Downloadable slide decks are a great tool for self study and teaching purposes. They are non-certified resources available to enhance your knowledge. Review a downloadable slide deck by Sandra E. Kurtin, MS, RN, ANP, AOCN®, covering the most clinically relevant new data reported from The 2012 Oncology Nurse Hematology Conference. Target Audience This activity has been designed to meet the educational needs of medical oncologists, radiation oncologists, surgical oncologists, APNs, RNs, pharmacists, managed care pharmacy directors, pathologists, medical directors, allied health professionals, and other physicians affiliated with medical facilities treating patients with head and neck cancers (HNC). Format: Microsoft PowerPoint (.ppt) | File size: 10.1 MB | Date posted: 4/19/2012 Slide Deck Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of April 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CE provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity. Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.

2. DISCLAIMER
Participants have an implied responsibility to use the newly acquired information
to enhance patient outcomes and their own professional development. The
information presented in this activity is not meant to serve as a guideline for
patient management. Any procedures, medications, or other courses of diagnosis
or treatment discussed or suggested in this activity should not be used by
clinicians without evaluation of their patients’ conditions and possible
contraindications on dangers in use, review of any applicable manufacturer’s
product information, and comparison with recommendations of other authorities.
DISCLOSURE OF UNLABELED USE
This activity may contain discussion of published and/or investigational uses of
agents that are not indicated by the FDA. IMER does not recommend the use of
any agent outside of the labeled indications.
The opinions expressed in the activity are those of the faculty and do not
necessarily represent the views of IMER. Please refer to the official prescribing
information for each product for discussion of approved indications,
contraindications, and warnings.

3. Disclosure of Conflicts of Interest
Sandra E. Kurtin, MS, RN, ANP, AOCN®
Reported a financial interest/relationship or affiliation in
the form of: Consultant, Celgene Corporation, Millennium
Pharmaceuticals, Inc., Novartis Pharmaceuticals
Corporation.

4. Activity Overview
Sandra E. Kurtin, MS, RN, ANP, AOCN®
Arizona Cancer Center

5. Learning Objectives
Upon completion of this activity, participants
should be better able to:
 Evaluate recent research highlights for patients with DLBCL, CLL, CML, TCL,
FL, MCL, MDS, and MM
 Describe the diagnostic work-up and various stages of hematologic
malignancies and their prognostic significance
 Explain how prognostic indicators are used to determine treatment options for
patients with DLBCL, CLL, CML, TCL, FL, MCL, MDS, and MM
 Identify the current and ongoing treatment regimens available for patients with
newly diagnosed, relapsed, and refractory DLBCL, CLL, CML, TCL, FL, MCL,
MDS, and MM
 Describe the optimal administration and schedule of current and novel agents
used in the treatment of DLBCL, CLL, CML, TCL, FL, MCL, MDS, and MM
 Apply effective oncology nursing toxicity assessment and monitoring
strategies to help patients achieve positive clinical outcomes
 Develop individualized patient and family education strategies for patients
receiving therapies for hematologic malignancies

6. Activity Agenda
 8:00 – 8:30 AM Registration and Breakfast
 8:30 – 8:35 AM Welcome and Activity Overview
 8:35 – 8:55 AM Introduction to Lymphoma
 8:55 – 9:25 AM Diffuse Large B-Cell Lymphoma
 9:25 – 9:55 AM T-Cell Lymphoma
 9:55 – 10:05 AM BREAK
 10:05 – 10:35 AM Follicular Lymphoma
 10:35 – 11:05 AM Mantle Cell Lymphoma
 11:05 – 11:25 AM Supportive Care Case Study Breakout Session 1
 11:25 – 11:35 AM Panel Discussion / Q&A
 11:35 – 12:35 PM LUNCH
 12:35 – 1:05 PM Chronic Lymphocytic Leukemia
 1:05 – 1:35 PM Chronic Myeloid Leukemia
 1:35 – 2:05 PM Multiple Myeloma
 2:05 – 2:15 PM BREAK
 2:15 – 2:45 PM Myelodysplastic Syndrome
 2:45 – 3:05 PM Supportive Care Case Study Breakout Session 2
 3:05 – 3:15 PM Panel Discussion / Q&A
 3:15 – 3:25 PM Survivorship
 3:25 – 3:30 PM Closing Remarks and Evaluations

7. Introduction to Lymphoma
Sandra E. Kurtin, MS, RN, NP, AOCN®
The University of Arizona Cancer Center

8. Incidence
 NHL
– A heterogeneous group of neoplasms with differing patterns of
growth and response to treatment
 Cases
– ~ 70,130 estimated new cases for 2012
– There were ~ 66,360 new cases in 2011
– NHL ranks 7th among men and women as the most frequently
newly diagnosed cancer in the US
 Deaths
– NHL accounted for ~ 19,320 deaths in 2011 (~ 3% of all cancer
deaths)
– NHL is the 9th leading cause of cancer deaths in men and the
7th leading cause of cancer deaths in women
NHL = non-Hodgkin lymphoma.
Siegel et al, 2012; ACS, 2012, 2011.

9. Risk Factors Associated With NHL
 Age
 Immunodeficiency
– AIDS, organ transplants, autoimmune disorders
 Infectious agents
– HTLV-1: Adult T-cell lymphoma
– EBV: Burkitt’s lymphoma (Africa)
– Helicobacter pylori (MALT lymphomas)
 Environmental exposure
– Drugs, chemicals, occupational exposure
AIDS = acquired immune deficiency syndrome; HTLV-1 = human T-lymphotropic virus type I; EBV = Epstein-Barr virus.
Lister, 2004.

10. Common Sites of Disease in Lymphoma
 Lymphatic vessels, nodes, Waldeyer’s ring
and organs
 Primary organs
– BM, thymus
 Secondary organs
– LNs
– Spleen
– MALT
– Waldeyer’s ring
BM = bone marrow; LNs = lymph nodes; MALT = mucosa-associated lymphoid tissue.
Lister, 2004.

11. Lymphoma: A Blood-Related Cancer
Yarbro et al, 2000; Canellos et al, 2006.

12. B-Cell Development
 Malignancies occur at all stages
 Specific disease depends upon when malignancy occurs
Yarbro et al, 2000; Canellos et al, 2006.

13. Where Do B-Cell Lymphomas Originate?
CLL = chronic lymphocytic leukemia; SLL = small lymphocytic lymphoma; MALT = mucosa-associated lymphoid tissue.
Jaffe et al, 2008.

14. Normal LN Organization
Adapted from Willard-Mack, 2006.

15. Ann Arbor Staging System
 Stage I
– Single LN group
 Stage II
– Multiple LNs on same side of
diaphragm
 Stage III
– Multiple LNs on both sides of the
diaphragm
 Stage IV
– Multiple extranodal sites or LNs
and extranodal disease
 Substaging
– Extranodal extension (E)
– Systemic symptoms (A/B)
– Bulk > 10 cm (X)
Lister, 2004; NCCN, 2012a.

16. NHL Subtypes
N = 1,403
REAL = Revised European American Lymphoma; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma;
MCL = mantle cell lymphoma; PTCL = peripheral T-cell lymphoma; SLL = small lymphocytic lymphoma.
Armitage et al, 1998; Lichtman, 2006.

17. Clinical Behavior of NHL Subtypes
Indolent Aggressive Very Aggressive
CLL/SLL MCL Precursor
B-lymphoblastic
Lymphoplasmacytic/WM Follicle center lymphoma, lymphoma/leukemia
follicular, grade 3
MZL B-cell acute leukemia
DLBCL
Follicle center lymphoma, Therapy undertaken
follicular, grade 1/2 Primary mediastinal large with curative intent
B-cell lymphoma
Most are incurable Cure rates vary
Require immediate therapy
Goal is control and
minimize symptoms Variable treatment goals
Cure rates vary
WM = Waldenström’s macroglobulinemia.
Ansell et al, 2005; Goroll et al, 2009.

