Overview of Lymphomas

1
Overview of Lymphomas

• Jessica Hals, DO
• June 16th 2005

2
(No Transcript)
3
Definition

• Lymphomas are malignant transformations of normal
  lymphoid cells which reside predominantly in
  lymphoid tissues
• They are divided into two major types
• Non-Hodgkins lymphoma (NHL)
• Hodgkins Lymphoma

4
Some Stats1

• It is estimated that there will be 63,740 new
  cases of lymphoma diagnosed in 2005.
• 56,390 are expected to be NHL
• 19,200 of these pts are expected to die from NHL
• 7,350 are expected to be Hodgkins Lymphoma
• 1,410 of these pts are expected to die

5
How to Diagnosis NHL

• The initial evaluation must establish
• The precise histologic type of NHL
• The extent and sites of disease
• The performance status of the patient
• All of this is important to establish prognosis
  and treatment

6
Where to start

• As always with the HP
• Key points to obtain in your history
• Lymphadenopathy more than 2/3 of pt will present
  with peripheral adenopathy
• Ask about waxing and waning of lymph nodes
• As about the duration of lymphadenopathy

7
The History Contd

• B Symptoms
• Fever defined as Tgt38ºC
• Weight loss defined by unexplained loss of gt10
  of body wt over 6 mos
• Night sweats defined by drenching night sweats

8
The Physical Exam

• Exam all sites of potential involvement
  including
• Waldeyers ring (tonsils, base of tongue,
  nasopharynx)
• Std L.N. sites (cervical, inguinal, etc)
• Liver and spleen
• Abdominal L.N. (mesenteric, retroperitoneal)
• Others occipital, preauricular, epitrochlear,
  etc.

9
Unusual Sites/Presentations

• 10-35 will have primary extranodal NHL and about
  50 will have extranodal disease during their
  illness
• Most common site of extranodal disease is the GI
  tract followed by the skin
• Symptoms from extranodal disease usually assoc
  with aggressive NHL

10
Extranodal Sites

• Testicular NHL accounts for 1 of NHL and 2 of
  extranodal NHL. It is the most common malign.
  involving the testis in men over 60 y.o
• NHL can present as solitary lesion of bone
• Renal involvement occurs in 2-14 of pts
• Rarer sites include prostate, bladder, ovary,
  orbit, heart, breast, salivary gland, thyroid and
  adrenal gland
• Examine skin carefully and bx any suspicious
  lesions
• NHL can account for poorly differentiated
  carcinoma of unknown primary

11
Diagnostic tests

• Lymph node biopsy
• Preferably to have an entire intact lymph node
  over FNA or core bx
• This allows the pathologist to accurately
  determine the pattern of involvement and allows
  for enough tissue for immunologic and molecular
  testing

12
Tests Contd

• Bone marrow bx
• This is to determine stage
• Controversial whether bilateral or unilateral
  bxs are required.
• Most oncologists advocate bilateral biopsy

13
Lab tests

• CBC
• Serum chemistries
• LDH
• Uric acid

14
Imaging tests

• CT chest/abd/pelvis
• PET scan

15
Classification3
16
Staging3
17
Prognostic Tools3
18
The FLIPI Score

• The IPI was designed for aggressive lymphomas.
  Few Follicular lymphomas fell into the high risk
  group based upon the IPI and therefore its
  application to FL was being questioned
• Therefore the FLIPI has been proposed as a
  prognostic score for follicular lymphomas

19
FLIPI

• Five factors
• Age gt60
• Ann Arbor stage III or IV
• Hb lt12g/dL
• Number of nodal areas gt4
• LDH gtULN

20
FLIPI Risk Groups

• Low risk 0-1 adverse factor (5 10yr OS91
  71 respectively)
• Intermediate Risk 2 adverse factors (510yr
  OS78 51 respectively)
• High risk 3 or more (510 yr OS52 36
  respectively)

21
(No Transcript)
22
Aggressive NHL3
23
Tx Aggressive NHL

• Are highly curable lymphomas
• If early disease present (localized, non-bulky
  stage I or II) may use XRT only for cure
• However, most advocate combined therapy for early
  stage disease

24
Historical tx of aggressive NHL

• In 1972 Levitt, et al reported curability of
  large cell NHL with combination chemo2
• In 1975 DeVita et al described curing pts using
  COPP (Cytoxan, adriamycin, vincristine,
  procarbazine and prednisone)2
• During the 70s this regimen was simplified to
  the classic CHOP regimen we use today (Cytoxan,
  adriamycin, vincristine and prednisone)

