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CLL & Other Hematologic Malignancies

Research Expertise

AbbVie's work within the area of hematologic malignancies focuses specifically on understanding chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). AbbVie scientists are exploring a vast array of pathways and proteins implicated in hematologic cancer cell growth, survival and motility in order to identify possible therapeutic targets.

Pathways & Targets

Selected pathways and potential targets include, but are not limited to, B-cell lymphoma-2 (BCL-2), CS1 (SLAMF7), and Bruton's tyrosine kinase (BTK).

BCL-2 Expression in Hematologic Malignancies

Overexpression of the antiapoptotic protein BCL-2 disrupts the dynamic balance of anti- and pro-apoptotic proteins. This decreases a cell's ability to undergo apoptosis in response to cellular stress, thereby promoting cancer cell survival.1 This overexpression is seen in a wide variety of hematologic malignancies and has frequently been associated with chemoresistance.1,2

Chronic Lymphocytic Leukemia (CLL)

  • Elevated levels of the BCL-2 protein are found in almost all CLL cases2,3
  • Impaired apoptosis caused by BCL-2 overexpression results in the accumulation of mature neoplastic lymphocytes in the blood and other lymphoid organs2

Acute Myeloid Leukemia (AML)

  • The BCL-2 protein is overexpressed in a high proportion of AML cases4,5
  • Elevated levels of BCL-2 correlate with poor prognosis and chemoresistance4,6-8

Mantle Cell Lymphoma (MCL)

  • The BCL-2 pathway is commonly deregulated in MCL cases and the BCL-2 gene is often amplified9,10

Follicular Lymphoma (FL)

  • BCL-2 protein overexpression is detected in over 60% of FL cases11
  • The vast majority of patients with BCL-2 protein overexpression develop chemoresistance and experience higher relapse rates compared with BCL-2-negative patients11

Diffuse Large B-Cell Lymphoma (DLBCL)

  • BCL-2 protein overexpression is detected in approximately 30% of DLBCL cases; in approximately 90% of those cases, BCL-2 protein levels are very high.11,12
  • Expressing both MYC and BCL-2 proteins correlates with an aggressive clinical course and a poor outcome1,12

Due to its role in both malignant cell survival and chemoresistance, BCL-2 has emerged as an attractive therapeutic target.

CS1 Proteins and Cancer Growth

CS1 is a cell surface glycoprotein that is minimally expressed on most, if not all, B cells. Expression is higher in pro-B cells and plasma cells.13

Multiple Myeloma (MM)

  • CS1 is highly expressed on the surface of malignant plasma cells in over 95% of cases of MM, irrespective of cytogenetic abnormalities13
  • High levels of CS1 are also observed in almost all cases of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM13
  • CS1 expression remains persistent throughout the course of the disease, despite treatment with proteasome inhibitors or chemotherapy-based autologous stem cell transplant (ASCT)13

Monoclonal antibody (mAb) binding to CS1 in MM cells induces cell lysis, probably due in part to antibody-dependent cell-mediated cytotoxicity (ADCC).13

Expression of BTK in Cancer

The BCR signaling pathway is a pivotal driver of normal B-cell functions, including proliferation, differentiation and antibody production.14

BTK is a tyrosine kinase principally expressed in B cells, and is a key kinase in the BCR signaling pathway.14,15

Chronic Lymphocytic Leukemia (CLL)

  • The BCR signaling pathway plays a central role in driving the proliferation of CLL cells, as well as mitigating the interaction of CLL cells with the tumor microenvironment16
  • The BCR signaling pathway is aberrantly active in CLL; BTK is uniformly overexpressed and constitutively phosphorylated17

Waldenström's macroglobulinemia (WM)

  • Myeloid differentiation primary-response protein 88 (MYD88), a key adaptor molecule in the Toll-like receptor (TLR) signaling pathway, is mutated in more than 90% of patients with WM18
  • BTK is a key downstream molecule activated by MYD8819
  • Overexpression of mutated MYD88 enhances BTK phosphorylation and contributes to proliferation and survival of WM cells20

Inhibiting BTK may block the initiation of multiple TLR/BCR-activated growth and survival pathways, reducing the tumor cell's ability to survive.

Visit AbbVieMedInfo.com to request additional information about BTK inhibitors such as ibrutinib.

