Hairy Cell Leukemia

Dabrafenib plus trametinib, as the first tumor-agnostic therapy, has been approved by the US Food and Drug Administration for the treatment of adult and pediatric patients aged 6 years and older harboring a BRAF V600E mutation with unresectable or metastatic solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. Therefore, we have established a universal and systematic strategy for diagnosing and treating solid tumors with BRAF mutations. In this expert consensus, we (1) summarize the epidemiology and clinical characteristics of BRAF mutations in different solid tumors, (2) provide recommendations for the selection of genetic testing methods and platforms, and (3) establish a universal strategy for the diagnosis and treatment of patients with solid tumors harboring BRAF mutations.

The association of Cladribine (CDA) with rituximab (R) is the standard first-line treatment in fit HCL and HCL variant patients. BRAF and BTK inhibitors are options in relapsed/refractory HCL patients. The optimal treatment sequences remain to be determined.

RFS of these 8 patients after purine analog monotherapy was also inferior compared to a control group of 34 patients who received cladribine monotherapy and began prospective follow-up before any relapses (19.9 vs 271.8 months, p<0.0001). Non-V600E BRAF mutations were observed in patients with classic HCL immunophenotype, some of which were co-mutations in BRAF with V600E. In view of the inferior RFS in these patients when purine analog was not combined with rituximab, these mutations may constitute a higher risk for relapse or chemoresistance. While those with BRAF V600 mutations might be candidates for BRAF inhibition, those with other BRAF mutations represent an opportunity for development of other specific inhibitors, not only for HCL/HCLv, but also for other malignancies.

Finally, all acute myeloid leukaemia (n = 52) and most T-cell non-Hodgkin lymphoma (n = 31/32) tested samples were negative for ROR1 via IHC. In conclusion, ROR1 shows a heterogeneous tumour cell expression profile across multiple leukaemias and lymphomas, making it a tumour target that would require different patient selection strategies to develop novel therapeutic modalities.

No abstract available

Hairy cell leukemia is an uncommon B-cell malignancy with excellent response to purine analogs and to targeted therapies such as ibrutinib and vemurafenib. Only one patient in our cohort passed away due to infection. Estimated 10-year overall survival was 99% suggesting that infections may not cause as much mortality as was seen prior to current therapies.

P1, N=130, Recruiting, MacroGenics | N=90 --> 130 | Trial completion date: Mar 2025 --> Oct 2025 | Trial primary completion date: Mar 2025 --> Oct 2025

P1, N=8, Active, not recruiting, Joseph Tuscano | Trial completion date: Dec 2024 --> Jul 2025 | Trial primary completion date: Apr 2024 --> Dec 2024

P2, N=86, Recruiting, Memorial Sloan Kettering Cancer Center | Not yet recruiting --> Recruiting

This review explores the rationale for discontinuing B-PLL and HCLv diagnoses. It then examines the concept of SBLPN, offers practical guidance for diagnosis and discusses future directions in classifying splenic B-cell lymphomas.

Care must be taken in the molecular diagnostic work-up of patients with typical HCL but without the BRAF V600E to include investigation of these uncommon mechanisms. Identification, functional characterization, and reporting of further such patients is likely to provide insights into the pathogenesis of HCL and enable rational selection of targeted inhibitors in such patients if required.

Our case provides further evidence supporting the hypothesis of a significant association between immunosuppression and MCC pathogenesis.

P2, N=36, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Oct 2025 --> Aug 2024 | Trial primary completion date: Oct 2025 --> Aug 2024

P2, N=86, Not yet recruiting, Memorial Sloan Kettering Cancer Center

Hairy cell leukaemia (HCL) is relatively uncommon, accounting for 2% of all leukaemia cases.Extramedullary and skeletal involvement in HCL is rare and shares morphological characteristics with other peripheral small B-cell lymphoma neoplasms.Spine biopsy is essential for diagnosis in these cases, since it is always helpful to narrow the differential diagnosis.Correct diagnosis is essential for treatment of HCL and leads most patients to clinical remission and sometimes long-term cures.

P2, N=19, Active, not recruiting, Kite, A Gilead Company | Recruiting --> Active, not recruiting | N=90 --> 19

The toxicity of R-CHOP in elderly people limited its usage, so we first chose rituximab. To summarize, a 95-year-old man diagnosed with two types of lymphomas, high-grade B-cell lymphoma and hairy cell leukemia, was successfully treated with venetoclax after other treatments failed. This case suggests that targeted therapy can be effective and safe for super-aged patients with multiple malignant lymphatic system diseases.

P=N/A, N=3, Terminated, Mustang Bio | N=331 --> 3 | Trial completion date: Jul 2041 --> Apr 2024 | Enrolling by invitation --> Terminated | Trial primary completion date: Apr 2041 --> Apr 2024; Business Reasons

Among the inhibitors described, 5c, 5g, and 5h were able to rescue the hematopoietic phenotype in vivo using the FLT3-ITD zebrafish model of AML. 5c (leuxinostat) proved its efficacy in cells from FLT3-ITD AML patients, promoting marked acetylation of α-tubulin compared to histone H3, thereby confirming HDAC6 as a preferential target for this new class of hydroxamic acid derivatives at the tested doses.

