Non hodgkin lymphoma
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Non-Hodgkin Lymphoma (NHL)
Overview
Non-Hodgkin's lymphomas are a heterogeneous group of cancers arising from mature B, T, and NK (natural killer) cells. They are distinguished from Hodgkin's lymphoma by the absence of Reed-Sternberg cells and differ substantially in biology, clinical behavior, and prognosis. Unlike Hodgkin's lymphoma (where ~80–85% of patients are cured), NHL has a more variable natural history — ranging from indolent, slow-growing forms to highly aggressive subtypes. (Harrison's, p. 3220)
Classification (WHO)
NHL is broadly divided by cell of origin:
| Category | Examples |
|---|---|
| Mature B-cell NHL | DLBCL, Follicular lymphoma, Marginal zone lymphoma, Mantle cell lymphoma, Burkitt lymphoma, CLL/SLL |
| Mature T/NK-cell NHL | Peripheral T-cell lymphoma (PTCL), Anaplastic large-cell lymphoma (ALCL), NK/T-cell lymphoma, Mycosis fungoides |
- ~85–90% of NHL in Western countries are B-cell origin
- Subtypes range from indolent (follicular, marginal zone, CLL/SLL) to aggressive (DLBCL, Burkitt, mantle cell)
Epidemiology & Etiology
Risk factors include:
- Immunodeficiency: HIV/AIDS, organ transplant (post-transplant lymphoproliferative disorder), congenital immunodeficiencies
- Infectious agents: EBV (Burkitt's, NK/T-cell), H. pylori (gastric MALT lymphoma), HCV (splenic marginal zone), HTLV-1 (adult T-cell leukemia/lymphoma)
- Autoimmune diseases: Sjögren's syndrome, rheumatoid arthritis, SLE
- Prior chemotherapy/radiation
- Age: incidence increases with age (median ~67 years); however, Burkitt's is more common in children
Clinical Presentation
Common Features
- Painless lymphadenopathy (most common presenting sign)
- B symptoms: fever >38°C, drenching night sweats, unintentional weight loss >10% body weight over 6 months
- Hepatosplenomegaly
- Cytopenias (bone marrow involvement)
Subtype-Specific Features
| Subtype | Typical Presentation |
|---|---|
| Follicular lymphoma | Waxing/waning lymphadenopathy, often widespread at diagnosis, typically indolent |
| DLBCL | Rapidly enlarging mass, often extranodal; may present with SVC syndrome or GI obstruction |
| Burkitt lymphoma | Very rapidly growing abdominal/jaw mass; common in HIV patients |
| Mantle cell lymphoma | Lymphadenopathy + GI involvement (lymphomatous polyposis); often aggressive |
| Mycosis fungoides | Skin patches/plaques/tumors (cutaneous T-cell lymphoma) |
| Gastric MALT | Epigastric pain, peptic ulcer-like symptoms; linked to H. pylori |
Diagnosis & Workup
Tissue Diagnosis (Essential)
- Excisional lymph node biopsy is preferred over fine-needle aspiration (FNA is inadequate for architectural assessment)
- Core needle biopsy acceptable in some cases
- Immunohistochemistry (IHC), flow cytometry, cytogenetics/FISH, and molecular studies are required for subtype classification
Key Markers
| Marker | Significance |
|---|---|
| CD20+ | Most B-cell lymphomas (targetable with rituximab) |
| CD10+, BCL6+, MUM1 | GCB vs. ABC subtype in DLBCL |
| Cyclin D1 | Mantle cell lymphoma |
| BCL2 | Follicular lymphoma |
| Ki-67 | Proliferation index (high in aggressive disease) |
| MYC rearrangement | Burkitt's; "double-hit" lymphoma with BCL2/BCL6 |
Staging Workup
- CT chest/abdomen/pelvis with contrast
- PET-CT — preferred for FDG-avid lymphomas (e.g., DLBCL, follicular)
- Bone marrow biopsy (if it changes management)
- CBC, CMP, LDH, uric acid, β2-microglobulin
- HIV, HBV, HCV serology (HBV reactivation risk with rituximab)
- Echocardiogram (if anthracycline-based therapy planned)
- Lumbar puncture (if CNS involvement suspected or high-risk features)
Staging: Lugano Classification (modified Ann Arbor)
| Stage | Definition |
|---|---|
| I | Single lymph node region or single extralymphatic site |
| II | ≥2 nodal regions, same side of diaphragm |
| III | Nodal regions on both sides of diaphragm |
| IV | Disseminated involvement (liver, bone marrow, multiple extranodal sites) |
"E" suffix = extranodal extension; "X" = bulky disease (>10 cm)
Prognostic Scoring
International Prognostic Index (IPI) — for aggressive NHL (DLBCL)
One point each for:
- Age >60
- Elevated LDH
- ECOG performance status ≥2
- Stage III or IV
-
1 extranodal site
| IPI Score | Risk | 5-Year OS |
|---|---|---|
| 0–1 | Low | ~73% |
| 2 | Low-intermediate | ~51% |
| 3 | High-intermediate | ~43% |
| 4–5 | High | ~26% |
Follicular Lymphoma IPI (FLIPI) — for indolent NHL
One point each for: age >60, stage III/IV, Hgb <12, >4 nodal areas, elevated LDH.
