Revised free light chain reference intervals enhance risk stratification in monoclonal gammopathy of undetermined significance and reduce overdiagnosis [Retrospective cohort] 

Highlights:

●      The free light chain (FLC) ratio is a critical part of risk stratification for monoclonal gammopathy of undetermined significance (MGUS).

●      Revised FLC reference intervals developed accounting for age and renal function, have reduced the rate of abnormal findings.

●      The findings validate the revised FLC reference intervals, enhancing prognostic accuracy and improving risk stratification to accurately identify MGUS individuals at risk of progression while reducing unnecessary classifications as high-risk.

Of 6993 MGUS individuals, 2641 had an abnormal FLC ratio by the original intervals, of whom 844 (32%) were reclassified as having a normal FLC ratio (See Table 1: “Original vs. revised reference intervals for FLC ratio using the Freelite assay” in original paper). Reclassified individuals had no significantly increased risk of progression compared to those with a normal FLC ratio (hazard ratio (HR): 1.07, 95% confidence interval (CI) 0.74–1.57). Those with an abnormal FLC ratio by the revised reference intervals had an increased risk of progression (HR 2.23, 95% CI 1.79–2.78). Using the revised reference intervals, 490 individuals (16%) were reclassified to low-risk from a higher risk group. These individuals had a progression risk comparable to other low-risk patients.

Molecular monitoring versus standard clinical care in younger adults with acute myeloid leukaemia: results from the UK NCRI AML17 and AML19 randomised, controlled, phase 3 trials.

Highlights: 

●      In patients with acute myeloid leukemia (AML) treated with curative intent, the detection of measurable residual disease (MRD) generally confers a poor prognosis.

●      This study aimed to identify whether altering treatment based on MRD results can improve survival.

●      Sequential molecular MRD monitoring, coupled with MRD-guided treatment, did not improve overall survival in the entire study population; however, in the subgroup of patients with baseline NPM1 and FLT3 ITD mutations, the authors observed a survival benefit for MRD monitoring.

These phase 3 trials, conducted in the UK, Denmark, and New Zealand, randomized patients with newly diagnosed AML for molecular markers suitable for disease monitoring. Patients with a marker were randomly assigned (2:1) to either sequential molecular MRD monitoring during treatment and for 3 years after, or standard clinical care only with no molecular monitoring.  637 patients were randomly assigned across both trials. With a median follow-up time of 4.9 years, overall survival at 3 years was 70% in patients in the monitoring group and 73% in patients in the no-monitoring group. Meta-analysis of the two studies showed no difference in overall survival (hazard ratio 1.11, 95% confidence interval 0.83–1.49; P = 0.25).

Updated recommendations for the management of hepatitis B, C, and E virus infections in patients with haematological malignancies and those undergoing haematopoietic cell transplantation: recommendations from the 9th European Conference on Infections in Leukaemia (ECIL-9) [Consensus].  

Key points: See Table 2 in the original article.

1. Hepatitis B Virus (HBV). 

●      All onco-hematological patients should be screened for HBV. Check HBsAg (hepatitis B surface antigen), anti-HBc (hepatitis B core antibody), and anti-HBs (hepatitis B surface antibody) levels. See Figure 2 in the original article.

○      HBV reactivation risk was classified into three categories: high (>10%), moderate (5–10%), and low (1–5%).

○      Patients not receiving antiviral prophylaxis should undergo quarterly HBV DNA monitoring to promptly detect HBV reactivation.

○      Highly potent nucleoside or nucleotide analogues, such as entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide, have become standard of care as antiviral treatments of HBV infection and should exclusively be used in preventing or treating HBV reactivation.

●      All HBsAg-positive patients treated with tyrosine kinase inhibitors should receive antiviral therapy.

●      The risk of HBV reactivation might persist in HBsAg-negative patients beyond 12 months after stopping depleting therapies or immunosuppressive therapy, so:

○      Antiviral treatment could be continued or alternatively, without antiviral treatment, patients should be monitored every 3 months for HBV reactivation with HBV DNA testing.

1. Hepatitis C Virus (HCV). 

●      HCV can be treated concomitantly with chemotherapy if treatment of hematological malignancy is urgent.

○      Direct-acting antivirals now include interferon-free regimens, which have an approximately 95% probability of viral eradication after just 8–12 weeks of treatment.

●      HCV can be treated before chemotherapy in patients with low-grade non-Hodgkin lymphoma if treatment of hematological malignancy is not urgent.

●      Patients with persistent cryoglobulinemia after sustained virological response to direct-acting antivirals should be informed about the residual risk for non-Hodgkin lymphoma development.

1. Hepatitis E Virus (HEV). 

●      Anti-HEV serology has no role in the evaluation of donors or patients; HEV RNA PCR should be done to diagnose infection.

