Blastoid variant Mantle Cell Lymphoma (MCL) with TP53 mutations represent an extremely high-risk disease with poor outcomes on standard chemoimmunotherapy. This case study represents the clinical challenges and therapeutic considerations in managing MCL with multiple high-risk features, including TP53 mutation, blastoid variant, CNS involvement and cutaneous dissemination. In the case study we describe clinical presentation, pathologic diagnosis, and treatment.

Granroth G, Peterson C, Easwar A (2026) Case Study: Multiorgan Involvement in Relapsed Blastoid Mantle Cell Lymphoma. J Cancer Biol Res 13(1): 1155.

Mantle cell lymphoma is a type of B-cell lymphoma characterized by a monomorphic proliferation of small lymphoid cells that carry t(11;14)(q13;q32) IGH:CCND1 [1]. MCL represents approximately 5–7% of all lymphomas typically affecting men and presenting at a median age of 65 years. Blastoid mantle cell lymphoma is considered a high-risk MCL with high Ki-67% in involved tissues, del 17p, TP53 mutations, and complex karyotypes often showing frequent relapses and overall poor survival [3]. Hematopathology evaluation of involved tissues is critical for diagnosis with the initial cytomorphology assessment, as blastoid MCL can show immunophenotypic variations, making it difficult to correctly diagnose [4]. The blastoid variant may show the loss of CD5 expressions, and may have the aberrant expression of CD10, BCL6, and CD234. Blastoid MCL cells are a medium-sized, homogenous population of cells, with fine chromatin and round nuclei, resembling lymphoblasts [3]. Exact incidence and prevalence of blastoid MCL remains unknown, however roughly 10-30% of newly diagnosed MCL show blastoid histologies [3]. Blastoid MCL is considered a more aggressive type of MCL with a median overall survival of roughly 18 months [3].

Clinically patients can present with extranodal involvement of the bone marrow, skin, pulmonary, gastrointestinal tract, and central nervous system with leptomeningeal involvement [2]. Most patients with mantle cell lymphoma present with nonlocalized, palpable lymphadenopathy [2]. Roughly 30% of patients at time of presentation have fevers, night sweats, weight loss, and fatigue [2]. Central nervous system involvement is rare at initial presentation and is associated with a very short overall survivival [2].

Typically, blastoid mantle cell lymphoma is treated with a combination of rituximab and chemotherapy [5]. The utilization of rituximab combined with high dose cytarabine induction chemotherapy, followed by autologous stem cell transplant consolidation has been commonly adopted in practice for younger patients that are transplant eligible [5]. Conventional chemo-immunotherapy treatments rarely result in long-term remission and have high refractory rates to treatment largely due to the prevalence of the TP53 mutation [6]. The results from the BOVen regimen: Zanubrutinib, obinutuzumab and venetoclax show promise in treatment for patients with blastoid MCL [7]. The BOVen study enrolled 25 treatment naïve patients that were diagnosed with TP53 mutated MCL, in which 44% of participants had blastoid/pleomorphic variant and median age was 65 years old with a high-risk MIPI score in 52%. The results of the study demonstrated remarkable efficacy with a 96% overall response rate, 88% complete response rate and a 2-year progression free survival of 72% [8]. Importantly 95% of patients achieved undetectable minimal residual disease (uMRD) at a sensitivity of 10-5, and treatment could be discontinued after 24 cycles in patients achieving complete remission with uMRD. This regimen is well tolerated with some low grade toxicities that include diarrhea (64%), neutropenia (32%), and infusion related reactions (24%) [8]. Specific blastoid variant outcomes from BOVen were not separately reported, but mentioned earlier, 44% of the BOVen cohort had blastoid/pleomorphic variant suggests that efficacy in this high-risk population. This is in contrast with other trials using ibrutinib plus rituximab in TP53 mutated MCL. They achieved only a median progression-free survival of 18.5 months [9]. The SYMPATICO trial demonstrated that ibrutinib plus venetoclax showed similar hazard ratios as the BOVen trial for progression-free survival in patients with and without blastoid variants. This suggests that the targeted combinations have the potential to overcome the poor prognosis of blastoid morphology [10]. However, the ibrutinib-venetoclax in first line achieved median progression-free survival of only 19.8 months. Based on the outcomes from the trials described, the low-grade toxicities and potential for a fixed duration approach, the NCCN now lists Venetoclax, Zanubrutinib + obinutuzumab as the preferred regimen suitable for all patients with TP53-mutated MCL, this includes those with blastoid variant [11]. CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) is another novel immunotherapy approach that has also demonstrated high response rates amongst patients with relapsed refractory blastoid mantle cell lymphoma [6].

