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Targeted drug combinations replace chemotherapy for common leukemia

Targeted drug combinations replace chemotherapy for common leukemia

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By Newzino Staff |

FDA approves first all-oral, fixed-duration regimen for chronic lymphocytic leukemia, capping a decade-long shift from indefinite chemotherapy to time-limited targeted treatment

Yesterday: FDA Approves First All-Oral Fixed-Duration CLL Regimen

Overview

For decades, patients diagnosed with chronic lymphocytic leukemia—the most common adult leukemia in Western countries, affecting roughly 23,000 Americans each year—faced a difficult choice: endure rounds of intravenous chemotherapy with harsh side effects, or take targeted pills indefinitely, sometimes for life. On February 20, 2026, the Food and Drug Administration (FDA) approved a combination of two oral drugs, venetoclax and acalabrutinib, that eliminates both burdens. Patients take pills for roughly one year, then stop. In a trial of 867 patients, 77% remained cancer-free at three years.

The approval marks the first time an all-oral, fixed-duration regimen has been cleared for previously untreated chronic lymphocytic leukemia (CLL). It caps a twelve-year transformation in how this disease is treated—from toxic chemotherapy cocktails delivered through IV lines, to precisely targeted pills that block two specific proteins cancer cells need to survive. Each drug attacks a different survival mechanism: acalabrutinib disables a signaling enzyme called Bruton's tyrosine kinase (BTK) that tells cancer cells to multiply, while venetoclax blocks a protein called BCL-2 that prevents cancer cells from dying naturally. Together, they reduced the risk of disease progression or death by 35% compared to standard chemoimmunotherapy.

Key Indicators

35%
Reduction in progression or death
Venetoclax plus acalabrutinib reduced the risk of disease progression or death by 35% compared to chemoimmunotherapy in the AMPLIFY trial
77%
Progression-free at 3 years
More than three-quarters of patients on the combination remained free of disease progression after three years
~14 cycles
Fixed treatment duration
Patients take the combination for up to 14 cycles of 28 days each—roughly one year—then stop treatment entirely
~23,000
New US CLL cases per year
Chronic lymphocytic leukemia is the most common adult leukemia in the Western world, with about 23,000 new American diagnoses annually

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People Involved

Jennifer R. Brown
Jennifer R. Brown
AMPLIFY Trial Principal Investigator; Director, CLL Center, Dana-Farber Cancer Institute (Led the Phase 3 AMPLIFY trial that supported the FDA approval)
Levi Garraway
Levi Garraway
Chief Medical Officer, Genentech (Oversaw Genentech's role in the venetoclax approval)

Organizations Involved

U.S. Food and Drug Administration
U.S. Food and Drug Administration
Federal Regulatory Agency
Status: Approved the venetoclax-acalabrutinib combination

The federal agency responsible for evaluating and approving prescription drugs in the United States.

AbbVie
AbbVie
Pharmaceutical company
Status: Co-manufacturer of venetoclax (Venclexta); submitted the supplemental new drug application

A global biopharmaceutical company that co-developed venetoclax with Genentech/Roche and markets it as Venclexta.

AstraZeneca
AstraZeneca
Pharmaceutical company
Status: Manufacturer of acalabrutinib (Calquence); sponsor of the AMPLIFY trial

A global biopharmaceutical company that developed acalabrutinib and sponsored the Phase 3 AMPLIFY trial.

Timeline

  1. FDA Approves First All-Oral Fixed-Duration CLL Regimen

    FDA approval

    The FDA approved venetoclax plus acalabrutinib as the first all-oral, fixed-duration combination for previously untreated CLL, eliminating the need for both IV infusions and indefinite daily treatment.

  2. AbbVie Submits FDA Application for the Combination

    Regulatory

    AbbVie submitted a supplemental new drug application to the FDA seeking approval for venetoclax in combination with acalabrutinib for untreated CLL.

  3. AMPLIFY Results Published in New England Journal of Medicine

    Publication

    The full AMPLIFY trial results were published in the New England Journal of Medicine, providing the peer-reviewed evidence base for the regulatory submission.

