Non-Hodgkin's Lymphoma -

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Non-Hodgkin's Lymphoma - Long-term Survivors and
Adverse Effects
Ron Epelbaum
Department of Oncology Rambam Medical
Center Haifa, Israel
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Non-Hodgkin's Lymphoma - Long-term Survival
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Late Effects of Therapy

• Toxicities that developed during therapy and
  continued after therapy
• New toxicities that occurred after therapy was
  completed

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Long-term Survival
Diagnosis
Treatment
Acute Toxicity
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Long-Term Sequelae of Treatment for Non-Hodgkins
Lymphoma
Secondary malignancies Gonadal dysfunction Neurolo
gic impairment Pulmonary toxicity Cardiac
toxicity Others Endocrine toxicity Immune
system abnormalities Psychological
problems Other organ toxicities
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Secondary Malignancies
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Risk for Secondary Malignancies (SM)
Secondary Malignancies
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Cumulative Risk of Second Cancers
Secondary Malignancies
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Obsereved to expected Ratio (O/E)
Secondary Malignancies
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ANLL Grouped by Time since Diagnosis of NHL
Secondary Malignancies
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Solid Tumors Grouped by Time since Diagnosis of
NHL
Secondary Malignancies
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Post-Therapeutic ANLL
Secondary Malignancies
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Risk Factors for ANLL
Drugs Alkylating agents Drugs binding to the
enzyme Topoisomerase II Irradiation Large
fields High doses Procedure ASCT
Secondary Malignancies
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Drugs as Risk Factors for ANLL
O/E Prednimustine 13.4 related to cumulative
dose and duration of treatment Mechlorethemin
Procarbozine 12.6 Chlorambucil 2.4 related to
cumulative dose and duration of
treatment Cyclophosphamide 1.8 (NS) VP-16 case
reports
Secondary Malignancies
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Radiation (RT) as Risk Factors for ANLL (O/E)
RT RT RT RT alone dose field CT Gomez, 1982
1 local RT 1 TLI 162 TLICT
1008 Greene, 1983 RTCT 105 Lavey, 1990
1 TLICT 10.6 CT alone 11.9 Travis,
1994 3.1 (NS) 1 RTCT CT Travis,
1996 TBICT 117
Secondary Malignancies
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Post-Transplant MDS/AML
Crude incidence
Actuarial
(time-median) Risk (time) Sobesks,
1999 1.0 (1.5 y) Miligan, 1999 3.0 (5
y) Dark, 2000 2.8 (2.5 y) 6.3 (10
y) Darrington, 1994 4.0 (3.5 y) 12.0 (5
y) Stone, 1994 7.6 (2.5 y) 18.0 (6 y) Micallef,
2000 12.0 (6 y) 14.2 (5 y) 36.5 (10y) Miller
, 1994 14.0 (5 y)
Secondary Malignancies
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Risk Factors for Secondary MDS/AML Post
Transplant

• Old Age
• Long interval between diagnosis and transplant
• Low grade histology
• Use of radiation therapy (TBI Pelvic
  irradiation)
• Bone marrow involvement at diagnosis
• Prior fludarabine therapy
• Low platelet count at the time of transplant

Secondary Malignancies
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Etiology of Secondary MDS/AML Post-Transplant

• Prior alkylator therapy
• Transplant-related factors
• - Residual damaged host cells
• - Altered bone marrow microenvironment which
  promote growth of mutated stem cell within
  the reinfused marrow

Secondary Malignancies
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Post-Therapeutic Solid Tumors
Lung Bladder Stomach Sarcoma
Tongue/Lip Melanoma
Libshitz, 1978 Konits, 1982 Green,
1985 Pedersen- Bjergaard, 1988 Lishner,
1991 Travis, 1993/95 Yamada, 1999 Brennan, 2000
Secondary Malignancies
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Risk Factors for Solid Tumors
Drugs Cyclophosphamide (bladder, lung) Shared
etiologic factors Tobacco (lung) Sunlight
exposure (melanoma,

tongue/lip) Chemicals (sarcoma) Immunologic
defects (melanoma) Genetic alterations
Secondary Malignancies
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Secondary Malignancies
Summary

• Patients with NHL are at increased risk of second
  primary cancer. This risk, especially of solid
  tumors, remains high in long-term survivors.
• The relative risk for ANLL has a wide range of
  3.8-341, and for various solid tumors is up to
  3.6.
• The crude incidence of MDS/AML after transplant
  varies from 1 to 12. The actuarial risk at 5 y
  is between 3 and 18.
• The excess risk of secondary malignancies is
  probably related to antecedent therapy and shared
  risk factors.