18. General Diagnostic Workup
for Lymphoma
 History and Physical
– Physical exam
• Particular attention to node-bearing areas, including Waldeyer’s
ring, hepatomegaly, splenomegaly, abdominal masses, skin nodules
• Presence of distal swelling or lymphedema
– Performance status
– B symptoms
 Laboratory analysis
 Tissue biopsy
 Bone marrow biopsy and aspirate
 Imaging studies for completion of staging
NCCN, 2012b.

19. Diagnostic Evaluation: Tissue Biopsy
Diagnostic Study Clinical Significance
Morphology – Review of cytology using low-power microscope to define basic
architecture of the lymphatic tissue
Immunohistochemistry – Excisional biopsy is the standard for initial diagnosis of NHL
(fine needle aspirates are inadequate)
– Used to isolate cellular proteins which correlate with phases of
B-cell differentiation
Flow cytometry – Immunophenotyping used to describe antigen expression on
B-cells using peripheral blood and bone marrow
– Used to correlate with the tissue biopsy for WHO classification
of subtype
Molecular profiling – Newer molecular profiling has identified key prognostic markers
as well as potential targets for new therapies
WHO = World Health Organization.
Kurtin, 2008; Morice et al, 2008; LeBien et al, 2008; NCCN, 2012b.

20. Diagnostic Evaluation: Peripheral Blood
Diagnostic Study Clinical Significance
CBC + differential + platelets – Evaluate presence of cytopenias, lymphocytosis,
reticulocyte count morphological abnormalities, and bone marrow response to
anemia
LDH, haptoglobin, coombs, and – Evaluate for underlying hemolysis - particularly important
reticulocyte count in CLL
LDH – Necessary for risk stratification
– Evaluate for aggressive disease, risk for TLS, and
hemolysis
Serum β2m – Prognostic relevance
– Reflects WBC membrane turnover
– Levels are affected by renal function
Hepatic profile – Treatments have potential renal and hepatic toxicities or
may be affected by renal or hepatic insufficiencies
– Dose modification may be required for elevated bilirubin
levels
– Serum albumin reflects nutritional status and is used to
estimate prognosis
CBC = complete blood count; LDH = lactate dehydrogenase; β2m = beta-2-microglobulin; IPI = International Prognostic Index;
TLS = tumor lysis syndrome; WBC = white blood cell.
Federico et al, 2007; NCCN, 2012b; Kurtin, 2009; WebMD, 2010; MedlinePlus, 2012.

21. Diagnostic Evaluation: Bone Marrow
Diagnostic Study Clinical Significance
Aspirate – Evaluation of morphological abnormalities of hematopoietic
Should include spicules and be precursors to allow WHO classification
cellular enough to assess at least – Used for flow cytometry, FISH analysis, and cytogenetics
500 cells
Biopsy Evaluate cellularity, topography, presence of lymphocytic infiltrates,
Should be of adequate size for exclusion of other bone marrow disorders or infiltration by solid
evaluation (1–2 cm) tumors
Cytogenetics – Evaluate for possible non-random chromosomal abnormalities
t(11;14) is the hallmark for MCL
– Based on evaluation of 20 metaphases
– Greater than 2 metaphases is considered non-random
Molecular Testing Newer molecular profiling has identified key prognostic markers as
well as potential targets for new therapies
FISH = fluorescent in situ hybridization.
Kurtin, 2008; Jaffe et al, 2008; NCCN, 2012b.

22. Flow Cytometry: The Zip Code for
Primary Cell Type of B-Cell Neoplasms
CML-LBC = chronic myeloid leukemia-lymphoid blast crisis; HL = Hodgkin lymphoma.
LeBien et al, 2008.

23. Immunohistochemistry:
Unraveling the Patchwork of B-Cell Malignancies
Normal LN With Germinal Center and Surrounding
MZL (C) Normal Germinal Center (F)
MCL (D)
ALL – Peripheral Growth Pattern
Blood (A) and May Be Diffuse,
BM (B) Nodular, or
Blastoid
FL (G)
CLL in
Peripheral Blood (E)
DLBCL (H)
Hodgkin
Disease (J) HCL in Peripheral
Blood (L) and BM (K)
BL (I)
MZL (M) PL (P)
WM (N) MM (O)
ALL = acute lymphoblastic leukemia; HCL = hairy cell leukemia; PL = plasmablastic lymphoma; MM = multiple myeloma.
LeBien et al, 2008.

24. Diagnostic Evaluation: Imaging
Diagnostic Study Clinical Significance
MUGA scan or – Baseline evaluation for patients receiving anthracycline therapy
echocardiogram
CT chest, abdomen, and – Current standard of care for initial staging on NHL
pelvis – Estimation of anatomic extent of disease and areas of abnormal
LNs (> 1 cm)
18
FDG-PET – PET with FDG shows functional metabolic status reported as SUV
– Useful in evaluation of LNs < 1 cm
– Not useful in all subtypes of NHL
– Scanning after a few cycles of therapy have been shown to predict
treatment outcomes in MCL
CXR – Baseline evaluation for any underlying disease and as a source of
comparison
MUGA = multi-gated acquisition scan; CT = computed tomography; 18FDG-PET = 18-fluorodeoxyglucose-positron emission tomography;
CXR = chest X-ray; LNs = lymph nodes; SUV = standardized uptake value.
NCCN, 2012b; Kurtin, 2009; Dupuis et al, 2007; Podolofff et al, 2007.

25. The Role of PET
 PET is most useful for
aggressive lymphomas
 More susceptible to false
positives
– Rituximab
– Myeloid growth factors
– If used for restaging, wait 8 wks
after completion of
chemotherapy/radiotherapy
 PET/CT  notable radiation
risk – NCCN: “optional”
 Cost and convenience
Pfreundschuh, 2010; Friedberg et al, 2003.

26. Recommendations for PET Scans
in Lymphoma Therapy and Trials
Histology Pre-Tx Mid-Tx Post-Tx F/U
DLBCL Yesa Trial Only Yes No
HL Yesa Trial Only Yes No
FL Nob Trial Only Nob No
MCL Nob Trial Only Nob No
Other Aggressive NHL Nob Trial Only Nob,c No
Other Indolent NHL Nob Trial Only Nob,c No
a
Strongly recommended but not mandated.
b
Only if response is a primary study end point.
c
Only if PET+ pretreatment.
HL = Hodgkin lymphoma; MCL = mantle cell lymphoma; Tx = treatment; F/U = follow-up.
Seam et al, 2007.

27. Risk Stratification in NHL:
IPI, FLIPI, MIPI, and Beyond
 Risk stratification systems
– IPI: Diffuse Large B-Cell Lymphoma
– FLIPI: Follicular Lymphoma
– MIPI: Mantle Cell Lymphoma
 Cytogenetic and molecular factors
– Hallmark translocations for common subtypes with
associated molecular abnormalities
NCCN, 2012b.

28. IPI Stratifies Risk by Clinical
Factors in Aggressive NHL
 Prognostic factors (APLES) 100 OS (all)
– Age > 60 yrs
– PS > 1 Patients 50
L
(%) LI
– LDH > 1 x normal HI
– Extranodal sites > 1 H
0
– Stage III or stage IV 0 2 4 6 8 10
 Risk category 100
OS (age ≤ 60)
 Factors L
Patients
Low (L) 0 or 1
(%)
50 LI
Low-Intermediate (LI) 2 HI
High-Intermediate (HI) 3 H
High (H) 4 or 5 0
0 2 4 6 8 10
Extranodal sites of disease are excluded from the AAIPI.
a
PS = performance status; AAIPI = age-adjusted IPI.
Sehn et al, 2007.

29. Revised IPI Criteria
 Proposes 3 risk groups based on the
number of IPI risk factors with
recommendations for treatment
strategies
 Very good = no risk factors
– 90% chance of long-term PFS
– Large trials will be necessary to propose
treatment approaches other than CHOP-R
 Good = 1–2 risk factors
– 80% chance of long-term PFS
– Treatment strategies without excessive toxicity
will be necessary due to favorable survival
 Poor = 3–5 risk factors
A = PFS in 365 patients treated with CHOP-R
– 50% chance of long-term PFS
– Clinical trials are recommended to evaluate
disease characteristics and novel treatment
approaches
CHOP-R = cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab; PFS = progression-free survival.
Sehn et al, 2007.

