A retrospective study of intravenous pentamidine for Pneumocystis jirovecii pneumonia prophylaxis in adult patients with hematologic malignancies-its utility during respiratory virus pandemics.

OBJECTIVES: In hematology, prophylaxis for Pneumocystis jirovecii pneumonia (PCP) is recommended for patients undergoing hematopoietic stem cell transplantation and in selected categories of intensive chemotherapy for hematologic malignancies. Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended first-line agent; however, its use is not straightforward. Inhaled pentamidine is the recommended second-line agent; however, aerosolized medications were discouraged during respiratory virus outbreaks, especially during the COVID-19 pandemic, in view of potential contamination risks. Intravenous (IV) pentamidine is a potential alternative agent. We evaluated the effectiveness and tolerability of IV pentamidine use for PCP prophylaxis in adult allogeneic hematopoietic stem cell transplantation recipients and patients with hematologic malignancies during COVID-19. RESULTS: A total of 202 unique patients who received 239 courses of IV pentamidine, with a median of three doses received (1-29). The largest group of the patients (49.5%) who received IV pentamidine were undergoing or had received a hematopoietic stem cell transplant. The most common reason for not using TMP-SMX prophylaxis was cytopenia (34.7%). We have no patients who had breakthrough PCP infection while on IV pentamidine. None of the patients developed an infusion reaction or experienced adverse effects from IV pentamidine. CONCLUSIONS: Pentamidine administered IV monthly is safe and effective.

Management of classical Philadelphia chromosome-negative myeloproliferative neoplasms in Asia: consensus of the Asian Myeloid Working Group.

Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized clinically by the proliferation of one or more hematopoietic lineage(s). The classical Philadelphia-chromosome (Ph)-negative MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The Asian Myeloid Working Group (AMWG) comprises representatives from fifteen Asian centers experienced in the management of MPN. This consensus from the AMWG aims to review the current evidence in the risk stratification and treatment of Ph-negative MPN, to identify management gaps for future improvement, and to offer pragmatic approaches for treatment commensurate with different levels of resources, drug availabilities and reimbursement policies in its constituent regions. The management of MPN should be patient-specific and based on accurate diagnostic and prognostic tools. In patients with PV, ET and early/prefibrotic PMF, symptoms and risk stratification will guide the need for early cytoreduction. In younger patients requiring cytoreduction and in those experiencing resistance or intolerance to hydroxyurea, recombinant interferon-α preparations (pegylated interferon-α 2A or ropeginterferon-α 2b) should be considered. In myelofibrosis, continuous risk assessment and symptom burden assessment are essential in guiding treatment selection. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in MF should always be based on accurate risk stratification for disease-risk and post-HSCT outcome. Management of classical Ph-negative MPN entails accurate diagnosis, cytogenetic and molecular evaluation, risk stratification, and treatment strategies that are outcome-oriented (curative, disease modification, improvement of quality-of-life).

A novel network pharmacology approach for leukaemia differentiation therapy using Mogrify®.

Acute myeloid leukaemia (AML) is a rapidly fatal blood cancer that is characterised by the accumulation of immature myeloid cells in the blood and bone marrow as a result of blocked differentiation. Methods which identify master transcriptional regulators of AML subtype-specific leukaemia cell states and their combinations could be critical for discovering novel differentiation-inducing therapies. In this proof-of-concept study, we demonstrate a novel utility of the Mogrify® algorithm in identifying combinations of transcription factors (TFs) and drugs, which recapitulate granulocytic differentiation of the NB4 acute promyelocytic leukaemia (APL) cell line, using two different approaches. In the first approach, Connectivity Map (CMAP) analysis of these TFs and their target networks outperformed standard approaches, retrieving ATRA as the top hit. We identify dimaprit and mebendazole as a drug combination which induces myeloid differentiation. In the second approach, we show that genetic manipulation of specific Mogrify®-identified TFs (MYC and IRF1) leads to co-operative induction of APL differentiation, as does pharmacological targeting of these TFs using currently available compounds. We also show that loss of IRF1 blunts ATRA-mediated differentiation, and that MYC represses IRF1 expression through recruitment of PML-RARα, the driver fusion oncoprotein in APL, to the IRF1 promoter. Finally, we demonstrate that these drug combinations can also induce differentiation of primary patient-derived APL cells, and highlight the potential of targeting MYC and IRF1 in high-risk APL. Thus, these results suggest that Mogrify® could be used for drug discovery or repositioning in leukaemia differentiation therapy for other subtypes of leukaemia or cancers.

