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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