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Treatment and the treatment process

BCL-2 and other targets

Targeted drugs act on specific weak points of leukemia cells. This topic explains the BCL-2 inhibitor venetoclax and the other main targets used in leukemia.

Last updated: ~2 min read
A golden clamp holding a leukemia cell’s mitochondrion opened by a teal beam on a dark navy background.
Figure 1.Venetoclax releases the BCL-2 brake and restores cell death.

01Short answer

BCL-2 is a cell’s "anti-death" protein: it stops a damaged cell from destroying itself. CLL cells and many AML cells depend heavily on BCL-2 to survive. Venetoclax blocks this protein and restores programmed cell death. In CLL it is used for a fixed time with obinutuzumab or ibrutinib; in AML, for people unsuitable for intensive chemotherapy, with azacitidine, decitabine or low-dose cytarabine. Other targets in leukemia include FLT3 (midostaurin, gilteritinib, quizartinib), IDH1/IDH2 (ivosidenib, olutasidenib, enasidenib), BCR::ABL1 (TKIs), BTK (ibrutinib and others), CD33 (gemtuzumab ozogamicin), CD19/CD22 (blinatumomab, inotuzumab) and menin (newer drugs such as revumenib for KMT2A rearrangements and NPM1 mutation). A target can only be identified by genetic or immunophenotyping tests.

02Simple explanation

A brake on death. BCL-2 stops the leukemia cell from dying.

Releasing the brake. Venetoclax releases that brake.

Many targets. Each leukemia may have its own weak points.

Testing matters. A target is found only by testing.

03Scientific explanation

BCL-2 and the mitochondria: BCL-2 holds back the BAX/BAK proteins; venetoclax is a BH3 mimetic that blocks BCL-2, so the mitochondrial membrane becomes permeable and apoptosis begins (NCI).

Tumour lysis and interactions: in CLL a 5-week dose ramp-up, hydration, uric-acid-lowering drugs and electrolyte monitoring are needed. Strong CYP3A inhibitors (such as posaconazole) raise venetoclax levels, so the dose must be adjusted — only by the doctor.

Other targets: FLT3 inhibitors with chemotherapy or at relapse; IDH inhibitors can cause differentiation syndrome; menin inhibitors are approved for relapsed AML with KMT2A rearrangement and NPM1 mutation (in some countries). Targeted drugs can also lead to resistance.

04What happens in the body?

How does venetoclax work?

A damaged cell normally destroys itself. The leukemia cell blocks this process using BCL-2. Venetoclax removes the block, and the cell "can die" again.

A map of targets

At diagnosis, a broad genetic panel is done to find possible targets. One person may have more than one target; new targets can appear at relapse.

A constellation of differently coloured glowing points joined by fine lines on a dark navy sky.
Figure 2.There are many molecular targets in leukemia.

Living with targeted treatment

Many targeted drugs are tablets taken as an outpatient. They also have side effects — low blood counts, nausea, diarrhoea, infections — and need regular monitoring.

Among healthy translucent cells, fine arrows of light converge on one abnormal cell.
Figure 3.Targeted treatment aims specifically at the abnormal cell.

05Starting venetoclax

A simplified outline.

Risk assessment — Tumour burden, kidneys.1Risk assessmentTumour burden, kidneys.
Dose ramp-up — Gradually.2Dose ramp-upGradually.
Fluids and monitoring — Blood salts.3Fluids and monitoringBlood salts.
Continue — As planned.4ContinueAs planned.
Apoptosis restoredLeukemia cells die.
TargetFound by testing.
SafetyTumour lysis monitored.

06Main molecular targets in leukemia

TargetExample drugsWhere
BCL-2VenetoclaxCLL, AML
FLT3Midostaurin, gilteritinib, quizartinibAML
IDH1 / IDH2Ivosidenib, olutasidenib, enasidenibAML
BCR::ABL1Imatinib and other TKIsCML, Ph+ ALL
BTKIbrutinib, acalabrutinib, zanubrutinib, pirtobrutinibCLL
MeninRevumenib and othersKMT2A, NPM1 AML (relapse)

* Availability varies by country; your doctor makes the choice.

07Key terms

BCL-2
A protein that prevents cell death.
Venetoclax
A BCL-2 inhibitor.
BH3 mimetic
A drug group that blocks BCL-2.
Targeted therapy
Treatment aimed at a specific molecule.
Menin
A protein important in KMT2A and NPM1 leukemias.
Tumour lysis syndrome
Disturbed blood salts from rapid cell breakdown.

08Key points

  • BCL-2 protects the leukemia cell from death.
  • Venetoclax removes that protection.
  • The dose is increased gradually.
  • There are many other targets.
  • A target is found only by testing.
  • Check for interactions.

09Frequently asked questions

Is targeted treatment gentler than chemotherapy?

It is often better tolerated, but not free of side effects.

Why drink so much?

Fluid helps the kidneys clear the products of broken-down cells.

Why does an antifungal change the dose?

Some antifungals slow down how venetoclax is broken down.

Does my leukemia have a target?

Your doctor will tell you based on your genetic test results.

10Questions for your doctor

Take these questions to your appointment. The ones you save are collected on the “My questions” page and stay on this device only.

  1. Is targeted treatment gentler than chemotherapy?

  2. Why drink so much?

  3. Why does an antifungal change the dose?

  4. Does my leukemia have a target?

My questions

12Sources

  1. National Cancer Institute (NCI). Targeted Therapy to Treat Cancer
  2. National Cancer Institute (NCI). Adult Acute Myeloid Leukemia Treatment (PDQ) – Patient Version
  3. National Cancer Institute (NCI). Chronic Lymphocytic Leukemia Treatment (PDQ) – Patient Version
  4. Cancer Research UK. Treatment for chronic lymphocytic leukaemia (CLL)
  5. MedlinePlus. Venetoclax
  6. American Cancer Society. Targeted Therapy Drugs for Acute Myeloid Leukemia (AML)
  7. National Cancer Institute (NCI). Cancer Pain (PDQ) – Patient Version
  8. National Cancer Institute (NCI). Pain and Cancer Treatment
  9. Macmillan Cancer Support. Pain
  10. Cancer Research UK. Cancer and pain control
Medical disclaimerThis information is for educational purposes only and does not replace medical advice.
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