Non-Hodgkin s Lymphoma

Non-Hodgkin s Lympoma Non-Hodgkin s Lymphomas Janet H. Van Cleave MSN, ACNP-CS, CS, AOCN Acute Care Nurse Practitioner The Mount Sinai Medical Center of New York City Doctoral Student, Yale University School of Nursing Mr. L. is a 65 year old gentleman Has enlarged cervical lymph node Surgeons remove lymph node Pathology shows small lymphocytic lymphoma Doctor recommends to watch and wait Non-Hodgkin s Lymphoma Mr. D is a 65 year old Has enlarged cervical lymph node Surgeons remove lymph node Shows Diffuse Large B-cell B Lymphoma Oncologist recommends R-CHOP R Non-Hodgkin s Lymphomas Why are these two patients treated differently? Normal Maturation of Lymphocytes Differentiation of healthy lymphocytes Stem cells in bone marrow Rearrangement of genes to form immunoglobulin or T-T cell receptors Exposure to antigen Large proliferating cells Hypermutation improves antigen specificity Hennessy et al., Lancet Oncology, 2004 Non-Hodgkin s Lymphoma Differentiation of healthy lymphocytes Lymphocyte differentiation and maturation Antigen profile determines B or T cell B Cell: CD19, CD20, CD22, CD40, CD45, CD 79a T Cell: CD3, CD4, CD5, CD8, CD 45 Hennessy et al., Lancet Oncology, 2004 1

Non-Hodgkin s Lymphoma: Definition Malignancy Chromosomal translocation Gene rearrangements Proto-oncogenes oncogenes Hennessy et al., Lancet Oncology, 2004 Epidemiology 2004 New cases Total: 54,370 Male: 28,850 Female: 25,520 Deaths Total: 19,410 Male: 10,390 Female: 9,020 5 th most common cause of cancer-related related deaths ACS Cancer Society, 2004 Epidemiology Slightly greater incidence in caucasian population Slightly more common in men Incidence rises steadily with age One of the most common cancers between ages 20 and 40 Incidence nearly doubled between 1970 and 1990 Epidemiology and Etiology Children: Burkitt, lymphoblastic, and diffuse large B-cell B lymphoma Adult: Diffuse large B-cell B lymphomas Follicular and small lymphocytic lymphoma increase with age Most cases occur in people over age 50 May be associated with immunodeficiency Freedman & Nadler, 2003; Hennessy, Hanrahan,, Daly, 2004 Exposure Epstein-Barr virus Human T-cell T leukemia lymphoma virus Helicobacter pylori HHV-8 Diphenylhydantoin Dioxin, phenoxyherbicides Radiation Prior Differential Diagnosis Infectious Bacterial, Viral, Mycobacterial, Parasitic Autoimmune SLE, Sjogren s syndrome, Hydantoin derivatives Ganulomatosis Sarcoidosis Neoplasms Hodgkin s disease, SCLC Freedman & Nadler, 2003 2

Diagnosis History and physical exam Systemic Symptoms or B Symptoms Fever > 38 o Night sweats Weight loss > 10% of body weight in past 5 months Diagnosis Initial biopsy of mass Bone marrow biopsy CBC, routine chemistries, liver function tests Beta2 microglobulin LDH Chest X ray CT Scans Radionuclide scans Freedman & Nadler, 2003 Non-Hodgkin s Lymphoma Non-Hodgkin s Lymphoma Diagnosis Morphology Cytogenetics 70-90% patients have chromosomal breakpoints Translocations more common Cell surface markers Molecular techniques Immunoglobulin and T cell receptor gene rearrangements Pathology Classification Schemes Evolved over 30 years Basis Pattern of lymph node architecture Cytologic classification of neoplastic cells 3