25
TX of Early Stage

• A SWOG protocol randomized pts to either 3 cycles
  of CHOP followed by involved field XRT vs. 8
  cycles of CHOP alone3
• This showed that pts had a better 5 yr. PFS and
  OS with combined therapy
• 76 vs. 67, PFS respectively
• 82 vs. 74, OS respectively

26
Early Stage Contd

• The GELA trial2
• A French group has investigated a more intensive
  chemo regimen. They randomized pts to either 3
  cycles of CHOP with XRT vs. ACVBP (adriamycin,
  Cytoxan, vindesine, bleomycin, prednisone
  followed with consolidation with ifosfamide,
  VP-16 and AraC)
• This new regimen did improve EFS and OS, but at
  significant toxicity

27
Early Tx Summary

• For most patients with early, non-bulky (lt10cm)
  stage I or II, 3 cycles of CHOP followed by
  involved field XRT is std
• The role of using rituximab in early stage is
  gaining evidence
• Early studies suggest a benefit to adding
  rituximab to chemotherapy

28
Advanced Stage Tx

• CHOP is still the most commonly used regimen, and
  now with the addition of rituximab
• Several groups are investigating more aggressive
  chemo regimens
• Here are a few

29
The German group2

• They divided pts into three groups young good
  px, young poor px, and elderly
• They then randomized pts to one of four arms
• Arm 1 CHOP 21 (traditional 21 day cycle)
• Arm 2 CHOP 14 (14 day cycle of CHOP)
• Arm 3 CHOEP 21 (CHOPVP-16 q 21 days)
• Arm 4 CHOEP 14 (above q 14 days)

30
The German Results

• CHOEP 21 improved EFS, but CHOP 14 and CHOEP 14
  improved EFS, CR and OS over std CHOP 21
• The Germans now consider CHOEP 14 preferred chemo
  for young good px pt
• Based on the results of the MInT tx in young good
  px pts (CHOP-like chemo w/ Rituxan), they also
  will add Rituxan to their chemo
• They are also using this same regimen for young
  poor px pts

31
The French Approach3

• Study randomized pts to 3 cycles CHOP XRT vs. 3
  cycles ACVBP followed by consolidation.
• EFS (82 vs. 74), OS (90 vs. 81) were in
  favor of the chemo only arm
• Ongoing study using above Rituxan

32
The North Americans

• CHOPRituxan considered std of care
• Trials are ongoing to improve outcomes

33
(No Transcript)
34
Indolent NHL

• Follicular lymphoma is most common type of
  indolent NHL
• Majority of pts present w/ stage III/IV disease
  with multiple enlarged LN that have been present
  for a long time
• Generally not considered curable

35
Natural Hx of Indolent NHL

• Can have long symptom free intervals
• Several studies show no OS advantage to early
  treatment vs. waiting until progression or
  symptoms develop.
• Can go for years w/o needing tx. and obs alone is
  a feasible approach. Median survival for stage
  III/IV is 7-10 yrs

36
Tx Early Stage I/II indolent NHL

• For stage I/II XRT may be reasonable sole tx

37
Tx for advanced disease

• Chemotherapy remains the mainstay of treatment.
• Various regimens exist
• CVP, Fludarabine, FC, FCR, CVP-R
• All appear to have same RR
• Rituximab can be used alone or in combo w/ other
  regimens
• Radio-labeled monoclonal antibodies are also
  available for refractory/relapsed disease (Bexxar
  and Zevalan)
• Transplantation has been investigated for
  relapsed disease

38
Summary of Tx Indolent NHL
39
Tx summary Contd
40
Marginal Zone Lymphomas (MZL)

• 3 main types
• Splenic
• MALT lymphoma
• Nodal
• Can occur in GI tract, salivary glands, thyroid,
  orbit, conjunctiva, breast and lung
• Surgery or XRT usually sufficient to treat

41
Splenic lymphoma

• lt5 NHL
• Median age 65
• Present w/ splenomegaly, lymphocytosis
• Course is indolent. Survival 70 _at_10yr
• Tx of choice is splenectomy

42
MALT lymphomas

• Extranodal lymphoma associated w/ mucosal tissue
• 5 of NHL, 50 of these are gastric
• Most are stage I/II at presentation
• Gastric MALTomas assoc w/ H.pylori infection. Tx
  w/ Abx causes regression of lymphoma in majority
  of cases
• XRT or resection can be used for other sites of
  MALToma

