Rituxitmab for the Treatment of AAV

8/3/2019 Rituxitmab for the Treatment of AAV

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Rituxitmab for the treatment of

AAV

Dr Sharath Kumar

ISIC, New Delhi


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Overview

Rituximab action

Rituximab use in AAV history

Rituximab for induction

RAVE

RITUXVAS

Rituximab for maintenece

Chug Struass

Questions which remain

Conclusion


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CD20

CD20 aka human B-lymphocyte-restricted differentiation antigen,Bp35

A hydrophobic transmembraneprotein

Molecular weight ~35 kD

CD20 regulates an early step(s) inthe activation process for cell cycleinitiation and differentiation, andpossibly functions as a calcium ionchannel. CD20 is not shed from thecell surface and does not internalize

upon antibody binding.[6]

Free CD20antigen is not found in thecirculation; thus a drug that reactswith CD20, such as an antibody,would not be neutralized beforebinding to its target cell.[7]


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CD20 Located on pre-B and mature B lymphocytes

Not found on stem cells, pro-B cells, normal plasma cells

or other normal tissues


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Rituximab

A chimeric murine/human monoclonal

antibody against CD20 antigen.

Complementarity determining regions of themurine anti-CD20 antibody 2B8 in conjunction

with human kappa and IgG1 heavy-chain

constant region sequences.

The vector was cloned into Chinese hamster

ovarian cells as the production source of

immunoglobulin


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Rituximab

Majority of pharmacokinetic and pharmacodynamic studiesin B-cell lymphoma.

375 mg/m2 as an IV infusion for four doses, the meanserum half-life was 59.8 h (range 11.1 to 104.6 h) after the

first infusion and 174 h (range 26 to 442 h) after the fourthinfusion.

Serum concentration of rituximab was directly correlatedwith response and inversely correlated with tumor burden.

The wide range of half-lives bcos variable tumor burden

among patients In rheumatoid arthritis, half-life after second dose was 20

days, which was similar to native IgG. Explanation notknown.


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Rituximab

In follicular lymphoma a small dose escalationstudy, 50 mg/m2 resulted in the same degree andduration of peripheral B-cell suppression, and

effect on antibody response as 375 mg/m2. In RA body surface area only contributed 19.7%

to the variability in clearance and made aninsignificant contribution to variability in drug

exposure as measured by AUC. DANCER trial 500 mg per dose gave similar but

slightly lower responses to the 1000 mg dose.


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Rituximab Three different

mechanisms complement-

dependentcytotoxicity (CDC),

antibody-dependent

cellular cytotoxicity(ADCC)

stimulation of theapoptotic pathway

Polymorphisms of Fcreceptors gammaRIIIa (CD16) andgamma RIIa (CD32)associated with anti-tumor efficacy and inlupus.


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Rituximab

Recent data from a transgenic mouse with humanCD20 antigen on B cells,

Sensitivity of CD20 expressing cells to depletion

by rituximab may depend on themicroenvironment, integrin-regulatedhomeostasis and circulatory dynamics of B cells.

Marginal zone B cells, are not as completelydepleted and their depletion is more dependenton complement.

However, the marginal B cells are susceptible toelimination when they are mobilized by theaddition of antibodies to L and 4 integrin.


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Rituximab Among lymphoma patients, B-cell recovery began at

approximately 6 months following completion oftreatment.

Median B-cell levels returned to normal by 12 months.

Similar rapid response in the rheumatoid arthritis] but

recovery was prolonged with depletion in some for > 2years.

When the total B-cell count returns to normal, thereappears to be a change in the phenotype, B cells present being relatively deficient in expression of CD27, a

surface marker of memory B cells. B cells that do repopulate are primarily nave.

There were only mild reductions in IgM and IgG serumlevels

11 months following rituximab only 14% of pts had values

below the normal range.


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Mech of action

2 With a half-life of 21 days, to eliminate 99% of circulating specificantibody would require at least 4 months, and this only if antibodyproduction completely and immediately ceased with rituximab.Since antibodies are made primarily by plasma cells that haveminimal expression of CD20 and therefore are not eliminated by

rituximab, such a mechanism is further questioned. as CD27+memory B cells are eliminated, and no source of alloantigen werepresent to re-stimulate newly appearing nave B cells, then thealloantibody titer and PRA should fall over time, at a rate controlledby the half-life of immunoglobulin and the half-life of plasma cells.

1 vIg and a commercially available humanized monoclonal antibody

were able to inhibit anaphylatoxin-C3a and -C5a-induced calciumresponses in vitro and to block cellular migration and lethal C5a-mediated circulatory effects in vivo in mice and pigs[46] at aconcentration of 10 mg/mL, a concentration easily surpassed at thepeak of a rituximab infusion.


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Mech of action

Third, rituximab may be acting by eliminating B cells. Bcells are very efficient antigen-presenting cells,particularly after they have been activated.[51,52] Suchactivation could occur at the time of rejection. The

rapidity with which rituximab eliminates circulatingand presumably tissue CD20+ B cells is consistent withthis mechanism of action. The control of the rejectionwould occur because of loss of antigen presentationresulting in less stimulation of T cells. However, it could

include elimination of B-cellproduced cytokines thatare either directly damaging to the organ or thatstimulate or recruit other cells that are damaging.


