1 What is non-Hodgkin lymphoma, how is it treated, and what is the unmet need? Tim Illidge BSc PhD MRCP FRCR FRCPath Institute of Cancer Sciences, University of Manchester Manchester Cancer Research Centre, Manchester, UK
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What is non-Hodgkin lymphoma, how is it treated, and what is the
unmet need?
Tim Illidge BSc PhD MRCP FRCR FRCPathInstitute of Cancer Sciences,
University of ManchesterManchester Cancer Research Centre,
Manchester, UK
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Professor Tim Illidge
• Professor of Targeted Therapy and Oncology at the Institute of Cancer Sciences, the Christie NHS Foundation Trust in Manchester, UK
• Fellow of the Royal College of Radiologists and the Royal College of Pathologists, and Member of the Royal College of Physicians
• Researches new antibody-based therapies for lymphoma
• Has led many early- and late-phase clinical trials
• Author of >100 publications
• Co-Chair of Nordic Nanovector's Scientific Advisory Board
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Non-Hodgkin lymphoma
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Non-Hodgkin lymphoma
• Approximately 1.5 million people worldwide are living with non-Hodgkin lymphoma (NHL)
• 81% increase in incidence of NHL between 1973–1990
• NHL is the third fastest growing cancer in the world (excluding the US) in terms of population
• An estimated 300,000 people die each year from NHL and it is the leading cause of death due to cancer in men aged 20–40 years
Based on US statistics4
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Frequency of NHL subtypes in adults
MALT: mucosa associated lymphoid tissue; NHL: non-Hodgkin lymphoma
Armitage JO, Weisenburger DD. J Clin Oncol 1998; 16: 2780–2795.
Follicular (22%)
Diffuse large B-cell (31%)
Small lymphocytic (6%)
Mantle cell (6%)
Peripheral T-cell (6%)
Marginal zone B cell, MALT (5%)
Other subtypes with a frequency <2% (9%)
Marginal zone B-cell, nodal (1%)Lymphoplasmacytic (1%)
Composite lymphomas (12%)
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B-cell NHL85%
NHL can be divided into several subtypes
*59% of indolent lymphomas, i.e. 24% of all B-cell NHL; ** 61% of aggressive lymphomas, i.e. 36% of all B-cell NHL
MALT: mucosa associated lymphoid tissue; NHL: non-Hodgkin lymphoma 6
• Follicular lymphoma (~59%*)
• Small lymphocytic lymphoma
• MALT lymphoma
• Lymphoblastic lymphoma
• Lymphoplasmacytic lymphoma
• Diffuse large B-cell lymphoma (~61%**)
• Mantle cell lymphoma
• Burkitt lymphoma
• Primary mediastinal large B-cell lymphoma
Aggressive lymphomas: More aggressive disease, may be cured by chemotherapy
Indolent lymphomas: Relatively long median survival, usually not curable in advanced stages
Indolent lymphomas~41%
Aggressive lymphomas~59%
NHL
T-cell NHL15%
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0 2 4 8 126 10
0
25
50
75
100
Pro
bab
ility
of
surv
ival
(%
)
Years
Indolent NHL(e.g. follicular lymphoma)
Aggressive NHL(e.g. diffuse large B-cell lymphoma)
Survival patterns for indolent and aggressive NHL in the 20th century
NHL: non-Hodgkin lymphoma
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Follicular lymphoma and diffuse large B-cell lymphoma are two NHL subtypes of interest
Follicular lymphoma
• Low-grade/indolent
• 20–30% of NHL cases
• 80–85% of patients are diagnosed in a late stage (stage III or IV) due to its slow growth
• Average age of diagnosis is 60 years
• May not always require treatment and for those who are asymptomatic with low disease burden - Watch-and-wait may be used.