43
Extra-nodal MZL

• Are extremely rare
• Usually indolent
• Surgery can be used w/ or w/o XRT

44
Mantle Cell Lymphoma

• Considered intermediate aggressive. Median
  survival is 3-4 yrs.
• Median age of 63 w/ male predominance.
• Usually stage IV at dx
• Distinctive features include Cyclin D1 and
  t(1114)

45
Tx Mantle Cell Lymphoma

• CVP (Cytoxan, vincristine, prednisone)
• Hyper-CVAD (mtx, adriamycin, Cytoxan,
  vincristine, dexamethasone, AraC-C) w/ and w/o
  rituximab has also been used.
• Relapses are common even after BMT

46
(No Transcript)
47
AID-related lymphomas

• AIDS defining malignancies
• Kaposis sarcoma, NHL, primary CNS lymphoma,
  invasive cervical carcinoma
• AIDS related NHL
• Primary CNS lymphoma (PCNSL)
• Systemic NHL
• 1º effusion NHL

48
HIV related NHL

• Usually in pts w/ CD4 count lt100cell/µL
• High grade NHL, (diffuse large B cell
  immunoblastic variant or Burkitts lymphoma are
  most common)
• Indolent NHL are much less common
• Most present w/o adenopathy and w/ stage IV dz.

49
TX systemic AIDS related NHL

• std chemo considered CHOP, although there is
  controversy.
• Rituximab is investigational but early studies
  suggest synergism
• HAART therapy should be continued or initiated
• These pts do worse than in HIV(-) pts

50
PCNSL in HIV

• Usually w/ CD4 counts lt50cell/µL
• Present w/ focal or non-focal neurological
  symptoms
• confusion, lethargy, memory loss, hemiparesis,
  aphasia, and/or seizures that have usually been
  present for less than three months
• DX w/ MRI/LP/EBV DNA in CSF/brain bx/rule out
  toxoplasmosis

51
TX PCNSL

• No established std since it is relatively rare
  and has a poor px
• XRT w/ steroids can prolong survival
• HAART can prolong survival
• Chemotherapy can be used but is generally poorly
  tolerated

52
Primary Effusion Lymphoma

• Originates on serosal surfaces of peritoneal,
  pericardial and pleural cavities and joint spaces
• Generally will have genetic material from HHV-8
  and EBV
• CD4 count typically lt100cells/µL

53
TX 1º Effusion NHL

• Very poor px so data is limited
• Some success reported w/ XRT
• Chemo has been used in the form of CHOP
• HAART should be administered also
• Clinical trial when available

54
(No Transcript)
55
Hodgkins Disease

• It is estimated that in 2005 there will be 7350
  new cases of HD
• There will be an estimated 1410 deaths from HD in
  2005

56
Clinical Presentation

• Bimodal distribution peak in 20s and a second
  peak over age 50
• Most will present with asymptomatic
  lymphadenopathy often in the neck
• Can manifest as mediastinal mass on CXR.
• If large enough can cause symptoms such as cough,
  retrosternal cp or SOB

57
Systemic Symptoms

• B symptoms similar to those seen with NHL often
  are present
• Fever Pel Ebstein (fever recurring at variable
  intervals of several days to weeks and lasts 1-2
  wks before waning)
• Night sweats
• Weight loss
• Fatigue
• Pruritus uncommon, but when present is usu.
  generalized and can precede overt HD by mos. to a
  yr.

58
Other possible Symptoms

• ETOH induced pain
• Skin lesions (ichthyosis, acrokeratosis (Bazex
  syndrome), urticaria, erythema multiforme,
  erythema nodosum, necrotizing lesions,
  hyperpigmentation, and skin infiltration )
• Nephrotic syndrome
• Hypercalcemia
• Anemia
• eosinophilia

59
Diagnosis

• As always a good HP is priceless
• CT C/A/P
• PET scan
• BM Bx if pt has B symptoms, clinical stage II-IV,
  anemia, leukopenia or thrombocytopenia
• CBC, LDH, CMP
• Lymph node bx (again an entire intact LN is
  preferable)

60
Classification

• WHO/REAL Classification
• Nodular Lymphocyte Predominant (CD30-/CD15-/pan-Bc
  ell ) non-classical RS cells
• Classical Hodgkins lymphoma (CD30/CD15/CD45-/p
  anB and panT antigen negative) Reed-Sternberg
  Cells
• Lymphocyte-rich
• Nodular sclerosis
• Mixed cellularity
• Lymphocyte depleted
• Unclassifiable classical HD

