Citations

Abstract Introduction Venetoclax combined with hypomethylating agents (VEN/HMA) is an approved frontline induction therapy for older or unfit patients with acute myeloid leukemia (AML). However, data comparing its efficacy and safety to intensive chemotherapy (IC) in intermediate-risk AML—characterized by molecular and cytogenetic heterogeneity—remain limited. Methods This multicenter, real-world retrospective study analyzed newly diagnosed intermediate-risk AML patients who received either VEN/HMA or IC. We evaluated composite complete remission (CRc) rates, transfusion and infection rates, long-term outcomes including overall survival (OS) and progression-free survival (PFS), and performed subgroup analyses to identify mutation-specific predictors of treatment response. Multivariable Cox regression was used to identify independent prognostic factors. Results A total of 229 intermediate-risk AML patients were included. VEN/HMA achieved a comparable CRc rate to IC (75.3% vs. 63.4%) with lower transfusion needs and fewer infections. Patients harboring FLT3-ITD, DNMT3A, or TET2 mutations showed greater benefit from VEN/HMA, while KIT-mutated patients responded more favorably to IC. Among patients who did not undergo allo-HSCT, VEN/HMA significantly improved 3-year OS (P = 0.001) and PFS (P = 0.008). No significant OS or PFS difference was observed in the allo-HSCT subgroup. In MRD-negative patients without transplant, those treated with VEN/HMA had superior OS compared to IC. Multivariable analysis identified VEN/HMA (HR = 0.613, P = 0.038) and allo-HSCT (HR = 0.11, P = 0.001) as independent predictors of better survival. Conclusions VEN/HMA is a safe and effective induction strategy for intermediate-risk AML, particularly in patients with BCL-2 inhibitor–sensitive mutations (FLT3-ITD, DNMT3A, TET2). These findings support a genotype-guided treatment approach in AML, complementing current risk stratification frameworks and informing individualized induction therapy decisions.

Abstract Background: De novo secondary central nervous system (CNS) lymphoma (SCNSL), characterized by concurrent systemic and CNS aggressive B-cell lymphoma at diagnosis, is a rare entity with a dismal prognosis. The prognostic significance of the initial anatomical compartment of CNS involvement (parenchymal vs. leptomeningeal) is not well-defined. We sought to analyze outcomes based on CNS localization in a single-institution cohort. Methods We retrospectively reviewed 34 patients with de novo SCNSL (including diffuse large B-cell lymphoma [DLBCL], high-grade B-cell lymphoma, not otherwise specified (HGBCL NOS), and double-/triple-hit lymphoma) treated at the Mayo Clinic between 2002 and 2025. Clinicopathological features, radiologic findings, treatment details, and survival outcomes were abstracted from the medical records. Patients were categorized by the primary site of CNS involvement. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and groups were compared with the log-rank test. Results The study cohort had a median age of 61.5 years (range 19-79) and a median International Prognostic Index score of 3 (range 2-4). Pathological subtypes included double-/triple-hit lymphoma (n=14, 41.2%), non-germinal center B-cell like (non-GCB) DLBCL (n=11, 32.4%), germinal center B-cell like (GCB) DLBCL (n=8, 23.5%), and HGBCL NOS (n=1, 2.9%). Among patients with available data, 14 (43.8%) were positive for MYC rearrangement, 13 (54.2%) for BCL2 rearrangement, and 10 (45.5%) for BCL6 rearrangement. First-line regimens received by patients included MR-CHOP (n=18, 52.9%), DA-R-EPOCH (n=5, 14.7%), combined CODOX-M/IVAC (n=4, 11.7%), R-CHOP with intrathecal methotrexate (n=3, 8.8%), miscellaneous therapies (n=3, 