[CIS-PAGID] CVID + LIP

[Terri Tarrant]

We would like to be a part of the trial and ongoing discussions.
After following much of the dialogue, my summary commentary would be the
following:
1. Agreed that a meeting or conference call would be best for all interested
parties to weigh in and so that everyone is on the same page.
2. Agreed that inclusion criteria must consider a reduction in pulmonary
functional parameter(s) (i.e. DLCO, 6 min walk, FEV1/FVC, or some
combination).
3. Agreed that immunohistochemistry for the inflammatory cell composition
must be performed, particularly since a B cell targetted therapy is a part
of the proposed treatment regimen, and if so, that B cells must be present
in the tissue for inclusion into the study.
4. I do not favor a placebo arm since patients with decompensation in
pulmonary function are typically unstable and need steroids at the least.
5.  As for the treatment arms, it depends what the primary and secondary
endpoints are and the population we chose to study that will determine what
treatments we propose.  If we do not have a steroid alone treatment arm, we
assume that the proposed therapies (Rituxan alone or in combination) are
superior or at a minimum are "steroid sparing" without having directly
tested this.  If we are assuming based on historical/anectodal data between
all of us that steroid sparing medications are always required or preferred
from a toxicity profile or that we are going to ask the question in
steroid-refractory patients, then we'll have to decide if we want to ask
whether B cell ablation alone is sufficient to treat the LIP, in which case
we need a Rituxan alone and a Rituxan + other DMARD arm.
6.  The peds vs adult CVID+LIP is an important question.  The disease may be
different, but the cases are few and we may need to include all cases
regardless of age for the purposes of statistical power.  I do believe that
including pediatrics will make us think differently about what
immunosupressants to use, and Rituxan would be a good one here.
7.  I don't believe that the mixed T/B cell inflammatory cell infiltrate of
LIP requires a B and T cell approach per se since it is used successfully as
monotherapy in inflammatory autoimmune diseases with good results (Hep C
mixed cryo, RA, etc), but this is where a Rituxan alone arm and a Rituxan +
Imuran or MMF could potentially address this question.

 Terri Tarrant, MD
Assistant Professor of Medicine
Thurston Arthritis Research Center
Lineberger Cancer Center Member
CB # 7280, 3300 Manning Dr.
Chapel Hill, NC 27599
(919) 843-4727
http://tarc.med.unc.edu/tarrant_welcome.php


On Tue, Jul 26, 2011 at 10:00 AM, Charlotte Cunningham-Rundles at mssm.edu <
charlotte.cunningham-rundles at mssm.edu> wrote:


> In my experience, steroids can alter the appearance of the nodules but not

> permanently and with more steroids that we’d like to use.   The question to

> me is still, are we treating the xray or the patient?  It is not comfortable

> for any of us to not want to ward off lung failure, but we don’t know how to

> do that.  And we don’t know that each case is the same and that lung failure

> is the result in all.  I have patients who have lung nodules  ( and some

> with granuloma too)  and they are just plain stable over a decade or

> more......

>

> I think the safest first approach is to maximize the IgG level, add

> azithromax or other macrolide daily, do budesonide daily by inhalation, and

> I still think that hydoxychloroquine daily has a lot in its favor.  (

> decreased antigen presentation and damps down TLRs)  I do not think that the

> nodules will ever go away, anymore than we can eliminate  lymphadenopathy or

> shrink the spleen in those with splenomegally.  We have to live with these,

> like it or not.

>

> As the conversation shows, we don’t have very much to go on here. But maybe

> rituxan alone would do something useful.   I am very comfortable with this

> RX , having used it a great deal in those with autoimmunity.  Maybe just

> mono rx in a few would be instructive so that a bit of data for a study

> could be obtained?

>

>

> On 7/25/11 10:15 PM, "Ashish Kumar" <Ashish.Kumar at cchmc.org> wrote:

>

>   I have a 21 yr old young woman with CVID and lung nodules, biopsy

> granuloma with mixed B and T cells; asymptomatic with normal PFTs. She was

> treated with steroids for 6 months with no change in CT picture, except she

> gained weight and acne.  When I saw her, I stopped her steroids since I

> didn't know what was being treated. Are you suggesting that we perform a

> preemptive strike with Ritux; every 6 months or so?

