OVERVIEW

ABBV-101 is an investigational drug under clinical development. Safety and efficacy have not been established.

ABBV-101 is a small molecule BTK degrader that is being investigated to treat B-cell malignancies.

PROPOSED MECHANISM OF ACTION

BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK’s role in signaling through the B-cell surface receptors leads to the activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion.

BTK degraders contain an E3 ligase-targeting moiety connected via a linker to a ligand targeting BTK. The BTK degrader enters the cell and brings endogenous E3 ligase into close proximity with BTK resulting in its ubiquitination by the E3 ligase. The E3 ligase is released and the BTK is targeted to the proteasome for degradation; the degrader is not consumed in the process and can continue to promote BTK degradation.

DEVELOPMENT

ABBV-101 is being investigated in a Phase 1 trial for the treatment of B-cell malignancies.

CLINICAL TRIALS

View select clinical trials with ABBV-101 now. To view a full list of clinical trials in which ABBV-101 is being investigated, please visit ClinicalTrials.gov.

References

  1. Dobrovolsky D, et al. Bruton tyrosine kinase degradation as a therapeutic strategy for cancer. Blood. 2019;133(9):952-961.
  2. Liu Z, et al. An overview of PROTACs: a promising drug discovery paradigm. Mol Biomed. 2022;3:46.

B-cell Malignancies


OVERVIEW

ABBV-319 is an investigational drug under clinical development. Safety and efficacy have not been established.

ABBV-319 is a CD19-GRM antibody-drug conjugate (ADC) composed of an optimized high-affinity immunoglobulin G1 antibody conjugated to a potent proprietary glucocorticosteroid payload.

PROPOSED MECHANISM OF ACTION

Systemic glucocorticosteroids (ie, glucocorticoid receptor modulators [GRMs]) show robust monotherapy activity against B-cell malignancies at high doses; however, they may be accompanied by steroid-associated toxicities that limit dosing.

CD19 is a marker essential for B-cell proliferation and has high expression across B-cell malignancies including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL).

ABBV-319 is a CD19-GRM ADC composed of an optimized high-affinity immunoglobulin G1 antibody conjugated to a potent proprietary glucocorticosteroid payload. ABBV-319 is a multimodal ADC that takes advantage of both:

  • Enhanced antibody-dependent cellular cytotoxicity (ADCC) via afucosylation
  • Targeted GRM payload delivery to maximize anticancer activity while lowering the risk of systemic steroid toxicities

DEVELOPMENT

ABBV-319 is being investigated in a Phase 1 trial for the treatment of B-cell malignancies, specifically DLBCL, FL and CLL.

CLINICAL TRIALS

View select clinical trials with ABBV-319 now. To view a full list of clinical trials in which ABBV-319 is being investigated, please visit ClinicalTrials.gov.

  1. Levy M, et al. A first-in-human phase 1 study of ABBV-319, an antibody-drug conjugate composed of a CD19 antibody linked to a potent propriety glucocorticosteroid, in patients with relapsed or refractory B-cell malignancies. Poster 1625 presented at: 64th ASH. December 10-13, 2022. New Orleans, LA.

B-cell Malignancies


ABBV-383 is an investigational drug under clinical development. Safety and efficacy have not been established.

OVERVIEW

ABBV-383 (previously known as TNB-383) is a fully human CD3 x BCMA bispecific antibody that is being investigated to treat multiple myeloma and AL amyloidosis. 

PROPOSED MECHANISM OF ACTION

BCMA (B cell maturation antigen) is only induced in late memory B cells committed to the plasma cell (PC) differentiation and is present on all PCs. BCMA supports the survival of long-lived PCs, the production of antibodies, and immunoglobulin class switching.1

Multiple myeloma (MM) is characterized by the expansion of malignant PCs in the bone marrow (BM), which is associated with excessive production of monoclonal immunoglobulins.  In MM, expression of BCMA is significantly increased on malignant versus normal PCs; overexpression of BCMA promotes proliferation and survival of MM cells.1

ABBV-383 is designed with a set of unique features, including an αCD3 moiety that allows for target cell lysis with minimal cytokine release, two αBCMA domains for high-affinity cell surface BCMA binding, and a silenced IgG4 backbone that prevents nonspecific immune activation and may permit longer interval dosing.2-4

DEVELOPMENT

ABBV-383 is a is being investigated in multiple trials to treat relapsed/refractory (R/R) MM and AL amyloidosis.