  4. AMPLIFY Phase 3 Results Presented at ASH

    Clinical trial

    Jennifer Brown presented interim results from the AMPLIFY trial at the American Society of Hematology annual meeting, showing fixed-duration acalabrutinib plus venetoclax reduced disease progression or death by 35% compared to chemoimmunotherapy.

  5. Zanubrutinib Approved as Third BTK Inhibitor for CLL

    FDA approval

    The FDA approved zanubrutinib (Brukinsa) for CLL, giving patients a third BTK inhibitor option. In head-to-head trials, zanubrutinib showed fewer cardiac side effects than ibrutinib.

  6. Acalabrutinib Approved for CLL

    FDA approval

    The FDA approved acalabrutinib (Calquence) as a monotherapy for CLL, giving patients a second-generation BTK inhibitor designed to be more selective and cause fewer off-target side effects than ibrutinib.

  7. First Fixed-Duration Targeted Regimen for Untreated CLL

    FDA approval

    The FDA approved venetoclax with obinutuzumab (an intravenous antibody) for previously untreated CLL, based on the CLL14 trial. This was the first fixed-duration targeted regimen but still required IV infusions.

  8. First BCL-2 Inhibitor Approved for CLL

    FDA approval

    The FDA approved venetoclax (Venclexta) for relapsed CLL with 17p deletion, opening a second targeted pathway for attacking leukemia cells. Venetoclax blocks the BCL-2 protein that helps cancer cells resist death.

  9. First BTK Inhibitor Approved for CLL

    FDA approval

    The FDA granted accelerated approval to ibrutinib (Imbruvica) for patients with CLL who had received at least one prior therapy, marking the first time a Bruton's tyrosine kinase inhibitor was available for this leukemia.

  10. Imatinib Proves Targeted Cancer Therapy Works

    Scientific milestone

    The FDA approved imatinib (Gleevec) for chronic myeloid leukemia, proving that drugs targeting specific molecular pathways in cancer cells could transform outcomes. It became the template for precision oncology.

Scenarios

1

All-Oral Fixed-Duration Therapy Becomes Standard of Care for Most CLL Patients

Discussed by: AJMC, oncology treatment guideline bodies including the National Comprehensive Cancer Network (NCCN), and CLL specialists at major academic centers

With the AMPLIFY data in hand and the FDA approval secured, oncologists rapidly adopt the venetoclax-acalabrutinib combination as the preferred frontline treatment for CLL patients without TP53 mutations. The fixed-duration, all-oral format proves decisive for community oncologists who previously defaulted to continuous single-agent BTK inhibitors. Within two years, chemoimmunotherapy use in frontline CLL drops below 10% in the United States.

2

Three-Drug Combinations Prove Superior for High-Risk CLL

Discussed by: Hematology researchers analyzing the AMPLIFY trial's three-arm design, including the acalabrutinib-venetoclax-obinutuzumab arm that showed a 58% risk reduction

The AMPLIFY trial also tested a three-drug arm adding obinutuzumab (an IV antibody) to the oral combination, which showed a 58% reduction in progression or death versus chemoimmunotherapy—compared to 35% for the two-drug regimen. If further data confirms this gap, guidelines may stratify treatment: the simpler all-oral regimen for standard-risk patients, and the three-drug combination for high-risk patients willing to accept IV infusions for potentially deeper responses.

3

Resistance Patterns Emerge, Spurring Next Wave of Combinations

Discussed by: Cancer researchers studying BTK and BCL-2 resistance mutations, including groups developing noncovalent BTK inhibitors like pirtobrutinib

As thousands of CLL patients complete the fixed-duration regimen and are monitored off treatment, a subset relapse due to acquired resistance mutations in BTK or BCL-2. This triggers development of next-generation combinations incorporating noncovalent BTK inhibitors like pirtobrutinib (already FDA-approved for relapsed CLL) or novel BCL-2 inhibitors. The fixed-duration model persists, but the specific drug pairings evolve.

