of all patients (before and after remission-induction) by one step delayed chemiluminescent micro particle immunoassay (CMIA).We compared 25(OH)D3 levels in all patients before and after the remission-induction chemotherapy. RESULTS: A total of 86 patients were analyzed, in which 60 patients were male. Mean age was 24.39 years (range, 1 to 60 years); the mean levels of 25(OH)D in group A1 (n=17) was 17.70±3.2 ng/ml, in group B1 (n=13) 14.06±2.4 ng/ml, 19.07±7.08 ng/ml in group A2 (n=31), while 10.59±3.9 ng/ml found in group B2 (n=25). CONCLUSION: 25(OH)D3 insufficiency was evident subnormal in majority of patients with acute leukemia and 25(OH)D3 were further reduced after remission-induction as compared to untreated group, difference was statistically significant when compared with each group.

The potential role of the thymus in immunotherapies for acute myeloid leukemia.

Understanding the factors which shape T-lymphocyte immunity is critical for the development and application of future immunotherapeutic strategies in treating hematological malignancies. The thymus, a specialized central lymphoid organ, plays important roles in generating a diverse T lymphocyte repertoire during the infantile and juvenile stages of humans. However, age-associated thymic involution and diseases or treatment associated injury result in a decline in its continuous role in the maintenance of T cell-mediated anti-tumor/virus immunity. Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that mainly affects older adults, and the disease's progression is known to consist of an impaired immune surveillance including a reduction in naïve T cell output, a restriction in T cell receptor repertoire, and an increase in frequencies of regulatory T cells. As one of the most successful immunotherapies thus far developed for malignancy, T-cell-based adoptive cell therapies could be essential for the development of a durable effective treatment to eliminate residue leukemic cells (blasts) and prevent AML relapse. Thus, a detailed cellular and molecular landscape of how the adult thymus functions within the context of the AML microenvironment will provide new insights into both the immune-related pathogenesis and the regeneration of a functional immune system against leukemia in AML patients. Herein, we review the available evidence supporting the potential correlation between thymic dysfunction and T-lymphocyte impairment with the ontogeny of AML (II-VI). We then discuss how the thymus could impact current and future therapeutic approaches in AML (VII). Finally, we review various strategies to rejuvenate thymic function to improve the precision and efficacy of cancer immunotherapy (VIII).

Impact of hematopoietic stem cell transplantation in glycogen storage disease type Ib: A single-subject research design using 13C-glucose breath test.

Background: Glycogen storage disease type Ib (GSD Ib) is an autosomal recessively inherited deficiency of the glucose-6-phosphate translocase (G6PT). Clinical features include a combination of a metabolic phenotype (fasting hypoglycemia, lactic acidosis, hepatomegaly) and a hematologic phenotype with neutropenia and neutrophil dysfunction. Dietary treatment involves provision of starches such as uncooked cornstarch (UCCS) and Glycosade® to provide prolonged enteral supply of glucose. Granulocyte colony-stimulating factor (G-CSF) is the treatment of choice for neutropenia. Because long-term stimulation of hematopoiesis with G-CSF causes serious complications such as splenomegaly, hypersplenism, and osteopenia; hematopoietic stem cell transplantation (HSCT) has been considered in some patients with GSD Ib to correct neutropenia and avoid G-CSF related adverse effects. Whether HSCT also has an effect on the metabolic phenotype and utilization of carbohydrate sources has not been determined. Objective: Our objective was to measure the utilization of starch in a patient with GSD Ib before and after HSCT using the minimally invasive 13C-glucose breath test (13C-GBT). Design: A case of GSD Ib (18y; female) underwent 13C-GBT four times: UCCS (pre-HSCT), UCCS (3, 5 months post-HSCT) and Glycosade® (6 months post-HSCT) with a dose of 80 g administered via nasogastric tube after a 4 h fast according to our patient's fasting tolerance. Breath samples were collected at baseline and every 30 min for 240 min. Rate of CO2 production was measured at 120 min using indirect calorimetry. Finger-prick blood glucose was measured using a glucometer hourly to test hypoglycemia (glucose <4 mmol/L). Biochemical and clinical data were obtained from the medical records as a post-hoc chart review. Results: UCCS utilization was significantly higher in GSD Ib pre-HSCT, which reduced and stabilized 5 months post-HSCT. UCCS and Glycosade® utilizations were low and not different at 5 and 6 months post-HSCT. Blood glucose concentrations were not significantly different at any time point. Conclusions: Findings show that HSCT stabilized UCCS utilization, as reflected by lower and stable glucose oxidation. The results also illustrate the application of 13C-GBT to examine glucose metabolism in response to various carbohydrate sources after other treatment modalities like HSCT in GSD Ib.

