Post on 10-Feb-2016
description
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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