61
Reed-Sternberg Cell
62
Nodular Sclerosis Classical HL

• Most common subtype
• Most common in women, adolescents and young
  adults
• often will have a mediastinal mass, lower
  cervical, supraclavicular L.N. w/ and orderly
  pattern of spread
• Good Px

63
Mixed Cellularity Classical HL

• More common in males
• More aggressive, but still curable
• Pts usually older and more likely to have B
  symptoms
• More commonly in underdeveloped countries

64
Lymphocyte depleted Classical HL

• Least common subtype
• Older men and HIV infected pts
• Less peripheral adenopathy, more abdominal
  adenopathy.
• HSM may be prominent
• BM often involved

65
Lymphocyte-rich Classical HL

• Older patients usually
• More frequently present w/ mediastinal mass
• Late relapses less common, but more fatal

66
Nodular Lymphocyte Predominant HL

• Only 3-8 of HL
• More common in adults (median age 34)
• More often localized disease
• More common in men
• Slowly progressive w/ very favorable outcomes
• Can progress to large B-cell NHL

67
Staging
68
Cotswold Staging
69
Overview of Treatment

• HD is highly curable even after relapse
• Stage and prognostic factors will determine high
  vs. low risk disease and will drive treatment
  choices

70
International Prognostic Score

• 7 factors
• Albumin lt4g/dl
• Hblt10.5g/dl
• Male
• Age gt45
• WBCgt15,000/mcl
• Lymphocyte count lt600/mcl

71
5yr freedom from progression

• No factors 84
• 1 factor 77
• 2 factors 67
• 3 factors 60
• 4 factors 51
• gt5 factors 42

72
EORTC definitions

• Adverse Px factors identified in CSI-II pts. Used
  to define tx for CSI-II HD
• Defined as follows
• Large mediastinal adenopathy
• Age over 50
• B symptoms
• gt4 LN regions involved
• B Symptoms ESRgt30 or ESR gt50 w/o B symptoms

73
Historical Tx HL

• In 1964 the NCI developed a four drug regimen
  that cured 50 of pts.
• Thus MOPP (mechlorethamine, vincristine,
  procarbazine, prednisone) became std
• Significant toxicity and secondary malignancies
  made it imperative to find alt. regimens

74
The birth of ABVD

• ABVD was originally developed for MOPP resistant
  disease
• In a head to head trial, ABVD had higher CR, PFS,
  and OS than MOPP
• It also had less short and long term toxicity.

75
Favorable Px Stage I-II

• 2-4 cycles ABVD (adriamycin, vinblastine,
  bleomycin, dacarbazine) followed by involved
  field XRT to original L.N. regions
• XRT alone to involved and uninvolved L.N. regions
• Stanford V (adriamycin, mechlorethamine,
  vinblastine, prednisone, vincristine, bleomycin,
  VP-16) for 8wks w/ involved field XRT

76
Favorable Px Contd

• Ongoing trials are attempting to identify newer
  regimens and determine the optimal number of
  chemotherapy cycles to administer to obtain the
  lowest relapse rate and improve overall survival

77
Unfavorable Stage I-II

• XRT alone not generally accepted due to high rate
  of relapses
• 4-6 cycles ABVD followed by XRT to involved sites
• Treat 2 cycles past maximum response as assessed
  on imaging studies to max. 8 cycles

78
Tx Stage III-IV HD

• 6-8 cycles of ABVD most common regimen used
• Hybrid regimens tested, but not better than ABVD
• BEACOPP (bleomycin, VP-16, adriamycin, Cytoxan,
  vincristine, procarbazine, prednisone) is alt.
  regimen
• Stanford V for 12 wks followed by IFXRT also
  being tested

79
Relapsed/Refractory HL

• Bx area of relapse to prove pt has truly relapsed
  and not developed an infection/other malignancy
• If tx w/ XRT only can still salvage w/ chemo
• If late (gt12mo) relapse after chemo, can use
  different regimen or autologous transplant

80
Summary

• The lymphomas represent a heterogeneous spectrum
  of disease
• Aggressive NHL are generally curable with modern
  chemotherapy
• Indolent NHL are not usually curable, but are
  very treatable w/ chemo

81
Summary Contd

• HL is considered a highly curable disease
• The best regimen remains to be determined
• Many salvage regimens exist including BMT

82
(No Transcript)
83
References

• 1. Jemal, Ahmedin DVM, PhD, etal. Cancer
  Statistics, 2005.CA A Cancer Journal for
  Clinicians5510-30. 2005
• 2. Armitage, James MD et al. The Treatment of
  patients with aggressive NHL. Oncology 19(4,
  supp1)1-34
• 3. Up to Date 2005