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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. - PowerPoint PPT Presentation
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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
CyclophosphamideDoxorubicin
VincristinePrednisone
• 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:
BacteriaAcid-fast bacilli PCP
• Cultures for cytomegalovirusWere 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 IgG1
Chimeric IgG1
Rybak et al. Proc Natl Acad Sci USA. 1992;89:3165.
Human kappa constant region
Rituximab: Mechanism of Action
Fc regionCD20
B cell
Rituximab
C1C1qC1sC1r
Pores(8-18 C9s)
H20/Ions
Lysis
Complement-mediated cell lysis
Fc regionCD20
B cell
Rituximab NK Cell
Fc receptor(FcγRIII)
Granules
Pores(perforin)
Granules release perforins and granzymes; cytokines
secreted (eg, IFN- )
H20, ions,
granzymes
Lysis
Antibody-dependent cellular cytotoxicity(ADCC)
Apoptosis
CD20
B cell
Rituximab
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
DTX 50 36 0.0001Ricin 40 5 0.004TNF alpha 43 7 0.0015ADR 53 28 0.0027CDDP 27 4 0.0456VP16 8.5 0.6 0.0263
Cytotoxic Agent + rituximab – rituximab P Value
% Cytotoxicity
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 CR CRu CR/CRu PR
57.2 7.5 2.5
10.0 47.2
80.9 30.2 10.5 40.7 40.1
<0.0001
<0.0001
Marcus R, et al. Blood 2003;102:28a (Abstract 87)
CVP ± Rituximab in previously untreated follicular NHL
MabThera + CVP: median not reached
Months
1.00.90.80.70.60.50.40.30.20.1
00 3 6 9 12 15 18 21 24 27 30 33
CVP: median 12 months
p<0.0001
Duration of responseTime to next antilymphoma treatment
Prob
abili
ty
MabThera + CVP: median not reached
Months
1.00.90.80.70.60.50.40.30.20.1
00 3 6 9 12 15 18 21 24 27 30 33
CVP: median 10 months
p<0.0001
Prob
abili
ty
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 inelderly patients with DLCL
399 patients aged 60–80 yearsStage II–IV
ECOG 3 excluded
CHOP21 x 8 R-CHOP21 x 8
R
Coiffier et al 2002. N Engl J Med;346:235–42
Coiffier et al 2002. N Engl J Med;346:235–42
CHOP (%)
R-CHOP (%)
p value
CR + CRu* 63 75 p=0.005
EFS 2 years 38 57 p<0.001
OS 2 years 57 70 p=0.007
*Unconfirmed CR
Results of the GELA study
GELA-LNH 98.5: 5-year PFS
100
80
60
40
20
00 1 2 3 4 5 6 7
Prog
ress
ion-
free
sur
viva
l (%
)
R-CHOP 54%
CHOP 30%
Feugier P, et al. J Clin Oncol 2005;23:EpubYears
p<0.00001
GELA-LNH 98.5: 5-year OS
p<0.007
R-CHOP 58%
CHOP 45%
0 1 2 3 4 5 6 7
Ove
rall
surv
ival
(%)
Years Feugier P, et al. J Clin Oncol 2005;23:Epub
100
80
60
40
20
0
CD20+ DLBCL18–60 years
IPI 0,1Stages II–IV,I with bulk
6 x CHOP-like+ 30–40 Gy (Bulk, E)
6 x MabThera + CHOP-like
+ 30–40 Gy (Bulk, E)
Randomisation
MInT – Design
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.
Months50454035302520151050
Prob
abili
ty
1.00.9
0.8
0.70.60.50.4
0.3
0.20.10.0
79.9% R-CHEMO
60.8% CHEMO
p<0.0001
Median observation time: 22 months
MInT full analysis - TTF
Pfreundshuh et al. 2004. Blood;104(Suppl. 1):Abst. 157.
94.6% R-CHEMO
86.2% CHEMO
Median observation time: 23 months
MInT full analysis - OS
5045403530252015105
Prob
abili
ty
1.00.9
0.8
0.70.60.50.4
0.3
0.20.10.0
0
Months
p=0.0002
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
Rituximab Rapidly Depletes B-cells:
100
10
00 1 2 3 4 5 6 7 8 9 10 11 12 13
Med
ian
abso
lute
CD
19 c
ount
in
per
iphe
ral b
lood
(/µl
)
Base- Pre- Pre- 3 months 6 months 9 months 12 monthsline dose dose post TX post TX post TX post TX
#2 #4
n=166
McLaughlin et al. J Clin Oncol. 1998;16:2825.
Serum Ig Concentrations in Patients Receiving Rituximab
60
100
140
180
220
IgA
(mg/
dL)
Months1 2 3 4 5 6 7 8 9 10 11 12 13
0
100
200
300
400
500
600
700
1 2 3 4 5 6 7 8 9 10 11 12 13
IgM
(mg/
dL)
Months
200
400
600
800
1000
1200
1 2 3 4 5 6 7 8 9 10 11 12 13
IgG
(mg/
dL)
Months
(N=235)
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 induced-pulmonary toxicity
• Incidence: is considered to be low• Symptoms and signs: effort dyspnea, dry cough,
fever • Chest X-ray: bibasilar reticular or reticulo-
nodular 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 pneumonitis2. 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-CSFincrease neutrophils number & enhance
their functionneutrophils 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 non-specific
• Re-treatment should seriously be
considered as contraindicated
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