30. Follicular Lymphoma IPI
Survival as defined by FLIPI
 FLIPI Risk Factors 1.0
Low Risk (0–1)
(1 patient each)
Survival Probability (%)
0.8
– Age > 60 yrs
Intermediate Risk (2)
– LDH > ULN 0.6
– Hgb < 12 g/dL High Risk (≥ 3)
0.4
– Ann Arbor stage III/IV
– > 4 involved node
0.2
regions
N = 1,795
0.0
12 24 36 48 60 72 84 96
Time (mos)
ULN = upper limt of normal; Hgb = hemoglobin.
Solal-Céligny, 2006.

31. Gene Profiling and Survival Rates in
Different DLBCL Genetic Groups
Activated B-cell–like diffuse Germinal center B-cell–like Primary mediastinal
large B-cell lymphoma (ABC) (GCB) B-cell lymphoma (PMBL)
G
e
n
e
s
Lymphoma Biopsies
1.0
0.8
5-Yr Survival
Probability (%)
0.6 PMBL 64%
GCB 59%
0.4
0.2 ABC 30%
0
0 2 4 6 8 10
OS (Yrs)
Dave et al, 2006; Rosenwald et al, 2003; Lenz et al, 2008.

32. Mantle Cell Lymphoma IPI
 Established in 2008 to identify OS According to MIPI
prognostic factors relevant to MCL
 Multivariate analysis of 455 patients 1.0
0.9
from 3 randomized clinical trials
Probability of OS (%)
0.8
 4 independent prognostic factors for 0.7
survival (age, PS, LDH, leukocyte 0.6
0.5
counts) 0.4
– LR: 0–3 points 0.3
– IR: 4–5 points 0.2
– HR: 6–11 points 0.1 p = .108
0
 Ann Arbor stage, BM involvement, 0 12 24 36 48 60 72 84 96
number of extranodal sites used in Time (mos since registration)
the IPI were not prognostically
relevant in MCL
LR: Median not reached
 More recent studies have added the
IR: Median 51
proliferation index (Ki67 > 30)
HR: Median 29
PS = performance score; LR = low risk; IR = intermediate risk; HR = high risk.
Hoster et al, 2008; Smith, 2008; Schaffel et al, 2010.

33. Molecular Indices in
Lymphocytic Malignancies
Lymphoma Morphology Immunophenotyping Common Molecular Testing
Subtype Favorable = f Cytogenetic
Unfavorable = u Abnormalities
Diffuse large Diffuse pattern with CD20+, CD45+, CD3- T(14;18), t(3;v), Testing for bcl-2, bcl-1,
B-cell (DLBCL) distortion of the normal t(8;14) c-myc
architecture of the All offer a survival
lymph node or advantage to the lymphoma
extranodal site cells. u
Follicular Nodal lymphoma with a CD10+,CD20+, sIg+, T(14;18)(q32;q21) IgH re-arrangement with
lymphoma (FL) follicular growth pattern CD23 , CD22 , CD25
+/- + +/-
85% bcl-2 expression which
leads to cellular resistance
to apoptosis u
Small Usually appear normal, CD5+, CD20dim+, sIgdim+, Trisomy 12 Patients with variable region
lymphocytic may be large, smudge CD23+, CD22-, CD25-(+) t(11q;v) u Ig mutations have a more
lymphoma/ cells may be present, CD38+ - u del(11q) u favorable prognosis u
chronic pro-lymphocytes are del(17p) u
lymphocytic common del(13q) f
leukemia
Kurtin, 2009.

34. Molecular Indices in
Lymphocytic Malignancies (cont.)
Lymphoma Morphology Immunophenotyping Common Molecular Testing
Subtype Favorable = f Cytogenetic
Unfavorable = u Abnormalities
Mantle cell Cells populating CD5+, CD20+, sIg+, t(11;14) IgH re-arrangement
lymphoma the mantle zone CD22+, CD45+ (q13;q32) with bcl-1 (increased
(MCL) of the follicle CD10-, CD23-, CD25- de-regulates cell proliferation), and
Cyclin D1+ Cyclin D1 bcl-6 expression
expression (resistance to
interfering with apoptosis) u
cell cycle
regulation
Peripheral Peripheral T- CD4+, CD7-, CD8- Clonal re-
T-cell cells and no arrangements of the
lymphoma features of other receptor genes seen
(PTLC) subtypes in non-cancerous
T-cell disease are
common
Kurtin, 2009.

35. Response Criteria for NHL
(not including PET)
Response Physical
LNs LN Masses BM
Category Examination
CR Normal Normal Normal Normal
Normal or
CRu Normal Normal > 75% decrease
indeterminate
Positive or
Normal or irrelevant if
Normal or ≥ 50% Normal or ≥ 50%
PR decrease in other
decrease decrease
liver/spleen parameters
are not normal
Enlarging
Relapse/ New or
liver/spleen or New or increased Reappearance
Progression increased
new sites
PET = positron-emission tomography; CR = complete response; CRu = complete response unconfirmed; PR = partial response.
NCCN, 2012b.

36. Revised Response Criteria for NHL
(including PET)
Response Definition Nodal Masses Spleen, Liver BM
Infiltrate cleared on
a) FDG-avid or PET+ prior to therapy; mass of repeat biopsy; if
Disappearance of any size permitted if PET- Not palpable,
indeterminate by
CR all evidence of nodules
morphology,
disease b) Variably FDG-avid or PET-; regression to disappeared
normal size on CT immunohistochemistry
should be negative
≥ 50% decrease
50% decrease in SPD of up to 6 largest in SPD of
dominant masses; no increase in size of other nodules (for
Regression of nodes Irrelevant if positive
single nodule in
measurable prior to therapy; cell
PR disease and no b)FDG-avid or PET+ prior to therapy; 1 or more greatest
type should be
PET+ at previously involved site transverse
new sites specified
diameter); no
c)Variably FDG-avid or PET-; regression on CT
increase in size
of liver or spleen
a) FDG-avid or PET+ prior to therapy; PET+ at
prior sites of disease and no new sites on CT
Failure to attain or PET
SD CR/PR or PD
b) Variably FDG-avid or PET-; no change in
size of previous lesions on CT
Appearance of new lesion > 1.5 cm in any axis,
Any new lesion or ≥ 50% increase in SPD of > 1 node or ≥ 50%
Relapsed > 50% increase
increase by ≥ 50% increase in longest diameter of a previously from nadir in the New or recurrent
Disease of previously identified node > 1 cm in sort axis SPD of any involvement
or PD involved sites from
Lesions PET+ if FDG-avid lymphoma or PET+ previous lesions
nadir
prior to therapy
SD = stable disease; PD = progressive disease; FDG = fludeoxyglucose; SPD = sum of the product of the diameter.
NCCN, 2012b.

37. General Treatment Strategies
 Dependent on
– Type of disease
– Indolent or aggressive
– Age of patient
– General health/comorbidities
– Initial/relapsed/refractory/transformed NHL
NCCN, 2012b.

38. Key Takeaways
 Non-Hodgkin lymphomas are a heterogeneous group of
neoplasms with differing patterns of growth and response
to treatment
 Several prognostic indices have been developed that have
predictive and prognostic significance
 Diagnosis requires bone marrow evaluation, peripheral
blood tests, tissue biopsy, and/or imaging
 Revised treatment response criteria take into account PET
scan results, physical exam, and bone marrow findings

39. Diffuse Large B-Cell
Lymphoma
Kevin E. Brigle, PhD, NP
Massey Cancer Center at
Virginia Commonwealth University Hospital System

40. Diffuse Large B-Cell Lymphoma
 Most common form of adult NHL: 30%
– Peak incidence in 6th decade
 Curable in 40% or more of cases but median survival
weeks to months if not treated
 Complex and heterogeneous disease with variable
clinical outcomes
– WHO classification includes 15 subtypes
– Molecular classification includes 3 subtypes
 Large cells with loss of follicular architecture of the node
– 30%–40% present with a rapidly enlarging, symptomatic mass with
B symptoms
– May present as extranodal disease (stomach, CNS, testis, skin)
Michallet et al, 2009.

