Risk of hospitalization with infection in adults with primary AIHA treated with rituximab: a French nationwide study [Retrospective study].  

Highlights:

●       Infections are frequent and often severe during the course of autoimmune hemolytic anemia (AIHA).

●       In this study, the 6-month cumulative incidence of hospitalization with infection was 18%; 30-day overall mortality after this event was 13%. All pneumocystosis occurred in patients who were not receiving prophylaxis and were receiving concomitant corticosteroids at the time of infection.

This cohort consisted of 959 adult patients (mean age 67 years, 60.5% were women) newly diagnosed with primary AIHA and treated with rituximab between 2012 and 2018 in the French national health database. The main outcome was hospitalization with infection, identified by a discharge diagnosis of infection during rituximab exposure. The most frequent infections were pulmonary (40.2%). Opportunistic infections were observed in 28 (16.6%) patients, including 11 cases of pneumocystosis.

How I treat iron overload in adult MDS [Review].

Key Points:

●       There is no universally accepted serum ferritin (SF) or cumulative number of RBC units at which to initiate ICT but guidelines recommend after 20 to 50 RBC units and SF of 1000 to 2500 ng/mL. In the clinic, the authors follow both SF and transferrin saturation (TSAT) with magnetic resonance imaging (MRI). Elevated SF without TSAT >70% is not a criterion for starting iron chelation therapy (ICT) in the absence of transfusion. See Table 1 for proposed criteria for severity of iron overload (IOL) in myelodysplastic syndrome (MDS).

●       Although data are largely retrospective, there is sufficient evidence of clinical benefit, including superior overall survival, event-free survival, possibly leukemia-free survival, hematologic improvement, and organ function associated with ICT in MDS to consider its use. See Figure 3 for a suggested approach to reducing IOL in lower-risk MDS when identified.

●       Because studies largely include lower-risk MDS, older guidelines recommend ICT in lower-risk patients with transfusional IOL and a life expectancy of at least 1 to 2 years or with IOL-related end-organ damage. However, it is reasonable to consider the use of ICT when the Revised International Prognostic Scoring System (IPSS-R) and molecular IPSS (IPSS-M) risk scores predict a life expectancy of 3 years or more.

●       Although IOL reduction may confer clinical benefit in hematopoietic stem cell transplantation (HSCT), chelation should be used with caution and close monitoring due to the potential for toxicity and delay/prevention of transplantation. Deferiprone (DFP) should be avoided because of the neutropenia expected with azacitidine, which may be difficult to distinguish from a DFP effect. After HSCT, IOL may be reduced by phlebotomy or ICT. Limited evidence in patients with higher-risk MDS not undergoing HSCT suggests that ICT with deferoxamine is feasible and reduces ferritin; however, there is currently insufficient clinical evidence to support routine ICT in these patients.

International myeloma working group immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma [Consensus].

Key recommendations:

1. There are no concerns about proceeding with T-cell redirecting therapies (TCRT) in patients receiving a proteosome inhibitor (PI), immunomodulatory agent (IMiD), (naked) monoclonal antibody, a corticosteroid, or any combination of these classes as most recent line of therapy. When used as “holding therapy” before T-cell collection, we recommend a washout of 2 weeks between last dose of conventional agent and apheresis of mononuclear cells for chimeric antigen receptor (CAR) T-cell therapy manufacturing. Similarly, we recommend a 2-week washout for these agents before the first dose of a bispecific T-cell engager (TCE).
2. If feasible, avoid collection of mononuclear cells for CAR T-cell manufacturing in patients receiving a TCE. If such a sequence is the best option for the patient, aim for a minimum of a 4-week washout between the last dose of the TCE and apheresis collection. Alternatively, if possible, consider T-cell collection prior to TCE initiation.
3. Avoid high-dose alkylators and bendamustine in patients for whom next therapy is likely to be CAR T-cells and/or a TCE.
4. Strongly consider bridging therapy after apheresis for CAR T-cell manufacturing in patients with high disease burden or at risk of developing morbidity from multiple myeloma during the 4-6 weeks of manufacturing. The ideal bridging therapy will contain agent(s) without known resistance from the patient’s myeloma, be short, with low risk of infection or prolonged cytopenias.
5. Assuming equal access, in patients who are reasonable candidates for both B-cell maturation antigen (BCMA)-targeted antibody-drug conjugate (ADC) and (BCMA)-targeted TCRT, we recommend pursuing TCRT first, given its higher activity and lower efficacy of TCRT after prior BCMA-targeted ADC.
6. Assuming equal access, in patients who are reasonable candidates for both BCMA-targeted CAR T-cells and TCEs, we recommend pursuing CAR T-cell therapy. This recommendation considers more robust data supporting activity of TCEs upon progression after CAR T-cell therapy, and also the extended treatment-free interval post-CAR T-cells that is typically associated with more salvage options at the time of progression.
7. For patients with rapidly progressing disease and unlikely to transit through apheresis and bridging without disease related morbidity, proceed with a TCE due to faster access.
8. Both BCMA-targeted and G protein–coupled receptor class C group 5 member D (GPRC5D)-targeted immunotherapy are safe and active in patients with prior BCMA-targeted CAR T-cell therapy. Post BCMA-targeted CAR T-cell therapy, responses to BCMA-targeting therapies are likely less frequent and durable than in patients not previously treated with BCMA-targeted CAR T-cell therapy.
9. There are limited data on the feasibility and efficacy of BCMA-targeted therapy of a different modality upon progression on BCMA-targeted TCE at the approved dose intensities until progression. Outcomes after lower dose intensity or fixed duration of therapy are unknown. We recommend therapy with a different mechanism of action or immunotherapy targeting a different antigen for patients progressing while receiving or shortly after receiving BCMA-targeting TCE.

Prognostic impact of expression of CD2, CD25, and/or CD30 in/on mast cells in systemic mastocytosis: a registry study of the European Competence Network on Mastocytosis [Retrospective study].  

Highlights: 

●       Expression of CD2, CD25 and/or CD30 on extracutaneous mast cells (MC) is a minor diagnostic criterion for systemic mastocytosis (SM) in the World Health Organization and International Consensus Classification. Whether the expression of these antigens on MC is of prognostic significance in SM remains unknown. 

●       Taken together, lack of CD2 expression on MC is a prognostic marker and indicator of reduced overall survival (p < 0.0001) and extramedullary disease extension (affecting the spleen, liver, and/or lymph nodes [odds ratio 2.63] compared to SM with CD2+ MC) in patients with SM.

This retrospective multi-center study of patients with SM included 5034 patients with various MC disorders. The percentage of CD2^-, CD25⁺ and/or CD30⁺ MC was significantly lower in patients with indolent SM compared to patients with advanced SM, including aggressive SM and MC leukemia.

Prospective Pharmacokinetic Evaluation of Venetoclax in AML Supports Re-Evaluation of Recommended Dose Adjustments With Azole Antifungals [Prospective study].

Highlights: 

●       Specific venetoclax (VEN) dose reductions are recommended when administered with CYP3A4 inhibitors (CYP3A4i). The FDA recommends VEN 70 mg (VEN70) daily in combination with posaconazole. Of note, in the VIALE-A trial, all patients receiving a potent CYP3A4i were dose-reduced to VEN 50 mg (VEN50).

●       VEN serum levels may be supratherapeutic when given in combination with posaconazole and higher VEN levels may be associated with prolonged myelosuppression.

●       This study demonstrates that VEN50 in combination with posaconazole results in pharmacokinetic parameters most similar to those observed with VEN without concomitant CYP3A4i and represents an appropriate dose reduction.

As part of an ongoing phase 2 study of VEN in combination with cladribine and low-dose ara-C in elderly patients with newly diagnosed acute myeloid leukemia (NCT03586609), the authors prospectively characterized VEN pharmacokinetics, including maximum VEN concentration (C_max), area under the curve (AUC), steady-state trough concentration (C_trough), and clearance when administered with or without a potent CYP3A4i during induction. VEN100 was co-administered with voriconazole, VEN50 and VEN100 with posaconazole, and VEN 400 mg (VEN400) with caspofungin. Thirty-nine patients, median age 68 years, were enrolled for pharmacokinetic analysis.