Real-World Experience of Measurable Residual Disease Response and Prognosis in Acute Myeloid Leukemia Treated with Venetoclax and Azacitidine.

The prognostic value of measurable residual disease (MRD) by flow cytometry in acute myeloid leukemia (AML) patients treated with non-intensive therapy is relatively unexplored. The clinical value of MRD threshold below 0.1% is also unknown after non-intensive therapy. In this study, MRD to a sensitivity of 0.01% was analyzed in sixty-three patients in remission after azacitidine/venetoclax treatment. Multivariable cox regression analysis identified prognostic factors associated with cumulative incidence of relapse (CIR), progression-free survival (PFS) and overall survival (OS). Patients who achieved MRD < 0.1% had a lower relapse rate than those who were MRD ≥ 0.1% at 18 months (13% versus 57%, p = 0.006). Patients who achieved an MRD-negative CR had longer median PFS and OS (not reached and 26.5 months) than those who were MRD-positive (12.6 and 10.3 months, respectively). MRD < 0.1% was an independent predictor for CIR, PFS, and OS, after adjusting for European Leukemia Net (ELN) risk, complex karyotype, and transplant (HR 5.92, 95% CI 1.34−26.09, p = 0.019 for PFS; HR 2.60, 95% CI 1.02−6.63, p = 0.046 for OS). Only an MRD threshold of 0.1%, and not 0.01%, was predictive for OS. Our results validate the recommended ELN MRD cut-off of 0.1% to discriminate between patients with improved CIR, PFS, and OS after azacitidine/venetoclax therapy.

Surgical management of invasive fungal infections in adult leukemia patients: experience from a large tertiary center in Southeast-Asia.

Objectives: Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in acute leukemia patients undergoing chemotherapy or hematopoietic stem cell transplantation (HSCT). Surgical interventions may be necessary to improve the survival outcomes of these patients. The aim of this study is to report a single-center experience using surgical intervention as adjunctive treatment for IFI in adult leukemia patients. Methods: A retrospective review was conducted to obtain clinical characteristics and outcomes of surgically managed IFI patients diagnosed between January 2005 and December 2015 in our center. Results: Nineteen acute leukemia patients, median age 46 years (range 19-65), underwent 20 surgical procedures as management for IFI. Three patients had proven IFI diagnoses prior to surgery. Sixteen patients underwent surgery for both diagnostic and therapeutic purposes. Post-surgery, the diagnostic yield for proven IFI increased by a factor of 5, and 15 patients had definitive IFI diagnoses. Surgical complications included 2 pleural effusions, 4 pneumothoraxes, and 1 hydropneumothorax. The median duration of hospitalization for patients with complications was 9 days (range 3-64). Thirteen patients benefited overall from the procedure, 3 had temporary clinical benefits, and 2 had progression of IFI. After surgery, the 3-month and 2-year overall survival rates were 89.5% and 57.9%, respectively. The median time from surgery to resumption of chemotherapy or HSCT was 25 days. Conclusions: Surgical interventions for IFI are feasible in selected leukemia patients, as they yield valuable information to guide antifungal therapy or enable therapeutic outcomes with acceptable risk, thereby allowing patients to proceed with curative chemotherapy and HSCT.

The utility of voriconazole therapeutic drug monitoring in a multi-racial cohort in Southeast Asia.