8.8%), and MRT (n=1, 2.9%). The complete response rate was 58.8% (n=20). Intrathecal chemotherapy was administered to 61.8% of patients, and consolidation with autologous stem cell transplant was performed in 35.3%. Based on the CNS compartment involved, de novo SCNSL (DN-SCNSL) were classified into two subtypes: the leptomeningeal subtype, defined as leptomeningeal involvement with or without parenchymal CNS disease (LM-DN-SCNSL; n=22, 64.7%), and the parenchymal subtype, defined as parenchymal-only CNS involvement (P-DN-SCNSL; n=12, 35.3%). Parenchymal disease was multifocal in 75% of cases, supratentorial in 58.3%, and associated with a midline shift in 30%. Although no tested factors (including pathological subtype, age, sex, and bone marrow involvement) were significantly associated with the anatomical compartment, a non-significant trend was noted for BCL6 rearrangement to be more common in the leptomeningeal group (8/13, 61.5%) than the parenchymal group (2/8, 25.0%) (P = 0.18). Survival outcomes were analyzed for both anatomical and pathological classifications. For the parenchymal versus leptomeningeal cohorts, 2- and 5-year Overall Survival (OS) rates were 75.0% vs. 45.1% and 41.0% vs. 38.7%, respectively (P = 0.34). For Progression-Free Survival (PFS), the 2- and 5-year rates were 48.6% vs. 32.5% and 29.2% vs. 26.0%, respectively (P = 0.53). The 2-year OS rates by pathological subtype were 81.8% for non-GCB DLBCL, 45.8% for DHL/THL, and 37.5% for GCB DLBCL (P = 0.27). Survival outcomes (OS/PFS) were not significantly associated with patient age, sex, pathological subtype, or anatomical compartment. Conclusion DN-SCNSL can be anatomically classified into two subtypes: LM-DN-SCNSL and P-DN-SCNSL. While a prognostic trend favoring the parenchymal subtype was observed, the difference did not achieve statistical significance, a finding likely attributable to the small cohort size. This classification may hold clinical utility for guiding risk stratification, and larger studies are needed to validate these findings and identify the most optimal treatments for each subtype of DN-SCNSL.

Abstract Introduction: Cilta-cel is approved in the US and the EU for the treatment of patients (pts) with lenalidomide-refractory multiple myeloma (MM) after ≥1 prior line of therapy (pLOT), including a proteasome inhibitor and an immunomodulatory agent based on the CARTITUDE-1 (CART-1, NCT03548207) and CARTITUDE-4 (CART-4, NCT04181827) studies. Cilta-cel led to deep and durable responses and significant survival benefit in pts with relapsed/refractory MM (RRMM) after ≥3 pLOT in CART-1. In CART-4, cilta-cel led to a significant overall survival benefit with a higher proportion of pts achieving deep, sustained minimal residual disease negativity vs standard of care in pts with lenalidomide-refractory MM after 1–3 pLOT. We investigated the mechanism of action of cilta-cel by correlating biomarkers from peripheral blood and the bone marrow TME with progression-free survival (PFS) and number of pLOT in pts with RRMM from CART-1 and CART-4. Methods: Biomarker analyses were performed using peripheral blood and bone marrow aspirates (BMAs) collected in both CART-1 and CART-4 studies. Immunophenotyping by flow cytometry was performed using peripheral blood at baseline/time of apheresis in samples from both studies. Immune fitness at baseline was assessed in pts by pLOT and in association with PFS. Gene set enrichment scores were derived from RNA sequencing data of the TME using BMAs. Mixed-effects models were used to identify signatures/pathways modulated over time (day [D] 28 and at 6 months [mo] post infusion vs screening) and in association with PFS and pLOT. Results: In total, 176 CART-4 and 97 CART-1 pts received