ABSTRACT:Oral ibrutinib and venetoclax (I+V) demonstrate activity as monotherapy in marginal zone lymphoma (MZL), with low complete response (CR) rates. I+V has shown good clinical activity with acceptable tolerability in other malignancies. We conducted a single-site, phase 2 trial of daily I+V in patients with MZL. Ibrutinib commenced at 560 mg daily; after 4 weeks, venetoclax commenced with weekly dose escalation to 400 mg daily. Combination therapy continued until disease progression or toxicity. The primary end point was week 16 CR. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and peripheral blood. Patients achieving eradication of MRD could enter elective treatment interruption (ETI). Fifteen patients with MZL were treated; 14 are included in efficacy analysis, and 15 were evaluable for safety. Overall response was 79% (95% confidence interval [CI], 49-95) by F-fluorodeoxyglucose-positron-emission tomography (CR rate, 43%; 95% CI, 18-71). By computed tomography, 16-week CR rate was 29% (95% CI, 8-58). Best response within 56 weeks was 57% CR (95% CI, 37-80), which is higher than historic ibrutinib-monotherapy control (3% CR; P< .001). MRD clearance at week 56 was 40%. Six MRD-negative CR patients entered ETI, with 4 remaining disease-free at a median of 4 years. With a median follow-up of 5.5 years for the whole cohort, the 5-year progression-free survival estimate was 56% (95% CI, 27-78). I+V is safe and effective for MZL, with higher CR than with ibrutinib. Durable, ongoing CR was observed in MRD-negative patients. This trial was registered at www.clinicaltrials.gov as #NCT02471391.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare T cell lymphoma in women with textured implants. Little is known about the cell of origin (COO) and whether the tumour immune microenvironment (TIME) is critical for BIA-ALCL survival. Single-cell RNA sequencing revealed BIA-ALCL cells were heterogeneous with unique gene profiles per patient and signature genes BATF3, SERPINS, TNFSFR8, and IL2RA. The COO is a CD4+ or CD8+ memory T cell identified through rearranged TCR and gene expression. The BIA-ALCL TIME included distinct myeloid clusters, dendritic cells (DCs), and monocytes, which may support lymphoma cells. Cytokines IL-13, IL-10, TNF and secretory PDL1 were increased in BIA-ALCL seroma, indicating an immunosuppressive TIME. Interactome analysis revealed a complex network among lymphoma cells, dominated by IL-13, IL-10, and TNF members. Endogenous CD8+ T cells exhibit higher checkpoint expression than benign seromas. No clonal relationship exists between BIA-ALCL and endogenous T cells. Tissue-archetype and gene-expression analysis revealed T-cell exclusion and immunosuppressive TIME in invasive disease. In summary, BIA-ALCL cells are diverse with markedly different TIME across stages. The TIME provides immunosuppressive signals to activated/exhausted T cells and homeostatic signals that promote BIA-ALCL proliferation. These new findings may offer novel therapeutic targets for advanced disease patients.

Idiopathic multicentric Castleman disease (iMCD) is a rare condition. The pathogenesis is incompletely understood; however, interleukin-6 (IL-6) is a major mediator. The clinical presentation is heterogeneous, from mild constitutional symptoms to severe multi-organ failure. The diagnosis is challenging, as it incorporates clinicopathologic criteria and requires careful evaluation to exclude various systemic disorders. Targeting IL-6 activity forms the cornerstone of modern therapy for iMCD, with siltuximab recommended as first-line therapy. Rituximab-based regimens are recommended for second-line therapy. However, many patients do not achieve adequate responses with limited evidence to guide further therapy. In the context of these substantial challenges, herein we provide a multidisciplinary Australasian clinical practice guideline to characterise clinical and pathological features, summarise treatment pathways and discuss clinical outcomes of the condition. The objective is to develop a multidisciplinary clinical practice guideline in the diagnosis and management of iMCD in Australia.

We present a case of BRAFV600E+ primary cutaneous Langerhan cell histiocytosis (LCH), with corresponding circulating cell free DNA (cfDNA), which responded to treatment with dabrafenib, and simultaneously saw corresponding BRAFV600E cfDNA become undetectable. A concomitant diagnosis of chronic myelomonocytic leukaemia (CMML) was suspected with identification of TP53, TET2, RAS and CBL variants identified through molecular testing on the initial skin biopsy, and CMML later confirmed on bone marrow biopsy. Whilst the link between LCH and several haematological malignancies is documented, the mechanism is still unclear. In this case, the LCH most likely developed from an already abnormal myeloid compartment and highlights the need for clinical vigilance and appropriate investigation, where effective treatments for these conditions exist.

