optimizing patient outcomes in non-hodgkin lymphoma: an update for oncology nurses barbara barnes...

Optimizing Patient Outcomes in Non-Hodgkin Lymphoma: An Update for Oncology Nurses

Barbara Barnes Rogers, CRNP, MN, AOCN, ANP-BC

Adult Hematology-Oncology Nurse Practitioner

Fox Chase Cancer Center

Disclosure of Conflicts of Interest

Barbara B. Rogers has an affiliation with Celgene (Advisory Board) and Allos, Cephalon, Seattle Genetics, and Millennium (Speaker’s Bureaus).

Learning Objectives

After completing this activity, the participant should be better able to:

• Discuss the classification, presentation, and diagnosis of NHL

• Explain the prognosis of NHL using established prognostic models

• Identify the different classes and mechanisms of therapeutic agents for treating NHL

• Recognize the signs and symptoms of side effects and complications associated with chemotherapy

• Manage chemotherapy side effects and complications in patients with NHL

Non-Hodgkin Lymphoma

• A heterogeneous group of lymphoid tumors that have distinct clinical and biologic behaviors

• Accurate diagnosis of specific NHL subtype important to understand management

• Biological and clinical heterogeneity can be noted within each subtype

Incidence of NHL• Incidence rising:

– Faster than that of all other malignancies except lung cancer in women, melanoma and prostate cancer

– Age-adjusted incidence in US increased from 11.1 per 100,000 in 1975 to 19.8 per 100,000 in 2008

• Reason for rising incidence:– NHL in patients with acquired immunodeficiency syndrome (AIDS)– Improvements in diagnosis– Other reasons (most likely primary cause)

• Estimated new cases in the US in 2011 is 66,360• Race:

– 30% higher in whites than blacks– Blacks > whites age less than 50– Whites > blacks age over 55

Greer J, Williams M. Wintrobe’s Clinical Hematology (12th Ed). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins, 2009.

American Cancer Society: Cancer facts and figures 2011.

Epidemiology

• Variable world-wide distribution• More common in males than females• Represent ~10% of all childhood cancers in

developed countries• More common in adults than children• Steady increase in incidence from childhood

through age 80 years• Seventh most common malignancy in US• Represent 4% of all cancers

Risk Factors– Abnormality of immune function:

• HIV infection• Iatrogenic immune suppression• Autoimmune diseases• Congenital immune deficiencies• Wiskott-Aldrich• X-linked lymphoproliferative disorder

– Infectious agents:• Gamma herpes viruses• Epstein-Barr virus - associated with African Burkitt lymphoma, AIDS-related

DLBCL, NK/T-cell nasal type lymphoma• Kaposi’s sarcoma-associated herpes virus (human herpes virus 8) - linked to

primary effusion lymphomas and multicentric Castleman’s disease• Human T-lymphotropic virus I (HTLVI) - adult T-cell leukemia/lymphoma• Helicobacter pylori - gastric malt• Hepatitis C virus - spenic marginal zone lymphoma; other B-cell lymphomas• Campylobacter jejuni - immunoproliferative small intestinal disease• Borrelia burgdorferi - primary cutaneous B-cell lymphoma• Chlamydia psittaci - ocular adnexal lymphoma


Environmental Factors Associated with NHL

– Environmental and occupational exposures• Organic compounds (organophosphate insecticides)• Drug exposure

– Phenytoin– Carbamazepine– Methotrexate– TNF-α inhibitors - etanercept, infliximab, adalimumab

• Toxic chemical exposure


Clinical Features of NHL

• Painless adenopathy - more common in cervical, axilla, or groin

• B symptoms - fevers, night sweats, weight loss• Extranodal disease can be detected in up to 40% of

patients– GI tract most common site– Skin– CNS involvement– Ocular

• Significant cytopenias rare• Hepatosplenomegaly - common feature of advanced

disease manifested by upper abdominal pain

Where Do B-Cell Lymphomas Originate?

Jaffe E, et al. Blood. 2008;112:4384-4399.