cilta-cel as study treatment. Immunophenotyping data were available from 248 peripheral blood samples (1 pLOT, n=56; 2 pLOT, n=61; ≥3 pLOT, n=131). At apheresis, CD4+ naïve T cells (%) were higher in pts with 1 or 2 pLOT, compared with those with ≥3 pLOT, while no difference was found in pts with ≥3 pLOT with further breakdown (i.e., 3–4 vs 5–6 vs ≥7 pLOT). Further, higher baseline levels of CD4+ naïve T cells were associated with longer PFS. These data suggest that the negative impact on peripheral immune fitness with the addition of LOT may plateau when pts have received ≥3 pLOT. TME gene expression data were available from 148 BMA samples (screening, n=50; D28, n=50; 6 mo, n=48) from CART-4. Analyses of gene expression signatures suggest depletion of B cells and antibodies at D28 post cilta-cel infusion, with partial recovery at 6 mo. This was corroborated in parallel by flow cytometry and immunoglobulin quantification. Further, elevated expression of genes associated with myeloid cells, including tumor-associated macrophages (TAM, likely M1), and of genes associated with cytotoxic T cells were also observed at D28. Elevated expression of genes associated with B-cell receptors, T-cell differentiation and activation, and cytokine signaling pathways were found at both D28 and 6 mo. Pts with longer PFS (>18 mo) had higher levels of M1 TAM at D28, while those with shorter PFS had higher levels of regulatory T cells and more suppressed interferon pathway genes at 6 mo, suggesting that relapse may be associated with a more suppressive immune response. In pts with fewer pLOT, more profound B-cell depletion on D28, better recovery at 6 mo, and elevated B-cell receptor signaling were inferred from gene expression data. Pts with 1 pLOT also demonstrated higher elevation of M1 TAM expression on D28 from screening as compared with pts with 3 pLOT, similar to what was observed in pts with longer PFS. Conclusions: Correlative biomarker data suggest that longer PFS is associated with better immune fitness at baseline and stronger immune responses post cilta-cel infusion, as observed in peripheral blood and within the TME of pts with RRMM in CART-1 and CART-4. The peripheral immune fitness was more pronounced in pts with 1 and 2 pLOT vs 3 pLOT and beyond, where deterioration plateaued. This suggests the impact of T-cell immune fitness on PFS may be limited beyond the third LOT. Importantly, other covariates, including factors within the immune TME and tumor burden, may play a significant role in balancing this compromised intrinsic T-cell immune fitness at apheresis, thereby contributing to PFS durability after 3 pLOT. Overall, these results support increased benefits in treating pts with MM with cilta-cel in earlier LOTs.

Abstract Background: Recent advances in computer vision have given rise to image foundation models (FMs), large-scale neural networks pre-trained on millions of unlabeled histopathology patches, which can learn generalizable representations of tissue morphology. In many cancers, these FMs have predicted genetic mutations and prognoses directly from histology, suggesting that morphology encodes “hidden” molecular information. In lymphoma, this field is nascent but growing.General-purpose histopathology FMs have limited representation of lymphoid morphology. We developed and evaluated LymphoVision, a lymphoma-specialized image foundation model pretrained with self-supervised learning, to extract clinically meaningful features from routine hematoxylin and eosin (H&E) histology. Methods: LymphoVision was pre-trained using knowledge distillation and consistency (DINOv2) on over 37 million multi-resolution patches (5x, 10x, 20x, 40x) sampled using a density-aware strategy from 31,211 H&E