BRAF was not frequently mutated in common feline tumours or in tumour types that frequently harbour BRAF mutations in human and canine cancers. As is seen in canine cancer genomics, the mutational profile in feline tumours may not parallel the histologic equivalent in human oncology.

The differential diagnosis between HCL, hairy cell leukemia variant (HCL-V) and splenic marginal zone lymphoma (SMZL) is of first importance. Currently, the main treatment for HCL involves the use of purine analogues, excluding pregnant women, individuals with severe infections, and those with relapsing HCL.

P2, N=20, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Trial completion date: Jul 2025 --> May 2027 | Initiation date: May 2024 --> Feb 2025 | Trial primary completion date: Jul 2025 --> May 2027

P2, N=40, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2024 --> Jul 2028 | Trial primary completion date: Apr 2024 --> Apr 2028

P2, N=45, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2024 --> Jul 2028 | Trial primary completion date: Apr 2024 --> Apr 2028

Altogether, our census of expression and splicing outliers for 24 hematologic malignancy entities and the companion computational workflow constitute unique resources to deepen our understanding of rare oncogenic events in hematologic cancers.

His HCL was put into remission with a single course of cladribine and rituximab chemotherapy; however, his M kansasii infection persisted for 6 months despite aggressive antimicrobial and surgical therapy. It was finally controlled using high-dose rifampin in combination with azithromycin and ethambutol...Notable possibilities include HCL cells acting as sanctuary sites for M kansasii to evade the immune system, and subclinical M kansasii infections causing NLRP3 inflammasome overactivation to trigger the oncogenic transformation to HCL. More research into the pathophysiologic link between HCL and M kansasii infections would allow for more effective prevention, diagnosis, and treatment of these severe atypical infections which are the major cause of morbidity in the cladribine era of HCL treatment.

P2, N=150, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

These data confirm an excellent prognosis for HCL patients treated with cladribine-based therapy. On the contrary, HCLv with its aggressive behavior represents a group of patients in whom novel treatment approaches are needed.

Although the acquisition of BRAF mutation during disease progression did not correlate with unfavorable outcomes, its clearance through chemotherapy or stem cell transplant exhibited favorable outcomes (median overall survival of 34.8 months versus 10.4 months, p = 0.047). Furthermore, G469A was the most frequently observed BRAF mutation, differing from solid tumors and hairy cell leukemia, where V600E mutations were predominant.

P2, N=90, Recruiting, Kite, A Gilead Company | Trial completion date: Dec 2027 --> Mar 2025 | Trial primary completion date: Dec 2027 --> Mar 2025

SBLPN is a rare entity, usually on-flow cytometry CD25 negative. However, in dim CD25-positive cases, BRAFV600E mutational analysis helps in discerning SBLPN diagnosis and differentiating it from HCL-c.

P1, N=120, Recruiting, Stanford University | Not yet recruiting --> Recruiting

P1, N=120, Not yet recruiting, Stanford University

Binding studies of IFN-α2b and BSA with the ABS phase-forming components were assessed by MST, showing the strong interaction between FILs aggregates and both proteins. In view of their biocompatibility, customizable properties, and selectivity, FIL-based ABSs are suggested as an improved purification step that could facilitate the development of biologics.

P2, N=20, Not yet recruiting, National Cancer Institute (NCI)

The use of chemo-immunotherapy combining cladribine (CDA) and rituximab (R) represents an increasingly used therapeutic approach. Management of relapsed/refractory disease is based on the use of BRAF inhibitors (BRAFi) plus R, MEK inhibitors (MEKi), recombinant immunoconjugates targeting CD22, Bruton tyrosine kinase inhibitors (BTKi), and Bcl-2 inhibitors (Bcl-2i). However, the optimal sequence of the different treatments remains to be determined.

No abstract available

P1, N=36, Completed, City of Hope Medical Center | Active, not recruiting --> Completed

P1/2, N=161, Active, not recruiting, Acerta Pharma BV | Phase classification: P1b/2 --> P1/2 | Trial completion date: Dec 2025 --> Apr 2026

P2, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P1, N=37, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

Hairy cell leukemia (HCL) is an uncommon B-cell neoplasm uniquely characterized by a high prevalence of the BRAFV600E mutation, which leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway.1 In fact, the BRAFV600E point mutation is identified in nearly all cases of HCL; however, it is absent in HCL variant (vHCL) and rare in other B-cell neoplasms.2,3 Notably, in contrast to melanoma or other BRAF mutant solid tumors, HCL exhibits very few other mutations, potentially explaining the high response rates observed in patients treated with mutant BRAF-targeted agents, such as vemurafenib.