A rare combination of acute myeloid leukemia with Vit B12 deficiency: Case report.

Introduction and importance: Acute myeloid leukemia (AML) is a malignant disease with several risk factors from hematologic disorders, which almost presents as anemia. AML is characterized by the presence of myeloblast in the blood picture. On the other hand, macrocytic anemia characterized by the presence of megaloblastic marrow morphology. We are presenting a rare case of combined Acute myeloid leukemia with macrocytic anemia. Case presentation: A 45 years old married woman was admitted for hyperthermia, dysuria, and chills. She had suffered from general malaise, weakness, and myalgia for two months. In her laboratories, the peripheral blood sample showed: HGB 26.1% (5.6 g/dL), RBCs 1.4 M/µL, WBC 13.3 K/µL. The blood smear showed megaloblastic features, so she was diagnosed with macrocytic anemia, and the treatment was blood transfusion, antibiotics, and muscular Vit B12. After one month, the peripheral blood sample showed an elevation of WBC, the bone marrow aspiration showed myeloblast infiltration represents 60% of the total events, and the flow cytometry for the bone marrow aspiration agrees with Acute Myeloblastic leukemia with Maturation M2 (AML-M2). Clinical discussion: The incidence of macrocytic anemia and leukemia in one patient is infrequent, case reports give scarce information concerning a potential increased occurrence of leukemia in patients putting up with macrocytic anemia. Several theories discussed the reasons for the association of the two conditions. Conclusion: we need more research on similar cases to identify the pathological mechanism.

FEV Maintains Homing and Expansion by Activating ITGA4 Transcription in Primary and Relapsed AML.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy that recurs in approximately 50% of cases. Elevated homing and uncontrolled expansion are characteristics of AML cells. Here, we identified that Fifth Ewing Variant (FEV) regulates the homing and expansion of AML cells. We found that FEV was re-expressed in 30% of primary AML samples and in almost all relapsed AML samples, and FEV expression levels were significantly higher in relapsed samples compared to primary samples. Interference of FEV expression in AML cell lines delayed leukemic progression and suppressed homing and proliferation. Moreover, FEV directly activated integrin subunit alpha 4 (ITGA4) transcription in a dose-dependent manner. Inhibition of integrin α4 activity with natalizumab (NZM) reduced the migration and colony-forming abilities of blasts and leukemic-initiating cells (LICs) in both primary and relapsed AML. Thus, our study suggested that FEV maintains the homing and expansion of AML cells by activating ITGA4 transcription and that targeting ITGA4 inhibits the colony-forming and migration capacities of blasts and LICs. Thus, these findings suggested that the FEV-ITGA4 axis may be a therapeutic target for both primary and relapsed AML.

Isolated Myeloid Sarcoma and Intracardiac Thrombus Resulting in Superior Mediastinal Syndrome.

Superior mediastinal syndrome (SMS) is a relatively common emergency in the practice of Pediatric Oncology. It typically results from the compression of large airways and superior vena cava by a swiftly growing mass. T-lineage acute lymphoblastic leukemia or lymphoma, neuroblastoma, and germ cell tumor are the common etiologies of SMS in children. Occasionally, SMS can be an unexpected presentation of less common childhood cancers and a surprise for the diagnostic and treating teams. The present paper reports the diagnostic and therapeutic challenge of managing a 9-y-old boy with SMS resulting from mediastinal myeloid sarcoma. The presence of a sizeable intracardiac thrombus, in addition, contributed to the SMS. The initial pleural fluid cytology and image-guided fine-needle aspiration cytology of the mediastinal mass were nondiagnostic. A thoracotomy was subsequently performed to debulk the tumor for symptomatic relief and obtain tissue for diagnosis.

Bacillus Cereus bacteremia complicated by brain abscess in a severely immunocompromised patient: Addressing importance of early recognition and challenges in diagnosis.

