Fatal Pneumonitis Related to
Rituximab Based Regimen
Yair Herishanu M.D.
Department of Hematology
Case presentation
• An 80 years old man, generally healthy
• On October 2004 he noticed an enlarged
right sub-mandibular mass.
• On physical examination and CT there
were both supra and infra-diaphragmatic
enlarged lymph nodes.
Lymph node biopsy:
Follicular grade 3 non-Hodgkin's lymphoma
Treatment
• Rituximab+CHOP
Cyclophosphamide
Doxorubicin
Vincristine
Prednisone
• Every 21 days
A mid-treatment PET-CT
A mid-treatment PET-CT
Clinical course after 3rd cycle of therapy
• The patient complained of mild effort
dyspnea
• On physical examination - bilateral basilar
crepitations were evident.
• Pulse oximetry was normal
• Chest X-ray was normal
• Treatment was continued as scheduled
• 2 days after starting the 5th cycle,
he complained of dry cough and
worsening dyspnea.
• On examination he was afebrile,
tachypneic, hypoxemic and had bilateral
basal inspiratory crepitiations
Bronchoscopy
• Was grossly normal
• Staining of the BAL fluid for:
Bacteria
Acid-fast bacilli
PCP
• Cultures for cytomegalovirus
Were all negative
Trans-bronchial Biopsy
Treatment
• IV methylprednisolone (1mg/Kg)
• Broad spectrum antibiotics
• The patient developed rapidly progressive
respiratory insufficiency requiring
mechanical ventilation
• Died 10 days after admission.
Rituximab (Mabthera)
Rituximab:
A Mouse/Human Chimeric MoAb
Murine variable regions bind
specifically to CD20 on B cells
Human kappa constant region
Human IgG1
Chimeric IgG1
Rybak et al. Proc Natl Acad Sci USA. 1992;89:3165.
Rituximab: Mechanism of Action
Complement-mediated cell lysis
CD20
Fc region
C1r
C1s
C1q
C1
Rituximab
B cell
H20/
Ions
Lysis
Pores
(8-18 C9s)
Antibody-dependent cellular cytotoxicity
(ADCC)
Granules
CD20
Fc receptor
(FcγRIII)
Fc region
Rituximab
NK Cell
B cell
Granules release perforins
and granzymes; cytokines
secreted (eg, IFN- )
Lysis
H20,
ions,
granzymes
Pores
(perforin)
Apoptosis
CD20
Rituximab
B cell
Rituximab - Clinical Data
Indolent Non-Hodgkin’s
Lymphoma
Monotherapy:
Relapsed low grade / follicular lymphoma
• ORR-50%, median time to progression -12
months.
• 62% bcl-2 PCR-negative in PB and/or BM
Re-treatment
• ORR-40% and median time to progression-18
months
Monotherapy:
Previously untreated follicular lymphoma
•
•
•
•
ORR-73%, CR-20%
Median time to progression-18 months
30% bcl-2 PCR-negative in PB and BM
Molecular response is associated with a lower
rate of disease progression
Rituximab Pre-treatment Sensitizes
Cells to Cytotoxic Agents
% Cytotoxicity
Cytotoxic Agent + rituximab
DTX
Ricin
TNF alpha
ADR
CDDP
VP16
50
40
43
53
27
8.5
– rituximab
36
5
7
28
4
0.6
P Value
0.0001
0.004
0.0015
0.0027
0.0456
0.0263
Demidem et al. Cancer Biother Radiopharm. 1997;12:177.