A 69-year-old male with a past medical history significant for hypertension, type 2 diabetes mellitus, and mantle cell lymphoma was seen in our clinic to establish care after undergoing a complete cycle of R-HyperCVAD part A and B at an outside facility. His initial chemotherapy course was complicated by a methicillin resistant staph aureus bacteremia from a right-hand cellulitis that was treated with incision and drainage and a prolonged course of antibiotics. He was also hospitalized for shortness of breath and pleuritic chest pain, found to have a pleural effusion, in which 2.5L of fluid were drained, however it is unclear on if the fluid was malignant in nature. At time of presentation in the clinic to establish care the patient had significant weight loss since time of diagnosis, was extremely fatigued, had severe neuropathy, and right eye ptosis. He also had blurry vision but denied double vision. He denied any bowel or bladder dysfunction. He also developed a non painful, non-pruritic bullous like rash on his bilateral groin area, bilateral lower extremities, and scattered bilaterally on his upper extremities. Due to his new right sided eyelid droop he was admitted to the hospital for concern of progressive disease with suspected CNS involvement. He exhibited cranial nerve III palsies with a right eye ptosis, inability to move the eye, and difficulty focusing on close up objects. At time of admission a brain MRI was obtained and showed mild microangiopathic white matter changes with no acute stroke or intracranial hemorrhage. He had no evidence of meningeal enhancements or evidence of intracranial disease. He did undergo MRI of the entire spine which showed diffuse heterogenous marrow signal and several lobe T1, T2, T9, T10, L1, L2, and L3 signal bony lesions suspicious for metastatic disease [Figure 1]. He also experienced left femur and thigh pain. An MRI of the femur showed abnormal lobulated low T1 central marrow signal from the intertrochanteric aspect of the left femur through the distal femoral diaphysis, which may represent metastatic lymphoma.

Figure 1: MRI of the thoracic spine. Diffuse heterogeneous marrow signal. Signal bony lesions concerning for progressive metastatic disease

A complete blood count at time of presentation showed leukocytosis with microcytic anemia. A peripheral blood flow cytometry was obtained and found to be consistent with a monoclonal B-cell lymphoproliferative disorder. He underwent a bone marrow biopsy that showed roughly 20% hypercellular marrow for age with roughly 60% cellularity of involved mantle cell lymphoma [Figure 2].

Figure 2: Bone marrow Biopsy The core biopsy showed hypercellular bone marrow for age (60% cellularity) with increased interstitial lymphocytes (Figure 2A - H&E stain, 40X magnification). Interstitial B-lymphocytes are highlighted by immunohistochemical stains PAX5 (Figure 2B – 100X magnification) and cyclin D1 (Figure 2C – 100X magnification) – which account for about 20% of total cellularity.

Flow cytometry revealed a small population of monoclonal B-cells (~0.8% of total cells) expressing CD5 without CD23, consistent with patient’s known mantle cell leukemia/ lymphoma. Cytogenetic analysis shows an abnormal male karyotype. Five cells show multiple structural and numerical chromosome abnormalities, including deletions of 9p and 11q. The abnormal cells are only present in the culture stimulated with interleukin-2 as a B-cell mitogen. Rearrangement involving 9p is a common finding of lymphoblastic leukemia and/or lymphoblastic lymphoma. Loss of the long arm of chromosome 11, resulting in ATM gene deletion, is generally considered an unfavorable prognostic indicator in CLL. Complex clonal abnormalities are generally associated with a less favorable prognosis. Neo Type Lymphoma FISH panel detected IGH::CCND1 supporting the diagnosis of Mantle Cell Lymphoma. He was also found to have a Tier 1 mutation in TP53 (VAF 7.8%), which is associated with a poor prognosis in Mantle Cell Lymphoma.

He did undergo a lumbar puncture with intrathecal methotrexate. Meningitis panel was obtained and found to be negative. CSF cultures were obtained and found to be negative. Afigunalysis of the CSF revealed an increased WBC count of 70, with atypical cells present on cytology [Figure 3]. CSF Flow cytometry did reveal B Cell Lymphoma.

Figure 3: CSF Cytology A cytology preparation (Wright Giemsa stained) of CSF revealed increased numbers of lymphocytes with irregular nuclear borders, open chromatin and prominent nucleoli – suggestive of blast morphology (600X magnification). By concurrent flow cytometry, these cells were CD19 positive B-cells with kappa light chain restriction and negative for CD5 and CD10, consistent with patient’s known Mantle Cell Lymphoma, blastoid variant.

He also presented with a non-painful, non-pruritic maculopapular rash with raised lesions and components of bullae on his bilateral groin area, bilateral lower extremities, and scattered bilaterally on his upper extremities [Figure 4].

Figure 4: Skin Manifestation Maculopapular rash with raised lesions and components of bullae, non-pruritic, non-tender.