OBJECTIVES: Voriconazole serum concentration, which is affected by several factors, is associated with treatment response and toxicity. There is paucity of data on voriconazole therapeutic drug monitoring (TDM) among Southeast Asians, who exhibit a higher prevalence of CYP2C19-poor metabolisers compared with Caucasians and East Asians. Hence, there are concerns for higher risk of voriconazole accumulation and toxicity. We aim to determine the utility of voriconazole TDM through establishing: (1) proportion of patients achieving therapeutic troughs without dose adjustments; (2) characterisation of patients with sub-therapeutic, therapeutic and supra-therapeutic levels; (3) appropriate dose titrations/dose required for therapeutic troughs; (4) correlation between troughs and adverse events, treatment response/fungal breakthrough. PATIENTS AND METHODS: A single-centre retrospective analysis of data from adults (≥21 years old) with ≥1 voriconazole trough measured at Singapore General Hospital from 2015 to 2017 was performed. RESULTS: Thirty-two patients (45.7%) among 70 patients achieved therapeutic troughs (defined as 2.0-5.5 mg/L) without dose adjustments. Eleven patients (15.7%) experienced hepatotoxicity (troughs 0.5 to >7.5 mg/L). Neurotoxicity occurred in three patients (4.3%) (troughs ≥6.7 mg/L) and all patients had symptom resolution upon dose reduction. Treatment failure of invasive fungal infection appeared less in patients with therapeutic troughs compared with sub-therapeutic troughs (11.4% vs. 14.2%). Two patients experienced treatment failure despite supra-therapeutic voriconazole troughs. CONCLUSIONS: TDM should be implemented due to significant unpredictability in dose exposure. TDM can reduce unnecessary switches to alternatives due to intolerability and rule in the possibility of resistant organisms in the event of treatment failure despite therapeutic troughs, alerting clinicians to switch to alternatives promptly.

Chromosomal microarray analysis is superior in identifying cryptic aberrations in patients with acute lymphoblastic leukemia at diagnosis/relapse as a single assay.

INTRODUCTION: Conventional cytogenetics (CC) is important in diagnosis, therapy, monitoring of post-transplant bone marrow, and prognosis assessment of acute lymphoblastic leukemia (ALL). However, due to the nature of ALL, CC often encounters difficulties of complex karyotype, poor chromosome morphology, low mitotic index, or normal cells dividing only. In contrast, chromosomal microarray analysis (CMA) showed a specificity >99% and a sensitivity of 100% in chronic lymphocytic leukemia (CLL) patients. Here, we report our experience with CMA on adult ALL patients. METHODS: Thirty-three bone marrow/blood samples from ALL patients (aged 18-79 years, median 44) at diagnosis/relapse, analyzed by CC and/or fluorescence in situ hybridization (FISH), were recruited. Chromosomal microarray analysis results were compared with CC. Fluorescence in situ hybridization analysis, if available, was applied when there was a discrepancy. RESULTS: Copy-neutral loss-of-heterozygosity (CN-LOH) was found in 8 cases (24.2%). Only CN-LOH at 9p was recurrent (3 cases, 9.1%). Copy number alterations (CNAs) were detected in 6 of 9 cases (66.7%) with normal karyotypes, in 3 of 5 cases (60.0%) with sole "balanced" translocations, and in 18 of 19 cases (94.7%) with complex karyotypes. Common CNAs involved CDKN2A/2B (30.3%), IKZF1 (27.3%), PAX5 (9.1%), RB1 (9.1%), BTG1 (6.7%), and ETV6 (6.7%), which regulate cell cycle, B lymphopoiesis, or act as tumor suppressors in ALL. Copy number alteration detection rate by CMA was 81.8% (27 of 33 cases) as compared to 57.6% (19 of 33 cases) by CC. CONCLUSION: Incorporation of CMA as a routine clinical test at the time of diagnosis/relapse, in conjunction with CC and/or FISH, is highly recommended.

Impact of an alternating first-line antibiotics strategy in febrile neutropenia.