41. Gene Profiling and Survival Rates in
Different DLBCL Genetic Groups
Activated B-cell–like diffuse Germinal center B-cell–like Primary mediastinal
large B-cell lymphoma (ABC) (GCB) B-cell lymphoma (PMBL)
G
e
n
e
s
Lymphoma Biopsies
1.0
0.8
5-Yr Survival
Probability (%)
0.6 PMBL 64%
GCB 59%
0.4
0.2 ABC 30%
0
0 2 4 6 8 10
OS (Yrs)
Dave et al, 2006; Rosenwald et al, 2003; Lenz et al, 2008.

42. Molecular Markers and Survival
Molecular Marker
bcl-2 bcl-6 Activated CD 10 GCET1 FoxP
Cell of Origin expression expression NF-kappa B expression expression expression
- + - + + -
Germinal Center
B-Cell like (GCB)
+ - + - - +
Activated B-Cell
like (ABC)
74%
40%
3-year
Lenz et al, 2010.

43. Evaluating the New Patient With DLBCL
All Patients Selected Patients
• Coagulation studies
• History and physical • Erythrocyte sed rate
• B symptoms •
General •
HBV, HCV, HIV
Performance status Serum β2m
workup • Labs: CBC, differential,
•
LDH, CMP • Uric acid, phosphate
• Pregnancy testing in women of child-bearing potential
• Lymph node biopsy
• Hematopathology review
Identification • Immunophenotyping • Ki-67 index
of subtypes • Molecular studies
• Cytogenetic studies
• CT scan: neck, trunk, pelvis • PET scan
Staging • MRI
• Bone marrow biopsy • Ultrasound
• Lumbar puncture, if paranasal sinus, testicular,
Site-specific epidural, bone marrow involvement with large cell
assessment, lymphoma, HIV lymphoma or ≥ 2 extranodal sites
occult • Thoracentesis
involvement • MUGA scan/echocardiogram
CBC = complete blood count; CMP = complete metabolic panel; CT = computed tomography; LDH = lactate dehydrogenase;
MRI = magnetic resonance imaging; MUGA = multigated acquisition scan; PET = positron emission tomography.
NCCN, 2012b.

44. The Fusion PET/CT Scan for Staging
 Provides information on both structure and activity
 Recommended both pre- and post-treatment
– PET negative complete response at end of treatment associated
with longer PFS
– Role of interim PET less clear
NCCN, 2012b.

45. Interim PET Analysis in DLBCL
 Study of 112 patients with DLBCL treated with rituximab-
anthracycline-based chemotherapy had an interim PET after
2 cycles of therapy
 Positive/Negative PET scans were significantly predictive of
both PFS and OS (p < .001 and p = .003, respectively)
– 3-yr PFS 84% with negative PET vs. 47% with positive PET
– 3-yr OS 88% with negative PET vs. 62% with positive PET
 May lead to an early change in treatment strategy
– Decrease therapy (side effects) for good responders
– Intensify treatment for poor responders
Safar et al, 2012.

46. Initial Treatment Regimens
First-Line Therapy NCCN Category
R-CHOP 1
Dose-Dense R-CHOP 14 2B
Dose-Adjusted R-EPOCH 2B
For Patients With Poor Left Ventricular Function
R-CEPP 2A
R-CDOP 2A
R-CNOP 2A
Dose-Adjusted R-EPOCH 2A
R-CEOP 2A
First-Line Consolidation
HDT with autologous stem cell transplant in high-risk 2B
patients
RCHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; EPOCH = etoposide, prednisone, vincristine, cyclophosphamide,
doxorubicin; RCEPP = rituximab, cyclophosphamide, etoposide, prednisone, procarbazine;
RCDOP = rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, prednisone; RCNOP = rituximab, cyclophosphamide,
mitoxantrone, vincristine, prednisone; DA-EPOCH = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin;
RCEOP = rituximab, cyclophosphamide, etoposide, vincristine, prednisone; HDT = high-dose therapy.
NCCN, 2012b.

47. First-Line Consolidation With
HDT and ASCT
 No clear consensus but recommended if
patient has high risk of recurrence
– < 60 yrs of age
– High LDH level at diagnosis
– Multiple extranodal sites of disease
– Ann Arbor stage III or stage IV disease
– IPI 4–5
ASCT = autologous stem cell transplant.
NCCN, 2012b.

48. Treatment by Stage for DLBCL
Disease Stage Regimens
Localized disease (stage I, II)
(considerations based on nonbulky vs. • R-CHOP x 3 cycles + RT
bulky > 10 cm and whether adverse risk • R-CHOP x 6 cycles ± RT
factors present in nonbulky disease)
• R-CHOP x 6 cycles
Advanced disease (stage III, IV)
• Clinical trials
R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; RT = radiation therapy.
NCCN, 2012b.

49. Second-Line Therapy for DLBCL
Patient Considerations Regimens
• DHAP ± rituximab
• ESHAP ± rituximab
Patients who are candidates for HDT
• GDP ± rituximab
with ASCT
• GemOx ± rituximab
• ICE ± rituximab
• MINE ± rituximab
• Clinical trial
• Rituximab
• CEPP ± rituximab
Patients who are not candidates for
• Lenalidomide ± rituximab
HDT with ASCT
• CEOP ± rituximab
• DA-EPOCH ± rituximab
• GDP ± rituximab
• GemOx ± rituximab
CEPP = cyclophosphamide, etoposide, prednisone, procarbazine; DHAP = dexamethasone, cisplatin, cytarabine;
DA-EPOCH = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; ESHAP = etoposide, methylprednisone, cytarabine,
cisplatin, GDP = gemcitabine, dexamethasone, cisplatin; GemOx = gemcitabine, oxaliplatin; ICE = ifosfomide, carboplatin, etoposide;
MINE = mesna, ifosfamide, mitoxantrone, etoposide; CEOP = cyclophosphamide, etoposide, vincristine, prednisone.
NCCN, 2012b.

50. HDT With ASCT in
Relapsed/Refractory DLBCL
 HDT with ASCT is the treatment of choice for relapsed or refractory
DLBCL
 Patients require salvage therapy prior to ASCT
– No single preferred salvage regimen
– Transplant recommended only for chemo-sensitive disease
– May be combined with radiotherapy for better local control
 Patients relapsing after ASCT should be treated on a clinical trial or
with best supportive care
 Allogeneic transplantation has shown limited benefit in multiple
relapsed disease
– High non-relapse mortality
– Minimal graft vs. lymphoma effect
NCCN, 2012b; Dreger, 2011; van Kampen et al, 2011; Rigacci et al, 2012.

51. Prevention of CNS Relapse
 CNS involvement uncommon at diagnosis
– Most events occur during therapy or shortly after completion of
treatment
– Risk estimated 2%–7% and median survival is < 6 months
 Risk factors include paranasal sinus, testicular, epidural, or bone
marrow involvement, HIV lymphoma, or ≥ 2 extranodal sites but
predictive models are poor
 Benefit of CNS prophylaxis is controversial as studies have been
equivocal
– Intrathecal chemotherapy with 4–6 doses methotrexate or cytarabine
• NCCN recommended but little supporting data, inconsistent tissue
concentrations, poor brain penetration
– High dose (> 3 g/m2 methotrexate)
• Higher toxicity but better CNS penetration and distribution
– Should be given early in the course of treatment for systemic disease
NCCN, 2012b.