Bacillus cereus (B. cereus) is a known cause of a food poisoning in the general population. However, it can cause life-threatening sepsis and shock in severely immunocompromised patients with hematologic malignancies, which frequently lead to central nervous system (CNS) infections associated with high mortality and morbidity. In this case report, we describe a patient with a newly diagnosed acute myeloid leukemia that underwent induction chemotherapy and developed B. cereus infection that was associated with septic shock and brain abscesses. Definitive diagnosis of multiple brain abscesses was not manifested with routine microbiological investigation but required the use of 16S ribosomal (rRNA) gene polymerase chain reaction (PCR) sequencing of the resected brain lesion. The patient was eventually treated with 8-week course of intravenous vancomycin and high-dose ciprofloxacin which led to a full recovery. This report highlights the significant risk posed by B. cereus infection in neutropenic patients, the use of 16S rRNA PCR sequencing test for definitive diagnosis and use of combination therapy for successful treatment of B. Cereus CNS infection.

Clinical usefulness of 2-hydroxyglutarate as a biomarker in IDH-mutant chondrosarcoma.

Background: Chondrosarcoma is a common form of malignant bone tumor with limited treatment options. Approximately half of chondrosarcomas harbor gain-of-function mutations in isocitrate dehydrogenase (IDH), and mutant IDH produces 2-hydroxyglutarate (2-HG), which is an oncometabolite that contributes to malignant transformation. Therefore, inhibiting 2-HG production is a novel and promising treatment for advanced chondrosarcoma. 2-HG is also expected to be a useful biomarker for the diagnosis and treatment of IDH-mutant tumors. However, few studies have confirmed this using chondrosarcoma clinical specimens. Non-invasive monitoring of 2-HG levels is useful to infer that mutant IDH inhibitors reach therapeutic targets and to confirm their therapeutic efficacy in clinical practice. Methods: To evaluate the clinical utility of 2-HG as a surrogate biomarker for diagnosis and therapeutic efficacy, we measured intra-tumor and serum levels of 2-HG using frozen tissues and peripheral blood from patients with chondrosarcoma. We also developed a non-invasive method to detect intra-tumor 2-HG signals in vivo using magnetic resonance spectroscopy (MRS). Results: Both intratumoral and serum 2-HG levels were significantly elevated in IDH-mutant tumors, and these levels correlated with decreased survival. Furthermore, we detected intratumoral 2-HG peaks using MR spectroscopy in a xenograft model of IDH-mutant chondrosarcoma, and observed that 2-HG peak signals disappeared after administering an inhibitor of mutant IDH1. Conclusions: Our findings suggest that both intratumoral and serum 2-HG levels represent potentially useful biomarkers for IDH-mutant tumors and that the 2-HG signal in MR spectra has potential value as a non-invasive biomarker. Taken together, these findings may positively impact the clinical development of mutant IDH inhibitors for the treatment of advanced chondrosarcoma.

Cardiovascular Disease Among Patients With AML and CHIP-Related Mutations.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel cardiovascular disease (CVD) risk factor in individuals without acute myeloid leukemia (AML). Objectives: The aim of this study was to examine the association between mutations associated with CHIP (CHIP-related mutations) identified in patients at AML diagnosis and the risk for cardiovascular events (CVEs). Methods: This was a retrospective cohort study of 623 patients with AML treated between 2015 and 2018 who underwent DNA analysis. Cause-specific hazard regression models were used to study the associations between pathogenic mutations in common CHIP-related genes (DNMT3A, TET2, ASXL1, JAK2, TP53, SRSF2, and SF3B1) and the rate of CVEs (heart failure hospitalization, acute coronary syndrome, coronary artery revascularization, ischemic stroke, venous thromboembolism, and CVD death) and between CVE development and all-cause mortality. Results: Patients were 64.6 ± 15.3 years of age, 265 (42.5%) were women, and 63% had at least 1 CHIP-related mutation. Those with CHIP-related mutations were older (69.2 ± 12.3 vs 56.6 ± 16.6 years; P < 0.001) and had a greater prevalence of CVD risk factors and CVD history. In adjusted analysis, the presence of any CHIP-related mutation was associated with a higher rate of CVEs (HR: 1.74; 95% CI: 1.03-2.93; P = 0.037) among intensively treated patients (anthracycline based) but not the whole cohort (HR: 1.26; 95% CI: 0.81-1.97; P = 0.31). TP53 (HR: 4.18; 95% CI: 2.07-8.47; P < 0.001) and ASXL1 (HR: 2.37; 95% CI: 1.21-4.63; P = 0.012) mutations were associated with CVEs among intensively treated patients. Interval development of CVEs was associated with all-cause mortality (HR: 1.99; 95% CI: 1.45-2.73; P < 0.001). Conclusions: Among patients with AML treated with intensive chemotherapy, mutations in CHIP-related genes were associated with an increased risk for developing incident CVEs after AML diagnosis.