whole slide images (WSIs) from 9,155 archival lymphoma and reactive lymphoproliferative cases. To ensure diverse, representative samples, our patch sampling method uses an efficient graph-based clustering algorithm and prioritizes morphologically informative regions by clustering patch embeddings and performing density sampling within each cluster. The pretrained encoder was evaluated using a clustering-constrained attention multiple instance learning (MIL) framework on three diagnostic tasks: (1) cell-of-origin (COO) classification in diffuse large B-cell lymphoma (DLBCL), distinguishing germinal center B-cell (GCB) from non-GCB subtypes based on the Hans immunohistochemistry algorithm; (2) follicular lymphoma (FL) grading, differentiating low-grade (grades 1–2) from high-grade (grade 3); and (3) multiclass lymphoma subtype classification across six categories: DLBCL, FL, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), classical Hodgkin lymphoma (CHL), and benign/reactive lymphoid conditions. WSI-level labels were derived from pathology reports, and none of the evaluation cases were included in pretraining. Models used a ViT-Giant LymphoVision backbone to generate 20x patch embeddings, followed by MIL using 50% training data and 2-fold cross-validation (25% validation, 25% test). Performance was assessed using area under the receiver operating characteristic curve (AUC), accuracy, recall (sensitivity) and F1 score. Results: For DLBCL COO classification (total n=358 cases), LymphoVision achieved a mean test AUC of 0.93 (range 0.92–0.94), accuracy of 84.5% and F1 of 0.85 across two independent test folds (n=91 per fold, 50% GCB). These results outperformed general-purpose FMs on the same task and cases, including Virchow-v2 (AUC 0.85) and UNI-v2 (AUC 0.88), despite those models being pretrained on 10–100 times more images. For FL grading (total n=660 cases), the test set in each fold included 166 cases (18% grade 3), yielding a mean test AUC of 0.88 (range 0.87–0.90), accuracy of 89.2% and F1 of 0.80. In multiclass lymphoma subtype classification (total n=1,176 cases), the test set included 296 cases per fold. LymphoVision achieved a mean test AUC of 0.98 (range 0.97-0.99), mean test accuracy of 87.1% and mean F1 of 0.84. Class-wise recall was 92.0% for DLBCL (n=112), 88.2% for FL (n=72), 77.2% for MZL (n=29), 70.8% for MCL (n=35), 87.5% for CHL (n=24), and 95.8% for benign/reactive lymphoid conditions (n=24). Conclusion: LymphoVision is a lymphoma-specialized FM trained using self-supervision that achieves high diagnostic accuracy across multiple clinically meaningful tasks using weak supervision and standard H&E images, suggesting the encoder has learned fine-grained lymphoma morphology. Based on historical benchmarks from the 1997 International Lymphoma Study Group classification project, expert hematopathologists achieved diagnostic agreement rates of 55% to 84% using H&E morphology alone for the non-Hodgkin lymphoma (NHL) entities included in our multiclass task. LymphoVision approached or exceeded these benchmarks. These findings underscore the value of our approach using disease-specialized pretraining and intelligent patch sampling for data-efficient histopathology learning. LymphoVision has the potential to augment diagnostics, enable scalable AI-powered classification in real-world workflows, and serve as a foundation for prognostic and theragnostic applications. External validation and multimodal integration are ongoing.