52. DLBCL Key Takeaways
 DLBCL is a heterogeneous disease with unique molecular subtypes
that respond differently to treatment
– Gene profiling may lead to tailored treatment plans
 R-CHOP chemotherapy continues to be the standard of care
– For patients with cardiac dysfunction, non-anthracycline containing
regimens are recommended
 CNS relapse is rare but occurs early in the course of the disease
and carries a poor prognosis
– Chemo-prophylaxis remains controversial
 PET scans are recommended pre- and post-treatment
– Use early in therapy to guide treatment requires further study
 HDT with ASCT is the standard for relapsed disease

53. Tumor Lysis Syndrome (TLS)
 Oncologic emergency that occurs as a result of rapid tumor cell
breakdown and the consequent release of intracellular contents
– Commonly occurs following cytotoxic therapy
– Occurs spontaneously in rapidly growing cells
 Mainly involves calcium, phosphorous, potassium, and uric acid
– Levels increase too rapidly for the body’s homeostatic mechanisms to
deal with
– Renal excretion is the primary means of clearing these ions and optimal
management involves preservation of renal function
 May lead to acute kidney failure, cardiac arrhythmias and sudden
death, seizures, and neuromuscular irritability
 Primary management involves identifying patients at risk and
starting treatment prior to initiating chemotherapy
NCCN, 2012b; Elitek® prescribing information, 2011.

54. Features of TLS
Salient Features of TLS
• High potassium (> 6.0 nmol/L), phosphorus (> 4.5 mg/dL),
Lab Hallmarks and uric acid (> 8.0 mg/dL)
• Low calcium (< 7.0 mg/dL corrected)
Clinical • Nausea and vomiting, shortness of breath, irregular heartbeat,
Symptoms clouding of urine, lethargy, joint discomfort
• Burkitt’s and lymphoblastic lymphoma, occasionally DLCBL and CLL
• Elevated WBC and bulky tumors
• Bone marrow involvement and organ infiltration by cancer cells
• Renal disease or renal involvement by tumor
High-Risk
• Dehydration
Features
• Exposure to nephrotoxins (IV contrast, NSAIDs)
• Spontaneous TLS
• Pre-existing elevated uric acid
• Ineffectiveness of allopurinol
NCCN, 2012b.

55. TLS Pathophysiology
Howard et al, 2011.

56. TLS: Prevention and Treatment
 Identify patients at risk
– Obtain baseline labs and identify disease- and patient-related risk factors
 Initiate allopurinol
– Oral xanthine-oxidase inhibitor that blocks production of UA (takes several
days to impact UA levels)
– Begin 2–3 days prior to chemotherapy and continue for 10–14 days
 Utilize rasburicase
– Recombinant urate oxidase (enzyme not found in humans) that catalyzes
UA to a soluble compound with a peak effect in 4 hours
– Given 0.2 mg/kg IV over 30 mins and may be repeated once daily
– Black box warnings: Anaphylaxis and hemolysis in patients with G6PD
deficiency
– Indicated for patients with high-risk features, especially compromised renal
function and those presenting with spontaneous TLS
UA = uric acid.
NCCN, 2012b.

57. TLS: Prevention and Treatment
(cont.)
 Aggressive intravenous fluid and monitoring of urine
output
 Frequent monitoring of electrolytes, UA, and creatinine
q4–8hrs
 Telemetry for hyperkalemia
 Decrease the rate of tumor lysis with the use of low
intensity initial therapy prior to starting initial therapy
– Common in Burkitt’s lymphoma regimens
NCCN, 2012b.

58. Anthracycline-Induced
Cardiomyopathy
 Clinical heart failure: 1%–5%
 Asymptomatic decrease in left ventricular
function: 5%–20%
 Impacts long-term survival and quality of life
 Reduces range of suitable anticancer therapies
 Cause unclear but likely multifactorial
– Free radical-mediated myocyte damage
– Circulating pro-inflammatory cytokines
Granger, 2006.

59. Anthracycline-Induced
Cardiomyopathy Risk Factors
Risk Factor Comment
• Cumulative dose • Higher incidence as cumulative dose
increases
• Rate of administration • Bolus dosing more toxic than CIV
• Concurrent or prior mediastinal • Especially radiation to left side of chest
radiation
• Concomitant administration of other • Cyclophosphamide, ifosfamide,
cardiotoxic drugs methotrexate, cytarabine
• Age at time of exposure • < 18 yrs or > 65 yrs have greater risk at
lower cumulative doses
• Female • Unclear
• Pre-existing cardiovascular disease • CAD, hypertension, left ventricular
dysfunction
• Longer duration of survival • Chronic cardiotoxicity may occur > 30 yrs
after completion of treatment
Dolci et al, 2008; Shakir et al, 2009.

60. Types of Anthracycline-Induced
Cardiomyopathy
Type Onset Main Features
• Uncommon and transient;
Immediately after • May involve transient ECG abnormalities (ST and T
Acute single dose or wave changes, QT interval prolongation and
course of therapy arrhythmias) and rarely, CHF and
pericarditis/myocarditis syndromes
• Most frequent type and related to cumulative
anthracycline dose
Within 1 yr of
Early-onset • Often starts with asymptomatic decline in myocardial
therapy; typically
chronic function and then manifests as CHF with ventricular
rapid onset and
progressive dilation, pulmonary and venous congestion, poor
progression
perfusion, and pleural effusions
• Frequently unresponsive to therapy
• Often starts with asymptomatic decline or with
Late-onset symptoms of clinical heart failure
1 yr to decades
chronic • Ultimately, manifests as symptomatic CHF as a result of
after therapy
progressive slowly progressive decline following earlier myocyte
injury
Maradia et al, 2009; Shakir et al, 2009.

61. Anthracycline-Induced
Cardiomyopathy
Cumulative Doxorubicin Dose (mg/m2) Incidence (%)
300 1–2
400 3–5
450 5–8
500 6–20
 The risk of developing CHF increases rapidly with increasing total
cumulative doses of doxorubicin in excess of 400 mg/m2
Adriamycin® prescribing information, 2006.

62. Common Cumulative Doses
of Doxorubicin
Regimen Cumulative
Doxorubicin (mg/m2)
R-CHOP x 6
50 mg/m2 per cycle 300
R-EPOCH x 6
40 mg/m2 per cycle (10 mg/m2/day CIV Days 1–4)
Note: Doxorubicin dose may progressively 240–397
increase with DA-EPOCH
R-HyperCVAD x 4
50 mg/m2 CIV Day 4 each cycle 200
 < 5% risk based on anthracycline exposure for first-line treatment

63. Monitoring High-Risk Patients
 There are no specific guidelines for monitoring for chemotherapy-
induced cardiomyopathy
 Serial monitoring: Baseline, throughout treatment, and post
treatment
 Monitor for signs and symptoms by
– Physical exam
– ECHO, radionuclide angiography (MUGA), EKG
– CXR
– Troponin levels
 Following therapy, provide a survivor care plan for the patient and
their other providers related to their cancer treatment and its
potential long-term side effects
Dolci et al, 2088; Cardinale et al, 2006.

64. Preventing Cardiomyopathy in
High Risk Patients
 Maintain adequate blood pressure control (all patients)
 Be aware of total cumulative anthracycline dose (all
patients)
 Use continuous infusion dosing
 Add cardioprotectants (dexrazoxane)
 Use anthracycline analogs
– Pixantrone (R-CPOP) 2011 ASH Annual Meeting Abstract 4966
– Liposomal anthracycline (R-COMP14)
 Use of non anthracycline-containing regimens
– Gemcitabine (R-GCVP) 2011 ASH Annual Meeting Abstract 1634
Cardinale et al, 2006; Fields et al, 2011; Herbrecht et al, 2011.

65. Anthracycline-Induced
Cardiomyopathy Treatment
 ACE inhibitors
– Enalapril
 Beta blockers
– Carvedilol
 Appropriate supportive care
– Diuretics
– Weight monitoring
– Fluid restriction
 Assistive devices
 Heart transplant if permanent damage
ACE = angiotensin-converting enzyme.
Dolci et al, 2008; Shakir et al, 2009.