Management
Aggressive NHL (e.g., DLBCL)
Frontline treatment: R-CHOP × 6 cycles (Frontline Treatment of DLBCL Guideline, p. 2)
- R = Rituximab (anti-CD20)
- CHOP = Cyclophosphamide, Doxorubicin (Hydroxydaunorubicin), Vincristine (Oncovin), Prednisone
Modifications based on risk:
- Bulky/localized disease: R-CHOP × 4–6 cycles ± consolidative radiotherapy
- Double/triple-hit lymphoma (MYC + BCL2 ± BCL6 rearrangement): more intensive regimens (e.g., DA-EPOCH-R)
- CNS prophylaxis: intrathecal methotrexate or high-dose IV methotrexate for high-risk patients
- Relapsed/refractory DLBCL: salvage chemotherapy (R-ICE, R-DHAP) → autologous stem cell transplant (ASCT) if chemosensitive; CAR-T cell therapy (axicabtagene ciloleucel, tisagenlecleucel) for relapsed/refractory disease
Indolent NHL (e.g., Follicular Lymphoma)
| Scenario | Approach |
|---|---|
| Asymptomatic, low-burden | Watch and wait (no immediate treatment benefit) |
| Symptomatic or high-burden | R-CHOP or BR (bendamustine + rituximab) |
| Maintenance | Rituximab maintenance q2 months × 2 years post-induction |
| Transformation to aggressive NHL | Treat as DLBCL |
| Relapsed | PI3K inhibitors (idelalisib, copanlisib), lenalidomide + rituximab, CAR-T |
Special Subtypes
| Subtype | Treatment Highlights |
|---|---|
| Burkitt lymphoma | Intensive short-course chemotherapy (CODOX-M/IVAC or DA-EPOCH-R); CNS prophylaxis mandatory |
| Gastric MALT | H. pylori eradication first; >75% achieve complete remission |
| Mantle cell lymphoma | Cytarabine-containing induction + ASCT in fit patients; ibrutinib (BTK inhibitor) for relapsed/elderly |
| Cutaneous T-cell | Skin-directed (phototherapy, topical steroids) for early; brentuximab, mogamulizumab for advanced |
| PTCL | CHOP-based ± autologous SCT; poor prognosis overall |
Complications & Emergencies
- Tumor lysis syndrome (TLS): especially with Burkitt's or bulky DLBCL — prophylax with allopurinol/rasburicase, aggressive hydration
- SVC syndrome: from mediastinal disease
- Spinal cord compression: epidural lymphoma
- Hyperviscosity: in lymphoplasmacytic lymphoma (Waldenström's macroglobulinemia)
- Secondary malignancies: AML/MDS from prior chemotherapy
Prognosis
| Subtype | General Outlook |
|---|---|
| DLBCL | ~60–70% cure rate with R-CHOP |
| Follicular lymphoma | Median OS >15 years; rarely cured with standard therapy |
| Burkitt lymphoma | ~80–90% cure in children; lower in adults |
| Mantle cell lymphoma | Median OS ~5–7 years; incurable with standard therapy |
| PTCL | Poor; 5-year OS ~30% for most subtypes |
| Marginal zone/MALT | Excellent; often manageable as chronic disease |
Key Takeaway: NHL is not a single disease — accurate subtype classification via biopsy and molecular testing is essential because it drives treatment decisions, prognosis, and surveillance strategy.