CLINICAL TRIALS

View select clinical trials with ABBV-383 now. To view a full list of clinical trials in which ABBV-383 is being investigated, please visit ClinicalTrials.gov.

  1. Cho SF, Anderson KC, Tai YT. Targeting B cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-based immunotherapy. Front Immun. 2018;9:1821.
  2. Foureau DM, et al. Ex vivo efficacy of BCMA-bispecific antibody TNB-383B in relapsed/refractory multiple myeloma. eJHaem. 2020;1:113–121.
  3. Buelow B, et al. Development of a fully human T-cell engaging bispecific antibody for the treatment of multiple myeloma. Poster presented at ASCO Annual Meeting; 2018.
  4. Buelow B, et al. T cell engagement without cytokine storm: a novel BCMA x CD3 antibody killing myeloma cells with minimal cytokine secretion. Blood. 2017;130(Suppl_1):501.

MM

AL Amyloidosis


OVERVIEW

ABBV-453 is an investigational drug under clinical development. Safety and efficacy have not been established.

ABBV-453 is an oral B-cell lymphoma 2 (BCL-2) inhibitor being investigated in relapsed or refractory (R/R) multiple myeloma (MM) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). 

PROPOSED MECHANISM OF ACTION

BCL-2 is an anti-apoptotic, pro-survival member of the BCL-2 family of proteins that function to regulate the intrinsic pathway of apoptosis, or programmed cell death, and help maintain cellular homeostasis.1,2 BCL-2 is a pro-survival oncoprotein that can be overexpressed as a result of cancer-specific mutations or gene amplifications.3

MM is a heterogenous disease with IgH translocations such as t(11;14), t(4;14), t(6;14), t(14;16), and t(14;20) in approximately 40% of MM patients. 4 The most common IgH translocation in MM is t(11;14). BCL-2 dependency varies across MM; MM cells with the t(11;14) translocation are primarily dependent on BCL-2 for survival. 

Relatively high levels of BCL-2 expression are documented in 95% of CLL cases compared to normal peripheral blood lymphocytes.5

ABBV-453 binds to BCL-2, preventing it from binding to pro-apoptotic proteins and thereby restoring the cell's ability to undergo apoptosis.6,7

DEVELOPMENT

ABBV-453 is being investigated in Phase 1 trials for the treatment of R/R MM and CLL/SLL. 

CLINICAL TRIALS

View select clinical trials with ABBV-453. To view a full list of clinical trials in which ABBV-453 is being investigated, please visit ClinicalTrials.gov.

References

  1. Cory S, et al. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003;22:8590-8607.
  2. Plati J, et al. Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb). 2011;3:279-296.
  3. Davids MS, et al. Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol. 2012;30(25):3127-3135.
  4. Rajkumar SV, et al. Multiple myeloma: 2022 update on diagnosis, risk stratification, and management. Am J Hematol. 2022;97:1086-1107.
  5. Hanada M, et al. bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood. 1993;82(6):1820-1828.
  6. Touzeau C, et al. Targeting Bcl-2 for the treatment of multiple myeloma. Leukemia. 2018;32:1899–1907.​
  7. Roberts AW, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311-322.

Multiple Myeloma (MM)

Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma 


OVERVIEW

ABBV-525 is an investigational drug under clinical development. Safety and efficacy have notbeen established.

ABBV-525 is an oral small molecule inhibitor of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) being investigated in B-cell malignancies.

PROPOSED MECHANISM OF ACTION

The human paracaspase MALT1 is a caspase homolog that is a key mediator of NF-ÎşB signaling and promotes cell proliferation and survival.1 Both the scaffolding and proteolytic functions of MALT1 contribute to NF-ÎşB signaling.2 As a scaffolding protein, MALT1 provides a platform for the assembly of NF-ÎşB signaling proteins. As a protease, MALT1 proteolytically cleaves over six NF-ÎşB antagonists.

MALT1 drives NF-κB expression in many cancers, leading to enhanced cell survival and proliferation.3  Specific B cell malignancies, including the aggressive non-germinal center B cell-like (GCB) subtype of diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), are driven by constitutive activation of NF-κB.4 Preclinical data with a tool MALT1 inhibitor compound (“MALT1i”) demonstrated single agent antitumor activity in malignant B cell models that were resistant to BTK inhibitors. Moreover, the combination of MALT1i with the BCL-2 inhibitor, venetoclax, showed synergistic cell killing of B cell tumors in vitro and tumor regression in vivo.5 

DEVELOPMENT

ABBV-525 is being investigated in a Phase 1 trial for the treatment of B-cell malignancies.