Secondary Malignancies
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Gonadal Dysfunction
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Pre-Treatment - Males
Lass, 1998 2/22 9.1 Azoospermia (HD
18.2) Pryzant, 1993 6/26 23 Oligospermia Nacca
che, 1996 13/24 54 Abnormal spermogram Botch
an, 1997 HDgtNHLgtControls
Gonadal Dysfunction
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Post-Treatment
Regimen Dysfunction Follow Up Time (median) Mu
ller, 1993 MACOP-B 1/22 5 2.3
y VACOP-B Radford, 1994 VAPEC-B 2/14 14 1.1
y (NHLHD) Bokemeyer,
1994 Various 4/24 17 all gt2.0 y Dumontet,
1992 LNH-80 4/15 27 9.2 y Pryzant,
1993 CHOP-Bleo 16/58 28 2.7 y
Gonadal Dysfunction
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Retention of Fertility after High-Dose Therapy
and Transplant
Fertility Test Jackson, 1997 10/23
43 Pregnancy (NHLHD, lt40y) Muller, 1993 5/10
50 Patient history, hormonal function
Gonadal Dysfunction
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Preservation of Fertility
Males Semen cryopreservation Females In-vitro
fertilization and embryo storage Ovarian tissue
cryopreservation Co-treatment with
gonadotropin-releasing hormone agonist
Gonadal Dysfunction
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Gonadal Dysfunction
Summary

• Patients with NHL have impaired pre-treatment
  sperm quality, compared with that of healthy
  controls. However, sperm quality is higher
  compared with HD.
• Therapy of NHL induce long-term gonadal toxicity
  in up to 1/3 of the patients. Thus, fertility may
  be preserved in the majority of patients.
• Fertility may be preserved also in patients
  receiving dose-intensification and transplant.
• High cummulative doses of cyclophosphamide and
  pelvic irradiation are associated with a high
  risk of long-term sterility.

Gonadal Dysfunction
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Neurotoxicity
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Primary CNS Lymphoma
Encephalopathy after Treatment
Clinical symptoms Dementia Ataxia Aphasia Hemipare
sia Urinary incontinence CT / MRI Cortical
thinning Ventricular enlargement White matter
changes
Neurotoxicity
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Primary CNS Lymphoma
Encephalopathy after CTRT
Neurotoxicity
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Primary CNS Lymphoma
Encephalopathy - Risk Factors
Age gt 60 y CT after RT IT-MTX RT dose gt 50 Gy CT
dose
Neurotoxicity
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Primary CNS Lymphoma
Encephalopathy after CT alone
Neurotoxicity
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Vincristine Peripheral Neuropathy (NHL HD)
Neurotoxicity
Haim et al., CANCER 1994
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Central and/or Peripheral Neuropathy
Drugs Procarbazine, Cytarabine, Fludarabine,
Ifosfamide, Cisplatin Course Usually during
treatment and reversible may last for weeks to
months, and rarely irreversible or progressive
Neurotoxicity
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Neurotoxicity
Summary

• The probability of late central neurotoxicity in
  patients with primary brain lymphoma is 22-32
  after chemotherapy combined with radiotherapy.
• Less neurotoxicity is caused by chemotherapy
  alone for primary brain lymphoma.
• The main risk factor for the development of late
  neurotoxicity is age gt60y.
• Various drugs used for lymphoma result in central
  or peripheral neurotoxicity. It is usually
  reversible, but may be associated with prolonged
  sequelae.

Neurotoxicity
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Pulmonary Toxicity
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Pulmonary Toxicity
Cause Irradiation, Chemotherapy Clinical
Syndrome Pneumonitis, progressive fibrosis Signs
Symptoms Dyspnea, cough, fever Imaging Opacifica
tion, infiltrates, consolidation, nodules Lung
Function Tests Decrease in lung volumes and in
diffusing capacity
Pulmonary Toxicity
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Low-dose Bleomycin
Pulmonary Toxicity
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Bleomycin-Containing Regimens
Pulmonary Toxicity
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Methotrexate-Containing Regimens
Pulmonary Toxicity
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Chemotherapy with Granulocyte Colony-Stimulating
Factor
Pulmonary Toxicity
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After High-Dose Therapy and Transplant
Pulmonary Toxicity
No. Patients Respiratory complications Jules-Elys
ee, 1992 77 45 (NHLHD) (26 fatal) Salloum,
1998 26 0 (NHLHD)
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Cardiac Toxicity
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... in Hodgkin's desease
Cardiac Toxicity
Coronary vessels Myocard Pericard Valves
Conduction system
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Doxorubicin Related
Short-term cardiac toxicity LVEF
symptoms Cardiac electrophysiology Late cardiac
toxicity Time to cardiac Dose of
Dox LVEF evaluation mg/m2 Haddy, 1998 0-13
y 80-240 1/28 4 median 9.9 y 240-560 7/29
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Cardiac Toxicity
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Second Cancers
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