We describe two patients in whom malignant monoclonal T-cell lymphoproliferation developed after administration of chimeric antigen receptor (CAR) T-cell therapy with ciltacabtagene autoleucel (cilta-cel) in the phase 3 CARTITUDE-4 trial. Monoclonal T cells from both patients had detectable CAR transgene expression and integration. The clinicogenomic features of these CAR transgenic T-cell lymphoproliferative neoplasms suggest that multiple potential intrinsic or extrinsic factors (or both) contributed to their pathogenesis, such as transduction of preexisting TET2-mutated T cells, followed by acquisition of further oncogenic genomic variants. Other potential contributors include germline genomic variation, viral infections, and previous treatment for myeloma. In the absence of direct evidence, the contribution of insertional mutagenesis to the development of T-cell lymphoma is currently unclear. (Funded by Johnson & Johnson and Legend Biotech USA; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).

BACKGROUND:Mycosis fungoides (MF) is the most prevalent subtype of primary cutaneous T-cell lymphoma. Large cell transformation of MF (LCTMF) is rare and confers a poor prognosis. Radiotherapy (RT) is an effective local treatment for LCTMF; however, dose-response data are limited. METHODS:Eligibility for this retrospective study required biopsy-proven LCTMF with clinico-pathological correlation, diagnosed 1/1/1990-1/10/2021, and managed at Peter MacCallum Cancer Centre. RESULTS:83 patients were eligible. Median age was 68 years, 63 (76 %) patients had cutaneous-only LCTMF at time of diagnosis. Median follow-up was 8.0 (95 % CI: 6-11) years. Details of 155 irradiated LCTMF lesions (from 49 patients) were available: 150 cutaneous, 5 extra-cutaneous. For cutaneous LCTMF, median equivalent dose in 2.0 Gy per fraction (EQD2, α/β of 10) was 30.6 (range, 4.7-46.3) Gy. Dose-response data were available for 141 cutaneous LCTMF lesions. Overall response rate (ORR) was 94 % (60 % complete response (CR), 35 % partial response). For cutaneous lesions treated with >12.0 Gy, ORR was 100 %. Increasing doses of RT were associated with greater CR rates: doses >36.0 Gy achieved 100 % CR rate. 22 (27 %) patients had unifocal cutaneous-only LCTMF and were treated with local RT-alone, median EQD2 36.0 Gy (range, 17.3-46.3 Gy). CR rate was 100 %. 9 (41 %) patients remained relapse-free (median follow-up, 3.2 years). Only 1 patient experienced infield-only recurrence at first relapse. CONCLUSION:LCTMF is radio-responsive, with EQD2 >12.0 Gy associated with 100 % ORR. Dose-response was observed, with EQD2 >36.0 Gy achieving 100 % CR rate. For unifocal cutaneous LCTMF, RT-alone achieved excellent infield control with possible curative potential in a proportion of patients.

Onycholemmal carcinoma is a rare subtype of squamous cell carcinoma deriving origin from the nailbed epithelium. With only 16 available reports in the literature, there is no standardized diagnostic or management algorithm. Treatment is largely center-specific, with most cases involving distal amputation of the affected digit. The purpose of this case report is to highlight challenges in diagnosis and advocate for a digit-sparing approach.

Germline homozygous loss-of-function mutations in TET2 result in significant childhood immunodeficiency that resembles autoimmune lymphoproliferative syndrome and predisposes one to lymphoma. The implications of heterozygous variants are less well understood. We describe four patients with heterozygous germline loss-of-function TET2 mutations who presented with B-cell lymphoma on a background of chronic lymphadenopathy and autoimmune features. This expands the association of germline TET2 mutations with lymphoma and an autoimmune lymphoproliferative syndrome-like phenotype to the heterozygous state. Assessment for TET2 mutations and germline origin should be considered in the appropriate context, as recognition of these variants may have implications on patient care.

ABSTRACT:Onycholemmal carcinoma is a rare subtype of squamous cell carcinoma deriving origin from the nailbed epithelium. With only 16 available reports in the literature, there is no standardized diagnostic or management algorithm. Treatment is largely center-specific, with most cases involving distal amputation of the affected digit. The purpose of this case report is to highlight challenges in diagnosis and advocate for a digit-sparing approach.

Large-cell transformation of mycosis fungoides (LCTMF) is rare, histologically distinct, with an aggressive clinical course; yet is not recognised as an independent entity in classification systems nor in staging systems for mycosis fungoides and Sézary syndrome (MF/SS). Herein, the patterns of care and survival outcomes for patients with LCTMF are described, with prognosis compared to published data of non-transformed MF/SS. Eligibility required clinicopathological diagnosis of LCTMF (1/1/1990-31/10/2021), managed at Peter MacCallum Cancer Centre. Eighty-three patients were eligible. Median follow-up was 8.0 years. At the time of LCTMF, 36% had early-stage MF (IA-IIA), 76% had cutaneous-only LCTMF. The most common first-line treatments were localised radiotherapy (48%) and multiagent chemotherapy (23%). Median overall survival (OS) from LCTMF diagnosis was 3.5 years (95% [confidence interval] CI: 2.2-8.2). Three prognostic groups of LCTMF were identified: unifocal cutaneous only, multifocal cutaneous only and extracutaneous (median OS: 4.6, 2.5 and 1.1 years, respectively; p = 0.005). Unfavourable prognostic factors were advanced age and extracutaneous LCTMF. In conclusion, treatment pathways for patients with LCTMF were varied, and prognosis was poor, despite >1/3 having early-stage MF. However, differences in prognosis were suggested, with unifocal cutaneous LCTMF associated with greater OS. Given prognostic differences from MF/SS, consideration to include LCTMF in staging systems is warranted.