CLINICAL TRIALS

View select clinical trials with ABBV-525 now. To view a full list of clinical trials in which ABBV-525 is being investigated, please visit ClinicalTrials.gov.

References

  1. Hachmann J, et al. The paracaspase MALT1. Biochimie. 2016;122:324-38.
  2. Afonina IS, et al. MALT1-a universal soldier: multiple strategies to ensure NF-vB activation and target gene expression. FEBS J. 2015; 282(17):3286-97.
  3. Solsona BG, et al. The paracaspase MALT1 in Cancer. Biomedicines. 2022;10(2):344.
  4. Yin W, et al. Identification of potent paracaspase MALT1 inhibitors for hematological malignancies. Blood. 2020;136(1)30.
  5. Plotnik JP, et al. MALT1 protease inhibition overcomes BTK inhibitor resistance and shows synergistic activity with venetoclax in models of B-cell lymphoma and leukemia. Poster 6156 presented at: AACR2023.

B-cell Malignancies


OVERVIEW

CLBR001+SWI019 is an investigational drug under clinical development. Safety and efficacy have not been established.

CLBR001+SWI019 is a two-component infusion therapy of autologous switchable chimeric antigen receptor-T (sCAR-T) cells (CLBR001) and CD19-targeted antibody Fab switch (SWI019) being investigated in relapsed or refractory (R/R) B-cell malignancies.1,2,3.

PROPOSED MECHANISM OF ACTION

The CLBR001+SWI019 sCAR-T system consists of two parts, including an autologous cell product composed of a humanized, third generation CAR-T cell (CLBR001) along with a humanized antibody Fab “switch” (SWI019) that is dosed following CLBR001 infusion.  SWI019 is designed to act as a switch to dynamically turn “on” or “off” CLBR001 cells, allowing for controllable activity of the adoptively transferred cells. CLBR001+SWI019 demonstrated target cell cytotoxicity in preclinical models.

DEVELOPMENT

CLBR001+SWI019 is being investigated in a Phase 1 trial for the treatment of R/R B-cell malignancies.

CLBR001/SWI019 developed by Calibr is in a first-in-patient trial and AbbVie hold options for additional development and other targets.

CLINICAL TRIALS

View select clinical trials with CLBR001+SWI019. To view a full list of clinical trials in which CLBR001+SWI019 is being investigated, please visit ClinicalTrials.gov.

References

  1. Young, T. CLBR001+SWI019: A novel switchable CAR-T cell platform enabling functionally reversible on/off control of CAR-T cell activity for B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr ND04.
  2. Nikolaenko L, et al. First in human study of an on/off switchable CAR-T cell platform targeting CD19 for B cell malignancies (CLBR001+SWI019). Blood. 2021;138(1):2822.
  3. Laborda E, et al. IND-enabling studies of a switchable chimeric antigen receptor-T cell (CLBR001+SWI019) to support first in human clinical study. Blood. 2021;138(1):1695.

B-cell Malignancies


OVERVIEW

Epcoritamab (GEN3013)* is an approved drug being investigated for additional uses. Safety and efficacy have not been established for these additional uses.

Epcoritamab (GEN3013) is an IgG1 bispecific antibody targeting CD3 and CD20.1,2

PROPOSED MECHANISM OF ACTION

Epcoritamab is a subcutaneously administered, bispecific CD3×CD20 antibody created via Fab-arm exchange using the unique DuoBody® technology platform that allows retaining of the native IgG1 antibody structure and a long plasma half-life.3

CD20 is a clinically well-established target that is expressed in a wide variety of B-cell malignancies and healthy B-cell lineage cells. Epcoritamab simultaneously binds to CD20 on B-cells and CD3 on T-cells, inducing activation and expansion of T-cells and T-cell-mediated killing of CD20–positive malignant B cells.1,3

®A registered trademark of Genmab A/S

DEVELOPMENT

Epcoritamab* FDA approval timeline4

  • May 2023 (accelerated approval): For the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), including DLBCL arising from indolent lymphoma, and high grade B-cell lymphoma (HGBL) after two or more lines of systemic therapy.
    This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

AbbVie and Genmab continue to investigate Epcoritamab in ongoing Phase 3 and early phase clinical trials for the treatment of DLBLC, as well as other cancers, including follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL).

EPCORITAMAB INDICATION AND SAFETY OVERVIEW FOR DLBCL (US PRESCRIBING INFORMATION)4

Indication:

Epcoritamab is a bispecific CD20-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after two or more lines of systemic therapy.