NHL: non-Hodgkin lymphoma8
Diffuse large B-cell lymphoma
• High-grade / Aggressive
• Most common NHL; 31% of all cases
• Occurs most frequently in those aged >50 years ( average age 62 years)
• Immediate combination chemotherapy treatment is essential and potentially curable
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Treating non-Hodgkin lymphoma
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Healthcare professionals that treat patients with NHL
FDG PET/CT: fluorodeoxyglucose positron emission tomography/computer tomography; HCP: healthcare professional; NHL: non-Hodgkin lymphoma10
Radiation oncologist/ nuclear medicine specialist
There is an established pathway to the radiation oncologist in NHL.This HCP may already administer radiopharmaceuticals to oncology patients e.g. Xofigo® (used in the treatment of prostate cancer)
Hematologist oncologistPart of the standard treatment process. Increasingly involved with HCPs in nuclear medicine largely due to the development of FDG PET/CT and radiopharmaceuticals
SurgeonLimited role for surgeons because surgery is not part of the standard treatment pathway for NHL
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Therapies used for NHL
• Cytotoxic chemotherapy e.g. CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone)
• Cell surface receptor-targeted therapies e.g. antibody therapies
• Includes drugs such as rituximab that target cell-surface proteins such as CD20
• Molecularly targeted therapies e.g. therapies targeting downstream signal transduction pathways—block cancer growth and spread by interfering with specific molecules involved in tumor growth and progression
• Targeted agents act on the tumor-specific genes, proteins or the tissue environment that contribute to growth and survival
• Targeted agents have several advantages over chemotherapy:
• Greater tumor specificity
• Potentially more favorable toxicity profile
NHL: non-Hodgkin lymphomaCancer.net, accessed October2015
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Rituximab: an engineered murine/human chimeric monoclonal antibody – granted US FDA approval for the treatment of cancer in 1997
FDA: Food and Drug AdministrationAdapted from: Ryback et al. 1992
Murine-variable regions bindspecifically to CD20 on B cells
Human k constant regions
Human IgG1 Fc domain works in synergywith human effector mechanisms
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Rituximab has revolutionized the treatment of B-cell malignancies through significantly improving patient outcomes
B-CLL: B-cell chronic lymphocytic leukemia; CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone; DLBCL: diffuse large B-cell lymphoma; Coiffier B et al. N Engl J Med 2002; 346: 235–242; Hallek M et al. Lancet 2010; 376: 1164–1174.
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Therapies used for NHL
• Cytotoxic chemotherapy e.g. CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone)
• Cell surface receptors e.g. antibody therapies
• Includes drugs such as rituximab that target cell-surface proteins, e.g. CD20
• Molecularly-targeted therapies e.g. therapies targeting downstream signal transduction pathways—block cancer growth and spread by interfering with specific molecules involved in tumor growth and progression
• Targeted agents act on the tumor-specific genes, proteins or the tissue environment that contribute to growth and survival
• Targeted agents have several advantages over chemotherapy:
• Greater tumor specificity
• Potentially more favorable toxicity profile
• Not all tumors express the same targets
NHL: non-Hodgkin lymphomaCancer.net, accessed October2015
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Immunochemotherapy has become the mainstay of NHL treatment
• Immunochemotherapy, combining rituximab and chemotherapy, is used in both indolent and aggressive disease +/- radiotherapy
• Specific treatments vary depending on the patient, disease subtype, and stage of disease
• Several common immunochemotherapy regimens include:
ARA-C: cytarabine; R: rituximab15
R-CHOPcyclophosphamide,
hydroxydaunomycin (doxorubicin), Oncovin® (vincristine), prednisone
R-CVPcyclophosphamiode, vincrostine,
prenisone
R-ICEifosfamide, carboplatin,
etoposide
R-EPOCHetoposide, prednisone, Oncovin®,
cyclophosphamide, halotestin
R-ESHAPetoposide, adiramycin
(doxorubicin), Ara-C, platinum
R-DHAPdexamethasone, cytarabine,
cisplatin
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Diffuse large B-cell lymphoma treatment pathway
16ASCT: allogeneic stem cell transplant
Rituximab chemotherapy
Eligible for transplantation?
Salvage chemotherapy followed by high-dose therapy
and transplantation
Palliative chemotherapy
Novel agents/clinical trialsNovel agents/clinical trials
Yes No
Two-thirds of patients fail to get to transplant and 50% relapse after ASCT
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Follicular lymphoma treatment pathway proposed at ASH 2004
*Symptoms, cytopenias, rapid growth of disease, potential organ compromise (e.g. hydronephrosis); **Consider collection of peripheral blood progenitor cells for future transplantation. ASH; American Society of HematologyWinter JN et al. Hematology Am Soc Hematol Educ Program 2004: 203–220.
