For Patients and Caregivers

VENCLEXTA efficacy results: undetectable minimal residual disease (uMRD)

Print page

Achieving uMRD in CLL means a patient has no detectable cancer cells, at a threshold of <1 detectable CLL cell per 10,000 leukocytes13

Tumor burden
Decreasing detectable CLL cells in peripheral blood and/or bone marrow

Tumor burden: Decreasing detectable CLL cells in peripheral blood and/or bone marrow. Arrow pointing down, text at the top reads "High (many CLL cells)" with "Undetectable MRD" and "Low (fewer CLL cells)" at the bottom. Undetectable MRD means less than 1 detectable CLL cell per 10,000 leukocytes
  • MRD was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) 3 months after treatment ended. uMRD was defined as having achieved <1 CLL cell per 10,000 leukocytes1
  • While undetectable MRD and response rates are both measures of disease, it is possible for a patient with a PR to be MRD negative, and for a patient with a CR to be MRD positive14 
  • The FDA does not yet consider MRD an established surrogate endpoint for clinical outcomes in patients with CLL15

CLL=chronic lymphocytic leukemia; CR=complete remission; MRD=minimal residual disease.

uMRD rates with VEN+G

CLL14: In a randomized (1:1), multicenter, actively controlled, open-label, phase 3 trial (CLL14), VEN+G was studied against chlorambucil plus GAZYVA (GClb) in 432 patients with previously untreated CLL with comorbid medical conditions (total CIRS score >6 or CLcr <70 mL/min). The primary endpoint was IRC-assessed progression-free survival. See full study design.1,2

IRC-assessed PFS (primary endpoint)1

reduction in risk of progression or death vs GClb (HR=0.33; 95% CI: 0.22-0.51 [P<0.0001])
After a median follow-up of 28 months (range: 0-36 months):

  • There were 29 events in the VEN+G arm (14 progressions and 15 deaths without disease progression) compared with 79 events in the GClb arm (71 progressions and 8 deaths without disease progression)*
  • Median PFS was not reached in either arm

*Number of events based on earliest event of disease progression or deaths without disease progression due to any cause.

See response rates here (secondary endpoint).

Rates of uMRD in peripheral blood in the ITT population (secondary endpoint)1

  • The rate of uMRD in bone marrow was 57% (123/216) for VEN+G (95% CI: 50-64) and 17% (37/216) for GClb (95% CI: 12-23) in the ITT population
  • 91% concordance: Of the 134 patients in the VEN+G arm with uMRD in peripheral blood who had matching bone marrow specimens, 122 patients had uMRD in bone marrow
  • In patients with a CR, the rate of undetectable MRD in peripheral blood was 87% (87/100) for VEN+G (95% CI: 79-93) and 62% (29/47) for GClb (95% CI: 46-75); P=0.0005

Rates of uMRD in peripheral blood in evaluable patients in the VEN+G arm4†

Chart showing rates of undetectable MRD in peripheral blood in evaluable patients. 87% of VENCLEXTA + GAZYVA patients showed undetectable MRD in peripheral blood. 42% of GClb patients showed undetectable MRD in peripheral blood.
  • Of evaluable GClb patients, 42% achieved uMRD (76/182)

The population with evaluable results (n=369) excludes results missing due to progressive disease (PD), withdrawal (including withdrawal due to toxicity), deaths without disease progression, MRD status unknown, and other missing samples or assessments.

Not prespecified or tested for statistical significance.

†Assessed 3 months after treatment completion.2
‡Evaluable patients.14

CI=confidence interval; CLcr=creatinine clearance; GClb=GAZYVA + chlorambucil; HR=hazard ratio; IRC=Independent Review Committee; ITT=intent to treat; PFS=progression-free survival; uMRD=undetectable minimal residual disease; VEN+G=VENCLEXTA + GAZYVA.

PFS by MRD status in the VEN+G arm

In an exploratory follow-up analysis, PFS was assessed among MRD-evaluable VEN+G patients10

Post hoc analysis chart of MRD for VENCLEXTA + GAZYVA
  • Not tested for statistical significance
  • The PFS estimates can be unreliable due to the small number of patients at risk at the tail end of the MRD positive curve
  • From the 5-year follow-up analysis of INV-assessed PFS at the clinical data cutoff date of November 8, 2021
Safety icon

Safety Data

Review a summary of safety data for patients treated with VEN+G from the CLL14 trial

View data
NEXT: Study Design

Important Safety Information & Indication

Indication

  • VENCLEXTA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Important Safety Information

Contraindication

  • Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated in patients with CLL/SLL due to the potential for increased risk of tumor lysis syndrome (TLS).