This indication is approved under accelerated approval based on response rate and durability of response.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

SAFETY INFORMATION

Boxed Warnings

  • Cytokine release syndrome (CRS), including serious or life-threatening reactions, can occur in patients receiving CD3 x CD20. Initiate treatment with the CD3 x CD20 step-up dosing schedule to reduce the incidence and severity of CRS. With hold Epcoritamab until CRS resolves or permanently discontinue based on severity.
  • Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), including life-threatening and fatal reactions, can occur with Epcoritamab. Monitor patients for neurological signs or symptoms of ICANS during treatment. Withhold epcoritamab until ICANS resolves or permanently discontinue based on severity.

Warnings & Precautions

  • Infections: Can cause serious or fatal infections. Monitor patients for signs or symptoms of infection, including opportunistic infections, and treat appropriately.
  • Cytopenias: Monitor complete blood cell counts during treatment.
  • Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception.

Adverse Reactions
The most common (≥ 20%) adverse reactions are CRS, fatigue, musculoskeletal pain, injection site reactions, pyrexia, abdominal pain, nausea, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) are decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, decreased hemoglobin, and decreased platelets.

Use in Specific Populations
Lactation:
Advise not to breastfeed.

Please see full US Prescribing information for additional information at: https://www.genmab-lpi.com/prescribing-information/epkinly-pi.pdf

CLINICAL TRIALS

View select clinical trials with Epcoritamab now. To view a full list of clinical trials in which CD3 x CD20 is being investigated, please visit ClinicalTrials.gov.

  1. Hutchings M, et al. Epcoritamab (GEN3013; DuoBody-CD3 × CD20) to induce complete response in patients with relapsed/refractory B-cell non-Hodgkin lymphoma: complete dose escalation data and efficacy results from a phase I/II trial. Poster presented at: 56th Annual ASCO Meeting and Exposition, Virtual Format; May 29–June 2, 2020.
  2. Engelberts PJ, et al. DuoBody-CD3xCD20 induces potent T-cell-mediated killing of malignant B cells in preclinical models and provides opportunities for subcutaneous dosing. EBioMedicine. 2020;52:102625.
  3. Hutchings M, et al. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet. 2021;398(10306):1157-1169.
  4. Epcoritamab [package insert]. North Chicago, IL: AbbVie, Inc. and Plainsboro, NJ: Genmab US, Inc.: May 2023.

Diffuse Large B-Cell Lymphoma (DLBCL)

Follicular Lymphoma (FL)

Non-Hodgkin Lymphoma (NHL)

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Chronic Lymphocytic Leukemia (CLL)

*Epcoritamab developed in partnership with Genmab


OVERVIEW

Ibrutinib (PCI-32765, CRA-032765) is an approved drug being investigated for additional uses. Safety and efficacy have not been established for these additional uses.

Ibrutinib (PCI-32765, CRA-032765) is a selective, orally bioavailable small-molecule BTK inhibitor.1

PROPOSED MECHANISM OF ACTION

Ibrutinib (PCI-32765, CRA-032765) is small-molecule inhibitor of Bruton’s tyrosine kinase (BTK). Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity.1 BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK’s role in signaling through the B-cell surface receptors results in the activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.2

Ibrutinib also inhibits the activity of interleukin-2-inducible-T-cell kinase (ITK).3

DEVELOPMENT

Ibrutinib FDA approval timeline4

  • Feb 2014 (accelerated approval): Monotherapy treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least one prior therapy
  • July 2014: Expanded indication to include patients with del(17p) CLL
  • Jan 2015: Monotherapy for the treatment of adult patients with Waldenström's macroglobulinemia (WM)
  • Mar 2016: Monotherapy for the treatment of previously untreated CLL
  • May 2016: Ibrutinib in combination with bendamustine+rituximab (BR) for adult patients with previously-treated CLL/SLL
  • Aug 2017: Monotherapy for the treatment of adult patients with chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy
  • Aug 2018: Ibrutinib with rituximab for the treatment of previously untreated and relapsed/refractory WM
  • Jan 2019: Ibrutinib plus obinutuzumab for the treatment of previously untreated CLL/SLL
  • Apr 2020: Ibrutinib with rituximab for the treatment of previously untreated adults with CLL/SLL
  • Aug 2022: Monotherapy for the treatment of adult and pediatric patients age 1 year and older with chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy
  • Feb 2024: Update of Ibrutinib label to expand use of oral suspension formulation to adult patients with CLL/SLL and WM

AbbVie and Janssen Biotech continue to ibrutinib in ongoing phase 3 and early phase clinical trials

Imbruvica (ibrutinib) is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company and Janssen Biotech, Inc.