●      HEV transmission from hematopoietic stem cell (HSC) donors is possible, but there is currently no way to calculate the risk to benefit ratio of systematically testing HSC donors for HEV RNA.

●      The ECIL-5 recommendation that HSC donors, including those with normal transaminase levels, should be screened for HEV by nucleic acid testing was removed.

●      Hematopoietic cell transplantation with an HEV RNA-positive donor can be considered if other donor options are inferior, in which case treatment with ribavirin of the recipient could be considered.

●      Patients with hematological malignancy and HSC donors should be informed about the risks of food-borne HEV transmission and should be advised to avoid raw or undercooked pork or game meat.

●      For patients with chronic HEV infection, reducing the dose of immunosuppressive drugs could be considered.

●      For patients with HEV infection, antiviral therapy with ribavirin can be considered with the help of an expert.

Treatment of Invasive Pulmonary Aspergillosis and Preventive and Empirical Therapy for Invasive Candidiasis in Adult Pulmonary and Critical Care Patients An Official American Thoracic Society Clinical Practice Guideline.  

Key Points: 

●      In patients with proven or probable IPA, the panel recommends either initial monotherapy with a mold-active triazole or initial combination therapy with a mold-active triazole plus an echinocandin.

●      In critically ill patients without neutropenia or a history of transplant, the panel recommends against routine administration of prophylactic or empiric antifungal agents targeting Candida species.

European guidelines on treatment and supportive measures in chronic neutropenias: A consensus between the European Hematology Association and the EuNet‐INNOCHRON COST Action based on a systematic evidence review.

Key points: see Box 1 to Box 13 in the original article.

1. Granulocyte‐colony stimulating factor (G‐CSF) treatment in severe congenital (CN) and cyclic neutropenia (CyN).

●      The panel considers that G‐CSF treatment either in severe CN or in CyN is beneficial because it reduces the frequency and severity of infection and improves the quality of life (reduced use of antibiotics, fewer hospitalizations, and decreased infection-related complications).

1. G‐CSF treatment in neutropenias other than severe congenital and cyclic neutropenia.

●      The panel does not recommend the continuous use of G‐CSF, based only on the  absolute neutrophil count (ANC), in patients with chronic idiopathic neutropenia (CIN) or autoimmune neutropenia (AIN).

●      The panel does not recommend the use of G‐CSF in atypical chemokine receptor‐1 gene/Duffy antigen receptor for chemokines gene associated neutropenia due to the lack of infection propensity.

1. ANC threshold during G‐CSF administration.

●      The panel considers ANC over 1.0 x 10⁹/L as the protective threshold against infections. For CyN, a lower nadir may be accepted.

●      As a general concept, the panel suggests using the lowest effective dose of G‐CSF for infection control (usually coinciding with ANC ≥ 1.0 x 10⁹/L) and to minimize marrow stimulation and potential side effects (bone pain and splenomegaly).

1. Filgrastim and lenograstim may be interchangeably used in patients with severe CN. Pegfilgrastim might be considered in cases of poor adherence to G‐CSF treatment.
2. In diseases carrying a high intrinsic risk of transformation such as Shwachman–Diamond syndrome or of splenomegaly such as glycogen storage disease type Ib, minimal effective dose of G‐CSF to prevent infections should be used.
3. Use of corticosteroids in neutropenia. The panel does not recommend the use of corticosteroids in any type of neutropenia as the lymphocyte depletion effect may worsen the propensity to infections.
4. Based on the lack of data on efficacy and on the risk of microbiological resistance, the panel suggests avoiding antibiotic prophylaxis in any type of neutropenia.
5. Hematopoietic stem cell transplantation (HSCT) in severe congenital neutropenia.

●      Strong indications for HSCT include:

○      (1) Established transformation to myelodysplastic syndrome/acute leukemia or bone marrow dysplastic features with high‐risk acquired cytogenetic abnormalities (monosomy 7, trisomy 8, and trisomy 21) or with a combination of acquired leukemia‐associated somatic mutations (i.e., RUNX1, ASXL1, and SETBP1). CSF3R mutations alone are not an indication of HSCT.

○      (2) CN due to mutations carrying an intrinsic high risk of leukemic transformation per se, i.e., GATA2 mutations, high‐risk ELANE mutations, or clones with biallelic TP53 mutations in SDS.

○      (3) No response to G‐CSF (doses > 20 mcg/kg/d to reach ANC of 1.0 x 10⁹/L), poor response to G‐CSF (doses between 10 and 20 mcg/kg/d failing to reach ANC of 1.0 x 10⁹/L) or poor control of infection irrespective of the G‐CSF dose.