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The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are a group of heterogenous hematologic malignancies characterized by the proliferation of blood cells and consist of myelofibrosis, polycythemia vera, and essential thrombocythemia. The NCCN Guidelines for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the aim of providing recommendations for the comprehensive care of adults with these diseases. The panel of experts convenes at least once a year to discuss requested changes to the Guidelines and to evaluate emerging data. These Guideline Insights focus on some of the recent updates for myelofibrosis.

ABSTRACT First‐line therapy for mantle cell lymphoma (MCL) represents a critical opportunity for clinical benefit via sustained complete response. We conducted a phase 2 multicenter trial in the academic and community cancer research united (ACCRU) network, testing a multitargeted 1st line regimen. CARiBOU (ACCRU‐LY‐1804) employs alternating VR‐CAP and R‐cytarabine with continuous acalabrutinib, in six 21‐day cycles, for previously untreated MCL. The primary endpoint was complete metabolic response (CMR) rate. Secondary endpoints included safety, feasibility of stem cell collection, proportion proceeding to ASCT, and progression‐free (PFS) and overall survival (OS). Peripheral blood measurable residual disease (MRD) was tested using the ClonoSEQ assay (Adaptive Biotechnologies). Of 41 patients enrolled, 39 (95%) responded to therapy, including 37 patients achieving CMR (90%). Two nonresponders discontinued therapy for toxicity early, prior to study‐defined restaging, and received alternate therapy. Undetectable MRD at a 10 6 threshold was achieved in 26/33 tested patients (79%), and 94% at 10 5 . 18‐month estimated PFS is 79% (95% CI 64%–97%), and OS is 96% (95% CI 88%–100%). Toxicities were primarily hematologic (grade 3 hematologic AE in 32 patients, [78%]). Twelve required platelet transfusions, and one grade 3 bleeding event occurred. Febrile neutropenia occurred in 4 patients, and 6 (14%) experienced SAEs. There were no treatment‐related deaths. CARiBOU is an efficient, highly effective outpatient 1st line MCL regimen, employing intermediate‐dose cytarabine and continuous acalabrutinib for 6 cycles. This multitargeted regimen addresses the biologic heterogeneity of MCL and permits flexible MRD‐guided decisions on consolidation and maintenance. Trial Registration: ClinicalTrials.gov identifier: NCT04626791