IBRUTINIB Indication and Safety Overview (US PRESCRIBING INFORMATION)5

Indication:

Ibrutinib is a kinase inhibitor indicated for the treatment of:

  • Adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
  • Adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with 17p deletion.
  • Adult patients with Waldenström's macroglobulinemia (WM).
  • Adult and pediatric patients age 1 year and older with chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy.

SAFETY INFORMATION

Warning and Precautions

  • Hemorrhage: Fatal bleeding events have occurred in patients who received ibrutinib. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) occurred in 4.2% of patients, with fatalities occurring in 0.4% of 2,838 patients who received ibrutinib in 27 clinical trials. Bleeding events of any grade including bruising and petechiae occurred in 39%, and excluding bruising and petechiae occurred in 23% of patients who received ibrutinib, respectively.
    The mechanism for the bleeding events is not well understood.
    Use of either anticoagulant or antiplatelet agents concomitantly with ibrutinib increases the risk of major hemorrhage. Across clinical trials, 3.1% of 2,838 patients who received ibrutinib without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with ibrutinib. Monitor for signs and symptoms of bleeding.
    Consider the benefit-risk of withholding ibrutinib for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.
  • Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with ibrutinib therapy. Grade 3 or greater infections occurred in 21% of 1,476 patients with B-cell malignancies who received ibrutinib in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with ibrutinib. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections. Monitor and evaluate patients for fever and infections and treat appropriately.
  • Cardiac Arrhythmias, Cardiac Failure, and Sudden Death: Fatal and serious cardiac arrhythmias and cardiac failure have occurred with ibrutinib. Deaths due to cardiac causes or sudden deaths occurred in 1% of 4,896 patients who received ibrutinib in clinical trials, including in patients who received ibrutinib in unapproved monotherapy or combination regimens. These adverse reactions occurred in patients with and without preexisting hypertension or cardiac comorbidities. Patients with cardiac comorbidities may be at greater risk of these events.
    Grade 3 or greater ventricular tachyarrhythmias were reported in 0.2%, Grade 3 or greater atrial fibrillation and atrial flutter were reported in 3.7%, and Grade 3 or greater cardiac failure was reported in 1.3% of 4,896 patients who received ibrutinib in clinical trials, including in patients who received ibrutinib in unapproved monotherapy or combination regimens. These events have occurred particularly in patients with cardiac risk factors including hypertension and diabetes mellitus, a previous history of cardiac arrhythmias, and in patients with acute infections.
    Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias and cardiac function. Obtain further evaluation (e.g., ECG, echocardiogram) as indicated for patients who develop symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, chest pain), new onset dyspnea, or other cardiovascular concerns. Manage cardiac arrhythmias and cardiac failure appropriately, follow dose modification guidelines, and consider the risks and benefits of continued ibrutinib treatment.
  • Hypertension: Hypertension occurred in 19% of 1,476 patients with B-cell malignancies who received ibrutinib in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients. Based on data from a subset of these patients, (N=1,124), the median time to onset was 5.9 months (range, 0 to 24 months). In a long-term safety analysis over 5 years of 1,284 patients with B-cell malignancies treated for a median of 36 months (range, 0 to 98 months), the cumulative rate of hypertension increased over time. The prevalence for Grade 3 or greater hypertension was 4% (year 0-1), 7% (year 1-2), 9% (year 2-3), 9% (year 3-4), and 9% (year 4-5); the overall incidence for the 5-year period was 11%. Monitor blood pressure in patients treated with ibrutinib, initiate or adjust anti-hypertensive medication throughout treatment with ibrutinib as appropriate, and follow dosage modification guidelines for Grade 3 or higher hypertension.
  • Cytopenias: In 645 patients with B-cell malignancies who received ibrutinib as a single agent, grade 3 or 4 neutropenia occurred in 23% of patients, grade 3 or 4 thrombocytopenia in 8% and grade 3 or 4 anemia in 2.8%, based on laboratory measurements. Monitor complete blood counts monthly.
  • Second Primary Malignancies: Other malignancies (10%), including non-skin carcinomas (3.9%), occurred among the 1,476 patients with B-cell malignancies who received ibrutinib in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).
  • Hepatotoxicity, Including Drug-Induced Liver Injury: Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including ibrutinib.
    Evaluate bilirubin and transaminases at baseline and throughout treatment with ibrutinib. For patients who develop abnormal liver tests after ibrutinib, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold ibrutinib. Upon confirmation of DILI, discontinue ibrutinib.
  • Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with ibrutinib. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.
  • Embryo-Fetal Toxicity: Based on findings in animals, ibrutinib can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ibrutinib and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during the same time period.