BACKGROUND/OBJECTIVES:Cutaneous manifestations of Waldenstrom's macroglobulinaemia (WM), a rare B-cell lymphoproliferative disorder, present a diagnostic challenge. The intent of this article is to raise awareness to clinicians of a potentially overlooked condition, particularly in the context of patients with a monoclonal IgM paraproteinaemia, but also to describe the diagnostic complexity of the disease from a clinicopathological perspective. METHODS:We describe the clinical presentation and histopathological findings of two patients with cutaneous involvement of WM. RESULTS:Cutaneous presentations included erythematous and salmon pink plaques, which were either tender or non-tender. Histopathology analysis in both cases demonstrated direct lymphocytic infiltration by malignant lymphocytes of WM, with case 1 demonstrating aberrant CD10 expression. CONCLUSION:The broad cutaneous signs of WM are sparsely described in the literature, and these can even precede formal diagnosis. Ongoing clinical suspicion is warranted from both a clinical and histopathological perspective where patients present with a monoclonal IgM paraproteinemia.

ABSTRACT:In the phase 2 clinical trial (AIM) of venetoclax-ibrutinib, 24 patients with mantle cell lymphoma (MCL; 23 with relapsed/refractory [R/R] disease) received ibrutinib 560 mg and venetoclax 400 mg both once daily. High complete remission (CR) and measurable residual disease negative (MRD-negative) CR rates were previously reported. With median survivor follow-up now exceeding 7 years, we report long-term results. Treatment was initially continuous, with elective treatment interruption (ETI) allowed after protocol amendment for patients in MRD-negative CR. For R/R MCL, the estimated 7-year progression-free survival (PFS) was 30% (95% confidence interval [CI], 14-49; median, 28 months; 95% CI, 13-82) and overall survival (OS) was 43% (95% CI, 23-62; median, 32 months; 95% CI, 15 to not evaluable). Eight patients in MRD-negative CR entered ETI for a median of 58 months (95% CI, 37-79), with 4 experiencing disease recurrence. Two of 3 reattained CR on retreatment. Time-to-treatment failure (TTF), which excluded progression in ETI for those reattaining response, was 39% overall and 68% at 7 years for responders. Beyond 56 weeks, grade ≥3 and serious adverse events were uncommon. Newly emergent or increasing cardiovascular toxicity were not observed beyond 56 weeks. We demonstrate long-term durable responses and acceptable toxicity profile of venetoclax-ibrutinib in R/R MCL and show feasibility of treatment interruption while maintaining ongoing disease control. This trial was registered at www.clinicaltrials.gov as #NCT02471391.