Classifications of NHL

• B-cell vs T-cell– B-cell NHL - 88% of all NHLs– T-cell NHL - 12% of all NHLs

• Indolent vs Aggressive• WHO classification includes:

– Immunophenotypic– Molecular– Genetic – Clinical elements

Diagnostic Work-Up

History and Physical

CBC with diff/plts

Viral Testing: HIV, HTLV-1, Hepatitis

Metabolic Panel with LDH

B2 microglobulin

CXR

CT of neck, chest, abdomen, pelvis

PET/CT

Biopsy with flow cytometry and cytogenetics

Bone marrow aspirate and biopsy

Lumbar puncture with cytology, if indicated

GI endoscopy in those with GI symptoms

Indications for Lumbar Puncture

• Small non-cleaved cell NHL• Lymphoblastic lymphomas• NHL of certain sites:

– Nasopharynx– Epidural space– Testes– Large cell with marrow involvement– HIV +


Subtypes of NHL

T and NK cell(12%)

Other subtypes(9%)

Burkitt(2.5%)

Diffuse large B cell(30%)

Follicular(25%)

Small lymphocytic lymphoma/CLL

(7%)

Nodal-type marginal-zone B cell

(< 2%)

Lymphoplasmacytic (< 2%)

MALT-type marginal-zone B cell (7.5%)

Lichtman MA. Williams Hematology. (7th Ed). New York, NY: McGraw Hill, 2006;1408.

Mantle cell(6%)

Antigen Expression Associated with B-Cell NHL

Bone Marrow Periphery (Spleen, Lymph Node)

Pro-B Pre-B Immature B Mature B GC BMature B

Memory B

Plasma Cell

CD19CD19 ++ ++ ++ ++ ++ ++ ++ ––

CD10CD10 ++ ++ +/–+/– –– –– ++ –– ––

CD20CD20 –– –– ––/+/+ ++ ++ ++++ ++ ––

CD38CD38 ++++ ++++ ++ ++ ++ ++++ ++ ++++

CD22CD22 –– –– ++ ++ ++ ++ ?? ––

CD52CD52 ++

CD80CD80 –– –– –– –– –– ––Activated B-cellsActivated B-cells

Plasmablast

WMWM MMMMALLALL CLL, CLL,

PLLPLL Burkitt’s, FL, DLBCL, HCLBurkitt’s, FL, DLBCL, HCLALL = acute lymphoblastic leukemia FL = follicular lymphoma HCL = hairy cell leukemia CLL = chronic lymphocytic leukemia DLBCL = diffuse large B-cell lymphoma MM = multiple myeloma

PLL = prolymphocytic leukemia WM = Waldenström’s macroglobulinemia

Jaffe ES, et al, eds. World Health Organization Classification of Tumours. 2001. Hale G, et al. Tissue Antigens. 1990;35:118-127.Freeman GJ, et al. J Immunol. 1989;143:2714-2722.

Molecular Indices in Lymphocytic Malignancies

Lymphoma Subtype Morphology ImmunophenotypingFavorable = fUnfavorable = u

Common Cytogenetic Abnormalities

Molecular Testing

Diffuse large B-cell (DLBCL)

Diffuse pattern with distortion of the normal architecture of the lymph node or extranodal site

CD20+, CD45+, CD3- t(14;18), t(3;v), t(8;14)

Testing for bcl-2, bcl-1, c-mycAll offer a survival advantage to the lymphoma cells u

Follicular lymphoma (FL)

Nodal lymphoma with a follicular growth pattern

CD10+,CD20+, sIg+, CD23+/-, CD22+, CD25+/-

t(14;18)(q32;q21) 85% IgH re-arrangement with bcl-2 expression which leads to cellular resistance to apoptosis u

Small lymphocytic lymphoma/chronic lymphocytic leukemia

Usually appear normal, may be large, smudge cells may be present, pro-lymphocytes are common

CD5+, CD20dim+, sIgdim+,

CD23+, CD22-, CD25-(+)

CD38+ u

Trisomy 12t(11q;v) udel(11q) udel(17p) udel(13q) f

Patients with variable region Ig mutations have a more favorable prognosis u

Mantle cell lymphoma (MCL)