Validation of atovaquone plasma levels by liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring in pediatric patients.

Background: Atovaquone has traditionally been used as an antiparasitic and antifungal agent, but recent studies have shown its potential as an anticancer agent. The high variability in atovaquone bioavailability highlights the need for therapeutic drug monitoring, especially in pediatric patients. The goal of our study was to develop and validate the performance of an assay to quantify atovaquone plasma concentrations collected from pediatric cancer patients using LC-MS/MS. Methods: Atovaquone was extracted from a 10 µL volume of K2-EDTA human plasma using a solution consisting of ACN: EtOH: DMF (8:1:1 v:v:v), separated using reverse-phase chromatography, and detected using a SCIEX 5500 QTrap MS system. LC-MS/MS assay performance was evaluated for precision, accuracy, carryover, sensitivity, specificity, linearity, and interferences. Results: Atovaquone and its deuterated internal standard were analyzed using a gradient chromatographic method that had an overall cycle-time of 7.4 min per injection, and retention times of 4.3 min. Atovaquone was measured over a dynamic concentration range of 0.63 - 80 µM with a deviation within ≤ ± 5.1 % of the target value. Intra- and inter-assay precision were ≤ 2.7 % and ≤ 8.4 %, respectively. Dilutional, carryover, and interference studies were also within acceptable limits. Conclusions: Our studies have shown that our LC-MS/MS-based method is both reliable and robust for the quantification of plasma atovaquone concentrations and can be used to determine the effective dose of atovaquone for pediatric patients treated for AML.

N1-methyladenosine modification in cancer biology: Current status and future perspectives.

Post-transcriptional modifications in RNAs regulate their biological behaviors and functions. N1-methyladenosine (m1A), which is dynamically regulated by writers, erasers and readers, has been found as a reversible modification in tRNA, mRNA, rRNA and long non-coding RNA (lncRNA). m1A modification has impacts on the RNA processing, structure and functions of targets. Increasing studies reveal the critical roles of m1A modification and its regulators in tumorigenesis. Due to the positive relevance between m1A and cancer development, targeting m1A modification and m1A-related regulators has been of attention. In this review, we summarized the current understanding of m1A in RNAs, covering the modulation of m1A modification in cancer biology, as well as the possibility of targeting m1A modification as a potential target for cancer diagnosis and therapy.

A Journey Across Oceans With a Heavy Heart: Rare Presentation of a Pediatric Malignancy.

Myeloid sarcoma, due to extramedullary deposition of myeloblasts, is one of the rare presentations in acute myeloid leukemia. We present an extremely rare case of a 5-year-old boy with cardiac myeloid sarcoma. Noninvasive mode of diagnosis, timely initiation of chemotherapy and meticulous supportive care are the keys to successful outcome. (Level of Difficulty: Intermediate.).

The first case of Janibacter hoylei bacteremia in an adult.

The Janibacter species are Gram positive, coryneform bacteria that belong to the Actinobacteria phylum and have been linked to bacteremia in immunocompromised children. We present the first documented adult case of Janibacter hoylei bacteremia. The patient was a 52-year-old woman with a history of recurrent Clostridioides difficile infection, sinus tachycardia and high-risk AML who had been admitted one month prior to presentation for matched unrelated donor hematopoietic stem cell transplant with reduced intensity fludarabine-melphalan. Thirty days post-transplant, the infectious disease team was consulted because blood cultures grew Janibacter hoylei, from one of two blood cultures It took nine days to identify the species. She was treated with linezolid and imipenem. Janibacter are rarely implicated in human pathology, and therein, usually identified in the context of malignancy and relative immunosuppression. J. hoylei was only previously reported from the bloodstream of a previously healthy 8-week-old infant without underlying medical conditions. Antimicrobial susceptibility testing is challenging as only in vitro susceptibility testing of Janibacter terrae has been reported. Given these challenges, it is our hope to illustrate the clinical approach to diagnosis as well as subsequent recommendations for treatment in a particularly challenging case of bacteremia in an AML patient.