BACKGROUND: Rising antibiotic resistance poses a challenge to the management of febrile neutropenia in patients with haematological malignancies receiving chemotherapy. AIM: We studied an alternating first-line antibiotic strategy to determine its impact on all-cause mortality and bacteremia rates in patients with febrile neutropenia. METHODS: An alternating first-line antibiotic strategy was established in mid-2013. Data for 2012 (before strategy implementation) and 2014 (post-strategy implementation) were compared. Antibiotic Heterogeneity Index (AHI) for each of the two time-periods was also calculated. FINDINGS: There were 2012 admissions (26082 patient-days) in 2012 and 1843 admissions (24331 patient-days) in 2014. There was no significant difference in the baseline characteristics of patients in the two groups. The defined daily doses (DDD) of cefepime (CEF) fell while the DDD of piperacillin-tazobactam (PTZ) rose in 2014 compared with 2012. Vancomycin DDD fell in 2014. The AHI was 0.466 in 2012 and 0.582 in 2014. The difference in all-cause mortality was not statistically significant. There was no difference in rates of bacteremia with CEF-resistant, PTZ-resistant and carbapenem-resistant gram-negative organisms in the two groups. Rates of new cases of Methicillin-resistant Staphylococcus aureus (MRSA) were 2.38/1000 and 2.59/1000 patient-days in 2012 and 2014 respectively. Rates of new cases of Vancomycin-resistant Enterococcus (VRE) were 1.84/1000 and 1.81/1000 patient-days in 2012 and 2014 respectively. There was no Carbapenem-resistant Enterobacteriaceae (CRE) bacteremia in 2012 and 1 in 2014. CONCLUSION: An alternating first-line antibiotic strategy resulted in an increase in antibiotic heterogeneity, without increasing mortality. There was also no significant increase in bacteremia rates.

Delayed diagnosis of Shwachman diamond syndrome with short telomeres and a review of cases in Asia.

Inherited bone marrow failure syndrome (IBMFS) including Shwachman Diamond Syndrome (SDS) can present initially to the hematologist with myelodysplastic syndrome (MDS). Accurate diagnosis affects choice of chemotherapy, donor selection, and transplant conditioning. We report a case of delayed diagnosis of SDS in a family with another child with aplastic anemia, and review reported cases of SDS in Asia. This highlights the gap in identifying inherited bone marrow failure syndromes in adults with hematologic malignancies.

Treatment of elderly patients with acute myeloid leukemia with azacitidine results in fewer hospitalization days and infective complications but similar survival compared with intensive chemotherapy.

AIMS: Azacitidine has been shown to prolong overall survival (OS) compared with best supportive care in elderly patients with acute myeloid leukemia (AML) with low blast counts but it is unknown if azacitidine has a similar efficacy in patients with blast counts of >30%. It is also unknown if azacitidine is comparable to intensive chemotherapy in terms of survival and morbidity. METHODS: Differences between the outcomes of elderly AML patients who received intensive chemotherapy, azacitidine-based therapy or best supportive care are studied in this retrospective review. Patients 60 years or older diagnosed with AML between January 2009 and June 2011 were included. Those who passed away within less than 2 weeks of diagnosis were excluded. RESULTS: At a median follow-up of 7.2 months (range: 0.5-26.4 months), estimated median OS for patients who received azacitidine-based therapy was 9.8 months (range: 2.4-22.5 months) compared with 8.9 months (range: 0.9-26.4 months) for patients who received intensive chemotherapy (P=0.89). Compared with azacitidine-based therapy, intensive chemotherapy is associated with more inpatient days and episodes of febrile illness requiring inpatient stay or intravenous antibiotics. CONCLUSIONS: Compared with intensive chemotherapy in elderly patients with AML, azacitidine-based therapy is associated with similar median survival but lower number of hospitalization days and infective episodes.

Genome-wide association study of B cell non-Hodgkin lymphoma identifies 3q27 as a susceptibility locus in the Chinese population.

To identify genetic risk factors underlying non-Hodgkin lymphomas (NHLs) from the B cell lineage, we conducted a genome-wide association study (GWAS) of 253 Chinese individuals with B cell NHL (cases) and 1,438 controls and further validation in 1,175 cases and 5,492 controls. We identified a new susceptibility locus, rs6773854, located between BCL6 (encoding B cell lymphoma protein 6) and LPP (encoding lipoma preferred partner) on oncogene-rich chromosome 3q27 that was significantly associated with increased risk of B cell NHL (meta-analysis P = 3.36 × 10⁻¹³, per-allele odds ratio (OR) = 1.44) and with diffuse large B cell lymphoma (DLBCL) in particular (meta-analysis P = 1.14 × 10⁻¹¹, OR = 1.47). We found no evidence of association of rs6773854 with non-B cell NHLs (T cell and natural killer (NK) lineages) (P = 0.17, OR = 1.12) and observed significant heterogeneity between B cell and non-B cell subtypes (Phet = 0.01, I² = 84%). Our results provide insight that germline variation in the intergenic region between BCL6 and LPP has a role in risk of B cell lymphomagenesis.