He did undergo a skin punch biopsy which showed sections of fragments of skin with dermal infiltration by monotonous intermediate sized cells with irregular nuclear borders, open chromatin, prominent nucleoli, and minimal cytoplasm. Immunostains show that these atypical cells are CD20/PAX5 positive B-cells with weak expression of CD5, cyclin D1, BCL2, and p52 (overexpressed in a large subset of tumor cells), while negative for BCL6, CD23, and CD10. The Ki-67 proliferation index is > 95%. Overall findings are consistent with the patient’s known Mantle Cell Lymphoma with blastoid variant with p53 mutation/overexpression [Figure 5].

Figure 5 : Skin Biopsy The skin punch biopsy section reveals a dermal infiltration by intermediate sized lymphocytes – with irregular nuclear borders, open chromatin and occasional nucleoli and scant cytoplasm (H&E stains, Figure 5A – 40X magnification, Figure 5B – 600X magnification). A panel of immunohistochemical stains were performed and show that the atypical lymphocytes are CD20 positive B-cells (Figure 5C), that coexpress CD5 (very dim expression, Figure 5D), cyclin D1 (Figure 5E), with markedly increased Ki-67 proliferation index of at least 95% (Figure 5F) and at least a subset with overexpression of p53 (Figure 5G). Figures 5C05G are at 100x magnification.

Skin flow cytometry revealed monoclonal B-cells (~40-45% of total cells) without discernible CD5 or CD10 expression (based on a limited antibody panel), the finding is consistent with known disease.

The patient started treatment with Obinutuzumab. He received 100 mg of IV Obinutuzumab on Day 1, 900 mg of IV Obinutuzumab on Day 2, then 1,000 mg of IV Obinutuzumab on Day 8 and Day 15. He also started on Zanubrutinib 160 mg po BID. Due to his positive CNS disease, he received triple intrathecal chemotherapy with 10 mg of Methotrexate, 30 mg of Cytarabine, and 50 mg of Solu-Cortef twice weekly, and will continue until his blasts clear. Once the blast clear in his CSF he will be transitioned to prophylactic weekly lumbar punctures with intrathecal chemotherapy for another 4-6 weeks.

This case study represents the clinical challenges and therapeutic considerations in managing MCL with multiple high-risk features, including TP53 mutation, blastoid variant, CNS involvement and cutaneous dissemination. The patient presented with an aggressive form of MCL, requiring a nuanced treatment approach that balances efficacy with tolerability. CNS involvement in MCL is uncommon with reported incidence ranges from 3.8% to 7.8% at 10 years and higher rates observed in patients with blastoid histology, Ki67>30% and elevated LDH [12]. In this case, the patient presented with cranial nerve III palsy and CSF cytology positive for atypical cells with flow cytometry confirming B-cell lymphoma, consistent with leptomeningeal involvement. The blastoid variant and Ki-67 >95% in this patient placed him at a high risk for CNS involvement. The selection of Zanubrutinib is based on evidence for BTK inhibitor efficacy in CNS MCL. Zanubrutinib has not been studied as extensively as ibrutinib for CNS MCL, however, a recent meta-analysis demonstrated that BTK inhibitors to include Zanubrutinib, show good efficacy in CNS lymphoma [13]. The decision to use triple intrathecal therapy rather than single agent methotrexate was based on the aggressive nature of the disease and documented CSF involvement with atypical cells. Randomized data comparing single agent to combination intrathecal therapy in MCL is lacking. The plan is to transition to prophylactic weekly treatments after blast clearance follows principles used in other aggressive lymphomas with CNS involvement [14].

As discussed earlier, cutaneous involvement in MCL is rare and when present are associated with aggressive morphologic features. The presence of cutaneous involvement in this patient, combined with bone marrow involvement (60%) cellularity), CNS disease and multiple vertebral lesions indicate widely disseminated disease requiring systemic therapy with CNS penetration rather than just localized approaches.

This case highlights several challenges in managing high risk MCL. The patient’s prior treatment -related complications (MRSA bacteremia, pleural effusion) and now current symptoms (severe neuropathy, significant weight loss, extreme fatigue and neurological symptoms) limited treatment options and necessitated a balance between efficacy and tolerability. The prognosis remains guarded despite optimal therapy. Even with the BOVen regimen in the first line setting, patient relapsed early after R-HyperCVAD with multiple adverse features.

This case demonstrates a rational, evidence-based approach to one of the most challenging scenarios in MCL: relapsed/refractory disease with TP53 mutations, blastoid variant, CNS involvement, and cutaneous dissemination. The combination of Zanubrutinib, Obinutuzumab and venetoclax provide systemic therapy with CNS penetration, while aggressive intrathecal chemotherapy addresses documented leptomeningeal disease. While the prognosis remains poor, this approach represents the best available therapy outside of a clinical trial.

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