CVP ± Rituximab in previously untreated
follicular NHL: response rates
CVP (%)
(n=159)
MabThera + CVP (%)
(n=162)
p value
ORR
57.2
80.9
<0.0001
CR
7.5
30.2
2.5
10.0
47.2
10.5
40.7
40.1
CRu
CR/CRu
PR
<0.0001
Marcus R, et al. Blood 2003;102:28a (Abstract 87)
CVP ± Rituximab in previously
untreated follicular NHL
Duration of response
Time to next antilymphoma treatment
1.0
0.9
0.8
0.8
0.7
0.7
0.6
0.5
0.4
MabThera + CVP:
median not reached
0.9
Probability
Probability
1.0
MabThera + CVP:
median not reached
0.6
0.5
0.4
0.3
0.3
CVP: median 12 months
0.2
0.1
0.2
CVP: median 10 months
0.1
p<0.0001
p<0.0001
0
0
0
3
6
9 12 15 18 21 24 27 30 33
Months
0
3
6
9 12 15 18 21 24 27 30 33
Months
Marcus R, et al. Blood 2003;102:28a (Abstract 87)
Aggressive Non-Hodgkin’s Lymphoma
CHOP vs 2nd and 3rd generation
regimens in aggressive NHL
Overall Survival
Fisher et al. NEJM 328 (1993)
R±CHOP in
elderly patients with DLCL
399 patients aged 60–80 years
Stage II–IV
ECOG 3 excluded
R
CHOP21 x 8
R-CHOP21 x 8
Coiffier et al 2002. N Engl J Med;346:235–
42
Results of the GELA study
CHOP
(%)
R-CHOP
(%)
CR + CRu*
63
75
p=0.005
EFS 2 years
38
57
p<0.001
OS 2 years
57
70
p=0.007
p value
*Unconfirmed CR
Coiffier et al 2002. N Engl J Med;346:235–42
GELA-LNH 98.5: 5-year PFS
Progression-free survival (%)
100
80
60
R-CHOP 54%
40
CHOP 30%
20
p<0.00001
0
0
1
2
3
Years
4
5
6
7
Feugier P, et al. J Clin Oncol 2005;23:Epub
GELA-LNH 98.5: 5-year OS
100
Overall survival (%)
80
R-CHOP 58%
60
40
CHOP 45%
20
p<0.007
0
0
1
2
3
Years
4
5
6
7
Feugier P, et al. J Clin Oncol 2005;23:Epub
MInT – Design
6 x CHOP-like
CD20+ DLBCL
18–60 years
IPI 0,1
Stages II–IV,
I with bulk
+ 30–40 Gy (Bulk, E)
Randomisation
6 x MabThera
+ CHOP-like
+ 30–40 Gy (Bulk, E)
Pfreundshuh et al. 2004. Blood;104(Suppl. 1):Abst. 157.
Early results of MInT trial
R-Chemo
Chemo
CR
81%
67%
TTF @ 2 yrs
80%
61%
OS @ 2 yrs
95%
86%
(Benefit seen in IPI 0 and 1)
Pfreundshuh et al. 2004. Blood;104(Suppl. 1):Abst. 157.
MInT full analysis - TTF
Median observation time: 22 months
1.0
0.9
79.9% R-CHEMO
Probability
0.8
0.7
0.6
0.5
60.8% CHEMO
0.4
0.3
0.2
p<0.0001
0.1
0.0
0
5
10
15
20
25
30
35
40
45
50
Months
Pfreundshuh et al. 2004. Blood;104(Suppl. 1):Abst. 157.
MInT full analysis - OS
Median observation time: 23 months
94.6% R-CHEMO
1.0
0.9
Probability
0.8
0.7
86.2% CHEMO
0.6
0.5
0.4
0.3
0.2
p=0.0002
0.1
0.0
0
5
10
15
20
25
30
35
40
45
50
Months
Pfreundshuh et al. 2004. Blood;104(Suppl. 1):Abst. 157.
Rituximab in NHL
•
•
Maintenance
BMT
–
–
–
–
In vivo purging agent
Combination with conditioning therapy
Post-transplant adjuvant immunotherapy
GVHD
Rituximab in other
lymphoproliferative disorders
• Post-transplant lymphoproliferative
disorder (PTLD)
• Waldenström’s macroglobulinemia
• Chronic lymphocytic leukemia
• B-cell (CD20+) acute lymphoblastic
leukemia
Rituximab in autoimmune disorders
• Warm and cold autoimmune hemolytic anemia
(AIHA)
• Idiopathic thrombocytopenic purpura (ITP)
• Trombotic trombocytopenic purpura (TTP)
• Acquired FVIII inhibitors and alloimmunization
in hemophilia A+B
Rituximab in autoimmune disorders
• Rheumatoid arthritis (RA)
• Lupus (SLE)
• Mixed cryoglobulinemia-type II
• IgM polyneuropathies
Rituximab - Adverse Effects
• Generally well tolerated
• Infusion-related reactions: usually during
the first infusion, fevers, chills,
hypotension and dyspnea
• Anaphylactic and other hypersensitivity
reactions
• Cytokine-release syndrome or
tumor lysis syndrome associated with high
number of circulating malignant cells
(>25,000)
Rare side effects
• Delayed neutropenia
• HBV reactivation and fulminant hepatitis
• Serum sickness
• Interstitial pneumonitis
Differential Diagnosis
1. Infection
2. Drug induced
– Rituximab
– Cyclophosphamide
– GCSF
3. Lymphoma
Rituximab-infectious complications
Median absolute CD19 count
in peripheral blood (/µl)
Rituximab Rapidly Depletes B-cells:
100
10
n=166
0
0
1
2
Base- Pre- Preline dose dose
#2
#4
3
4
3 months
post TX
5
6
7
6 months
post TX
8
9
10
11
9 months
post TX
12 13
12 months
post TX
McLaughlin et al. J Clin Oncol. 1998;16:2825.
