Zanubrutinib for the treatment of Bing–Neel syndrome [Case series].

Highlights: 

●       Malignant lymphoplasmacytic cells infiltrating the central nervous system is a rare complication of Waldenström macroglobulinemia (WM), referred to as Bing–Neel syndrome (BNS). It occurs in 1% of patients.

●       Traditionally, chemotherapy was used to treat BNS but more recently, the oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib, commonly used to treat WM, has become the standard therapy for BNS due to its tolerability and ability to cross the blood-brain barrier.

●       Zanubrutinib, a second-generation covalent BTK inhibitor with fewer off-target effects, is also effective in WM.

●       In this study, the authors demonstrated the efficacy of zanubrutinib in a series of patients with BNS who were previously treated with ibrutinib or BTK inhibitor naïve.

S. Sarosiek et al. from the Dana-Farber Cancer Institute report the outcome of nine patients treated for BNS with zanubrutinib (5 had prior exposure to ibrutinib; 4 were naïve to BTK inhibitors). All patients had MYD88 L265P, and zero patients had a CXCR4 mutation (3 had unknown CXCR4 status). Three of six patients (50%) had a TP53 mutation (3 had unknown TP53 status). In all patients, the BNS diagnosis followed the WM diagnosis by a median of 4.3 years (range, 0.1–23.1). The median age at BNS diagnosis was 71 years (range, 66–78). Six patients had been previously treated for WM at the time of BNS diagnosis, with a range of 1–6 prior treatments. All nine patients maintained or achieved a partial response of their BNS on zanubrutinib, and no one had progression of their BNS at the time of this report. Based on these findings, zanubrutinib can be considered an effective treatment option for newly diagnosed BNS or for patients transitioning from ibrutinib due to the potential for or the presence of adverse effects.

How I treat patients who are refractory to platelet transfusions [Review].

Key points: 

●       Platelet refractoriness (PR) describes a poor response to platelet transfusion, and conventional thinking has divided etiologies into two broad categories: immune and non-immune causes.

●       PR is common, but only a minority of cases will have demonstrated potential immune etiologies. The challenge is identifying which refractory patients need detailed investigations and would benefit clinically from human leukocyte antigen (HLA) selected/matched platelets. The diagnosis of non-immune PR is one of exclusion.

●       Investigation of immune causes of refractoriness is most commonly performed in patients with underlying hematological malignancies, as they are the most heavily platelet-transfused cohort.

●       The definition of PR established by The Trial to Reduce Alloimmunization to Platelets (TRAP) study is two consecutive corrected count increments at 1 hour following platelet transfusion measuring < 5x10⁹/L. In clinical practice, unadjusted post-transfusion increments (PI) are often used due to the absence of available platelet dose information. The thresholds clinicians use for defining their “poor” increments are variable, with PR ranges at or below 5, 7.5, 10, or 20x10⁹/L described in the literature. A common pragmatic approach considers the response suboptimal if the platelet count has not changed after 20-24 hours.

●       Immune factors, if identified, may be single or a combination of antibodies against the following: Class I HLA; human platelet antigen; blood group ABO; drugs directed at platelet antigens; or autoantibodies to platelet glycoproteins. However, HLA alloimmunization is the most clinically relevant and studied immune etiology, reflecting ~80-90% of immune PR cases.

●       In the management of non-immune PR, given uncertain evidence of superiority for platelet transfusions and recognition of more risks of transfusion from some randomized trials, it may be prudent to withhold repeated transfusions in non-bleeding patients and rather apply the clinical context to the need for platelet transfusion.

●       The provision of HLA-matched platelets for patients with HLA alloimmune refractoriness is a current standard of care.

Diagnosis, management, and outcomes of drug-induced erythrocytosis: A systematic review.

Highlights: 

●       Medications, including testosterone and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, are increasingly recognized causes of secondary erythrocytosis.

