Histiocytosis of the orbit and its association with KRAS mutations [Retrospective study]

Highlight(s): Isolated orbital histiocytosis has significantly distinct clinical features compared with orbit-involving multisystemic disease, namely, a predominance of KRAS mutations, unilaterality, xanthogranuloma subtype, extraconal disease, and lacrimal gland infiltration. KRAS-driven isolated orbital disease may necessitate more aggressive treatment.

Histiocytoses are rare myeloid-derived clonal hematopoietic disorders in which tissue infiltrates with activated histiocytes. The subtypes are Langerhans-cell histiocytosis (LCH) and non-LCH, which include Rosai-Dorfman-Destombes disease, Erdheim-Chester disease, and numerous xanthogranuloma disorders. Recently, a pivotal discovery demonstrated that disease pathophysiology is characterized by recurrent activating mutations in the MAPK pathway. Histiocytoses are clinically heterogeneous, exhibiting as localized or diffuse, multisystem diseases. One ophthalmic site of accumulation is the orbit, which may exhibit variable frequencies depending on the histiocytosis subtype and age of the patient.

This retrospective, single-center study included 33 eligible patients from Memorial Sloan Kettering Cancer Center. Eligible patients had biopsy-confirmed histiocytosis involving orbital structures, as identified by clinical examination and/or radiologic imaging with positron emission tomography/computed tomography, computed tomography, or magnetic resonance imaging (MRI), along with molecular sequencing for the driver mutation. Patients without genetic testing were not included. Patients were subcategorized into orbit-involving multisystemic disease and isolated orbital disease (defined as orbital disease inclusive of the eyelid and conjunctiva without other sites of disease). For evaluation of tumor mutations, genomic DNA was extracted from formalin-fixed paraffin-embedded samples and underwent mutational analysis.

Isolated orbital disease was significantly characterized by unilateral disease (p=0.02), xanthogranuloma subtype (p=0.0001), KRAS mutations (p=0.0002), periorbital swelling (p=0.006), and extraconal disease, particularly lacrimal gland involvement, on MRI (p=0.03). Within the isolated orbital disease group alone, 6 patients (67%) had KRAS-mutant disease. All patients with the latter had xanthogranuloma compared with 1 patient in the non-KRAS-mutant group. In addition to the differences in mutational status, there were no other significant differences between the groups.

Testicular large B‐cell lymphoma is genetically similar to PCNSL and distinct from nodal DLBCL [Retrospective study]

Highlight(s): These findings demonstrated that testicular large B‐cell lymphoma (TLBCL) has a distinctive genomic signature, supporting its recognition as a separate entity from diffuse large B-cell lymphoma (DLBCL), encouraging the grouping of primary large B‐cell lymphoma of the testis and central nervous system (CNS), and might provide relevant information to tailor therapeutic approaches.

The study included 61 patients with TLBCL and targeted next‐generation sequencing, copy number arrays, and fluorescent in situ hybridization were performed to assess chromosomal rearrangements in 40 cases with available material. Seventy percent of the cases showed localized stages. BCL6 rearrangements were detected in 36% of cases, and no concomitant BCL2 and MYC rearrangements were found. TLBCL had fewer copy number alterations (p<0.04) but more somatic variants (p<0.02) than nodal DLBCL and had more frequent 18q21.32‐q23 (BCL2) gains and 6q and 9p21.3 (CDKN2A/B) deletions. PIM1, MYD88^L265P, CD79B, TBL1XR1, MEF2B, CIITA, EP300, and ETV6 mutations were more frequent in TLBCL, and BCL10 mutations in nodal DLBCL. There were no major genetic differences between TLBCL and primary large B-cell lymphoma of the CNS. Localized or disseminated TLBCL displayed similar genomic profiles. Using the LymphGen algorithm, most cases were classified as MCD genotype (co-occurrence of MYD88 and CD79B mutations). However, we observed a subgroup of patients classified as BN2 (BCL6 gene fusions and NOTCH2 gene mutations), both in localized and disseminated TLBCL, suggesting a degree of genetic heterogeneity in the TLBCL genetic profile.

How I Treat: Maintenance Therapy in Acute Myeloid Leukemia [Review]

In this “How I Treat,” using published studies and emerging clinical data, G. Roboz and J. Canaani (both from Weill Medical College of Cornell University, New York, USA) discuss their approach to maintenance therapy in acute myeloid leukemia (AML) emphasizing that the selection of a specific strategy is an individualized decision based on leukemia biology and risk stratification, presence of targetable selectable mutations, initial treatment approach, performance status, and the feasibility of allogeneic stem cell transplantation (alloSCT).

The algorithm (Figure 1 of the original article) illustrates the practical approach to this heterogeneous disease. 