Cells populating the mantle zone of the follicle

CD5+, CD20+, sIg+, CD22+, CD45+

CD10-, CD23-, CD25-

Cyclin D1+

t(11;14)(q13;q32)de-regulates cyclin D1 expression interfering with cell cycle regulation

IgH re-arrangement with bcl-1 (increased cell proliferation), and bcl-6 expression (resistance to apoptosis) u

Peripheral T-cell lymphoma (PTLC)

Peripheral T-cells and no features of other subtypes

CD4+, CD7-, CD8- Clonal re-arrangements of the receptor genes seen in non-cancerous T-cell disease are common

Kurtin S. Oncology Nurse. 2008;1(5):1-2.

Differences Between Childhood and Adult Non-Hodgkin Lymphomas

Children Adults

Incidence Rare Common

Median Age 10-15y 55-70y

Presentation Extranodal > nodal Nodal > extranodal

Most common histologic diagnoses

B cell: Burkitt, diffuse large cellT cell: Lymphoblastic; ALK+ anaplastic large cell

B cell: diffuse large cell (DLBCL), small cleaved (follicular center) cellT cell: Peripheral T-cell unspecified; anaplastic large cell; angioimmunoblastic

Immunophenotype 50-70% B cell 85-90% B cell (US & Europe)

Paraprotein None Rare (<5%)

Clinical course Aggressive Variable - often indolent

Curability 70-90% <30% except 40-70% in aggressive subtypes, particularly DLBCL


Indolent NHL

• Long median survival

• Slow but continuous decline in survival

• Usually advanced stage at presentation

• Respond to therapy but relapse

• May transform to aggressive lymphoma

• Rarely, can spontaneously regress

Indolent Lymphoma Subtypes

• Follicular lymphoma• Small lymphocytic lymphoma• Lymphoplasmacytic lymphoma

(Waldenström macroglobulinemia)• Marginal zone lymphoma• Splenic marginal zone lymphoma• Primary cutaneous anaplastic large cell

lymphoma• Mycosis fungoides (Sézary syndrome)

National Cancer Institute: Adult Non-Hodgkin Lymphoma Treatment (PDOR), cellular classification of adult NHL.

Aggressive Lymphomas

• Present acutely or sub-acutely with:– A rapidly growing mass– Systemic B symptoms:

• Fever• Night sweats• Weight loss

– Elevated serum LDH (lactate dehydrogenase)– Elevated uric acid

• Examples:– Diffuse large B cell lymphoma– Burkitt lymphoma– Adult T cell leukemia/lymphoma – Precursor B and T lymphoblastic leukemia/lymphoma– Mantle cell lymphoma


Peripheral T-cell Lymphoma Subtypes

O’Leary. Curr Opin Hematol. 2009;16:292.International T-Cell Lymphoma Project. J Clin Oncol. 2008;26:4124.de Leval. Hematology Am Soc Hematol Educ Program. 2008;272.

ALCL = anaplastic large-cell lymphomaALK = anaplastic lymphoma kinasePTCL = peripheral T-cell lymphoma.

Ann Arbor Staging SystemStage Description

I Single lymph node region or single extralymphatic organ or site

II Two or more lymph node regions on the same side of the diaphragm or single exanodal site with adjacent nodes

III Nodal regions on both sides of the diaphragm or involving single extranodal site with adjacent nodes, or spleen or both

IV Diffuse or disseminated involvement of one or more extralymphatic organs, bone marrow, liver, brain involvement

A No symptoms

B Fevers, chills, night sweats, weight loss

E Extranodal involvement

X Bulky

S Spleen involvement

Prognostic IndexesIPI AA-IPI FLIPI MIPI PIT

Age >60 years Performance Status 2 or more

Age >60y Age Age

Performance Status

LDH above normal

Stage III/IV Performance Status

Performance Status

LDH above normal

Stage III or IV Hemoglobin <12 g/L

LDH LDH

Two or more extranodal sites

Number of nodal areas >4

Leukocyte count

BM Involvement

Stage III or IV LDH> normal

IPI = International Prognostic IndexAA-IPI = Age Adjusted IPIFLIPI = Follicular Lymphoma IPIMIPI = Mantle Cell IPIPIT = Peripheral T cell NHL IPI