Hypomethylating Agent-Based Combination Therapies to Treat Post-Hematopoietic Stem Cell Transplant Relapse of Acute Myeloid Leukemia.

Allogeneic stem cell transplantation still represents the best curative option for most patients with acute myeloid leukemia, but relapse is still dramatically high. Due to their immunologic activity and safety profile, hypomethylating agents (HMAs) represent an interesting backbone for combination therapies. This review reports mechanism of action, safety, and efficacy data on combination strategies based on HMAs in the setting of post-allogeneic stem cell transplant relapse. Several studies highlighted how HMAs and donor lymphocyte infusion (DLI) combination may be advantageous. The combination strategy of HMA with venetoclax, possibly in association with DLI, is showing excellent results in terms of response rate, including molecular responses. Lenalidomide, despite its well-known high rates of severe graft-versus-host disease in post-transplant settings, is showing an acceptable safety profile in association with HMAs with a competitive response rate. Regarding FLT3 internal tandem duplication (ITD) mutant AML, tyrosine kinase inhibitors and particularly sorafenib have promising results as monotherapy and in combination with HMAs. Conversely, combination strategies with gemtuzumab ozogamicin or immune checkpoint inhibitors did not show competitive response rates and seem to be currently less attractive strategies. Associations with histone deacetylase inhibitors and isocitrate dehydrogenase 1 and 2 (IDH1/2) inhibitors represent new possible strategies that need to be better investigated.

Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering.

Donor lymphocyte infusion (DLI) is a key strategy for the treatment of AML relapse after allogeneic hematopoietic cell transplantation (allo-HCT) and has been used for either prophylactic, pre-emptive, or therapeutic purposes. However, the prognosis of these patients remains dismal even after DLI infusion (2-year overall survival, ~25%), and the efficacy is achieved at the cost of toxicities such as graft-versus-host (GVH) disease. Attempts to optimize DLI efficacy and safety, such as dose/timing modification and the use of cytoreduction, before DLI have been performed previously. Recently, a great number of novel targeted and immunomodulatory agents have emerged. Some of them, such as hypomethylating agents, FLT3 and Bcl-2 inhibitors, have been used in combination with DLI, aiming to enhance the graft-versus-leukemia effect. Moreover, manipulation of the DLI graft through cell selection (e.g., donor NK cells) or cell engineering (donor CAR-T cells) has shown potentially superior anti-tumor effects but less GVH effect than conventional DLI in clinical trials. This review summarizes the recent advances on the use of DLI for the prophylaxis/treatment of AML relapse and discusses future strategies which may further improve the treatment efficacy.

Case Report: Opposite Effects of BRAF Inhibition on Closely Related Clonal Myeloid Disorders.

Langerhans cell histiocytosis (LCH) commonly co-occurs with additional myeloid malignancies. The introduction of targeted therapies, blocking "driver" mutations (e.g., BRAF V600E), enabled long-term remission in patients with LCH. The effect of BRAF inhibition on the course and the prognosis of co-existing clonal hematopoiesis is poorly understood. We report on a 61-year-old patient with systemic BRAF V600E positive LCH and concomitant BRAF wild-type (wt) clonal cytopenia of unknown significance (CCUS) with unfavorable somatic mutations including loss of function (LOF) of NF1. While manifestations of LCH improved after blocking BRAF by dabrafenib treatment, the BRAF wt CCUS progressed to acute myeloid leukemia (AML). The patient eventually underwent successful allogeneic hematopoietic stem cell transplantation (HSCT). We performed an in-depth analyzes of the clonal relationship of CCUS and the tissue affected by LCH by using next-generation sequencing (NGS). The findings suggest activation of the mitogen-activated protein (MAP) kinase pathway in the CCUS clone due to the presence of the RAS deregulating NF1 mutations and wt BRAF, which is reportedly associated with paradoxical activation of CRAF and hence MEK. Patients with LCH should be carefully screened for potential additional clonal hematological diseases. NGS can help predict outcome of the latter in case of BRAF inhibition. Blocking the MAP kinase pathway further downstream (e.g., by using MEK inhibitors) or allogeneic HSCT may be options for patients at risk.