Mao B inhibitors
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MAO-B Inhibitors
Mechanism of Action
Monoamine oxidase type B (MAO-B) is the primary enzyme responsible for central dopamine catabolism. MAO-B inhibitors block this enzyme, thereby reducing dopamine breakdown and increasing synaptic dopamine concentrations in the brain. (Harrison's, p. 12336)
There are two isoforms of MAO:
| Isoform | Location | Primary Substrate | Clinical Relevance |
|---|---|---|---|
| MAO-A | Gut, liver, brain | Serotonin, norepinephrine, tyramine | Non-selective inhibition → "cheese effect" (hypertensive crisis) |
| MAO-B | Brain (basal ganglia), platelets | Dopamine, phenylethylamine | Selective inhibition → antiparkinsonian effect without cheese effect |
Drugs in Class
| Drug | Type | Route | Notes |
|---|---|---|---|
| Selegiline | Irreversible, selective MAO-B inhibitor | Oral / transdermal patch | Metabolized to amphetamine derivatives; transdermal form also inhibits MAO-A (dietary tyramine restriction required) |
| Rasagiline | Irreversible, selective MAO-B inhibitor | Oral | More potent than selegiline; no amphetamine metabolites; cleaner side-effect profile |
| Safinamide | Reversible, selective MAO-B inhibitor | Oral | Additional mechanism: voltage-gated Na⁺/Ca²⁺ channel blockade + glutamate release inhibition; adjunct therapy only |
Selegiline and rasagiline are suicide (irreversible) inhibitors — they covalently bind MAO-B permanently; recovery requires synthesis of new enzyme. (Harrison's, p. 12336)
Clinical Uses
1. Parkinson's Disease (Primary Indication)
A. Monotherapy — Early Disease
- Used in newly diagnosed, mild Parkinson's disease to provide symptomatic benefit and delay need for levodopa
- Modest but meaningful improvement in motor symptoms
B. Adjunct to Levodopa — Motor Fluctuations
- Reduce "off" time (periods when levodopa effect wanes) by prolonging dopamine availability
- May require dose reduction of levodopa if dyskinesias worsen (Harrison's, p. 12336)
2. Depression (Selegiline Transdermal — Emsam)
- At low oral doses, selegiline is MAO-B selective (no dietary restriction needed)
- Transdermal selegiline achieves higher systemic levels → inhibits both MAO-A and MAO-B → approved for major depressive disorder
- Dietary tyramine restriction required at higher transdermal doses (≥9 mg/24h)
Adverse Effects
| Effect | Details |
|---|---|
| Dyskinesia | Worsened in levodopa-treated patients; manage by reducing levodopa dose |
| Insomnia / vivid dreams | Particularly with selegiline (amphetamine metabolites are stimulatory) |
| Nausea, headache | Common at initiation |
| Orthostatic hypotension | Mild; additive with other antiparkinsonian drugs |
| Hypertensive crisis | NOT seen with selective MAO-B inhibitors at therapeutic doses (MAO-A is spared); IS a risk with selegiline transdermal (high dose) or non-selective MAOIs |
| Serotonin syndrome | Rare but potentially fatal with concurrent serotonergic drugs (SSRIs, SNRIs, tramadol, meperidine) — avoid combination |
Drug Interactions (Critical)
| Interacting Drug | Reaction | Severity |
|---|---|---|
| SSRIs / SNRIs / TCAs | Serotonin syndrome | Contraindicated |
| Meperidine (pethidine) | Serotonin syndrome / hyperpyrexia | Contraindicated |
| Tramadol, fentanyl, methadone | Serotonin syndrome risk | Avoid / use caution |
| Sympathomimetics (e.g., pseudoephedrine) | Hypertensive crisis (high doses) | Caution |
| Levodopa | Enhanced dopaminergic effect → dyskinesia | Monitor; reduce levodopa dose if needed |
| Tyramine-rich foods | Only relevant with transdermal/high-dose selegiline or non-selective MAOIs | Dietary restriction required |
Washout period: After stopping an MAO-B inhibitor, wait ≥14 days before starting serotonergic agents. Conversely, SSRIs/SNRIs should be washed out before starting MAO-B inhibitors (fluoxetine requires 5 weeks due to long half-life).
The "Cheese Effect" — Why MAO-B Inhibitors Are Safer Than Non-Selective MAOIs
Tyramine in food (aged cheese, cured meats, red wine) is normally inactivated by MAO-A in the gut. Non-selective MAOI inhibition of MAO-A allows tyramine to enter systemic circulation → mass norepinephrine release → severe hypertensive crisis.
Selective MAO-B inhibitors (selegiline at low/oral doses, rasagiline, safinamide) do NOT inhibit MAO-A at therapeutic doses, so dietary tyramine restriction is not required for standard oral dosing. (Harrison's, p. 12336)
Neuroprotection Controversy
There is ongoing debate about whether MAO-B inhibitors have a disease-modifying (neuroprotective) effect in Parkinson's disease, in addition to symptomatic benefit:
- MAO-B oxidizes MPTP-like toxins into neurotoxic metabolites → blocking MAO-B may reduce oxidative stress and dopaminergic neuron death
- Clinical trials (DATATOP with selegiline, ADAGIO with rasagiline) suggested delayed disease progression, but it remains unclear whether this reflects true neuroprotection or simply symptomatic masking
- Currently, no MAO-B inhibitor is formally approved as neuroprotective
Summary Table
| Feature | Selegiline | Rasagiline | Safinamide |
|---|---|---|---|
| Selectivity | MAO-B (selective at low doses) | MAO-B | MAO-B |
| Reversibility | Irreversible | Irreversible | Reversible |
| Extra mechanism | — | — | Na⁺/Ca²⁺ channel block, ↓ glutamate |
| Dietary restriction | Not needed (oral, low dose) | Not needed | Not needed |
| Amphetamine metabolites | Yes (CNS stimulation, insomnia) | No | No |
| Use in depression | Yes (transdermal patch) | No | No |
| Approved use in PD | Monotherapy + adjunct | Monotherapy + adjunct | Adjunct only |
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