What is the recommended initial treatment approach for a patient with high-grade B cell Non-Hodgkin Lymphoma (NHL) that is CD20 positive, MUM1 positive, MYC positive, with a high Ki-67 (proliferation index) of 99%, involving nasal mucosa and lymph nodes above and below the diaphragm?

High-Grade B-Cell NHL: Stage IV Disease with MYC Positivity

This patient requires intensive systemic immunochemotherapy with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) given the CD20-positive, MYC-positive high-grade B-cell lymphoma with disseminated disease (Stage IV), and mandatory CNS prophylaxis due to multiple high-risk features including nasal mucosa involvement, elevated Ki-67, and likely elevated LDH. 1

Critical Initial Staging and Risk Assessment

Before initiating treatment, complete the following workup:

• CT scan of chest and abdomen to fully delineate disease extent 1
• Bone marrow aspirate and biopsy (likely already done given stage IV disease) 1
• Complete blood count, LDH, uric acid levels 1
• HIV and hepatitis B/C screening (mandatory before rituximab) 1
• Calculate International Prognostic Index (IPI) - this patient likely has high-intermediate or high-risk IPI given Stage IV disease with multiple extranodal sites 1
• PET scan at baseline for response evaluation later 1
• Cardiac function assessment before anthracycline therapy 2

Tumor Lysis Syndrome Prevention (Critical First Step)

Given the extremely high Ki-67 of 99% indicating massive proliferative activity:

• Administer prednisone 100 mg orally daily for 5-7 days as "prephase" treatment before starting R-CHOP 3, 2
• Ensure aggressive hydration 3
• Consider prophylactic allopurinol or rasburicase for this highest-risk patient 3

Primary Treatment Regimen

The age of the patient determines the specific approach:

If Patient is ≤60 Years Old with High-Risk Disease:

• Six to eight cycles of R-CHOP given every 14-21 days 1
• Eight doses of rituximab total 1
• Consider enrollment in clinical trials as dose-intensive regimens or high-dose chemotherapy with stem-cell transplantation remain experimental but show promise in phase II trials 1
• Do NOT reduce chemotherapy doses for hematological toxicity unless absolutely necessary, as this significantly compromises outcomes 1, 3
• Use prophylactic hematopoietic growth factors if febrile neutropenia occurs 1

If Patient is 60-80 Years Old:

• Eight cycles of R-CHOP given every 21 days with eight doses of rituximab 1
• Alternatively, six cycles of R-CHOP every 14 days with eight doses of rituximab is sufficient 1

Mandatory CNS Prophylaxis

This patient absolutely requires CNS prophylaxis due to multiple high-risk features:

• High-intermediate or high-risk IPI (Stage IV disease) 1
• Multiple extranodal sites (nasal mucosa plus lymph nodes) 1
• Paranasal sinus involvement is specifically mentioned as requiring prophylaxis 1
• Likely elevated LDH given high tumor burden 1

Important caveat: Intrathecal methotrexate injections are "probably not an optimal method" per ESMO guidelines, though the optimal CNS prophylaxis approach remains somewhat controversial 1. Consider systemic high-dose methotrexate if feasible, or intrathecal therapy if systemic approach not possible.

Radiotherapy Considerations

Consolidation radiotherapy to sites of bulky disease has NOT proven benefit and should be avoided 1. The nasal mucosa involvement does not change this recommendation - systemic therapy is the priority.

Response Evaluation Timeline

• Repeat imaging after 3-4 cycles of R-CHOP 1
• Repeat imaging after completion of all treatment 1
• PET scan is highly recommended for post-treatment assessment to define complete remission 1
• If PET positive and therapeutic consequences are considered, obtain histological confirmation 1
• Repeat bone marrow biopsy only at end of treatment if initially involved 1

Special Considerations for MYC-Positive Disease

The MYC positivity raises concern for "double-hit" or "triple-hit" lymphoma (high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements) 4. If FISH studies confirm MYC rearrangement along with BCL2 or BCL6 rearrangements, this represents an even higher-risk subset that may benefit from more intensive approaches or clinical trial enrollment 4.

Follow-Up Protocol After Achieving Remission

• History and physical examination every 3 months for 1 year, every 6 months for 2 more years, then annually 1, 5
• Blood count and LDH at 3,6,12, and 24 months 1, 5
• CT scan at 6,12, and 24 months after treatment completion 1, 5
• Routine surveillance PET is NOT recommended 1, 5
• Monitor for secondary malignancies and long-term chemotherapy side effects 1, 5

Salvage Therapy if Primary Treatment Fails

If the patient does not achieve complete remission or relapses:

• Obtain histological confirmation, especially if relapse occurs >12 months after diagnosis 5, 2
• For patients <65 years with good performance status: rituximab-based salvage chemotherapy (R-DHAP, R-ICE, or R-ESHAP) followed by high-dose chemotherapy with autologous stem cell transplant 1, 5, 2
• For transplant-ineligible patients: alternative salvage regimens (R-GEMOX) with or without involved-field radiotherapy 1, 2

Critical Pitfalls to Avoid

• Do not treat nasal involvement with local radiotherapy alone - this is disseminated Stage IV disease requiring systemic therapy 3
• Do not skip CNS prophylaxis - this patient has multiple high-risk features 1
• Do not reduce chemotherapy doses unnecessarily - maintain dose intensity for curative intent 1, 3
• Do not delay treatment for extensive molecular workup - begin therapy promptly after confirming CD20 positivity and completing staging 1