66. Anthracycline-Induced
Cardiomyopathy Patient Education
 Discuss short- and long-term risks based on individual patient
risk assessment and treatment
 Discuss the plan for monitoring before, during, and after
treatment
 Educate patients about the signs and symptoms of heart
failure and convey the importance of prompt reporting
 Encourage strict compliance with current cardiac medications
to avoid serious, negative, long-term sequelae
 Provide a survivor care plan for the patient and their other
providers related to their cancer treatment and its potential
long-term side effects
Shakir et al, 2009; Granger, 2006.

67. TLS Case Study
 62-yr-old Caucasian man with a PMH of hypertension and
hypercholesterolemia both well controlled with HCTZ,
amlodipine, and simvastatin. He also takes ASA 81 mg.
 Diagnosis: Ann Arbor Stage IVB DLBCL with bulky
abdominal LAN, spleen and bone marrow involvement
– IPI stage high intermediate (age > 60, stage IV, ↑LDH)
– Drenching night sweats, 20 pound unintentional weight loss
– Persistent nausea
 Baseline studies
– Echocardiogram 62% LVEF
– Normal EKG
PMH = past medical history; LAN = lymphadenopathy; LDH = lactate dehydrogenase; LVEF = left ventricular ejection fraction.
Shakir et al, 2009; Granger, 2006.

68. TLS Case Study (cont.)
 Baseline laboratory analysis
– WBC: 6.0 × 109/L (normal); Hgb: 11.2 g/dL (low); Platelets: 135 × 109/L (low)
– Potassium: 5.9 nmol/L (high), Phosphorous: 3.8 mg/dL (normal), UA: 10.8 mg/dL
(high), Corrected Calcium: 7.2 mg/dL (low)
– LDH: 920 U/L (250 U/L ULN - high)
– BUN/creatinine: 30/1.3 mg/dL (high), Creatinine Clearance: 70 ml/min (low)
– LFTs: normal
 Clinical Decisions:
– What therapy would he receive to treat his disease?
– How would you interpret his laboratory data?
– What are his risk factors for TLS?
– What specific steps should be taken to prevent or treat TLS in this patient?
Shakir et al, 2009; Granger, 2006.

69. Cardiotoxicity Case Study
 67-yr-old Caucasian woman with PMH of HTN and
osteoporosis. Meds include HCTZ, monthly ibandronate,
and Calcium-Vitamin D.
 Diagnosis: Ann Arbor Stage IIIA DLBCL with cervical,
axillary, and inguinal LAN
– IPI stage high intermediate (age > 60, ↑ LDH, stage III)
– Asymptomatic
 Baseline studies
– Echocardiogram 54% LVEF
– Normal EKG
Shakir et al, 2009; Granger, 2006.

70. Cardiotoxicity Case Study (cont.)
 Baseline laboratory analysis
– WBC: 5.2 × 109/L (normal); Hgb: 11.5 g/dL (low); Platelets: 205 × 109/L
(normal)
– Potassium: 3.5 nmol/L (low), Phosphorous: 2.7 mg/dL (normal), UA: 5.1 mg/dL
(normal), Corrected Calcium: 8.1 mg/dL (low)
– LDH: 305 U/dL (250 U/L ULN - high)
– BUN/creatinine: 17/1.0 mg/dL (normal), Creatinine Clearance: 80 ml/min (low)
– LFTs: normal except ALT 75 U/L (high)
 Clinical Decisions:
– What therapy would she receive to treat her disease?
– How would you interpret her laboratory data?
– What are her risk factors for anthracycline-induced cardiomyopathy?
– What specific steps would you take to monitor for or prevent anthracycline-
induced cardiotoxicity?
Shakir et al, 2009; Granger, 2006.

71. T-Cell Non-Hodgkin
Lymphoma
Barbara Barnes Rogers, MN, CRNP, ANP-BC, AOCN®
Fox Chase Cancer Center

72. NHL Subtypes
N = 1,403
REAL = Revised European American Lymphoma; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma;
MCL = mantle cell lymphoma; PTCL = peripheral T-cell lymphoma; SLL = small lymphocytic lymphoma.
Armitage et al, 1998; Lichtman, 2006.

73. 2008 WHO Classification of
T-Cell Neoplasms
Cutaneous Extranodal Nodal Leukemic
T-cell Prolymphocytic
Mycosis Fungoides Extranodal NK/TCL, Peripheral TCL-NOS
Leukemia
Nasal Type
T-Cell Large Granular
Sézary Syndrome Angioimmunoblastic Lymphocytic Leukemia
Enteropathy- TCL
Primary Cutaneous Aggressive NK-cell
Associated TCL Leukemia
CD30+
Lymphoproliferative Anaplastic Large Cell Adult T-Cell
Disorders: Hepatosplenic TCL Lymphoma (ALK +) Leukemia/Lymphoma
•Primary Cutaneous ALCL Chronic
•Lymphomatoid Papulosis*
Lymphoproliferative
•Borderline Lesions Subcutaneous Anaplastic Large Cell disorders of NK cells
Panniculitis-Like TCL Lymphoma (ALK -)
Primary cutaneous EBV+ T-cell
peripheral T-cell Lymphoproliferative
disorders of Childhood
lymphomas, rare
subtypes: Systemic EBV+ T-cell
•Primary Cutaneous γδ TCL Lymphoproliferative
•Primary Cutaneous CD8+ Disease of Childhood
aggressive epidermotropic TCL
•Primary Cutaneous CD4+ Hydroa Vacciniforme-like
small/medium TCL Lymphoma
Jaffe et al, 2008.

74. Peripheral T-Cell Lymphoma Subtypes
ALCL = anaplastic large-cell lymphoma; ALK = anaplastic lymphoma kinase; PTCL = peripheral T-cell lymphoma.
International T-Cell Lymphoma Project, 2008; O’Leary et al, 2009; de Leval et al, 2008.

75. Presenting Symptoms of PTCL
 Generalized lymphadenopathy
 Mild anemia or thrombocytopenia
 B symptoms (fevers, weight loss, and night sweats)
 Extranodal disease
– Spleen
– Liver
– Bone Marrow
– Skin
 Rash
Rodriguez-Abreau, 2008.

76. Clinical Presentations of PTCL and
B-Cell Lymphoma
Clinical Characteristics PTCL (%) BCL (%)
Disseminated disease 78 58
B symptoms 57 40
Bone marrow positive 31 17
Skin lesions 21 4
Gisselbrecht et al, 1998.

77. Workup of Patients With
Suspected TCL
 Physical exam  Radiographic test
 Biopsy – CT scan of
– Lymph node chest/abdomen/pelvis
– Bone marrow – PET/CT scan
– Head CT or MRI
 Laboratory tests
(if appropriate)
– Complete blood count with
differential, platelets  Calculation of IPI or PIT
– Comprehensive metabolic panel  Discussions of fertility issues
• Hepatic transaminase levels
(AST, ALT)
• Alkaline phosphatase
• LDH
• Uric Acid
ALT = alanine aminotransferase; AST = aspartate aminotransferase; LDH = lactate dehydrogenase;
IPI = International Prognostic Index; PIT = Prognostic Indicator PTCL-NOS.
Yarbro et al, 2000.

78. IPI/PIT: Prognostic Indices for PTCL-NOS
Prognostic Factors OS: PIT
N = 322
IPI PIT
Age Age
PS PS
LDH LDH
Stage BM
involvement
No. of
extranodal
sites
Gallamini et al, 2004; Ansell et al, 1997.

79. Overall Survival in PTCL
The International PTCL and NK/T-Cell Lymphoma Study
PTCL Subtypes
ALK+ ALK– PTCL- NK/T-Cell
AITL ATLL
ALCL ALCL NOS Lymphoma
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.