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Rituximab

Most fatal infusion-related events occurred in thefirst infusion.

In autoimmune diseases because of reduced

numbers of B cells, the side effect profile muchbetter only cough and mild decrease in bloodpressure.

Agarwal et al. demonstrated that cytokine levels,

particularly TNF, increase immediately after thefirst dose of rituximab and that this can beassociated with a febrile response.


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Rituximab

No clear increase in infections

Concern for activation of hepatitis B

Rituximab is used effectively to treat hepatitis C-

associated cryoglobulinemia. Rituximab used in transplant patients with hepatitis C

as the cause of liver failure in about there was noincrease in recurrent hepatitis C

Rituximab is relatively safe in patients with hepatitis C.

Rituximab had little effect on circulating T cells or exvivo T-cell reactivity in humans.


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Rituximab use in AAV history

Untreated systemic AAV followed a progressivecourse with a fatal outcome.

Glucocorticosteroids (GCS) in combination with

cyclophosphamide (CYC) changed the prognosisto a manageable chronically relapsing illness.

However

not all patients respond satisfactorily to CYC

up to half of the patients who initially achieveremission relapse within the first 35 years [13].

substantial toxicity


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Rituximab in AAV history

B lymphocytes have been implicated in the pathogenesis of GPA for more than twodecades,

They were proposed as the primary target of the therapeutic effects of CYC in thisdisease.

The frequency of activated B lymphocytes associated with both disease activityand severity .

B lymphocytes were also thought to be essential for the production of potentiallypathogenic ANCA

First use of RTX in AAV was reported in 2001.

A 66-year-old male diagnosed with GPA in 1994 had developed CYC toxicity duringsubsequent treatment of disease flares, precluding its repeated use.

Prednisone in combination with AZA or mycophenolate mofetil (MMF)

RTX used on a compassionate-use basis under the hypothesis that remission couldbe induced by B-lymphocyte depletion resulting in rapid removal of potentiallypathogenic ANCA.

Remission was achieved quickly in this patient, and prednisone could bediscontinuedd


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Rituximab in AAV

Compassionate use of RTX in an additional 10

patients with severe refractory AAV .

At least 19 reports involving more than 200patients reporting on the use of RTX in

patients with AAV refractory to standard

therapies.

2 trials regarding RTX for induction in AAV


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Rituximab in AAV induction

RITUXVAS RAVEStudy design Randomized 3 : 1; open label,

two-group, parallel-designed

trial

Randomized 1 : 1, double-

blind, double-dummy,

noninferiority trial

Number patients 44 197 follow-up at 6

months completed in 165

Inclusion criteria Newly diagnosed AAV with renal

involvement

Newly diagnosed (49%) or

severe relapsing AAV (51%)

Patient characteristics GPA=22; MPA=16; Renal-limited

vasculitis=6

Older and more advanced renal

GPA=148; MPA=48;

Undetermined=1

Baseline BVAS RTX=19 (1424) vs

CYC=18(1225)

RTX=8.5+3.2 vs.

CYC=8.2+3.2

ANCA RTX 20=cANCA;13=pANCA;

CYC 5=cANCA; 6=pANCA

RTX 66=cANCA;33=pANCA;

CYC 62=cANCA;34=pANCA


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RITUXVAS RAVE

Induction therapy RTX+CYC (IV)+GCS vs.

CYC+GCS

RTX+GCS vs.

CYC(oral)+GCS

RTX dose 4 x 375mg/m2 4 x 375mg/m2

Methylprednisolone (g) 12 13

Target GCS dose 5mg at 6 months 0 at 6 months

Maintenance therapy RTX =low-dose GCS;

CYC=AZA+low-dose GCS

RTX = placebo; CYC = AZA

Antibiotic prophylaxis Recommended Mandatory

Primary endpoints Sustained remission rates

at 12 months and serious

adverse events

Complete remission and

successful prednisone

taper by 6 months


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RITUXVAS RAVE

Severe adverse events Similar in both groups (RTX

42%; control 36%)

Mortality 18% (? CYC, ?Older)

More selected adverse

events in CYC group

Mortality 1.5%

Main outcomes RTX-based therapy not

superior to CYC-based

treatment;sustained remissions achieved

in (25/33) 76% of RTX-based

group and (9/11) 82% of the

CYC-based group (P=0.68)

RTX-based therapy not

inferior to daily CYC

treatmentfor induction of remission;

primary endpoint achieved

in (63/99) 64% in RTX group

and (52/98) 53% in

CYC group (P


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On the basis of the primary endpoint results of the RAVE trial, the FDA approvedthe use of RTX for remission induction in severe GPA and MPA.

Some observational studies have suggested that similar results can be achievedwith two doses of 1 g of RTX given 2 weeks apart.