Serum Ig Concentrations in Patients
Receiving Rituximab
1000
800
600
400
200
1
2
3
4
5
6
7
8
9
10
11
12
13
Months
IgA (mg/dL)
220
180
140
100
60
1
2
3
4
5
6
7
8
9
10
11
12
9
10
11
12
13
Months
700
IgM (mg/dL)
(N=235)
IgG (mg/dL)
1200
600
500
400
300
200
100
0
1
2
3
4
5
6
7
Months
8
13
Infections following rituximab
• 30.3 % of 356 treated patients
suffered from infectious events
–
–
–
–
Bacterial infections - 18.8%
Viral infections - 10.4%
Fungal infections - 1.4%
Severe infectious events (grade 3 or 4)
occurred in 3.9 % of patients
• Despite B-cell depletion, the incidence of
infection did not appear to be greater than
observed in chemotherapy trials
• Majority were typical of those common in
normal hosts
Lung Toxicity Related to Rituximab
• Recently, a few cases of interstitial lung
toxicity related to rituximab therapy have
been reported
• These patients were mostly elderly and
had received therapy with alone or
rituximab–containing regimens
• Onset: After 1 or more cycles of therapy
• Symptoms & signs: dyspnea, dry cough,
hypoxemia and occasionally fever
• Radiographic studies: "ground glass"
shadowing
• Pulmonary functional tests: restrictive
pattern and reduced diffusion capacity
• In all cases, rituximab was discontinued
and the majority of patients gradually
recovered
• The role of steroids in clinical recovery
remained unclear
• Re-treatment was uneventful in 1 patient
but in 2 others re-treatment resulted in
pulmonary deterioration which was fatal in
one case
In only two cases a pulmonary biopsy was
performed
In the first patient (treated with R-CHOP):
•
TBB- loose non-necrotic granulomas with mild
fibrosis
•
At autopsy- intra-alveolar hemorrhages with
diffuse alveolar damage and infiltration by
foamy macrophages
In the second patient (with a background of
rheumatoid arthritis):
• TBB- interstitial fibrosis
• At autopsy- extensive interstitial fibrosis
associated with extensive arterial thrombosis
•
The mechanism of this pulmonary injury
remains unclear:
1. Cytokine release such as TNF-α, IL-6
and IL-8
2. Complement activation
3. Indirect cytotoxic T lymphocytes
activation
Cyclophosphamide inducedpulmonary toxicity
• Incidence: is considered to be low
• Symptoms and signs: effort dyspnea, dry cough,
fever
• Chest X-ray: bibasilar reticular or reticulonodular infiltrates
• CT scan: "ground-glass" shadowing
• Pulmonary functional tests: restrictive
abnormalities with reduced diffusion capacity
•
Early-onset toxicity: 1-6 months after
exposure to cyclophosphamide
•
Late-onset toxicity: in patients treated
with low dosages of cyclophosphamide
given over a prolonged period of time
Histopathological findings
1. Non-specific interstitial pneumonitis
2. Diffuse alveolar damage
3. Bronchiolitis obliterans with organizing
pneumonia (BOOP)
4. Diffuse alveolar hemorrhage
Prognosis:
• Early-onset toxicity is generally good and
corticosteroids may be beneficial
• Late-onset toxicity has a poorer outcome
and often progresses despite therapy with
corticosteroids
GCSF - Lung Toxicity
• Presents as ARDS or intestitial pneumonitis
• Occurs during or after neutropenia recovery
• 2 cases are reported in which ARDS occurred during
treatment with G-CSF alone
• >70 cases are reported in combination with other
potentially toxic agents
• May exacerbate pulmonary toxicity caused primarily by
bleomycin, methotrexate, and cyclophosphamide
G-CSF
increase neutrophils number & enhance
their function
neutrophils are entrapped in the pulmonary
vascular capillaries
release oxygen radicals & proteolytic
enzymes
endothelial damage
pulmonary damage
Summary
We presented an elderly patient with FL who
developed a fatal interstitial pneumonitis,
probably related to the treatment with
Rituximab ± cyclophosphamide
Conclusions
• Although rare, Rituximab can cause
interstitial lung injury
• This lung toxicity appears to be nonspecific
• Re-treatment should seriously be
considered as contraindicated
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