Tumor Lysis Syndrome

  • Tumor lysis syndrome, including fatal events and renal failure requiring dialysis, has occurred in patients treated with VENCLEXTA.
  • VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS at initiation and during the ramp-up phase in all patients, and during reinitiation after dosage interruption in patients with CLL/SLL. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase. TLS, including fatal cases, has been reported after a single 20 mg dose.
  • In patients with CLL/SLL who followed the current (5 week) dose ramp-up and the TLS prophylaxis and monitoring measures, the rate of TLS was 2% in the VENCLEXTA CLL/SLL monotherapy trials. The rate of TLS remained consistent with VENCLEXTA in combination with obinutuzumab or rituximab. With a 2- to 3-week dose ramp-up and higher starting dose in patients with CLL/SLL, the TLS rate was 13% and included deaths and renal failure.
  • The risk of TLS is a continuum based on multiple factors, particularly reduced renal function, tumor burden, and type of malignancy. Splenomegaly may also increase the risk of TLS in patients with CLL/SLL.
  • Assess all patients for risk and provide appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities promptly. Employ more intensive measures (IV hydration, frequent monitoring, hospitalization) as overall risk increases. Interrupt dosing if needed; when restarting VENCLEXTA follow dose modification guidance in the Prescribing Information.
  • Concomitant use of VENCLEXTA with P-gp inhibitors or strong or moderate CYP3A inhibitors increases venetoclax exposure, which may increase the risk of TLS at initiation and during the ramp-up phase, and requires VENCLEXTA dose reduction.

Neutropenia

  • In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients when treated with VENCLEXTA in combination and monotherapy studies. Febrile neutropenia occurred in 4% to 6% of patients.
  • Monitor complete blood counts. Interrupt dosing for severe neutropenia and resume at same or reduced dose. Consider supportive measures including antimicrobials and growth factors (e.g., G-CSF).

Infections

  • Fatal and serious infections such as pneumonia and sepsis have occurred in patients treated with VENCLEXTA. Monitor patients for signs and symptoms of infection and treat promptly. Withhold VENCLEXTA for Grade 3 and 4 infection until resolution and resume at same or reduced dose.

Immunization

  • Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery occurs. Advise patients that vaccinations may be less effective.

Embryo-Fetal Toxicity

  • VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment and for 30 days after the last dose.

Increased Mortality in Patients with Multiple Myeloma when VENCLEXTA is Added to Bortezomib and Dexamethasone

  • In a randomized trial (BELLINI; NCT02755597) in patients with relapsed or refractory multiple myeloma, the addition of VENCLEXTA to bortezomib plus dexamethasone, a use for which VENCLEXTA is not indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with VENCLEXTA in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials.

Adverse Reactions

  • In patients with CLL receiving combination therapy with obinutuzumab, serious adverse reactions were most often due to febrile neutropenia and pneumonia (5% each). The most common adverse reactions (≥20%) of any grade were neutropenia (60%), diarrhea (28%), and fatigue (21%). Fatal adverse reactions that occurred in the absence of disease progression and with onset within 28 days of the last study treatment were reported in 2% (4/212) of patients, most often from infection.
  • In patients with CLL receiving combination therapy with rituximab, the most frequent serious adverse reaction (≥5%) was pneumonia (9%). The most common adverse reactions (≥20%) of any grade were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), fatigue (22%), and nausea (21%). Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of the last VENCLEXTA treatment and/or 90 days of the last rituximab were reported in 2% (4/194) of patients.
  • In patients with CLL/SLL receiving monotherapy, the most frequent serious adverse reactions (≥5%) were pneumonia (9%), febrile neutropenia (5%), and sepsis (5%). The most common adverse reactions (≥20%) of any grade were neutropenia (50%), diarrhea (43%), nausea (42%), upper respiratory tract infection (36%), anemia (33%), fatigue (32%), thrombocytopenia (29%), musculoskeletal pain (29%), edema (22%), and cough (22%). Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of venetoclax treatment were reported in 2% of patients in the VENCLEXTA monotherapy studies, most often (2 patients) from septic shock.

Drug Interactions

  • Concomitant use with a P-gp inhibitor or a strong or moderate CYP3A inhibitor increases VENCLEXTA exposure, which may increase VENCLEXTA toxicities, including the risk of TLS. Consider alternative medications or adjust VENCLEXTA dosage and monitor more frequently for adverse reactions. Resume the VENCLEXTA dosage that was used prior to concomitant use of a P-gp inhibitor or a strong or moderate CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor.
  • Patients should avoid grapefruit products, Seville oranges, and starfruit during treatment as they contain inhibitors of CYP3A.
  • Avoid concomitant use of strong or moderate CYP3A inducers.
  • Monitor international normalized ratio (INR) more frequently in patients receiving warfarin.
  • Avoid concomitant use of VENCLEXTA with a P-gp substrate. If concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before VENCLEXTA.

Lactation

  • Advise women not to breastfeed during treatment with VENCLEXTA and for 1 week after the last dose.

Females and Males of Reproductive Potential

  • Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for 30 days after the last dose.
  • Based on findings in animals, VENCLEXTA may impair male fertility.

Hepatic Impairment

  • Reduce the dose of VENCLEXTA for patients with severe hepatic impairment (Child-Pugh C); monitor these patients more frequently for adverse reactions. No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

Please see full Prescribing Information.

TOP

VENCLEXTA® and its design are registered trademarks of AbbVie Inc.
GAZYVA® is a registered trademark of Genentech, Inc.

    • VENCLEXTA Prescribing Information.