Adverse Reactions

  • B-cell malignancies: The most common adverse reactions (≥30%) in adult patients with B-cell malignancies were thrombocytopenia (55%)*, diarrhea (44%), fatigue (39%), musculoskeletal pain (39%), neutropenia (39%)*, rash (36%), anemia (35%)*, bruising (32%), and nausea (30%).
    The most common Grade ≥ 3 adverse reactions (≥5%) in adult patients with B-cell malignancies were neutropenia (21%)*, thrombocytopenia (14%)*, pneumonia (8%), and hypertension (8%).
    Approximately 9% (CLL/SLL), and 14% (WM) of adult patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL) and 5% (WM) of adult patients discontinued due to adverse reactions.
  • cGVHD: The most common adverse reactions (≥20%) in adult or pediatric patients with cGVHD were fatigue (57%), anemia (49%)*, bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, musculoskeletal pain (30%), pyrexia (30%), muscle spasms (29%), stomatitis (29%), hemorrhage (26%), nausea (26%), abdominal pain (23%), pneumonia (23%), and headache (21%).
    The most common Grade 3 or higher adverse reactions (≥5%) reported in adult or pediatric patients with cGVHD were pneumonia (14%), anemia (13%)*, fatigue (12%), pyrexia (11%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), osteonecrosis (9%), stomatitis (9%), hypokalemia (7%), headache (5%), and musculoskeletal pain (5%).
    Discontinuation of ibrutinib treatment due to an adverse reaction occurred in 24% of adult patients and 23% of pediatric patients. Adverse reactions leading to dose reduction occurred in 26% of adult patients and 19% of pediatric patients.
    *Treatment-emergent decreases (all grades) were based on laboratory measurements.

Drug Interactions

  • CYP3A Inhibitors: Co-administration of ibrutinib with strong or moderate CYP3A inhibitors may increase ibrutinib plasma concentrations. Increased ibrutinib concentrations may increase the risk of drug-related toxicity. Dose modifications of ibrutinib are recommended when used concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt ibrutinib if strong inhibitors are used short-term (e.g., for ≤ 7 days). Avoid grapefruit and Seville oranges during ibrutinib treatment, as these contain strong or moderate inhibitors of CYP3A. See dose modification guidelines in USPI sections 2.3 and 7.1.
  • CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

Specific Populations

  • Pediatric Use: The safety and effectiveness of ibrutinib have not been established for the treatment of cGVHD after failure of one or more lines of therapy in pediatric patients less than 1 year of age. The safety and effectiveness of ibrutinib in pediatric patients have not been established in CLL/SLL, CLL/SLL with 17p deletion, WM, or in patients with mature B-cell non-Hodgkin lymphoma.
  • In the randomized population from a study that included 35 patients (26 pediatric patients age 5 to less than 17 years) with previously treated mature B-cell non-Hodgkin lymphoma, major hemorrhage and discontinuation of chemoimmunotherapy due to adverse reactions occurred more frequently in the ibrutinib plus chemoimmunotherapy arm compared to the chemoimmunotherapy alone arm.
  • Adult Patients with B-cell Malignancies: Hepatic Impairment (based on Child-Pugh criteria): Avoid use of ibrutinib in patients with severe hepatic impairment. In patients with mild or moderate impairment, reduce recommended ibrutinib dose and monitor more frequently for adverse reactions of ibrutinib.
  • Patients with cGVHD: Avoid use of ibrutinib in patients with total bilirubin level > 3x upper limit of normal (ULN) (unless of non-hepatic origin or due to Gilbert’s syndrome). Reduce recommended dose when administering ibrutinib to patients with total bilirubin level > 1.5 to 3x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome).

Review full US prescribing information for additional information at https://www.rxabbvie.com/pdf/imbruvica_pi.pdf

CLINICAL TRIALS

View select clinical trials with ibrutinib now. To view a full list of clinical trials in which ibrutinib is being investigated, please visit ClinicalTrials.gov.