Abstract Introduction: First-line therapy for mantle cell lymphoma (MCL) represents a critical opportunity for clinical benefit via sustained complete response. Multitargeted combinations, including optimized chemotherapy with novel agents targeted to MCL, may best address the biologic heterogeneity of this disease. Building on prior experience using modified VR-CAP and R-cytarabine, we enhanced this regimen by adding acalabrutinib while reducing cytarabine, aiming for improved efficacy and safety without impeding stem cell collection. To evaluate this regimen, we conducted a phase 2 multicenter trial at four centers in the Academic and Community Cancer Research United (ACCRU) network. Methods: CARiBOU (ACCRU-LY-1804) employs alternating VR-CAP and R-cytarabine with continuous acalabrutinib, in six 21-day cycles, for previously untreated MCL. Eligible patients (pts) were at least 18 years old with adequate organ function, measurable disease, no CNS involvement; and were ASCT-eligible per investigator. VR-CAP (cycles 1, 3, and 5) employed bortezomib 1.3 mg/m² subcutaneously days 1,8, and 15; rituximab 375 mg/m² day 1; cyclophosphamide 750 mg/m² day 1; doxorubicin 50 mg/m2 day 1; and prednisone 100 mg PO days 1-5. Cycles 2,4, and 6 used outpatient rituximab with cytarabine at 3 g/m² x 2 daily doses in the first 5 pts, after which the dose was reduced to 2 gm/m2 x 2 daily doses due to thrombocytopenia. Acalabrutinib 100 mg p.o. twice daily was given continuously but held for grade 4 thrombocytopenia or clinically significant toxicity. Growth factors and prophylactic antimicrobials were required. Responses were assessed after six cycles using FDG PET/CT, bone marrow aspirate/biopsy (BM Bx), and endoscopy when indicated (Lugano 2014). The primary endpoint was complete metabolic response (CMR) rate at end of treatment (EOT). Secondary endpoints included safety, feasibility of stem cell collection, proportion proceeding to ASCT, and progression-free (PFS) and overall survival (OS). Peripheral blood measurable residual disease (MRD) was evaluated using the ClonoSEQ assay (Adaptive Biotechnologies). A Simon two-stage design was used, targeting a CMR rate ≥ 70% versus a null rate of 50%, with a total sample size of 39 evaluable pts. Results: 41 pts were accrued from October 2021 through May 2025, 37 of whom completed all 6 cycles and are evaluable for response; two are still on therapy, and two discontinued therapy early for toxicity. Median age was 63 years (range 41-73), 22% were female, and 85% were White. MIPI risk groups were low (44%), intermediate (39%), and high (17%), and Ki-67 was ≥ 30% in 54% of pts. Three pts (7%) had known TP53 mutations by sequencing. At EOT, the CMR rate was 85.3% among all pts (35/41; 95% CI 67.9%-92.9%), or 94.5% among evaluable pts (35/37). BM Bx was performed in 31 pts at EOT, 30 of which (96.8%) were negative for MCL. Undetectable peripheral blood MRD using a 10^6 threshold (uMRD6) was achieved at EOT in 78.1% (25/32) of tested pts, and 93.8% (30/32) achieved uMRD5. Nine of 41 pts underwent ASCT; no patient failed stem cell collection. Maintenance therapy was not protocol-defined but included rituximab in 91.9% of pts and a BTK inhibitor in 21.6% of pts. With a median follow-up of 16.7 months, PFS and OS rates at 18 months were 76.7% (95% CI: 60.7%-96.9%) and 95.5% (95% CI: 87.1%-100%). Toxicities were primarily hematologic. Grade 3+ toxicities included thrombocytopenia (66.6%), neutropenia (28.2%), and anemia (25.6%). Grade 3+ febrile neutropenia was observed in 10.2% of pts. Peripheral neuropathy was seen in 20.5% of pts and all grade 1-2. Bleeding events included purpura in 2 pts (5.2%) and epistaxis in 1 patient (2.6%). One case of atrial fibrillation was observed. Eighteen pts required temporary dose hold of acalabrutinib for toxicity (mainly thrombocytopenia), and 2 had acalabrutinib dose reductions. Serious adverse events occurred in 6 pts, and no treatment-related deaths occurred. Conclusions: CARiBOU is an efficient, highly effective outpatient regimen for 1st line MCL, employing intermediate dose cytarabine with continuous acalabrutinib. With supportive care and platelet monitoring, this approach safely yielded high rates of CMR and uMRD6, supporting multitargeted induction therapy for appropriate pts with untreated MCL.

