What is the diagnosis and treatment approach for a patient with a lymphoproliferative disorder, particularly in older adults or those with compromised immune systems?

Lymphoproliferative Disorders: Definition and Clinical Overview

Lymphoproliferative disorders (LPDs) are a heterogeneous group of diseases characterized by the uncontrolled proliferation of lymphoid or plasmacytic cells, encompassing both benign and malignant conditions that primarily affect B-cells (80% of cases), with T-cell variants comprising 15-20% and NK-cell lymphomas being rare. 1

Disease Classification and Subtypes

Major Categories

• B-cell lymphoproliferative disorders include chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphomas (NHL), mantle cell lymphoma (MCL), and post-transplant lymphoproliferative disorders (PTLD) 1

• CLL represents the most common leukemia in adults, with a median age at diagnosis of 72 years and 70% of patients diagnosed after age 65 1

• Post-transplant lymphoproliferative disorders occur following solid organ or hematopoietic stem cell transplantation, with nearly all cases in HSCT recipients being EBV-related 1

• Cutaneous lymphoproliferative disorders include CD30+ variants such as lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma (pcALCL) 1

Pathophysiology

• EBV infection drives the majority (75-80%) of HIV-associated PTLD cases through anti-apoptotic effects on B cells 1

• Immunosuppression from transplantation, HIV infection, or primary immunodeficiency creates the permissive environment for lymphoproliferation 1, 2

• Genetic abnormalities play critical roles, including del(17p), del(11q), unmutated IGHV genes in CLL, and MYC translocations in aggressive variants 1

Diagnostic Approach

Essential Diagnostic Elements

• Tissue diagnosis is mandatory through excisional lymph node biopsy or core biopsy; fine-needle aspiration is inadequate 1, 3

• Immunophenotyping must include specific markers: CD19, CD20, CD5 for CLL; CD30 for cutaneous variants; cyclin D1 or t(11;14) for MCL 1

• EBV detection via quantitative PCR and tissue biopsy is essential for PTLD diagnosis, establishing proven versus probable disease 1

• Complete blood count with differential can diagnose CLL when lymphocytosis exceeds 5 × 10⁹/L with characteristic small mature lymphocytes 4, 5

Staging Investigations

• CT imaging with contrast of neck, chest, abdomen, and pelvis is mandatory for all patients except those with LyP 1, 5

• PET-CT scanning is optional for fit elderly patients but particularly useful for stage I-II disease candidates for radiotherapy 1

• Bone marrow examination (aspirate and biopsy) should be performed in fit patients but may be omitted in vulnerable or terminally ill individuals 1, 4

• Lactate dehydrogenase (LDH) serves as a marker for hemolysis or malignancy and should be measured in all cases 5

Treatment Strategies by Patient Population

Older Adults and Fit Patients

• R-CHOP followed by rituximab maintenance represents the standard first-line option for elderly fit patients with MCL based on phase III trial data 1

• Bendamustine-rituximab (BR) serves as an alternative induction regimen, shown to be at least as effective as R-CHOP in phase III trials 1

• FCR regimen (fludarabine, cyclophosphamide, rituximab) is standard of care for younger or fit CLL patients, with significantly improved outcomes versus FC alone 1

• VR-CAP (bortezomib/rituximab/cyclophosphamide/doxorubicin/prednisone) demonstrates superior efficacy to R-CHOP in newly-diagnosed MCL but with increased hematological toxicity 1

Vulnerable and Elderly Patients

• Asymptomatic patients should undergo watch-and-wait strategy rather than immediate treatment 1

• Symptomatic patients with mild symptoms should receive chemotherapy-free approaches such as rituximab monotherapy when possible 1

• Dose-adapted regimens are appropriate for patients with comorbidities or impaired organ function, with bendamustine dose reduction or fewer treatment cycles as needed 1

• R-CLB (rituximab-chlorambucil) represents an oral treatment option avoiding intravenous applications for vulnerable patients 1

Post-Transplant Lymphoproliferative Disorder

• Reduction of immunosuppression (RIS) serves as the initial therapeutic maneuver in SOT-PTLD 1, 6

• Rituximab is recommended as first-line therapy for PTLD, either alone or combined with RIS 1, 6

• EBV-specific cytotoxic T-cell therapy represents a first-line option alongside rituximab and RIS 1

• Donor lymphocyte infusions or chemotherapy are reserved as second-line options after failure of initial approaches 1

• Antiviral drugs are discouraged as they lack efficacy in established PTLD 1

Cutaneous Lymphoproliferative Disorders

• Expectant monitoring is acceptable for LyP patients with limited disease and infrequent eruptions 1

• Low-dose weekly methotrexate is highly effective for LyP but rarely produces durable remission after withdrawal 1

• Surgical excision and/or radiotherapy constitute treatment for localized CD30+ pcALCL 1

• Brentuximab or combination chemotherapy may be appropriate for extensive CD30+ pcALCL or systemic progression 1

Prognostic Factors and Risk Stratification

Poor-Risk Features in CLL

• Unmutated IGHV gene associates with significantly decreased progression-free and overall survival even with FCR treatment 1

• Del(17p) cytogenetic abnormality results in only 18% 3-year PFS with FCR, with similar OS outcomes to FC alone 1

• TP53 mutations confer significantly decreased PFS and OS regardless of FCR or FC treatment 1

• Del(11q) shows improved outcomes with FCR versus FC but remains a poor prognostic marker 1

PTLD Risk Factors

• EBV-negative recipient with EBV-positive donor (D+/R-) represents the highest risk scenario requiring pre-emptive monitoring 1

• Degree of immunosuppression directly correlates with PTLD risk, with historical mortality of 84.6% before modern approaches 1

• Time from transplant influences presentation, with early graft dysfunction suggesting hepatic involvement versus later disseminated disease 1

Critical Management Pitfalls

• Avoid empiric antibiotics without infection evidence, as they delay malignancy diagnosis in persistent lymphadenopathy 3

• Never dismiss persistent cervical lymphadenopathy (>2 months) without proper evaluation, particularly in adolescents 3

• Do not delay bone marrow evaluation when peripheral blood shows concerning findings 5

• Recognize that spontaneous regression in LyP makes treatment efficacy assessment challenging; cessation of new lesions defines complete response 1

• Avoid myelosuppressive regimens in elderly patients with comorbidities who cannot tolerate intensive therapy 1

• Monitor for bendamustine-associated infections and consider antibacterial/antiviral prophylaxis when using BR regimens 1

Monitoring and Follow-up

• Quantitative EBV viral load measurement via PCR enables pre-emptive therapy in HSCT recipients at risk for PTLD 1

• PET imaging serves for both staging and remission assessment at end of therapy in FDG-avid lymphomas 1

• Follow-up is essential until complete resolution or definitive diagnosis in all cases of unexplained lymphadenopathy 3

• Bone marrow biopsy confirms complete remission in treated LPDs, requiring <30% lymphocytes, normocellular morphology, and absence of lymphoid nodules 4