  1. Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA. 2010;107(29):13075-80.
  2. Herman SEM, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117(23):6287-96.
  3. Dubovsky JA, Flynn R, Du J, et al. Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest. 2014;124(11):4867-76.
  4. Drugs@FDA: FDA Approved Drug Products – IMBRUVICA. Accessed at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=208573.
  5. Ibrutinib [package insert]. South San Francisco, CA: Pharmacyclics LLC, and Horsham, PA: Janssen Biotech, Inc.: 2/2024.

MCL

FL

CLL/SLL

WM

cGVHD


OVERVIEW

Pivekimab sunirine is an investigational drug under clinical development. Safety and efficacy have not been established.

Pivekimab sunirine (PVEK; IMGN-632) is an antibody-drug conjugate (ADC) designed to target CD123 in development for the treatment of acute myeloid leukemia (AML) in combination with venetoclax and azacitidine, and as a single agent for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).

PROPOSED MECHANISM OF ACTION

CD123 is the alpha-subunit of the interleukin-3 receptor (IL-3Rα).1,2 CD123 expression is low on normal hematopoietic stem cells and is overexpressed in multiple hematologic malignancies including AML and BPDCN.3,4 CD123 is not expressed or weakly expressed on most normal cells and therefore is a useful biomarker and therapeutic target.5,6 Virtually all cases of BPDCN are CD123 positive and detection of CD123 is required for BPDCN diagnosis.7 CD123 is overexpressed in most AML cases, correlates with mutations in NPM1 and FLT3, is associated with negative prognosis which may be due to increased sensitivity to IL-3 binding and downregulation of CXCR4.4,8-11

Pivekimab sunirine (PVEK, IMGN632) is an antibody-drug conjugate comprising a high-affinity CD123 antibody, cleavable linker, and an indolinobenzodiazepine pseudodimer (IGN) payload.5 The IGN payload alkylates DNA and causes single strand breaks without crosslinking. IGNs are designed to have activity against tumor cells, while demonstrating less toxicity to normal marrow progenitors.5

DEVELOPMENT

Pivekimab sunirine is being investigated in Phase 1/2 trials for the treatment of AML and BPDCN.

CLINICAL TRIALS

View select clinical trials with pivekimab sunirine now. To view a full list of clinical trials in which pivekimab sunirine is being investigated, please visit ClinicalTrials.gov.

 

  1. Rothenberg ME, et al. Human eosinophils have prolonged survival, enhanced functional properties, and become hypodense when exposed to human interleukin 3. J Clin Invest. 1988;81(6):1986-92.
  2. Lantz CS, et al. Role of uinterleukin-3 in mast-cell and basophilk development and in immunity to parasites. Nature. 1998;392(6671):90–93.
  3. Testa U, Pelosi E, Frankel A. CD 123 is a membrane biomarker and a therapeutic target in hematologic malignancies. Biomark Res. 2014;2(1):4.
  4. Jordan CT, Upchurch D, Szilvassy SJ, et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia. 2000;14(10):1777-1784.
  5. Kovtun Y, Jones GE, Adams S, et al. A CD123-targeting antibody-drug conjugate, IMGN632, designed to eradicate AML while sparing normal bone marrow cells. Blood Adv. 2018 Apr 24;2(8):848-858.
  6. Pemmaraju N, et al. Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm. N Engl J Med. 2019;380:1628-1637.
  7. Pemmaraju N, Kantarjian H, Sweet K, et al. North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: position on standards of care and areas of need. Blood. 2023;141(6):567-578.
  8. Muñoz L, Nomdedéu JF, López O, et al. Interleukin-3 receptor alpha chain (CD123) is widely expressed in hematologic malignancies. Haematologica. 2001;86(12):1261-9.
  9. De Smet D, Trullemans F, Jochmans K, et al. Diagnostic potential of CD34+ cell antigen expression in myelodysplastic syndromes. Am J Clin Pathol. 2012;138(5):732-43.
  10. Ehninger A, Kramer M, Röllig C, et al.  Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer J. 2014;4(6):e218.
  11. Rollins-Raval M, Pillai R, Warita K, et al. CD123 immunohistochemical expression in acute myeloid leukemia is associated with underlying FLT3-ITD and NPM1 mutations. Appl Immunohistochem Mol Morphol. 2013;21:212-17.

AML

BPDCN


OVERVIEW

Venetoclax (ABT-199/GDC-0199) is an approved drug being investigated for additional uses. Safety and efficacy have not been established for these additional uses.