Introduction PET-directed therapy using ABVD with or without radiation therapy (RT) is considered standard in early stage classic Hodgkin lymphoma (cHL). Brentuximab vedotin (BV) and nivolumab (NVB) have transformed the treatment paradigm in advanced stage disease, but their roles remain uncertain in the management of early stage cHL. CALGB 50604 evaluated 2 cycles of ABVD followed by 2 more cycles of ABVD in patients with negative interim PET or 2 cycles of escalated BEACOPP and RT (3060 cGy) in patients with positive interim PET. More recently, ACCRU-LY1601 evaluated 3 cycles of BV+AVD followed by NVB consolidation in interim PET-negative patients. Interim PET-positive patients received 4 cycles of BV+NVB prior to NVB consolidation. Both studies had similar eligibility criteria as phase 2 trials in early stage non-bulky cHL. We hypothesize that patients who receive novel agents as part of frontline therapy (ACCRU-LY1601) may have superior clinical outcomes compared to those who receive conventional chemotherapy with or without RT (CALGB 50604) in adjusted analysis. Methods The primary endpoint was the progression free survival (PFS) rate at 3 years for both studies. The following secondary endpoints were analyzed: PET negativity (defined as Deauville score 1-3) at interim assessment, response rates, and adverse events (AEs). Data from the ACCRU-LY1601 up to May 2024 were included. Patient characteristics, complete metabolic response (CMR) rates, and AE incidence were compared with Fisher's exact tests. Kaplan-Meier techniques were used to estimate landmark survival rates; the 95% confidence intervals (CI) for probabilities of PFS at 3 years landmark rates were assessed. Results of a formal propensity-matched analysis are forthcoming. Results Two-hundred twenty-nine participants receiving frontline therapy for early stage, non-bulky cHL were identified for analysis (N=149 from CALGB 50604; N=80 from ACCRU-LY1601). Median age in both cohorts was 31 (ranges: 18-58 in CALGB 50604 and 19-60 in ACCRU-LY1601). The majority of patients were white (84.6% in CALGB 506048 and 82.5% in ACCRU-LY1601; P=0.58) and had stage II cHL (85.2% in CALGB 50604 and 88.8% in ACCRU-LY1601; P=0.83) with ECOG score of 0 (75.2% in CALGB 50604 and 75.0% in ACCRU-LY1601; P=0.87). B symptoms were present in 27.4% and 32.9% of patients in CALGB 50604 and ACCRU-LY1601, respectively (P=0.44). At time of analysis, the median follow-up was 3.8 years for CALGB 50604 and 3.6 years for ACCRU-LY1601. Interim PET results were available for 140/149 CALGB 50604 and 77/80 ACCRU-LY1601 cohorts; 90.1% and 94.8% were interim PET negative in CALGB 50604 and ACCRU-LY1601, respectively (P=0.31). Thirteen patients (8.7%) received RT after positive interim PET per the study protocol in CALGB 50604. No patient received RT while enrolled in ACCRU-LY1601 although 2 patients (2.5%) received RT off protocol. Seventeen PFS events (11.4%) were observed in CALGB 50604 while one event (1.3%) was observed in ACCRU-LY1601. Reported estimates of 3-year landmark PFS were 89.0% (95% CI, 84-95%) in CALGB 50604 and 97.5% (95% CI, 83.6-99.6%) in ACCRU-LY1601. Grade ≥ 3 AEs, including febrile neutropenia (6.3% in CALGB 50604 vs. 8.8% in ACCRU-LY1601; P=0.59), were similar between the trial cohorts. All grade peripheral sensory neuropathy was reported in 41.6% and 37.5% (Grade ≥ 3: 2.8% and 2.5%; P>0.99) of patients in CALGB 50604 and ACCRU-LY1601, respectively. Conclusion CALGB 50604 and ACCRU-LY1601 represent two recent studies aimed at developing new strategies to reduce exposure to cytotoxic chemotherapy and RT in early stage cHL. Both studies share the same primary endpoint with similar eligibility criteria, making the comparative analysis feasible. There was no significant difference in major baseline patient characteristics between the two studies. They also showed similar toxicity profiles, including comparable rates of febrile neutropenia and peripheral sensory neuropathy. ACCRU-LY1601 was associated with a higher rate of estimated 3-year PFS rate compared to CALGB 50604 (97.5% vs. 89.0%) although their CIs overlapped. Overall, the current data demonstrate the potential role of incorporating novel agents in frontline therapy to further reduce the use of cytotoxic chemotherapy and RT while improving survival outcomes, providing a strong basis for designing future trials in early stage cHL.

The determination of an optimal treatment plan for an individual patient with rectal cancer is a complex process. In addition to decisions relating to the intent of rectal cancer surgery (ie, curative or palliative), consideration must also be given to the likely functional results of treatment, including the probability of maintaining or restoring normal bowel function/anal continence and preserving genitourinary functions. Particularly for patients with distal rectal cancer, finding a balance between curative-intent therapy while having minimal impact on quality of life can be challenging. Furthermore, the risk of pelvic recurrence is higher in patients with rectal cancer compared with those with colon cancer, and locally recurrent rectal cancer is associated with a poor prognosis. Careful patient selection and the use of sequenced multimodality therapy following a multidisciplinary approach is recommended. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Rectal Cancer, including the addition of endoscopic submucosal dissection as an option for early-stage rectal cancer, updates to the total neoadjuvant therapy approach based on the results of recent clinical trials, and the addition of a “watch-and-wait” nonoperative management approach for clinical complete responders to neoadjuvant therapy.