80. Front-Line Treatment Regimens
for Management of PTCL
 Front-line chemotherapy typically consists of doxorubicin-containing
regimens
– CHOP
– HyperCVAD alternating with high-dose methotrexate and cytarabine
 No clear benefit from use of anthracycline-containing regimen
 No universally agreed-upon standard treatment
 Other combinations
– CHOP plus alemtuzumab (ORR 75%–80%; OS 2 yrs 53%; PFS 2 yrs
48%)
– CHOP plus denileukin diftitox (ORR 80%–100%, depending on subtype;
PFS 2 yrs 41%)
– CHOP plus rituximab (ORR 80%, CR 44%, 2-yr PFS 43%, OS 62%): No
better than CHOP alone
CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone;
HyperCVAD = cyclophosphamide, vincristine, doxorubicin, dexamethasone.
Lichtman, 2006; Foss, 2009.

81. ASCT in the Management of PTCL
 Front-line consolidation with high-dose chemotherapy and stem
cell rescue
– For all patients except those who are low risk and those with
ALK+ ALCL
– Is controversial, based on retrospective and phase II data
– Multiple phase II trials
• Overall Survival = 39%–73% (3 yrs)
• Event-free Survival = 30% (4 yrs)
• Transplant-related Mortality = 4%
– Patients with high IPI/PIT score might not benefit from ASCT
IPI = International Prognostic Index; PIT = Prognostic Index for T-cell lymphoma.
Reimer et al, 2009; Mercadal et al, 2008; Rodriguez et al, 2007.

82. ASCT as First-Line Therapy in
PTCL: Survival
OS in Transplanted and Non-Transplanted Patients
Transplanted (n = 55)
(n = 83)
Non-transplanted (n = 28)
Reimer et al, 2009.

83. Treatment Options for PTCL
 Romidepsin  Pralatrexate
– ORR 30%–38%, CR 16% – ORR 27%, CR 6%
– DOR 8.3–12 mos – DOR 9.4 mos
– Side effects: Anemia, leukopenia, – Side effects: Stomatitis,
neutropenia, thrombocytopenia, thrombocytopenia, nausea, fatigue,
infection, EKG changes, asthenia, anemia, neutropenia, dyspnea,
decreased appetite, headache, hypokalemia, altered LFTs,
cough, rigors, weight loss abdominal pain, leukopenia, febrile
neutropenia, sepsis, hypotension
 Brentuximab Vedotin – B12 and folate supplements
– ORR 86%, CR 53% administered to minimize toxicity
– DOR 12.6 mos (myelosuppression and stomatitis
– Side effects: Peripheral
neuropathy, nausea, fatigue,
pyrexia, diarrhea, rash,
constipation, neutropenia
ORR = overall response rate; DOR = duration of response.
O’leary & Salvage, 2008.

84. Treatment Options for PTCL (cont.)
 Denileukin diftitox  Alemtuzumab
– ORR 50%, Cr 30% for CD25+, – ORR 36%–50%, CR 21%–33%
18% for CD25- – Side effects: Anemia, neutropenia,
– DOR 8 mos thrombocytopenia, fever, infection,
– Side effects: Fever, fatigue, rigors, viremia (CMV, EBV), hypotension,
nausea, headache, edema, cough, rash, urticaria, diarrhea, nausea,
dyspnea, pruritus, rash, vomiting, myalgias, insomnia,
hypotension, back pain, myalgia, anxiety, bronchospasm, dyspnea
chest pain, tachycardia,
hypoalbuminemia, asthenia,
altered LFTs, capillary leak
syndrome, infusion reactions,
visual impairment
ORR = overall response rate; DOR = duration of response.
O’leary & Salvage, 2008.

85. Therapies Under Investigation for
the Management of PTCL
Class of Agent Agent
HDAC inhibitors • Vorinostat
Farnesyl transferase inhibitors • Tipifarnib
Multikinase inhibitors • Dasatinib
IMIDS • Lenalidomide
Proteasome inhibitors • Bortezomib
Investigational agents • Belinostat
• Plitidepsin
• Zanolimumab
Clinicaltrials.gov

86. Management of PTCL:
How to Improve Beyond CHOP?
 CHOP will not cure most patients with PTCL
 Transplant might consolidate remissions
– But we need better front-line therapies
 New combinations make sense with the blockade of
different pathways
 Limited number of patients on clinical trials
 Slow to make progress

87. Cutaneous T-Cell Lymphoma

88. Patient With Stage IB Disease With
Folliculotropic Plaques on the Trunk
© 2009 by American Society of Hematology; Prince et al, 2009.

89. Patient With Stage IB Disease
With Patches and Thin Plaques
© 2009 by American Society of Hematology; Prince et al, 2009.

90. Mycosis Fungoides: Tumor Stage
Habif, 2010.

91. Mycosis Fungoides:
TNM Staging System
 Primary Tumor (T)
– T1: Limited patch/plaque (< 10% of skin surface involved)
– T2: Generalized patch/plaque (> 10% of skin surface involved)
– T3: Cutaneous tumors (one or more > 1cm in diameter)
– T4: Generalized erythroderma (with or without patches, plaques or tumors) > 80% body
surface area
 Regional Lymph Nodes (N)
– N0: No clinically abnormal peripheral lymph nodes; biopsy not required
– N1: Clinically abnormal peripheral lymph nodes; histopathology Dutch Gr1 or NCI LN 0–2
– N2: Clinically abnormal peripheral lymph nodes; histopathology Dutch Gr2 or NCI LN 3
– N3: Clinically abnormal peripheral lymph nodes; histopathology Dutch Gr3–4 or NCI LN 4
– NX: Clinically abnormal peripheral lymph nodes; no histologic confirmation
NCCN, 2012b.

92. Mycosis Fungoides:
TNM Staging System (cont.)
 Visceral (M)
– M0: No visceral organ involvement
– M1: Visceral disease present (must have pathology confirmation)
 Blood Involvement (B)
– B0: Absence of significant blood involvement: < 5% of peripheral blood
lymphocytes are atypical (Sézary) cells
– B1: Low tumor burden: > 5% of peripheral blood lymphocytes are atypical
(Sézary) cells but does not meet the criteria for B2
– B2: High tumor burden: > 1,000/mcL Sézary cells
NCCN, 2012b.

93. Mycosis Fungoides:
TNM Staging System (cont.)
 Stage IA: T1, N0, M0, B0-1
 Stage IB: T2, N0, M0, B0-1
 Stage IIA: T1-T2, N1-2, M0, B0-1
 Stage IIB: T3, N0-N2, M0, B0-1
 Stage IIIA: T4, N0-2, M0, B0
 Stage IIIB: T4, N0-2, M0, B1
 Stage IVA1: T1-T4, N0-2, M0, B2
 Stage IVA2: T1-4, N3, M0, B0-2
 Stage IVB: T1-4, N0-3, M1, B0-2
NCCN, 2012b.

94. Sézary Syndrome
 Leukemic form of mycosis fungoides
 Aggressive lymphoma
 Accounts for 2.5% of CTCL
 Estimated 5-yr survival rate 11%
 Consists of triad of
– Erythroderma
– Lymphadenopathy
– Cerebriform lymphocytes (Sézary Cells) in peripheral
blood, lymph nodes, and skin
Willemze et al, 1997; Sibaud et al, 2003.

95. Sézary Cell
Anderson & Poulsen, 2003.

96. General Approach to Management
of Cutaneous T-Cell NHL
 Lack of evidence based approach
 Appreciate unique features of skin disease
– Chronic control of skin infections (staph, HSV)
– Use anti-itch regimens and emollients/sealants
– Agents that work in lymph nodes may not work in
skin
– Can recycle therapies
– Therapy is stage-based
Kim, 2011.

97. Skin Directed Therapies
 Topical steroids: Triamcinolone, clobetasol
– ORR 75%–95%
 Topical chemotherapy-mechlorethamine, carmustine
– ORR mechlorethamine 75%–90%
 Topical retinoids (bexarotene)
– ORR 50%–75%
 Phototherapy-UVB (narrow or broad band) or PUVA
– ORR nb UVB 75%–100%
– ORR PUVA 85%–100%
– TSEBT (> 30Gy) 100%
 Radiation-local or total skin electron beam therapy
nb = narrow-band; ORR = overall response rate; PUVA = psoralen and ultraviolet A; TSEBT = total skin electron-beam therapy.
Zackheim, 2003; Navi et al, 2011.