Introduction: High-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBL-MYC/BCL2-R) has worse prognosis compared to diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) when treated with R-CHOP. Given this and historically poor outcomes with salvage therapy in HGBL-MYC/BCL2-R, intensification of front-line induction and consolidation with autologous stem cell transplant (ASCT) in first complete remission (CR1) have emerged as popular treatment strategies despite a lack of prospective randomized studies indicating superior outcomes. CAR-T and novel antibody-based therapies have shown promise in patients with relapsed/refractory (R/R) DLBCL, but data in the “double-hit lymphoma” setting remain limited. We aimed to assess the impact of initial treatment intensification and salvage with CAR-T for HGBL-MYC/BCL2-R in the contemporary era. Methods: We performed a retrospective analysis of 79 consecutive patients newly diagnosed with HGBL-MYC/BCL2-R, as detected by fluorescence in situ hybridization (FISH), at our center from 06/2013 to 03/2023. MYC, BCL2, and BCL6 disruptions were identified by Vysis break apart probes. Baseline clinicopathologic variables, treatment, response, and outcome data were collected from electronic records. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS) with data cut-off date of 26/07/2024. Results: Median age at diagnosis was 62 (33-93) years. At baseline, 76% patients had advanced stage (Ann Arbor 3-4) disease, 56% had elevated LDH, 52% had bulky disease (largest tumor diameter ≥10 cm), and 3% had CNS involvement. Forty-nine cases arose de novo and 30 cases were transformed from follicular lymphoma. Regarding rearrangement status, 66 cases had MYC/BCL2-R and 13 had MYC/BCL2/BCL6-R. Front-line induction therapy included R-CHOP (n=29), DA-R-EPOCH (n=29), R-CODOX-M/IVAC (n=4), Pola-R-CHP + glofitamab (n=2), R-ICE (n=2), R-HyperCVAD/MA (n=1), obinutuzumab (G)-CHOP (n=1), R-CHOP + glofitamab (n=1), R-CHOP + tafasitamab (n=1), R-CHOP + lenalidomide (n=1), DA-G-EPOCH (n=1), and R-ESHAC (n=1), as well as palliative regimens including R-mini-CHOP (n=2), PEP-C (n=1), and rituximab + prednisolone (n=1). Patients with age >60 years at diagnosis were more likely to receive standard R-CHOP compared with an intensified induction regimen (DA-R-EPOCH, R-CODOX-M/IVAC, R-HyperCVAD/MA) (χ2, p=0.011). Forty received CNS prophylaxis with high-dose methotrexate (MTX) (n=15), intrathecal MTX (n=11), or both (n=14). A total of 17 patients received consolidative ASCT at any time (15 in CR1, 2 in CR2); conditioning regimens were CBV (n=15), BEAM (n=1), and unknown (n=1). After a median follow-up of 42 (2-91) months, median PFS and OS for the entire cohort were 9 and 88 months, respectively, and 7-year PFS and OS rates were 31% and 52%, respectively. Compared to standard R-CHOP, an intensified induction regimen (DA-R-EPOCH, R-CODOX-M/IVAC, R-HyperCVAD/MA) was associated with higher CR rate (44% vs 66%) and improved PFS (p=0.045), but no significant difference in OS (p=0.182). Of the 40 patients who achieved CR to frontline therapy, no significant difference in PFS or OS were observed between those who received consolidation with ASCT and those who did not (7-year PFS rate 83% vs 30%, p=0.178; 7-year OS rate 92% vs 55%, p=0.113). Among patients without CNS involvement identified at diagnosis who received curative-intent induction, use of MTX-containing CNS prophylaxis was associated with a lower rate of CNS relapse and improved OS compared to those who did not (CNS relapse rate 3% vs 6%; median OS 88 months vs 29 months, p=0.044). For the 42 patients with R/R disease, the median OS was 16 months from date of initial diagnosis. Nineteen patients received CAR-T therapy (8 at first relapse, 11 at subsequent relapse), including axicabtagene ciloleucel (n=10), tisagenlecleucel (n=5), rapcabtagene autoleucel (n=2), and CTX110 (n=2); the 4-year PFS and OS rates from date of CAR-T infusion were 62% and 55%, respectively. Conclusions: Our series indicates that intensification of front-line induction in patients with HGBL-MYC/BCL2-R maximizes first response and PFS, and incorporation of CNS prophylaxis into initial therapy minimizes risk of CNS relapse and improves OS. CAR-T represents a promising salvage option for patients with R/R disease.

CD19-directed chimeric antigen receptor T cells (CAR-T) achieve high response rates in patients with relapsed/refractory mantle cell lymphoma (MCL). However, their use is associated with significant toxicity, relapse concern, and unclear broad tractability. Preclinical and clinical data support a beneficial synergistic effect of ibrutinib on apheresis product fitness, CAR-T expansion, and toxicity. We evaluated the combination of time-limited ibrutinib and CTL019 CAR-T in 20 patients with MCL in the phase 2 TARMAC study. Ibrutinib commenced before leukapheresis and continued through CAR-T manufacture for a minimum of 6 months after CAR-T administration. The median prior lines of therapy was 2; 50% of patients were previously exposed to a Bruton tyrosine kinase inhibitor (BTKi). The primary end point was 4-month postinfusion complete response (CR) rate, and secondary end points included safety and subgroup analysis based on TP53 aberrancy. The primary end point was met; 80% of patients demonstrated CR, with 70% and 40% demonstrating measurable residual disease negativity by flow cytometry and molecular methods, respectively. At 13-month median follow-up, the estimated 12-month progression-free survival was 75% and overall survival 100%. Fifteen patients (75%) developed cytokine release syndrome; 12 (55%) with grade 1 to 2 and 3 (20%) with grade 3. Reversible grade 1 to 2 neurotoxicity was observed in 2 patients (10%). Efficacy was preserved irrespective of prior BTKi exposure or TP53 mutation. Deep responses correlated with robust CAR-T expansion and a less exhausted baseline T-cell phenotype. Overall, the safety and efficacy of the combination of BTKi and T-cell redirecting immunotherapy appears promising and merits further exploration. This trial was registered at www.ClinicalTrials.gov as #NCT04234061.

XLS file - 22KB, Ontological enrichment in epithelial and stromal compartments in PMCC_gastric datset.