Most recently, Mansfield et al. [46] reported on a unique RTX-based treatment

regimen for remission induction in 23 consecutive patients with AAV and renal. Two 1 g doses of RTX and six 2 weekly pulses of CYC (10mg/kg) were combined

with prednisolone tapered to 10mg daily by week 13.

Patients were then switched to AZA (2 mg/kg) to be continued together withprednisolone 10 mg/daily until completion of month 12.

All patients achieved clinical remission by 6 months and improvement of renalfunction was sustained for 36 months.

However a comparison of RAVE vs RITUXVAS suggets

CYC addition to RTX no benefit, increased adverse events andrisk of death


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2 major questions remain

1)Both RAVE and RITUXVAS included only ANCA-positive patients with severe disease.

Only anecdotal reports suggesting that RTX

may also be effectiv

e in ANCA-negativ

epatients or those with limited disease.

(Analogy is RF +ve better response in RA)


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Rituximab in AAV induction2) Non efficacy of Granulomatous vs Vasculitic manifestations

Case reports of lack of efficacy of RTX in patients with predominantgranulomatous manifestations.

However, most other studies have clearly shown that both vasculitic andgranulomatous respond well to RTX, ? other factors

differences in RTX dosing or

patient-specific resistance mechanisms.

Taylor et al. recently reported on the successful remission induction withRTX in all of 10 patients with primary refractory ophthalmic disease.

Holle et al ARD online publication Oct 2011

59 patients received 75 cycles of RTX.

overall response rate of refractory GPA to RTX was high (61.3% complete

remission or improvement). Response rates ofvasculitic manifestations were excellent;

Failure of response/progress was mostly due to granulomatousmanifestations,(orbital granuloma and pachymeningitis) .

Relapse rates were high (40%) despite maintenance treatment.


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Maintanence

Patients assigned to the CYC groups in both RAVE and RITUXVAS received maintenance with AZA,whereas patients in the RTX groups received placebo.

Retrospective cohort of 39 patients with AAV in complete or partial remission were treatedpreemptively with 1 g of RTX every 4 months and were followed for at least 1 year . All patientsachieved disease control, and no patient experienced organ-threatening disease activity.

72 patients with history of refractory AAV received RTX in a protocolized manner (1 g two timesfollowed by 1 g once every 6 months for 2 years) in order to prevent the relapse of the disease.Seventy patients (97%) achieved complete remission and only four patients were still onimmunosuppression at 6 months.

Retrospective 10-year experience with RTX for long-term maintenance therapy in 53 patients withrefractory GPA. These patients received a median of four individually timed consecutive courses of

RTX (total of 200 courses of four weekly infusions at 375mg/m2 and 10 courses of two weeklyinfusions of 1 g).

A total of 72 (34%) courses of RTX were given to treat relapses(achieving remission in allindividuals) and 138 (66%) courses were given preemptively following B-lymphocyte reconstitutionor following an increase of PR3-ANCA levels that occurred subsequently to B lymphocytereconstitution


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Maintenence

French Vasculitis Group published in J Rheumatol Nov 2011

Retrospective review of 28 patients [4 MPA and 24 GPA; median age 55.5 yrs (range 1878); whoreceived a median of 4 (range 210) RTX maintenance infusions, with median followup of 38months (range 2197) since diagnosis or last flare.

Regimen, n 375 mg/m2 biannually 13

1 g biannually 4

1 g annually 3 Others 8

At the beginning of maintenance therapy, 6 in complete remission (BVAS and p-BVAS = 0);

12 were in partial remission, with grumbling ENT disease (n = 12) and/or persistent lung nodules (n = 3);

10 were in complete remission with irreversible damage from their last flare (n = 9) and/or an earlier flare (n= 3)

2 patients had pulmonary flares both of which responded to RTX however one died of H1N1

At last evaluation, 6 patients in complete remission;

9 patients had partial remissions: 7 with persistent grumbling ENT manifestations, 2 with lung nodules;

11 patients were in complete remission with irreversible damage:


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Maintenance

French group based on this retrospective review

A prospective open-label trial

MAINRITSAN; NCT00748644

Patients with AAV who achieved remission withconventional CYC-based induction therapy.

Enrolled at remission and randomized to receive

maintenance therapy with either RTX (1 systematic infusion every 6 months for 18

months)

or AZA (for 21 months).


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Chug Strauss

Several case reports reporting efficacy in ChugStrauss.

Recently, a single center prospective pilot

study evaluated the safety and efficacy of RTXfor remission induction in patients with EGPAwith active renal disease.

RTX was well tolerated and successful incontrolling renal disease activity in threepatients.


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Conclusions

Rituximab useful for induction therapy in AAV (GPA,MPA) at 4 x 375mg/m2/wk (better w/o CYC)

Clarification needed for

Dosage and regimen for induction, (?1gm x 2) Use for granulomatous manifestations

Use in ANCA negative vasculitis and EPGA

Retrospective reviews and open label pilots have found

utility of Rituximab in maintanence therapy with singleinfusion 4 to 6 monthly

MAINRITSAN will answer whether this is better thanAZA which is the current gold standard maintenence


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Thank you for your attention

Documents

Rituxitmab for the Treatment of AAV