Additional information:

CLL is a type of indolent cancer in which too many mature-appearing B cells are found mainly in the peripheral blood, bone marrow and lymphoid tissues.21 While CLL and small lymphocytic lymphoma (SLL) are histologically and immunophenotypically identical, by definition, peripheral blood involvement is more pronounced in patientswith CLL.22

Mechanism of Disease

The cause of CLL is unknown. Vast genetic and epigenetic heterogeneity among patients and within individual patient samples has been observed; this likely contributes to the variability in clinical course among patients with CLL.23

The most recurrent genomic lesions that have been identified are deletions of chromosome 13q, 17p, and 11q and trisomy of chromosome 12.23

As the TP53 tumor suppressor gene is located on chromosome 17p, TP53 mutations and 17p deletions are overlapping predictors of relapsed/refractory disease.24

Diagnosis & Staging

CLL is a slow-progressing disease. Many patients are incidentally diagnosed with asymptomatic disease when lymphocytes are detected in the peripheral blood during evaluation for other illnesses or in a routine physical exam.24

A diagnosis of CLL is based on the International Workshop on CLL (iwCLL) criteria25:

  • Presence of at least 5 x 109 (5000/μL) B lymphocytes in the peripheral blood
    • Clonality of circulating B lymphocytes must be confirmed by flow cytometry
    • Cells are characteristically small, mature lymphocytes with a narrow border of cytoplasm and a dense nucleus lacking discernible nucleoli and having partially aggregated chromatin
  • CLL cells coexpress B-cell surface antigens CD19, CD20, and CD23 and the T-cell surface antigen CD5
  • Each leukemic cell clone is restricted to expression of either kappa or lambda immunoglobulin light chains, indicating monoclonality
Peripheral blood smear showing CLL

Peripheral blood smear showing CLL

Staging helps to determine the type of treatment that should be used, as well as the patient's treatment prognosis.

Two staging systems, the Rai and Binet systems, are currently used worldwide in the evaluation of patients with CLL both in routine practice and clinical trial settings. Both systems describe 3 major subgroups with discrete clinical outcomes and rely solely on physical examination and blood parameters to assess tumor burden.25

Modified Rai Staging System25:

  • Low Risk—patients with lymphocytosis with leukemia cells in the blood and/or marrow (lymphoid cells >30%)
  • Intermediate Risk—patients with lymphocytosis, enlarged nodes in any site, and splenomegaly and/or hepatomegaly (lymph nodes being palpable or not)
  • High Risk—patients with disease-related anemia (as defined by a hemoglobin [Hb] level <110 g/L [11 g/dL]) or thrombocytopenia (as defined by a platelet count <100 x 109/L)

Binet Staging System25:

  • Stage A—Hb ≥100 g/L (10 g/dL), platelets ≥100 x 109/L, and ≤2 areas of nodal or organ enlargement
  • Stage B—Hb ≥100 g/L (10 g/dL), platelets ≥100 x 109/L, and ≥3 areas of nodal or organ enlargement
  • Stage C—all patients with Hb <100 g/L (10 g/dL) and/or a platelet count <100 x 109/L, irrespective of organomegaly

Generally, newly diagnosed patients with asymptomatic early stage disease (Rai 0, Binet A) should be monitored without therapy unless or until they have evidence of disease progression.26 Many of these patients have indolent disease and may have the potential for a normal life expectancy.27

Response Criteria

The updated iwCLL guidelines provide a lengthy and detailed description of the assessment of treatment response.25 In short, response is categorized as follows:

  • Complete remission (CR)—blood lymphocytes <4000/μL and bone marrow lymphoid cells ≤30%
  • Partial remission (PR)—a decrease in the number of blood lymphocytes by 50% or more from the value before therapy (documented for a minimal duration of 2 months)
  • Stable disease (SD)—patients who have not achieved a CR or a PR, and who have not exhibited progressive disease
  • Progressive disease (PD)—at least one of the following: lymphadenopathy, an increase in previously noted enlargement of the liver or spleen by ≥50%, or an increase in the number of blood lymphocytes by ≥50% with B lymphocytes ≥5000/μL

The assessment of minimal residual disease (MRD) is an additional category of response assessment26:

  • MRD negativity—blood or marrow with <1 CLL cell/10 000 leukocytes25

Attaining CR with MRD negativity has been shown to improve long-term clinical outcomes and correlates with significant increases in disease-free survival (DFS) and overall survival (OS) in patients treated with chemoimmunotherapy.28

Relapsed/Refractory CLL

Relapse occurs when a patient who has previously achieved a CR or a PR demonstrates evidence of disease progression 6 months or more after the last antileukemic therapy.25

Refractory disease is defined as treatment failure or disease progression within 6 months of the last antileukemic therapy. Treatment failure includes SD, PD or death (any outcome other than CR or PR).25

Treatment Challenges

Newly diagnosed later-stage disease and relapsed/refractory (R/R) CLL have historically been difficult to treat.25,26

Patients with CLL cells showing chromosomal aberrations del(11q) or del(17p) often do not respond to standard chemotherapy and usually have inferior outcomes and relatively short survival compared with patients whose leukemia cells show a normal karyotype or del(13q) as the sole genetic abnormality.25

The choice of therapy for patients with the chromosomal aberration del(17p) is challenging.

Unmet Need

Treatment goals in CLL have evolved from palliation to maximized response and prolonged survival (overall response rate [ORR], progression-free survival [PFS] and OS).

Allogenic stem cell transplant (Allo-SCT) remains the only potentially curative option but is a risky procedure suitable for more fit patients.29

Alternative strategies that improve patients' responses are needed.