Pathology: Classification Revised European American classification of lymphoid neoplasms (REAL) Morphology Immunophenotype Genotype Clinical features Pathology: Classification Indolent lymphomas Follicular lymphoma B-chronic lymphocytic leukemia/small lymphocytic lymphoma Lymphoplasmacytic lymphoma Marginal zone lymphoma T/natural killer large cell granular lymphocyte leukemia T-chronic lymphocytic leukemia/prolyphocytic leukemia Pathology: Classification Aggressive lymphomas Mantle cell lymphoma Diffuse large B-cell B lymphoma Peripheral T-cell T lymphoma (unspecified) Peripheral T-cell T lymphoma (angioimmuoblastic angiocentric) T/natural killer cell, hepatosplenic gamma/delta, intestinal T cell lymphoma Anaplastic large cell lymphomas Pathology: Classification Highly aggressive lymphomas Precursor T or B lymphoblastic leukemia/lymphoma Burkitt and Burkitt-like lymphoma Adult T-cell T leukemia/lymphoma (HTLV-1+) Staging: Ann Arbor Staging System Stage I Single lymph node or single extralymphatic organ/site Stage II Two or more lymph node regions on same side of diaphragm or localized involvement of extralymphatic site Stage III Involvement on both sides of diaphragm Stage IV Diffuse or disseminated involvement one or more extralymphatic organs AJCC Cancer Staging Manual (2002) Staging Staging in Non-hodgkin s Lymphomas has less impact on decisions Prognosis depends more on histology and clinical parameters Age Extranodal disease Performance status Ann arbor staging LDH NCCN (2004) 4

Adverse Risk Factors Age >60 Serum LDH > 1 X normal ECOG performance status 2-42 Ann Arbor Stage III or IV Extranodal involvement > 1 site Group Risk Groups Risk Factors 5yr Survival Low risk 0-1 73% High risk 4-5 26% International Non-Hodgkin s Lymphoma Prognostic Factors Project (1993) NEJM, 329, 987 Risk Groups-Age < 60 Non-Hodgkin s Lymphoma Risk Factors 5 yr Survival 0 83% 1 69% 2 46% 3 32% Chemotherapy Regimens: Indolent Lymphomas Cyclophosphamide, Fludarabine +/- Bactrim FND (Fludarabine( Fludarabine, mitoxantrone, dexamethasone, bactrim DS) CVP (Cyclosphosphamide, Vincristine, Prednisone) CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) NCCN (2004), Chu & DeVita, Jr (2003) Chemotherapy Regimens: Aggressive Lymphomas R-CHOP (CHOP + Rituximab) ICE (Ifosfamide( Ifosfamide, Cisplatin, Etoposide) R-HyperCVAD ( Rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) R-EPOCH (Rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) ESHAP (Etoposide, methylprednisolone, cisplatin, cytarabine) Bortezomib NCCN (2004), Chu & DeVita, Jr. (2003) 5

Treatment: Indolent Lymphomas Stage I/II Radiation therapy Benefit of in stage I/II indolent NHL remains uncertain Advanced stage Close observation Systemic Rituximab Targeted radiotherapy NCCN (2004), Treatment: Aggressive Lymphomas Based on Diffuse Large B-Cell B Lymphoma (DLBCL) guidelines Approximately ~40% cured with induction R-CHOP standard treatment Radiotherapy in local disease Number of cycles dependent on stage and size of masses Consider clinical trial for high-intermediate/high intermediate/high risk categories NCCN (2004) Treatment: Aggressive Lymphomas in Older Patients Age over 60 in low and low-intermediate risk prognostic group Lower relapse-free and overall survival rates?less intensive regimens R-CHOP improved survival Treatment: Mantle Cell Lymphoma Chemotherapy resistant and aggressive disease Median survival 3 4 years No standard treatment Chemotherapy regimens used Rituxan-CHOP R-HyperCVAD R-EPOCH Autologous or allogeneic stem cell transplantation in clinical trialt Needs further study NCCN (2004) Marginal Zone Lymphoma Heterogeneous group Gastric versus nongastric Gastric associated with helicobacter pylori Gastric treatment Stage I/II: Antibiotic Advanced stage: similar to indolent lymphoma Nongastric treatment Stage I/II: Surgery, Radiation therapy Advanced: similar to follicular lymphoma NCCN (2004) Treatment: High Grade Lymphomas Lymphoblastic Lymphoma: Standard vincristine/prednisone -> > intensification Hyper-CVAD alternating w/ MTX + cytarabine Burkitt s and Burkitt s Like Lymphoma Intensive short course in clinical trial setting or combination with alkylating agents, anthracycline, intrathecal and high dose methotrexate NCCN (2004) 6