Mastocytosis is a heterogeneous group of disorders comprising cutaneous mastocytosis, systemic mastocytosis, and mast cell sarcoma. It is associated with a variety of symptoms related to the release of mast cell mediators and mast cell tissue infiltration. Referral to specialized centers with expertise in the management of mastocytosis and multidisciplinary collaboration with subspecialists (eg, allergists for the management of anaphylaxis and drug hypersensitivities, anesthesiologists for invasive procedures or surgery, high-risk obstetrician for pregnancy) is recommended. The NCCN Guidelines for Systemic Mastocytosis provide evidence- and consensus-based recommendations for the diagnosis and comprehensive care of patients with systemic mastocytosis. The multidisciplinary panel of experts convenes at least once a year to review requested changes to the guidelines from both internal and external entities as well as to discuss data on existing and new therapies. These NCCN Guidelines Insights focus on some of the recent updates to the guidelines.

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.

This discussion summarizes the NCCN Clinical Practice Guidelines for managing squamous cell anal carcinoma, which represents the most common histologic form of the disease. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is necessary. Primary treatment of perianal cancer and anal canal cancer are similar and include chemoradiation in most cases. Follow-up clinical evaluations are recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. Biopsy-proven evidence of locally recurrent or persistent disease after primary treatment may require surgical treatment. Systemic therapy is generally recommended for extrapelvic metastatic disease. Recent updates to the NCCN Guidelines for Anal Carcinoma include staging classification updates based on the 9th edition of the AJCC Staging System and updates to the systemic therapy recommendations based on new data that better define optimal treatment of patients with metastatic anal carcinoma.

Background and objectives: Area of residence may adversely affect survival and outcomes in many cancers. The objective of this study was to evaluate the impact of geographical and demographic disparities on survival of patients with colorectal cancer. Materials and methods: Data were obtained from the National Cancer Database (NCDB) colon, rectosigmoid, and rectal datasets. Patients were categorized by area of residence, namely, metropolitan (MA), urban (UA), or rural (RA). Sociodemographic and tumor-related data were collected and analyzed to evaluate variables affecting overall survival (OS). Results: In total, 973,139 patients between 2004 and 2013 were included in the study, of which 83%, 15%, and 2% were MA, UA, and RA residents, respectively. RA and UA patients were mostly white male with low income and no comorbidities. In univariate analysis, OS was worse for RA (hazard ratio [HR] 1.10) and UA (HR 1.06) colorectal cancer patients than that for MA colorectal cancer patients. In multivariate analysis revealed significant association between OS and geographic residence, with worse OS for RA (HR 1.02, p = 0.04) and UA (HR 1.01, p = 0.003) patients. Black (HR 1.14) and Native American (HR 1.17) patients had worse outcomes, while Asians (HR 0.8), women (HR 0.88), and patients with higher income had improved OS (HR 0.88). Conclusion: The differences in the OS for RA and UA patients with colorectal cancer were significantly driven by economic disparity. Area of residence represents an important factor independently limiting access to care, particularly in geographically isolated individuals.

Abstract The prognostic relevance of diagnosis to treatment interval (DTI) in patients with newly diagnosed mantle cell lymphoma (MCL) is unknown. Hence, we sought to evaluate the impact of DTI on outcomes in MCL using 3 large datasets (1) the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource, (2) patients enrolled in the ALL Age Asthma Cohort/CALGB 50403, and (3) a multisitecohort of patients with MCL. Patients were a priori divided into 2 groups, 0 to 14 days (short DTI) and 15 to 60 days (long DTI). The patients in whom observation was deemed appropriate were excluded. One thousand ninety-seven patients newly diagnosed with MCL and available DTI were included in the study. The majority (73%) had long DTI (n=797). Patients with short DTI had worse eastern cooperative oncology group performance status (ECOG PS ≥2), higher lactate dehydrogenase, bone marrow involvement, more frequent B symptoms, higher MCL International Prognostic Index (MIPI ≥6.2), and were less likely to receive intensive induction therapy than long DTI group. The median progression-free survival (2.5 years vs 4.8 years, p<0.0001) and overall survival (7.8 years vs. 11.8 years, p<0.0001) were significantly inferior in the short DTI group than the long DTI cohort and remained significant for progression-free survival and overall survival in multivariable analysis. We show that the DTI is an important prognostic factor in patients newly diagnosed with MCL and is strongly associated with adverse clinical factors and poor outcomes. DTI should be reported in all the patients newly diagnosed with MCL who are enrolling in clinical trials and steps must be taken to ensure selection bias is avoided.