AbbVie is committed to helping address these challenges and is actively conducting research in this area to help address this unmet need.

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MM is usually defined as "a clonal plasma cell malignant neoplasm." In actuality, it is a collection of several different cytogenetically distinct plasma cell malignant neoplasms.30

Mechanism of Disease

It is hypothesized that transformation from an MM precursor cell into a malignant one occurs in a multistep process initiated during class switch recombination.31 Additional genetic events follow. Interactions with the bone marrow microenvironment lead to active proliferation of the neoplastic plasma cells.31

MM evolves from monoclonal gammopathy of undetermined significance (MGUS), a clinically recognized premalignant condition present in 3% to 4% of people older than 50 years.30 However, MGUS is mostly asymptomatic and usually only detected as an incidental laboratory finding. As a result, only 10% of patients with newly diagnosed MM have a history of preexisting MGUS.30

Dysregulated signaling pathways have been identified that contribute to MM tumor cell growth and survival, immunologic responses in the bone marrow microenvironment, and the development of resistance to therapy.31

Diagnosis & Staging

Patients with MM most commonly present with fatigue (due to anemia) or bone pain or fracture at diagnosis. Approximately 80% of patients present with osteolytic skeletal lesions.30

If MM is suspected, serum protein electrophoresis, serum immunofixation, and either a serum free light chain (FLC) assay or 24-hour urinary protein electrophoresis with immunofixation are recommended for confirmation.30

The International Myeloma Working Group updated the diagnostic criteria for MM in 2014, adding 3 highly specific biomarkers to the existing markers of end organ damage in order to allow for early diagnosis before end organ damage occurs.30,32

A diagnosis of MM requires that both criteria must be met30:

  • Clonal bone marrow plasma cells ≥10% or biopsy proven bony or extramedullary plasmacytoma
  • Any one or more of the following myeloma-defining events:
    • Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
      • Hypercalcemia—serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
      • Renal insufficiency—creatinine clearance <40 mL/min or serum creatinine >177 µmol/L (>2 mg/dL)
      • Anemia—hemoglobin value of >2 g/dL below the lower limit of normal or <10 g/dL
      • Bone lesions—one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography CT (PET-CT)
    • Clonal bone marrow plasma cell percentage ≥60%
    • Involved-to-uninvolved serum FLC ratio ≥100 (involved FLC level must be ≥100 mg/L)
    • >1 focal lesion on magnetic resonance imaging (MRI) studies (at least 5 mm in size)

In 2005, during the era of conventional agents, the International Staging System (ISS) for MM was developed as a risk stratification algorithm based on 2 measures of tumor burden.33 However, the outcome of MM has since significantly changed, primarily due to the introduction of novel and targeted agents. Thus, the ISS was revised in 2015 to include relevant biomarkers, ie, chromosomal abnormalities and elevated serum lactate dehydrogenase (LDH) levels (R-ISS).34

Revised International Staging System34:

  • Stage I (low risk)—serum albumin ≥3.5 g/dL, serum β2-microglobulin <3.5 mg/L, no high-risk cytogenetics, normal LDH
  • Stage II (intermediate risk)—not R-ISS Stage I or III
  • Stage III (high risk)—serum β2-microglobulin >5.5 mg/L and either presence of high-risk cytogenetics [t(4;14), t(14;16) or del(17p)] or elevated LDH

Treatment Challenges

While the prognosis for patients with MM has improved substantially over the past decade, nearly all will eventually relapse, including those who experience a complete response (CR) to initial therapy. In addition, MM is a genetically heterogeneous disease. As MM progresses to a more aggressive stage, the increasing genetic complexity contributes to resistance to therapy.35

Unmet Need

The incidence of MM is 5.9 cases per 100 000 people in the United States and 5.5 per 100 000 in the European Union, with approximately 50% of patients aged less than 66 years. The incidence of MM is expected to increase due to an aging population.30,36

While 8% to 20% of MM patients are asymptomatic at diagnosis, approximately 50% of these patients develop symptoms within 5 years.30,37

Until 2000, alkylators and corticosteroids were standard therapy for the typical MM patient not eligible for high-dose chemotherapy with autologous stem cell transplant (ASCT).38 While an improved understanding of the biology of MM has led to the introduction of new effective treatments over the last 15 years, many challenges still remain for the ~86 000 people diagnosed worldwide each year.36 Although survival rates have approximately doubled over the past 10 years, over 20% of patients die within a year of diagnosis.36,39

Patients with relapsed/refractory MM often have poor clinical outcomes. Median survival ranges from as little as 6 to 9 months, and responses to treatment are usually of a short duration.35

AbbVie is committed to helping address these challenges and is actively conducting research in this area to help address this unmet need.

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Focus Areas

Access in depth information on chronic lymphocytic leukemia and multiple myeloma.

BCL-2

See how a dysregulated BCL-2 pathway promotes tumor survival.

Related Pathways & Targets

References

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