The International Non-Hodgkin’s Lymphoma Prognostic Factor Project. N Engl Med. 1993;329:987-994.Solal-Celigny, et al. Blood. 2004;104:1258-1265. Gallamini A, et al. Blood. 2004;103:2474-2479. Geisler C, et al. Blood. 2010;115:1530-1533.

Progression-Free Survival Based on IPI

Sehn L, et al. Blood. 2007;109:1857-1861.

Overall Survival of Patients with PTCL Based on Prognostic Index for PTCL (PIT)

Group 1 - 0 risk factorsGroup 2 - 1 risk factorGroup 3 - 2 risk factorsGroup 4 - 3-4 risk factors

Gallamini A, et al. Blood. 2004;103:2474-2479.

Treatment Related Issues

• Ability of patient to tolerate treatment dependent on:– Age– Performance status– Immunodeficiency from pre-lymphomatous

condition

• Higher mortality in elderly– Increased treatment related toxicities– Death from unrelated causes are increased– Greater lymphoma related mortality

Management of Indolent Lymphoma:Treatment Options

• Watchful waiting• Local radiation for limited

stage disease• Chemotherapy:

– Alkylating agent– Nucleoside analog– Combination chemotherapy

• Immunotherapy:– Unconjugated monoclonal

antibody– Radioimmunotherapy– Interferons– Interleukins– Vaccines

• Combined modality therapy:– Chemotherapy and radiation

therapy– Chemotherapy and

immunotherapy• Transplantation:

– Autologous – Allogeneic:

• Myeloablative• Non-myeloablative

• Selective therapies:– Antibiotics in selected

maltomas– Splenectomy


Management of Diffuse Large B-Cell Lymphoma (DLBCL)

• Initial: R-CHOP =/- IFRT– Management of aggressive (high Ki67) DLBCL

• Relapsed: +/- autologous transplant– RICE

– R-DHAP

– R-ESHAP

– R-GemOx

– R-MINE

– R-GDPNCCN. Non-Hodgkin’s Lymphoma. Version 2.2012.

Management of Follicular Non-Hodgkin’s Lymphoma

Frontline: Bendamustine/Rituximab R-CHOP R-CVP Rituximab R-Fludarabine Clinical Trial

Relapsed: Rituximab Bendamustine/Rituximab R-CHOP R-CVP Lenolidomide Radioimmunotherapy Clinical Trial

NCCN. Non-Hodgkin’s Lymphoma. Version 2.2012.

Management ofPeripheral T-Cell Lymphoma

Frontline: CHOP Hyper CVAD Clinical Trial Autologous Peripheral Stem Cell Transplant as consolidation

Recurrent/Refractory: DHAP ESHAP GDP ICE Pralatrexate Romidepsin Brentuximab vedotin Alemtuzumab Cyclosporine Bortezomib Denileukin diftitox Gemcitabine Clinical Trial

Foss F, et al. Blood. 2011;117:6756-6767.

Role of Transplant in the Management of NHL

• Outcomes dependent on:– Disease State:

• Type of lymphoma• Remission status - best outcome in patients in first CR or have

minimal disease before transplant– Patients with disease that is responsive to therapy have 30-60%

salvage rate– Patients with resistant relapse have 0-15% salvage rate

– Patient factors:• Age• Performance Status

– Source of stem cells• Autologous• Allogeneic - higher mortality rate

• No superior preparative regimen

Overall Survival in PTCL The International PTCL and NK/T-Cell Lymphoma Study

PTCL Subtypes

ALK+ ALCL

ALK– ALCL

PTCL-NOS

AITLNK/T-Cell

LymphomaATLL

5-Yr OS Rate (%) 70 49 32 32 32 14

ATLL = adult T-cell leukemia/lymphoma; OS = overall survival.