Abstract Background Primary central nervous system lymphoma (PCNSL) is a rare but aggressive non-Hodgkin lymphoma with limited prospective data to guide optimal therapy. This study evaluates real-world treatment patterns and survival outcomes using a large national cohort. Methods We analyzed data from the National Cancer Database (NCDB) for patients diagnosed with PCNSL between 2004 and 2020. Baseline demographics and treatment characteristics were analyzed using descriptive statistics. Survival outcomes were estimated using the Kaplan-Meier method and compared using log-rank tests. Multivariable Cox proportional hazards models were constructed to identify independent predictors of overall survival (OS). Results A total of 14,450 patients with PCNSL were included; 14,439 had first-line treatment data available, and 13,390 had survival data. Median age at diagnosis was 67 years (range 18-90), 49.2% were female, and 6.6% were African American. Chemotherapy alone was the modality of treatment for 81.6% (n=11,787), 12.2% (n=1,769) received chemoradiation, 3.8% (n=545) received chemotherapy and underwent autologous stem cell transplant (ASCT) but no radiation, and 2.4% (n=348) received radiation only. The median follow-up time was 73.5 months (95% CI 71.4-75.6), and the median OS for the group was 17.4 months (95% CI 16.2-18.6). Survival differed significantly by age group (median OS: <65 yrs, 46.1 months [95% CI 41.7 -50.6]; 65-79 yrs, 12.5 months [95% CI 11.2-13.7]; ≥80 yrs, 3.2 months [95% CI 2.9-3.5]; p<0.001), by year of diagnosis (median OS: 2004-2009, 11.0 months [95% CI 9.9-12.1]; 2010-2015, 20.0 months [95% CI 17.4-22.6], 2016-2020, 29.7 months [95% CI 26.0-33.4]; p<0.001), and by frontline treatment strategy (p<0.001). Patients treated with chemotherapy followed by ASCT had the longest median OS (not reached), while those receiving radiation alone had the poorest outcomes with a median OS of 3.9 months (95% CI 3.2-4.7); chemoradiation patients had a median OS of 31.8 months (95% CI 27.5-36.1), and chemotherapy only patients had a median OS of 13.9 months (95% CI 12.7-15.1)(p<0.001). African American patients had an inferior outcome with a median OS of 10.2 months [95% CI 7.2-13.1], compared to “other” races with a median OS of 36.9 months [95% CI 27.6-46.1] (p<0.001), although this is more similar to the median outcome for white patients (17.0 months [95% CI 15.8-18.3]). Treatment at an academic center (25.7 vs 11.0 months) and a high case-volume center (defined as >median number of cases per facility) (18.6 vs 10.5 months), and lower Charlson-Deyo comorbidity scores (CDS) (defined as CDS 0-1) (21.7 vs 6.8 months) were also associated with superior OS (p<0.001). In multivariable analysis, increasing age ( 65-79 y.o HR 1.60 [1.52-1.1.68], ≥80 y.o HR 2.95 [2.75-3.17]), CDS≥2 (HR 1.36 [1.28-1.44]), and African American race (HR 1.12 [1.02-1.24]) were adverse predictors of OS (all p<0.001), while treatment strategy (ASCT [HR 0.17], chemoradiation [HR 0.53], chemotherapy only [HR 0.68] compared to radiation alone), more recent year of diagnosis (2010-2015 [HR 0.81], 2016-2020 [0.70]), and treatment at an academic center [HR 0.81] remained predictors of superior OS (all p<0.001). Conclusion In this large national cohort of patients with PCNSL, treatment with chemotherapy followed by ASCT was associated with the most favorable survival outcomes. Patients treated with chemoradiation or multi-agent chemotherapy also demonstrated improved survival compared to those receiving radiation monotherapy or single-agent chemotherapy alone, respectively. Age, comorbidities, race, and treatment at academic centers were also significant independent predictors of OS. These findings highlight substantial disparities in outcomes and underscore the importance of optimizing treatment strategies, improving access to high-intensity therapies, and supporting timely referral to academic or high case-volume centers, particularly for younger and medically fit patients.