98. Stage Based Therapy for CTCL
 IA: Limited Patch/Plaque  IB/IIA: Generalized Patch/Plaque
– Topical steroids - – Topical steroids-triamcinolone,
triamcinolone, clobetasol clobetasol
– Retinoid (bex)
– Retinoid (bex)
– Local XRT
– Phototherapy – Phototherapy
– Local XRT – TSEBT + ECP, IFN
– Clinical Trial – Bex, denileukin diftitox, IFN, vorinostat,
romidepsin (single agent or in
combination)
– Clinical Trial
 Bex = bexarotene - topical retinoid
 Topical chemotherapy - mechlorethamine, carmustine
 Phototherapy = UVB (narrow or broad band) or PUVA (psoralen + UVA)
 Radiation-local or total skin electron beam therapy
 TSEBT = total skin electron beam therapy
 ECP = extracorporeal phototherapy (photopheresis)

99. Stage Based Therapy for CTCL (cont.)
 IIB Tumors
– Topical steroids-triamcinolone, clobetasol
– Retinoid (bex)
– Phototherapy
– Local XRT
– Single-agent chemotherapya
– Phototherapy
– TSEBT + ECP, IFN
– Bexarotene, denileukin diftitox, IFN, vorinostat, romidepsin
(single agent or in combination)
– Clinical Trial
– Allo-HSCT
Methotrexate, liposomal doxorubicin, gemcitabine, chlorambucil, pentostatins, pralatrexate.
a
NCCN, 2012b.

100. Stage Based Therapy for CTCL (cont.)
 III Erythroderma
– Topical steroids-triamcinolone, clobetasol
– Retinoid (bex)
– Phototherapy
– Local XRT
– ECP
– Single-agent chemotherapy
– Phototherapy = bexarotene or IFN
– Alemtuzumab
– TSEBT + ECP, IFN
– Bex, denileukin diftitox, IFN, vorinostat, romidepsin (single agent or in
combination)
– Clinical Trial
– Allo-HSCT
 ECP = photopheresis
NCCN, 2012b.

101. Stage Based Therapy for CTCL (cont.)
 IV Extracutaneous Disease
– ECP
– Single-agent chemotherapy
– Combination chemotherapy
– Phototherapy = bexarotene or IFN
– Alemtuzumab
– TSEBT + ECP, IFN
– Bexarotene, denileukin diftitox, IFN, vorinostat, romidepsin
(single agent or in combination)
– Clinical Trial
– Allo-HSCT
NCCN, 2012b.

102. Systemic Therapies for MF or SS
CTCL
 Category A in NCCN Guidelines  Category C in NCCN
(Milder) Guidelines/Use for aggressive
– Retinoids disease
– IFN – Liposomal doxorubicin
– HDAC inhibitors – Gemcitabine
– Photopheresis – Denileukin diftitox
– Denileukin diftitox – Romidepsin
– Low-dose methotrexate – Pralatrexate
 Category B in NCCN Guidelines – PTCL regimens
(Single-agent cytotoxic therapies)
– First-line: Liposomal doxorubicin,
gemcitabine
– Other single-agent cytotoxic
therapies
NCCN, 2012b.

103. Systemic Therapies
 Pralatrexate
– Dose 15 mg/m2 wkly for 3 wks (4-wk cycle)
– B12 IM q9wks
– Folic acid 1 mg/day
– ORR 58%; OS 13 mos; DOR 4.4 mos
 Alemtuzumab
– ORR 55%–86%
– CR 32%
IM = intramuscular; OS = overall survival; DOR = duration of response.
Folotyn® prescribing information, 2011; Campath® prescribing information, 2012.

104. TCL Key Takeaways
 T-cell lymphomas are rare disorders
 Behavior is different from B-cell lymphomas-often less
responsive to therapies
 CTCL should first be treated with therapies focused to
the skin, unless aggressive
 New therapies need to be developed to optimize
response and survival

105. Chemotherapy-Induced Peripheral
Neuropathy (CIPN)
 Common dose-limiting side effect of:
 Occurs in 30% – 40% of patients
 Symptoms of peripheral neuropathy:
– Include sensory neuropathies with parasthesias and pain
– Start in fingers and toes and spread in glove and stocking distribution
– Can begin weeks to months after initial treatment
– In most cases is only partially reversible and can be permanent
Pachman et al, 2011.

106. CIPN
 Exact mechanism not clear
 Can be disabling and negatively impact functional ability
and quality of life
 Should assess for common metabolic causes of
neuropathy:
– Diabetes
– Vitamin B12 deficiency
– Hypothyroidism
– Paraproteinemias
 No universally-accepted, well-validated measurement of
assessment of CIPN
Pachman et al, 2011.

107. CIPN
 No well-accepted proven therapy for CIPN
 Agents with strongest preliminary data for preventing CIPN:
– IV calcium and magnesium infusions
– Glutathione
 Therapies with strongest evidence for first-line treatment of CIPN:
– Gabapentin
– Topical pain relievers such as baclofen/amitriptyline/ketamine gel or
5% lidocaine patch
– Seratonin and norepinephrine reuptake inhibitors such as venlafaxine
and duloxetine
– Opioid analgesics
– Tramadol hydrochloride
– Tricyclic antidepressants (nortriptyline hydrochloride or desipramine
hydrochloride)
– Cutaneous electrostimulation
Pachman et al, 2011; Vadalouca et al, 2006.

108. Neuropathy Case Study
 68-yr-old man with anaplastic large cell NHL (ALK neg) that
presented in his right calf
 Treatment
– 6 cycles of CHOP
– Slight increased FDG uptake on PET/CT at the completion of therapy
and was treated with involved field XRT
– He achieved a metabolic CR
 6-mos follow-up
– Complained of right upper arm discomfort and was diagnosed with
recurrent ALCL
– Radiation therapy to the site with a PR
– Given pralatrexate with gemcitabine on a clinical trial with SD
– Treated with MINE with anticipation of an autologous transplant

109. Neuropathy Case Study (cont.)
 He had PD while receiving MINE
 Brentuximab vedotin was initiated on a clinical trial
 Clinical findings
– Numbness and tingling in his hands and feet
– Sensitivity to cold and feeling “like his hands were always cold”
 Clinical decision
– How would you assess for PN?
– How do you manage PN at your institution?
– What co-morbidities are frequently associated with neuropathy?
– What is the best evidence-based management strategy for
peripheral neuropathy?

110. BREAK

111. Follicular Lymphoma
Amy L. Goodrich, MSN, RN, CRNP-BC
The Sidney Kimmel Comprehensive Cancer Center
at Johns Hopkins

112. Follicular Lymphoma (FL)
 Median age: 60 yrs
 Treatment is not curative in most cases
 Focus is disease control and quality of life
 Median survival: 9 yrs or 4.5 yrs after first
relapse
 Transformation common (affects ~ 30% of
patients)
Tan et al, 2008.

113. Follicular Lymphoma: Grades 1–3
Grade 1 Grade 2 Grade 3
Predominantly Mixture of small and Predominantly
small cells large cells large cells
Accounts for Accounts for Accounts for
40%–45% of FL 30% of FL 20% of FL
Indolent Indolent Clinically aggressive
Generally incurable Generally incurable May be curable
Tan et al, 2008.

114. Follicular Lymphoma: Grades 1–2
 70%–85% present with Stage III or IV disease
 Grade 1: 50% with bone marrow involvement
 Grade 2: 30%–35% with bone marrow involvement
 Patients typically present with painless adenopathy
 < 20% with symptoms
– Fever
– Night sweats
– Weight loss
 Clinical course highly variable
 Leukemic phase uncommon
Friedberg et al, 2009; Tan et al, 2008.

115. Follicular Lymphoma: Grade 3
 Biology not well-defined due to routine
exclusion from clinical trials
 No specific treatment guidelines
 Recent A and B designations do not drive
treatment decisions
 Most commonly treated like DLBCL without
watch and wait
 Only 40%–50% are cured
Buske et al, 2008.