Venetoclax (ABT-199/GDC-0199) is a selective, orally bioavailable small-molecule BCL-2 inhibitor.1

PROPOSED MECHANISM OF ACTION

The balance between pro-death and pro-survival molecules determines whether a cell lives or dies.2,3 BCL-2 is a pro-survival protein that binds and sequesters pro-death (pro-apoptotic) proteins, such as BIM, limiting their ability to initiate apoptosis (cell death).

Venetoclax is designed to bind to BCL-2, preventing it from binding to pro-apoptotic proteins and thereby helping to restore the cell's ability to undergo apoptosis.1

DEVELOPMENT

Venetoclax FDA approval timeline:4

  • April 2016 (accelerated approval): Monotherapy for the treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) with 17p deletion, who have received at least one prior therapy
  • June 2018: Venetoclax in combination with rituximab for the treatment of CLL or SLL, with or without 17p deletion, who have received at least one prior therapy.
  • November 2018 (accelerated approval): Venetoclax in combination with azacitidine or decitabine or low-dose cytarabine (LDAC) for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults ≥75 years, or who have comorbidities that preclude use of intensive induction chemotherapy
  • May 2019: Expanded indication to include the treatment of adult patients with CLL or SLL, based on the data from the CLL14 study of venetoclax plus obinutuzumab in first-line CLL patients
  • October 2020: Venetoclax in combination with azacitidine, or decitabine, or low-dose cytarabine (LDAC) for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy

AbbVie and Roche continue to investigate venetoclax in ongoing Phase 3 and early phase clinical trials for the treatment of CLL and SLL as well as a variety of other cancers, including AML, multiple myeloma (MM), myelodysplastic syndromes (MDS), subtypes of non-Hodgkin lymphoma (NHL) [mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL)] and acute lymphoblastic leukemia (ALL).

Venetoclax jointly developed with Roche

VENETOCLAX INDICATION AND SAFETY OVERVIEW FOR AML/CLL (US PRESCRIBING INFORMATION).5

Indications:

Venetoclax is a BCL-2 inhibitor indicated:

  • For the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
  • In combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults:
    • Who are age 75 years or older, or
    • Who have comorbidities that preclude use of intensive induction chemotherapy.

SAFETY INFORMATION

Contraindications

  • Strong CYP3A Inhibitors: Concomitant use with strong CYP3A inhibitors at initiation and during ramp-up phase in patients with CLL/SLL is contraindicated.

Warnings and Precautions

  • Tumor Lysis Syndrome (TLS): TLS, including fatal events and renal failure requiring dialysis, has occurred in patients treated with venetoclax. Anticipate TLS; assess risk in all patients. Premedicate with anti-hyperuricemics and ensure adequate hydration. Employ more intensive measures (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases.
  • Neutropenia: Monitor blood counts. Interrupt dosing and resume at same or reduced dose. Consider supportive care measures.
  • Infections: Fatal and serious infections such as pneumonia and sepsis have occurred in patients treated with venetoclax. Monitor for signs and symptoms of infection and treat promptly. Withhold venetoclax 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 venetoclax treatment until B-cell recovery.
  • Embryo-Fetal Toxicity: May cause embryo-fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.
  • Increased mortality in patients with multiple myeloma (MM) when venetoclax is added to bortezomib and dexamethasone. In a randomized trial in patients with relapsed or refractory MM, the addition of venetoclax to bortezomib plus dexamethasone, a use for which venetoclax is not indicated, resulted in increased mortality. Treatment of patients with MM with venetoclax in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials.

Adverse Reactions

  • In CLL/SLL, the most common adverse reactions (≥20%) for venetoclax when given in combination with obinutuzumab or rituximab or as monotherapy were neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema.
  • In AML, the most common adverse reactions (≥30%) in combination with azacitidine, or decitabine, or low-dose cytarabine were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, musculoskeletal pain, dizziness, cough, oropharyngeal pain, and hypotension.

Please see full Prescribing Information for additional information at  www.rxabbvie.com.

CLINICAL TRIALS

View select clinical trials with venetoclax now. To view a full list of clinical trials in which venetoclax is being investigated, please visit ClinicalTrials.gov.

  1. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202-208.
  2. Billard C. Apoptosis inducers in chronic lymphocytic leukemia. Oncotarget. 2014;5(2):309-25.
  3. Davids MS, Letai A. Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol. 2012;30(25):3127–3135.
  4. Drugs@FDA: FDA Approved Drug Products – VENCLEXTA. 
  5. Venetoclax [package insert]. North Chicago, IL: AbbVie, Inc. and South San Francisco, CA: Genentech, Inc.: June 2022.

CLL/SLL

AML

MDS

MM

MCL