      VENCLEXTA Prescribing Information.

    • Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225​-2236.

      Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225​-2236.

    • GAZYVA Prescribing Information.

      GAZYVA Prescribing Information.

    • Data on file, AbbVie Inc. ABVRRTI69608.

      Data on file, AbbVie Inc. ABVRRTI69608.

    • Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23)(suppl):2225​-2236.

      Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23)(suppl):2225​-2236.

    • Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120.

      Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120.

    • Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12)(suppl):1107-1120.

      Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12)(suppl):1107-1120.

    • Data on file, AbbVie Inc. ABVRRTI69609.

      Data on file, AbbVie Inc. ABVRRTI69609.

    • Seymour JF, Kipps TJ, Eichhorst B, et al. Four-year analysis of MURANO study confirms sustained benefit of time-limited venetoclax-rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: 61st American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

      Seymour JF, Kipps TJ, Eichhorst B, et al. Four-year analysis of MURANO study confirms sustained benefit of time-limited venetoclax-rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: 61st American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

    • Data on file, AbbVie Inc. ABVRRTI72219.

      Data on file, AbbVie Inc. ABVRRTI72219.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V.2.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed January 25, 2023. To view the most recent and complete version of the guidelines, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V.2.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed January 25, 2023. To view the most recent and complete version of the guidelines, go online to NCCN.org.

    • Data on file, AbbVie Inc. ABVRRTI71322.

      Data on file, AbbVie Inc. ABVRRTI71322.

    • Owen C, Christofides A, Johnson N, Lawrence T, MacDonald D, Ward C. Use of minimal residual disease assessment in the treatment of chronic lymphocytic leukemia [published online ahead of print May 16, 2017]. Leuk Lymphoma. 2017;58(12):2777​-2785.

      Owen C, Christofides A, Johnson N, Lawrence T, MacDonald D, Ward C. Use of minimal residual disease assessment in the treatment of chronic lymphocytic leukemia [published online ahead of print May 16, 2017]. Leuk Lymphoma. 2017;58(12):2777​-2785.

    • Thompson PA, Wierda WG. Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL. Blood. 2016;127(3):279-286.

      Thompson PA, Wierda WG. Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL. Blood. 2016;127(3):279-286.

    • US Food and Drug Administration. Hematologic malignancies: regulatory considerations for use of minimal residual disease in development of drug and biological products for treatment. Guidance for industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/hematologic-malignancies-regulatory-considerations-use-minimal-residual-disease-development-drug-and. January 2020. Accessed February 28, 2020.

      US Food and Drug Administration. Hematologic malignancies: regulatory considerations for use of minimal residual disease in development of drug and biological products for treatment. Guidance for industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/hematologic-malignancies-regulatory-considerations-use-minimal-residual-disease-development-drug-and. January 2020. Accessed February 28, 2020.

    • Seymour JF, Kipps TJ, Eichhorst B, et al. Four-year analysis of MURANO study confirms sustained benefit of time-limited venetoclax–rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: 61st American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

      Seymour JF, Kipps TJ, Eichhorst B, et al. Four-year analysis of MURANO study confirms sustained benefit of time-limited venetoclax–rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: 61st American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

    • Greer JA, Amoyal N, Nisotel L, et al. A systematic review of adherence to oral antineoplastic therapies. Oncologist. 2016;21(3):354-376.

      Greer JA, Amoyal N, Nisotel L, et al. A systematic review of adherence to oral antineoplastic therapies. Oncologist. 2016;21(3):354-376.

    • Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anticancer treatment. CA Cancer J Clin. 2009;59(1):56-66.

      Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anticancer treatment. CA Cancer J Clin. 2009;59(1):56-66.

    • Giacomini KM, Huang S-M, Tweedie DJ, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215-236.

      Giacomini KM, Huang S-M, Tweedie DJ, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215-236.

    • Wessler JD, Grip LT, Mendell J, Giugliano RP. The P-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol. 2013;61(25):2495-2502.

      Wessler JD, Grip LT, Mendell J, Giugliano RP. The P-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol. 2013;61(25):2495-2502.

    • CRESEMBA Prescribing Information. December 2019.

      CRESEMBA Prescribing Information. December 2019.

    • Drug development and drug interactions: table of substrates, inhibitors and inducers. US Food and Drug Administration website.
      https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#cypEnzymes. Updated November 14, 2017. Accessed March 11, 2021.

      Drug development and drug interactions: table of substrates, inhibitors and inducers. US Food and Drug Administration website.
      https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#cypEnzymes. Updated November 14, 2017. Accessed March 11, 2021.

    • RITUXAN Prescribing Information.

      RITUXAN Prescribing Information.

    • Souers AJ, Leverson JD, Doghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202-203.

      Souers AJ, Leverson JD, Doghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202-203.

    • Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukemia (CLL14); follow-up results from a multicentre, open-label, randomized, phase 3 trial. Lancet Oncol 2020;21:1188-1200.

      Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukemia (CLL14); follow-up results from a multicentre, open-label, randomized, phase 3 trial. Lancet Oncol 2020;21:1188-1200.