Treatment: Recurrent Disease New Therapeutic Approaches Low survival rate with conventional salvage Allogeneic stem cell transplantation Autologous stem cell transplantation Poor disease free survival in chemo resistant disease Poor survival in > 0 IPI prognostic risk factors New Therapeutic Approaches Dose dense (biweekly CHOP) in aggressive lymphoma age> 60 years with GCSF support Improved 5 year event-free and overall survival rates Increased myelosuppression Increased infection Increased cardiac toxicity Pfreundschuh et al. (2004) Blood, 104, 634-641 641 New Therapeutic Approaches Patients aged 18 to 60 years with good prognosis aggressive lymphomas w/ GCSF support CHOP with etoposide achieved better complete remission Interval reduction achieved better results Increased myelosuppression Pfreundschuh et al. (2004) Blood, 104, 626-633 633 Novel Therapies: Antisense Oligonucleotides G3139 (Oblimersen( [Genta Incorporated]) Targets BCL-2 Inhibits expression of target gene Dose limiting event Thrombocytopenia Hypotension Fever Asthenia Hennessy et al., Lancet Oncology, 2004 Novel Therapies Proteasome Inhibitors Ubiquitin-proteasome pathway Degradation of intracellular proteins Cell cycle control Apoptosis Bortezomib Bortezomib Phase I & II results promising Hennessy et al, Lancet Oncology (2004) 7

Novel Therapies Monoclonal Antibodies Rituximab Chimeric IgG1 anti CD20 monoclonal antibody First monoclonal antibody approved by FDA Proposed mechanisms of action Antibody-dependent dependent cellular cytotoxicity Complement-mediated mediated cytotoxicity Induction of apoptosis Recruitment of effector cells Cytokines Novel Therapies Monoclonal Antibodies Newer uses Combine with various chemotherapeutic agents Combination uses in transplantation regimens Use with other immunomodulatory agents Cheson,, Seminars in Oncology, 2002 Novel Therapies Monoclonal Antibodies Radioimunotherapy I 131 + anti-cd20 (tositumomab( [Bexxar]) Dosimetric dose Next week dosimetric dose followed by tositumomab Overall response rate 65% c/w 28% for last prior chemo Hematologic toxicities Evaluated in clinical trials for transplant setting Cheson,, Seminars in Oncology, 2002 Novel Therapies Monoclonal Antibodies Radioimmunotherapy 90-Yitrium anti-cd20 (ibritumomab( tiuxetan [Zevalin]) Indium-labeled tracer dose for dosimetry Overall response rate 74% in patients refractory to rituximab Grade IV neutropenia and thrombocytopenia in 35% and 9% patients Ineligible if > 25% bone marrow invasion Cheson 2002; Hennessy et al., 2004 Novel Therapies Monoclonal Antibodies Other monoclonal antibodies Alemtuzumab/Campath-1H Targets CD52 Present on most B and T lymphocytes Approved for CLL patients pretx d w/ fludarabine Epratuzumab Anti CD22 Aplizumab/Hu1d10 Directed against HLA-DR Hennessy 2004 Novel Therapies - Vaccines Idiotype markers present on all lymphoma cells Tumor cells harvested Tumor sequence identified by PCR Gene cloned Transfected into mammalian cells Produced for vaccine Ongoing trials Investigating methods to enhance the immune response Vose et al 2002 8

Summary Slide Not Available Non-Hodgkin s Lymphoma is a diagnosis comprising different types of diseases Low grade lymphoma has longer average survival but decreased response to Aggressive lymphoma has greater response to but shorter average survival Summary Diffuse large B-cell B lymphoma is the most common aggressive lymphoma and most common subtype of NHL First line treatment for diffuse large B-cell B lymphoma is R-CHOP R Approximately 40% can patients w/ diffuse large B-cell B lymphoma can be cured with Nursing Implications R-CHOP Chemotherapy Adverse Effects Doxorubicin/Vincristine strong vesicants Nausea/Vomiting Myelosuppression Cardiotoxicity Neuropathy Anaphylactic reactions Hemorrhagic cystitis Alopecia Chu & DeVita, Jr. (2003) Nursing Implications: R-CHOPR Generally outpatient except for co- morbid conditions or concern for risk for tumor lysis syndrome in setting of bulky disease Assess patient for adequate vascular access in setting of strong vesicants Evaluate cardiac left ventricular ejection fraction prior to initiating Evaluate for need for hematological growth factor support Use with caution in setting of liver dysfunction Fischer et al (2003), Chu & DeVita, Jr. (2003), Pfreundschuh et al (2004) Why did one patient receive and the other patient did not receive? Why did the doctor Watch and wait for recommend asymptomatic Mr. D indolent lymphoma (aggressive Chemotherapy lymphoma) and none aggressive lymphoma for Mr. L (indolent lymphoma)? 9

Thank You Mount Sinai Medical Center Thomas Smith RN Takao Ohnuma MD 10