International T-Cell Lymphoma Project, 2008.Vose J, et al. J Clin Oncol. 2008;26:4124-4130.

Side Effects of Agents Used in the Treatment of B-Cell Lymphomas-

CHOPCyclophosphamide - hemorrhagic cystitis, nausea and vomiting, anorexia, stomatitis, diarrhea, hepatotoxicity, neutropenia, alopecia, sexual dysfunction, SIADH, pulmonary toxicity.

Doxorubicin - neutropenia, thrombocytopenia, cardiac toxicity, nausea and vomiting, anorexia, stomatitis, alopecia, radiation recall, nail and skin changes, drug extravasation, sexual dysfunction.

Vincristine - peripheral neuropathy, constipation, alopecia, mild neutropenia, mild thrombocytopenia, impotence.

Prednisone - gastric irritation, decreased carbohydrate metabolism, hyperglycemia, edema, fluid and electrolyte alterations, immunosuppression, cushingoid changes, cataracts, glaucoma, ocular infections, behavioral changes, muscle weakness.

Wilkes G, Barton-Burke M. Oncology Nursing Drug Handbook (2011 Ed). Sudbury, MA: Jones and Bartlett Publishers, 2011.

Side Effects of Agents Used in the Management of NHL

Rituximab - infusion reactions, tumor lysis, lymphopenia, mucocutaneous reactions, reactivation of hepatitis B, nausea and vomiting, pruritus, myalgias.

Fludarabine - neutropenia, thrombocytopenia, pulmonary toxicity, nausea and vomiting, diarrhea.

Bendamustine - neutropenia, anemia, thrombocytopenia, infusion reaction, tumor lysis, nausea and vomiting, diarrhea, rash.

Lenalidomide - neutropenia, thrombocytopenia, anemia, rash, fatigue, light headedness, leg cramps, diarrhea, constipation, nausea, electrolyte imbalance, birth defects.


Side Effects of Agents Used in the Treatment of B-Cell

Lymphomas-Radioimmunotherapy

90Y Ibritumomab tiuxetan (Zevalin) - infusion reaction, neutropenia, anemia, thrombocytopenia, nausea, abdominal pain, headache, secondary malignancies.

131I tositumomab (Bexxar) - infusion reaction, neutropenia, anemia, thrombocytopenia, secondary malignancies, thyroid dysfunction.


Side Effects of Agents Used in the Management of T-Cell NHL

Romidepsin - anemia, leukopenia, neutropenia, thrombocytopenia, infection, EKG changes, asthenia, decreased appetite, headache, cough, rigors, weight loss.

Pralatrexate - stomatitis, thrombocytopenia, nausea, fatigue, anemia, neutropenia, dyspnea, hypokalemia, altered LFTs, abdominal pain, leukopenia, febrile neutropenia, sepsis, hypotension.

Brentuximab vedotin - peripheral neuropathy, nausea, fatigue, pyrexia, diarrhea, rash, constipation, neutropenia.

Alemtuzumab - anemia, neutropenia, thrombocytopenia, fever, infection, viremia (CMV, EBV), hypotension, rash, urticaria, diarrhea, nausea, vomiting, myalgias, insomnia, anxiety, bronchospasm, dyspnea.

Denileukin Diftitox - fever, fatigue, rigors, nausea, headache, edema, cough, dyspnea, pruritus, rash, hypotension, back pain, myalgia, chest pain, tachycardia, hypoalbuminemia, asthenia, altered LFTs, capillary leak syndrome, infusion reactions, visual impairment.