Abstract Background: Immune checkpoint inhibitors (ICIs) have been established as standard of care for patients with classical Hodgkin lymphoma (cHL), including relapsed or refractory (r/r) disease. However, ICIs discontinued in some patients due to treatment-related toxicities or disease progression may later be re-initiated. The outcomes of this common clinical practice of ICI re-initiation, or ‘rechallenge,‘ have not been evaluated. Here, we present real-world efficacy and safety data of ICI rechallenge in patients with cHL. Methods: We conducted a retrospective cohort study of patients with cHL treated with ICIs between 2015 and 2024 at Mayo Clinic sites. Patients were identified via institutional records using diagnostic and treatment codes. Included patients were adults ≥18 years with histologically confirmed diagnosis of cHL receiving ≥1 cycle of ICI therapy. Patients in the rechallenge cohort received a second course of ICI therapy following discontinuation of the initial ICI for any reason. The control cohort included patients with ICI discontinuation without subsequent rechallenge. Primary outcomes included progression-free survival (PFS), event-free survival (EFS), and duration of response (DOR), defined respectively as time from first ICI initiation to disease progression, time from first ICI initiation to disease progression, adverse events, treatment change, or death, and time from first recorded response per positron emission tomography–computed tomography until the occurrence of disease progression. Secondary outcomes included overall survival (OS), and incidence and severity of irAEs following ICI rechallenge. Survival outcomes were compared using propensity-score-matched (PSM) cohorts with a proportional Cox model. Results: A total of 145 patients were included. Of these, 30 (21%) underwent ICI rechallenge, while 115 (79%) received no subsequent ICI treatments. The median age was 40 years (interquartile range [IQR] 26-66). Most were male (59%), predominantly nodular sclerosis subtype (71%), Ann Arbor stage III-IV disease (65%), and ECOG ≤ 1 (96%). ICIs were utilized for r/r disease in 66%, with median 6 (IQR 4-13) cycles and follow up of 40.8 months (IQR 21.1–78.1). Patients received median 1 prior line of therapy (IQR 0-2.5). During initial ICI treatment, 34/145 patients (23%) experienced irAEs, including 17 patients (57%) in the rechallenge group and 17 (15%) in the non-rechallenge group. Most irAEs were of grade 1–2 severity, though 10 (30%) experienced grades ≥3 irAEs. irAE severity did not differ between groups. Among patients who underwent ICI rechallenge, the majority (53%) discontinued due to irAEs. The decision to pursue ICI rechallenge was driven predominantly by disease progression (63%). Among the 1:1 PSM cohorts using bone marrow transplant status and the International Prognostic Score, PFS did not significantly differ between rechallenged vs. non-rechallenged groups (HR 1.7, 95% CI 0.60–4.5, p=0.32). Similarly, no difference was noted among the groups in EFS and DOR using 1:3 PSM cohorts using the number of ICI cycles (HR 1.6, 95% CI 0.83–3.0, p = 0.16 and HR 1.6, 95% CI 0.37–7.0, p = 0.53, respectively). In the 1:1 matched cohort, ICI rechallenge was not associated with inferior OS compared to those without rechallenge (HR 1.6, 95% CI 0.48–5.4, p=0.43). irAE occurred in 20%, including pneumonitis (n=2), hepatitis (n=1), and pancreatitis (n = 1). Of the patients who had experienced irAEs during their initial ICI course, only two developed recurrent irAEs of the same type upon rechallenge, both at reduced severity. Overall, 80% of rechallenged patients did not experience any irAE with their second ICI course. Conclusions: ICI rechallenge was not associated with inferior PFS, EFS, DOR or OS compared patients without rechallenge. Among patients receiving ICI rechallenge after irAE, recurrence of same irAE was rare. ICI rechallenge may be a feasible and potentially effective strategy in selected patients with cHL.

Abstract Purpose This study investigates a novel optimization framework that integrates the newly developed MCF MKM relative biological effectiveness (RBE) model into intensity modulated particle therapy (IMPT) planning for carbon ion therapy. Unlike conventional RBE models such as MKM or LEM, the MCF MKM provides detailed microdosimetric information, which improves predictive accuracy of cell survival but elevates both memory and time requirement in the optimization process. Furthermore, to the implicit nature of the MCF MKM, the gradient information, which is essential in inverse planning, is hardly accessible. In response, a randomized gradient‐free optimization method (RGFM) was developed to mitigate the computational challenge and achieve improved RBE dose distributions. Materials and Methods An RBE dose optimization problem was formulated based on the discretized MCF MKM, known as the Abridged Microdosimetry Distribution Model (AMDM). The RGFM was derived to find feasible and high‐quality settings of monitor unit for IMPT plans without the need for explicit gradient calculations. To verify the clinical plausibility of the proposed method, it was tested on two clinical scenarios—prostate and brain cases in comparison with benchmark plans derived solely from physical dose optimization. Computational times and dose‐volume histograms (DVHs) for both physical and RBE doses were evaluated. Results The RGFM algorithm successfully optimized the MCF MKM‐based IMPT plans. Compared to the benchmark, the RBE dose distributions showed improved coverage of the target and reduced hot spots. Such improvements were observed to coincide with trade‐offs in physical dose distributions. The complexity of the MCF MKM extended the computational time, yet high‐quality solutions were attainable in a clinically reasonable timeframe. Multi‐field optimization (MFO) further enhanced target coverage and critical organ sparing over single‐field optimization (SFO). Conclusions This proof‐of‐principle study confirmed the feasibility of using a randomized gradient‐free method to optimize RBE dose based on the MCF MKM in IMPT planning for carbon ion therapy. The approach provides a pathway for clinical adoption of advanced RBE models, potentially leading to more biologically informed and effective carbon ion therapy treatments. Future work involves refining algorithms, incorporating parallel computing, and performing additional case studies to improve computational efficiency and generalizability.