●       The incidence of SGLT-2 inhibitor-associated erythrocytosis ranges from 2.1–22%, occurring at a median of 2.3 years after exposure to an SGLT-2 inhibitor. Thromboembolic events were reported in 2.4–10% of cases, though whether these were attributable to SGLT-2 inhibitor-associated erythrocytosis is uncertain, and baseline risk in study populations is unknown.

●       Individuals on testosterone with erythrocytosis have a higher risk of thromboembolic events. The authors suggest that physicians regularly monitor patients starting these medications with a complete blood count every 3 months, select an alternate medication or non-intramuscular route if feasible, use the lowest possible dose of that medication, and manage any other cardiovascular risk factors.

●       Drug-induced erythrocytosis is a heterogeneous condition for which there is no clear consensus among clinicians about its diagnosis and management.

Of the 2,036 articles screened for eligibility, 45 studies were included in this systematic review, with 35 studies on testosterone and other androgen use, 5 studies on SGLT-2 inhibitors, 3 studies on anti-angiogenic tyrosine kinase inhibitors, 1 study on erythropoiesis-stimulating agents, and 1 study on a treatment regimen for multidrug-resistant tuberculosis.

Clinically relevant bleeding according to location of metastases in cancer-associated thrombosis [Retrospective study].

Highlights: 

●       Patients with cancer-associated thrombosis (CAT) face a heightened risk of clinically relevant bleeding (CRB).

●       The bleeding rate seems to differ depending on the location of metastasis. Additionally, lung metastasis was found to be associated with a long-term risk of CRB. These findings may justify the use of low dose of anticoagulation, although clinical trials need to demonstrate the efficacy and safety of this strategy.

This single-center (Seville, Spain), non-interventional study of consecutive patients was conducted between 2007 and 2022, involving patients aged ≥ 18 years, with CAT but excluding hematological neoplasms (n = 1,277). Fifty-two percent had metastases.  The primary objectives were: 1) To estimate the rate of CRB based on metastasis location. 2) To assess the long-term risk of CRB.  Over a median follow-up of 14.2 months, 144 CRB were observed. The most frequent cancers were colon (19.2 %), lung (16.1 %), and breast (12.4 %).

Clinical-genomic profiling of MDS to inform allo-HSCT: Recommendations from an international panel on behalf of the EBMT

 Key Recommendations: 

●       The patient's eligibility for allogeneic transplantation should be assessed at the time of diagnosis of MDS (myelodysplastic syndrome).

●       Disease- and patient-related risk factors, as well as donor availability and the patient's 583 values and wishes, should be considered when assessing eligibility for transplantation.

●       Evaluation of MDS risk requires calculation of the Molecular International Prognostic Scoring System (IPSS-M score) based on conventional cytogenetics, genomic profiling, and TP53 allelic state. Additionally, germline testing is needed for identifying genetic predisposition to MDS.

●       All patients with higher-risk MDS (according to IPSS-M) are potential candidates for immediate transplantation. A subset of patients with lower-risk MDS may also benefit from this procedure at an earlier stage of the disease.

●       Assessment of patient-related risk factors should consider performance status, comorbidities, and frailty.

●       While accurate assessment of biological age has made allogeneic hematopoietic cell transplantation (allo-HCT)  a feasible option for MDS patients up to the 8^th decade of life, this procedure should generally be avoided in patients older than 80 years.

●       Human leukocyte antigen-matched relatives, matched unrelated donors, and haploidentical donors can be used in MDS patients undergoing allo-HCT, with a preference for younger donors in the selection algorithm.

●       The choice of intensity of the conditioning regimen must consider not only chronological age, but also a comprehensive assessment of organ/system function and disease characteristics.

●       MDS patients with blast excess (≥10%) may benefit from cytoreductive therapy prior to allo-HCT, but results of ongoing clinical trials are needed for more definitive conclusions.

●       Measurable residual disease assessment is recommended after allo-HCT regardless of MDS risk, while there is insufficient evidence to recommend prophylaxis or maintenance.

●       Post-transplant therapeutic strategies for measurable residual disease-positive or relapsed patients include treatment with hypomethylating agents and donor lymphocyte infusion.