4

Cost and Access Barriers Limit Real-World Adoption

Discussed by: Health economists and patient advocacy groups including the CLL Society

Both venetoclax and acalabrutinib carry substantial list prices, and the combination's cost—even for a fixed duration—creates access challenges for patients with inadequate insurance coverage or in countries without public reimbursement. If pricing negotiations stall or generic competition is delayed, the clinical advance may not reach many of the patients who would benefit most, particularly older adults on fixed incomes.

Historical Context

Imatinib for Chronic Myeloid Leukemia (2001)

May 2001

What Happened

The FDA approved imatinib (Gleevec), a pill that targeted the specific molecular defect—the BCR-ABL fusion protein—driving chronic myeloid leukemia (CML). Before imatinib, CML patients had a median survival of three to five years. After five years of imatinib therapy, 89% of patients were still alive, and relapse rates were only 17%.

Outcome

Short Term

Imatinib transformed CML from a near-certain death sentence into a manageable chronic condition. It became one of the fastest drug approvals in FDA history at two and a half years from application to approval.

Long Term

Imatinib established the template for precision oncology—designing drugs that target specific molecular abnormalities in cancer cells rather than killing all rapidly dividing cells. It spawned an entire class of tyrosine kinase inhibitors and proved the concept that would eventually reach CLL.

Why It's Relevant Today

The venetoclax-acalabrutinib approval follows the same playbook imatinib pioneered: identify the molecular vulnerabilities keeping cancer cells alive, then design drugs to block them. CLL's version just required two targets instead of one.

Combination Antiretroviral Therapy for HIV (1996)

1996

What Happened

Researchers demonstrated that combining three antiretroviral drugs targeting different steps in HIV's replication cycle—dubbed "highly active antiretroviral therapy" or HAART—could suppress the virus to undetectable levels. Before combination therapy, HIV was effectively a death sentence; single drugs alone quickly bred resistant virus.

Outcome

Short Term

AIDS death rates in the United States dropped 47% within two years of widespread HAART adoption. Patients who had been preparing to die began returning to work.

Long Term

Combination therapy became the universal model for treating HIV, eventually simplified into single-pill, once-daily regimens. The principle—attack multiple biological pathways simultaneously to prevent resistance—reshaped treatment strategies across infectious disease and oncology.

Why It's Relevant Today

The CLL combination follows the same logic: venetoclax and acalabrutinib each block a different survival mechanism, making it harder for cancer cells to develop resistance to both simultaneously. The parallel extends to treatment simplification—from complex IV regimens to oral pills.

Venetoclax Plus Obinutuzumab for Untreated CLL (2019)

May 2019

What Happened

The FDA approved venetoclax combined with obinutuzumab as the first fixed-duration targeted regimen for previously untreated CLL, based on the CLL14 trial of 432 patients. The regimen reduced the risk of progression by 67% compared to chlorambucil-based chemotherapy. However, obinutuzumab required intravenous infusions administered at a hospital or clinic.

Outcome

Short Term

The approval proved that fixed-duration targeted therapy could work in frontline CLL, moving beyond the model of indefinite daily pills. It became a widely used option, particularly for older patients and those with other health conditions.

Long Term

The CLL14 results established venetoclax-based fixed-duration combinations as a viable treatment model and set the stage for the next question: could the IV component be replaced with an oral drug, making the entire regimen take-at-home pills?

Why It's Relevant Today

The 2026 venetoclax-acalabrutinib approval directly answers the question the 2019 approval raised. By replacing the IV antibody obinutuzumab with oral acalabrutinib, the new regimen completes the shift to an entirely oral, entirely outpatient fixed-duration treatment.

10 Sources:
+4
U.S. Food and Drug Administration AbbVie News American Journal of Managed Care (AJMC) New England Journal of Medicine Blood (American Society of Hematology) AstraZeneca US PR Newswire Dana-Farber Cancer Institute National Cancer Institute SEER Program National Cancer Institute