Abstract Introduction Penile augmentation or penis enlargement surgery refers to any technique aimed at enhancing penile length or girth. These male enhancement surgical techniques can increase total penile length, either flaccid or erect, while others add to the penile shaft’s girth and/or glans size. Proposed strategies include physical methods such as various penile exercises, mechanical traction devices, and medical therapy, while surgical interventions include cosmetic and phallic reconstructive techniques and use of fillers, sleeves, grafts, and flaps to augment penile size. Objectives The International Consultation on Sexual Medicine (ICSM) consensus statements provide evidence-based recommendations and aim to guide a clinical framework in penile aesthetic and augmentation. Methods A comprehensive literature search was conducted to identify published literature relevant to penile augmentation or enhancement. Preliminary consensus was presented to the delegates attending the 5th ICSM meeting, and feedback was incorporated into the final document. Results Twenty new recommendations are provided with corresponding levels of evidence and grades of recommendation. Conclusions Due to the controversies and lack of longer-term data regarding penile augmentation and cosmetic procedures, comprehensive assessments and careful patient counseling weighing the pros and cons, as well as potential complications, are mandatory before embarking on any treatment. Surgeons should be experienced in anatomy and various surgical techniques, and it is important to individualize surgical options based on patient condition(s) and needs, surgeon expertise, and local resources.

Abstract Introduction There is no ideal treatment for Peyronie’s Disease (PD) since every patient has different needs with varying perceived risks versus benefits of individual treatment options, coupled with the degree of impact relating to PD on sexual function and beyond. Objectives The 5th International Consultation on Sexual Medicine (ICSM) guideline on PD provides an update to the previous ICSM with an aim to provide a clinical framework and best-evidenced consensus recommendations to assist clinicians in managing PD. Methodology Available literature was reviewed, and a modified Delphi consensus was undertaken by leading sexual medicine experts to achieve a set of Quality of Evidence and strength of recommendations. This guideline was developed as an authoritative best-evidenced consensus incorporating state-of-the-art knowledge and contemporary literature. Results A total of thirty-one recommendations were made on PD guidelines. New updates to the 4th ICSM on PD have been made in definition, pathophysiology, and treatment strategies. The presence of penile pain with erection could occur in the chronic phase due to torque or stretch on the penile scar and surrounding tissue. Oral therapy works best during the acute phase and should be provided concurrently with other treatment modalities. Penile traction therapy can reduce penile deformity as monotherapy or may be offered as part of a multimodal therapy approach. There is no convincing evidence supporting cellular-based therapy. The type of plication procedure used depends on the surgeon and patient preference, although excision of the tunica followed by plication may have a higher complication rate. There is currently no ideal graft, and graft contracture can occur postoperatively. Adjunctive procedures such as penile modeling, tunical plication, plaque incision/excision and grafting can be performed when penile deformity and/or penile curvature persist following penile prosthesis implantation. Conclusions The management of PD should be individualized based on the patient’s needs and preferences while balancing the benefits and risks of each treatment option.