1. Define whether the patient is a candidate for intensive or non-intensive induction therapy.  If for non-intensive therapy (e.g., hypomethylating with venetoclax, or with low-dose cytarabine), after induction, define whether the patient goes into remission. If so, continue with initial induction therapy, with dose and frequency modifications to mitigate cytopenias and toxicity. 
2. If the patient is a candidate for intensive therapy and goes into remission, evaluate if eligible for an alloSCT. 
If a candidate for alloSCT, and after transplantation, maintenance depends on whether FLT3 is mutated. 
a) If FLT3 is mutated, one can use: 
•    Quizartinib (only in FLT3-internal tandem duplication [ITD]).
•    Sorafenib (only in FLT3-ITD)
•    Gilteritinib (in FLT3-ITD or FLT3-tyrosine kinase domain [TKD])
•    Midostaurin (in FLT3-ITD or FLT3-TKD)
b) If FLT3 is not mutated, one should await the results of the AMADEUS and VIALE-T clinical trials. Consider recombinant human granulocyte colony-stimulating factor (in the full text, the authors refer to a phase 2 clinical trial in combination with decitabine; these data are considered promising, but they have not been universally adopted). 
3. If not a transplant candidate and FLT3 is mutated, Quizartinib may be considered (ITD only). There are doubts about Gilteritinib (see the full text for reason: “The trial did not meet its primary endpoint because the overall improvement in relapse-free survival did not reach statistical significance. However, post-transplant gilteritinib maintenance did show a significant benefit in relapse-free survival for patients with detectable minimal residual disease [MRD] before and/or after transplant using a highly sensitive next-generation sequencing FLT3-ITD MRD assay polymerase for next-generation sequencing FLT3-ITD MRD assay [quantified at a threshold as low as 1 × 10^-6]])”. 
4. If not a transplant candidate, and FLT3 is not mutated, and is classified as European LeukemiaNet (ELN) 2022 favorable-risk, consider oral azacitidine. 
5. If not a transplant candidate and has ELN 2022 intermediate- or adverse-risk, use oral azacitidine.

How I treat Blastic Plasmacytoid Dendritic Cell Neoplasm [Review]

M. Kharfan-Dabaja (Mayo Clinic, USA) A. Lane (Dana-Farber Cancer Institute, Harvard Medical School, USA) and N. Pemmaraju (MD Anderson Cancer Center, USA) in a “How I Treat” from Blood journal, show us their approach to treat this rare entity. Here, some key aspects summarized.

Regarding first-line therapy of blastic plasmacytoid dendritic cell neoplasm (BPDCN), participation in clinical trials is preferred whenever possible. In previously untreated patients, tagraxofusp (novel therapy targeting anti-CD123) demonstrated a complete remission (CR) rate of 57% and a median CR duration of approximately 24.9 months. No randomized controlled studies have been performed comparing tagraxofusp with conventional chemotherapy-based combinations (e.g., HyperCVAD). However, regardless of treatment choice, achieving a first CR  represents the main goal of therapy because it represents the best opportunity to prolong survival in BPDCN if offered an allogeneic hematopoietic cell transplant (allo-HCT) as consolidative therapy. Although no specific conditioning regimen is considered standard-of-care in allo-HCT-eligible patients, recent data from two large registries have shown a survival advantage when offering total body irradiation-based myeloablative conditioning (MAC) regimens. Unfortunately, the applicability of MAC regimens is not feasible in older/unfit patients, who constitute a considerable proportion of patients. In such cases, reduced-intensity conditioning regimens represent the next best option. Autologous-HCT could be considered in older/unfit patients who do not have bone marrow involvement at initial presentation and at the time of the procedure. However, data supporting this option is less abundant in those with lacking a donor. Central system fluid analysis at the initial work-up and prophylactic intrathecal chemotherapy is recommended. Figure 1 and the “Visual abstract” of the original article illustrate a practical therapeutic approach.  

Hairy-Cell Leukemia [Review]

In a recent N Eng J Med review, B. Falini, and E. Tiacci (from University and Hospital of Perugia, Italy), enlighten us on the previously named “leukemic reticuloendotheliosis”. The name “hairy-cell leukemia” (HCL) was proposed in 1966 by Schrek and Donnelly, based on cytoplasmic projections observed in the leukemic cells in the peripheral blood from two patients. Here is a summary of the critical points of this paper. 

HCL is a rare, indolent neoplasm of mature B cells with hair-like surface projections that circulate in the blood and preferentially infiltrate the bone marrow and spleen. The clinical picture is characterized by male predominance, onset in adulthood with cytopenias and splenomegaly, a remitting–relapsing pattern of response to sequential treatments, and an almost normal life expectancy with current therapies.
The BRAF V600E kinase-activating mutation is the genetic cause of HCL in at least 95% of cases and shapes key disease traits, including the peculiar morphologic features. The consequent aberrant signaling through the RAF–MEK–ERK pathway (constitutive kinase activity) shapes key traits of HCL, including its unique expression signature, hairy appearance, and inhibition of apoptosis. Testing for the BRAF V600E mutation or protein and for HCL-specific immunophenotypic markers (including annexin A1) allows for the differential diagnosis of diseases that mimic HCL (e.g., HCL variant, and splenic marginal-zone lymphoma), which require distinct clinical management. Myelotoxic chemotherapy with cladribine or pentostatin, alone or combined with the anti-CD20 monoclonal antibody rituximab, is a highly effective standard care for patients with HCL. Chemotherapy-free strategies based on BRAF inhibitors (e.g., vemurafenib or dabrafenib) are increasingly being used in patients with relapsed or refractory HCL and in those with active infections and are being explored in the front-line context as an alternative to chemotherapy. See Figure 3 of the original article for management of newly diagnosed HCL and Figure 4 for therapy for refractory or relapsed HCL.