Toxicity Interventions

Myelosuppression (neutropenia, anemia, thrombocyopenia)

1. Assess baseline CBC2. Assess CBC throughout therapy3. Assess for signs/symptoms of

infection or bleeding4. Teach patient the signs and

symptoms of infection or bleeding and to report these immediately

5. Teach patient self-care measures to minimize risk of infection and bleeding

6. Transfuse as necessary7. Discuss need for dose

modifications with prescriber/physician


Management of Side Effects of Agents Used in the Management of NHL


Nausea and vomiting 1. Teach patient to take antiemetic as needed2. Administer antiemetic prior to administration of

chemotherapy3. Encourage patient to eat small, frequent meals4. Teach dietary modifications as needed5. Teach patient to notify healthcare

professionals if antiemetics not successful in relieving nausea

Peripheral Neuropathy 1. Assess sensory/motor changes prior to each treatment

2. Notify prescriber/physician of alterations in neurologic function

3. Discuss need for dose modifications4. Teach patient about potential for neuropathy and

need to notify healthcare providers for difficulty in performing ADLs


Stomatitis 1. Perform oral assessment prior to each treatment

2. Teach patient to perform good oral hygiene and use mouthwash with salt water or salt and soda mouthwash

3. Recommend patient have dental exam prior to starting treatment

4. Teach patient to contact health professional for any mouth discomfort



Management of NHL in the Elderly

• Over half of new cases occur in those over the age of 60 years

• Prognosis poor in the elderly– Poor performance status– Reduced vital organ reserve– Comorbid diseases– Biologic features of lymphoma

Management of NHL in Pregnancy• Lymphoma during pregnancy is rare (about 100 reported cases)• Therapy is based on histologic type and the point of gestation at diagnosis• Most women who develop NHL during pregnancy have aggressive histologies

and advanced-stage disease• Unusually high incidence of breast, ovarian, uterine and cervix involvement -

most likely due to hormonal influenced and increased blood flow to these organs

• Placental involvement rare• Transmission to fetus uncommon• Staging studies are limited due to concerns about radiation exposure during

pregnancy– CXR can be done– MRI can be used but to be avoided during first trimester– Ultrasound and echocardiograms can be useful– PET can be performed after delivery but since FDG is concentrated in breast tissue,

patients should avoid breast feeding for 72 hours after the scan• Prognosis for mother relatively poor:

– EFS 40-45%– Due to aggressive nature of disease and advanced stage

Brenner B, et al. Lancet. 2012;379:580-587.

Management of NHL During Pregnancy

• Abortion should be considered when aggressive lymphoma is diagnosed during first trimester unless localized above diaphragm– In that situation, can use involved field radiation therapy (with abdominal

shielding)• Radiation should be avoided until third trimester• Combination chemotherapy can be given in second or third trimester

– Anthracyclines have been given without untoward effects to mother or fetus but should be avoided if possible

– Rituximab plus chemotherapy has been given without evidence of harm• Early delivery should be considered:

– Avoid myelosuppression– To initiate intensive chemotherapy

• Complete staging after delivery• Low-grade lymphomas can be observed until after delivery

Brenner B, et al. Lancet. 2012;379:580-587.

Long-term Effect of Therapy

• Not as well defined as in HL• Appear to be similar to HL and depend on:

– Therapy used– Age of patient– Comorbid illnesses

• Long-term effect:– Endocrine - infertility, hypothyroid, panhypopituitarism, growth

retardation– Psychosocial issues – Transfusion - induced viral infections – Second neoplasms

• Radiation is main cause of endocrine and neurologic toxicities and secondary solitary neoplasms

• Cardiotoxicity from anthracyclines is manifested as CHF– Cumulative incidence of cardiovascular disease in NHL treated with

anthracycline was:• 12% at 5 years• 22% at 10 years

Secondary Malignancies

• Increased risk over time for: – AML– Bladder cancer– Kidney cancer– Lung cancer– Malignant melanoma– HL

• Up to 10% of patients with NHL treated with chemotherapy or autologous transplant may develop MDS or AML within 10 years of their initial therapy


Key Takeaways

• NHL is a heterogeneous group of malignancies that have distinct morphologic and molecular differences

• The distinct subtypes of NHL require specific management

• There are multiple prognostic indexes that can be used to calculate the level of risk of the patient’s lymphoma

• The prognosis is poorer in the elderly diagnosed with NHL than in younger patients

• Nursing interventions can assist patients in managing side effects from their treatment

optimizing patient outcomes in non-hodgkin lymphoma: an update for oncology nurses barbara barnes...

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