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Stage I–II disease
Involved field radiotherapy
Stage III–IV diseaseIndications to treat*
Watch and wait
Rituximab chemotherapy
Rituximab maintenanceIndications to treat
Radioimmunotherapy
Transplantation (age/fitness limitation!)
**
Yes No
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The unmet clinical need: Patients who ‘fail’ rituximab-chemotherapy treatment or are unfit for multi-agent treatment
• Rituximab has been successful in improving patient outcomes
• Rituximab-chemotherapy regimens have become the standard of care in first- and second-line
• Although there is a substantial number of patients with DLBCL can be cured by these treatments, many are refractory or relapse
• In follicular lymphoma, many patients eventually relapse and become refractory to rituximab
• Novel agents are required and targeting the cell surface receptors with improved antibodies and antibody conjugates allows the majority of lymphomas to be targeted
DLBCL, diffuse large B-cell lymphoma18
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B cells express several antigens that can be targeted
• CD20 is only one of the antigens expressed by B-cell lymphomas that could be targeted by antibody-based therapies
• CD37 is expressed by adult B cells and has been measured on the vast majority of B-cell lymphomas
• Targeting alternate antigens, such as CD37, could bypass the cellular mechanisms that lead to rituximab-refractory disease
• CD37 is therefore a useful therapeutic target for novel therapies in lymphoma patients that have relapsed after CD20-based therapy
Dahle J et al. Anticancer Res 2013; 33: 85–95; Figure adapted from Press OW. Semin Oncol 1999; 26 (5 Suppl 14): 58–65.
DR
sIg
CD20
CD37
CD22
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Radioimmunotherapy: Antibody-radionuclide conjugates
• Lymphoma cells are inherently sensitive to radiation
• Radiotherapy can be effective in chemotherapy-refractory and rituximab-refractory disease
• Continuous delivery of low-dose radiation and antibody effector mechanisms
• Radiation also destroys tumor cells distant from targeted tumor cell
Press WO. Semin Hematol 2000; 37(4 Suppl 7): 2–8; Krasner C, Joyce RM. Curr Pharm Biotechnol 2001; 2: 341–349; Zelenetz AD. Curr Opin Oncol 1999; 11: 375–380.
Betalutin®
177Lu
177Lu
177Lu
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Defining features of single treatment antibody-radionuclide conjugate in relapsed follicular lymphoma
• High response rates (ORR and CR)
• Durable long-term responses
• Simple and effective treatment; high quality-of-life for both older and younger patients
• Limited uptake and availability
CR: complete response; ORR: overall response rate
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The unmet need innon-Hodgkin lymphoma
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Where is the unmet need in NHL?
NHL: non-Hodgkin lymphoma23
Relapsed NHL No standard therapy past second-line
Rituximab resistance Patients who have developed resistance to the CD20-targeted antibody
Older patientsPatients aged >65 years might not be able to tolerate some chemotherapies
Comorbidities Some comorbidities can impact tolerability of treatment
Lack of response Patients with a poor response to first- or second-line treatment
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What features should we look for in a novel therapy to help us meet these unmet needs?
• Antibody-radionuclide conjugate therapy (radioimmunotherapy) that has a strong efficacy and safety profile in relapsed and refractory patient populations, including:
• Patients who have failed previous therapies
• Patients who are have relapsed or are refractory to rituximab
• Patients who are considered ‘frail’ that might not be eligible for current therapies, e.g. older patients, those with comorbidities
• A treatment that does not have strict compliance requirements
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Summary
• NHL has several subtypes; the most common are follicular lymphoma and diffuse large B-cell lymphoma
• Chemotherapy, rituximab, radiotherapy and targeted treatments are commonly used to treat NHL
• There is no standard treatment beyond second line, and there is an unmet need for new therapeutic options for patients who have failed previous therapies
• A novel antibody-radionuclide conjugate treatment could be a future option for second- or third-line therapy in patients with follicular lymphoma or diffuse large B-cell lymphoma, who are unable to tolerate transplantation or chemotherapy
NHL: non-Hodgkin lymphoma25