denileukin diftitox-cxdl (LYMPHIR) Clinical Pearl

CTCL is a rare type of non-Hodgkin lymphoma in which malignant T lymphocytes primarily involve the skin.

It is a cancer of skin-homing CD4+ T cells, often expressing markers such as CD3, CD4, and sometimes CD25 (IL-2 receptor).

Unlike many lymphomas that begin in lymph nodes, CTCL originates in the skin and may later involve:

• Lymph nodes
• Blood
• Internal organs

It often behaves as a chronic, relapsing disease in early stages.

1️⃣ Mycosis Fungoides (MF)

• Most common form (~50–70%)
• Starts as patches → plaques → tumors
• Can mimic eczema or psoriasis early on

2️⃣ Sézary Syndrome (SS)

• Leukemic variant
• Characterized by:
• • Erythroderma (diffuse redness)
  • Circulating malignant T cells (Sézary cells)
  • Lymphadenopathy

CTCL uses TNMB staging:

• T = Skin involvement
• N = Nodes
• M = Metastasis
• B = Blood involvement

Early stage:

• Limited skin patches/plaques

Advanced stage:

• Tumors, erythroderma, nodal or blood involvement

LYMPHIR is approved for Stage I–III relapsed or refractory disease

Some CTCL cells express CD25 (IL-2 receptor).
LYMPHIR targets this receptor to deliver diphtheria toxin into malignant T cells

In the pivotal trial, patients were required to have ≥20% CD25 expression on malignant cells

Patients may present with:

• Chronic pruritic patches or plaques
• Persistent rash unresponsive to steroids
• Skin thickening
• Erythroderma
• Lymphadenopathy
• Recurrent infections (in advanced disease)

Early stage:

• Topical steroids
• Phototherapy
• Total skin electron beam therapy

Advanced/refractory:

• Systemic retinoids
• Methotrexate
• HDAC inhibitors
• Brentuximab vedotin
• Mogamulizumab
• IL-2–targeted cytotoxins like LYMPHIR

CTCL is often misdiagnosed early because it mimics inflammatory dermatoses.
Diagnosis frequently requires repeated biopsies + immunophenotyping.

Capillary Leak Syndrome (CLS) is a potentially life-threatening condition in which plasma fluid and proteins leak from the intravascular space into the interstitial space due to increased capillary permeability.

The result is:

• Intravascular volume depletion
• Hypotension
• Edema
• Hypoalbuminemia
• Potential organ hypoperfusion

Pathophysiology (Clinical-Level Explanation)

Under normal conditions:

Capillaries regulate fluid movement via:

• Hydrostatic pressure
• Oncotic pressure (albumin-driven)

In CLS:

• Endothelial integrity is disrupted
• Plasma + albumin shift into tissues
• Intravascular oncotic pressure drops
• Fluid continues to third-space
• Blood pressure falls

It resembles:

• Severe systemic inflammatory response
• Cytokine-mediated endothelial injury

CLS is the boxed warning for LYMPHIR

Trial Data:

• Occurred in 27% of patients
• Grade 3 in 8%
• 1 fatal case reported

Defined in trials as ≥2 of:

• Hypotension
• Edema
• Serum albumin <3 g/dL

Most events:

• Occurred within first 2 cycles
• Median onset: ~6.5 days
• Median duration: ~14 days

Clinical Signs to Watch For

• Rapid weight gain
• Peripheral or generalized edema
• Hypotension (including orthostatic)
• Dyspnea
• Pleural or pericardial effusion
• Hypoalbuminemia

Why It’s Dangerous

Even though patients look “fluid overloaded,”
they are actually intravascularly depleted.

This can lead to:

• Acute kidney injury
• Shock
• Organ hypoperfusion
• Respiratory compromise

Lab Clues

• ↓ Serum albumin
• Hemoconcentration (early phase)
• Rising creatinine
• Elevated lactate (if severe)

Management Principles (General)

1. Immediate recognition
2. Hold causative drug
3. Careful fluid management
4. • Avoid reflexive aggressive diuresis
4. Consider:
5. • IV albumin
   • Vasopressors if hypotensive
5. Steroids (case-dependent)

For LYMPHIR specifically:

• Withhold for Grade 2 until resolves to Grade 1
• Withhold for Grade 3 then resume at 50% dose
• Permanently discontinue for Grade 4

Edema + hypotension + low albumin during IL-2–based therapy = think CLS immediately.

Do not mistake it for:

• Simple fluid overload
• CHF exacerbation
• Nephrotic syndrome

The management approach differs significantly.

ADA refers to antibodies produced by a patient’s immune system against a therapeutic drug, most commonly biologics (e.g., monoclonal antibodies, fusion proteins, cytokine-based therapies).

When the immune system recognizes a biologic drug as “foreign,” it can generate antibodies against it.

These antibodies may:

1. Bind to the drug → change drug levels
2. Neutralize the drug → block its activity
3. Increase clearance → reduce exposure
4. Trigger immune reactions → infusion reactions or hypersensitivity

1️⃣ Binding Antibodies

• Attach to the drug
• May or may not affect function

2️⃣ Neutralizing Antibodies (NAbs)

• Block the drug’s biological activity
• More clinically significant

LYMPHIR (denileukin diftitox-cxdl) is a fusion protein containing diphtheria toxin + IL-2, making it highly immunogenic.

From the prescribing information:

• 88% developed treatment-emergent ADAs
• 80% developed neutralizing antibodies

Interestingly:

• ADA presence reduced measured serum concentrations
• But did not clearly reduce efficacy or worsen safety

This high ADA rate is expected because most adults have prior immunity to diphtheria (via vaccination).

With biologic oncology agents:

• High ADA incidence ≠ automatic loss of efficacy
• Clinical correlation matters more than lab detection alone
• Always interpret ADA data in context of:
• • Exposure levels
  • Response durability
  • Infusion reactions