>

> Ashish

>

>

> Ashish Kumar, MD, PhD

> Assistant Professor

> Cincinnati Children's Hospital Medical Center

> Cincinnati, OH

>

> >>> "Jack Bleesing" <Jack.Bleesing at cchmc.org> 7/25/2011 12:12 PM >>>

>

> Lagging behind this discussion a bit, couple of questions (mainly out of

> feeling unsure about what to do, especially with young patients):

>

> - what is the pathology that we are treating? The patients we have seen

> typically have a mixture of T-cells, B-cells and plasma cells in these

> lesions, such that I don't see the complete logic in combining imuran with

> rituximab. Using a T-cell agent +  B-cell (or plasma cell) agent seems to

> make more sense to me (after perhaps induction with short-term steroids).

>

> - once diffusion abnormalities have occurred, are these reversible? It

> would make more sense to me to treat early - as per the "Warnatz/Ehl"

> approach, when ritux or steroids/MMF may be enough to reverse the disorder?

> Why not rituximab/MMF, as these patients are already on IVIG and they may be

> better off being a CVID patient with no B-cells than a CVID patient with

> "renegade" B-cells (keeping the steroids in reserve).

>

> - Is HHV-7 and/or HHV-8 routinely included in the diagnostic workup and if

> found in the lungs, does anybody treat?

>

> - If "our" approach would be 2 treatment arms, rather than a

> placebo-controlled approach, could we consider a cross-over design

> (following evaluation of bench marks - imaging, BAL, PFTs. etc.)

>

> - are kids with CVID (+ lung disease) different than the adults with this?

> Feel much more alarmed about our young patients with pulmonary

> complications, and have a hard time just watching them, or defining an

> endpoint of therapy.

>

> - would love to be part of a CVID workshop, where things are discussed (as

> well as uniform diagnosis and agreement about definitions of LIP/ pulmonary

> complications, agreement about workup/benchmarks and hashing out treatment

> options).

>

> Regards,

>

> JB

>

> ---------------------------------------------------------------------------

> Jack J.H. Bleesing, M.D., Ph.D.

> Associate Professor of Pediatrics

> Cincinnati Children's Hospital Medical Center

> Division of Bone Marrow Transplantation & Immune Deficiency

> 3333 Burnet Avenue, MLC 7015

> Cincinnati, OH 45229

> 513-636-4266 (phone)

> 513-636-3549 (fax)

> Jack.Bleesing at CCHMC.org

> http://www.cincinnatichildrens.org/immunodeficiencies/

>

> >>> "Routes, John" <jroutes at mcw.edu> 7/25/2011 11:44 AM >>>

> Elie

> I think we need to get all interested parties together either in person or

> by conference call to discuss. As we have had pretty good experience with

> several patients using rituxin with imuran, it makes sense to have that as

> one arm--plus If the patient does not tolerate imuran, we can substitute

> MMF

> or another agreed upon drug-------the other arm is totally open and

> personally would favor an arm without imuran----

> Jack

>

>

>

> John M. Routes, MD

> Chief, Section of Allergy and Clinical Immunology

> Professor of Pediatrics, Medicine, Microbiology and Molecular Genetics

> Department of Pediatrics

> Children's Hospital of Wisconsin

> Medical College of Wisconsin

> 9000 W. Wisconsin Ave.

> Milwaukee, WI  53226-4874

>

> Phone: 414-456-4802; 414-266-6997

> Fax: 414-456-6487 (Clinical)

> Fax: 414-456-6323 (Laboratory)

> Email: jroutes at mcw.edu

>

>

>

>

> > From: Elie Haddad <elie.haddad at umontreal.ca>

> > Reply-To: "pagid at list.clinimmsoc.org" <pagid at list.clinimmsoc.org>

> > Date: Mon, 25 Jul 2011 09:56:30 -0500

> > To: "pagid at list.clinimmsoc.org" <pagid at list.clinimmsoc.org>

> > Subject: Re: [CIS-PAGID] CVID + LIP

> >

> > Dear all,

> > what do you think about comparing Rituximab to something else than

> Rituximab.

> > Indeed, in the proposed protocol, Rituximab is in both arms meaning that

> we

> > consider Rituximab as the gold standard therapy for this condition... I

> am a

> > pro RTX in this condition but maybe there are other options, as outlined

> by

> > Klaus.

> > I would suggest to compare RTX to Steroids alone or also another

> possibility

> > would be to compare RTX to Infliximab.

> > Also, if finally we stay with the idea of RTX in both arms, what about

> MMF

> > instead of Imuran ?

> > Yours

> > Elie

> >

> >

> >

> > Elie Haddad, MD, PhD;

> > Professor of Pediatrics, University of Montreal,

> > Head, Pediatric Immunology and Rheumatology Division,

> > CHU Sainte-Justine, 3175 Cote Sainte-Catherine

> > Montreal, QC, H3T 1C5, Canada

> > Ph: 1 514 345 4713

> > fax: 1 514 345 4897

> > e-mail: elie.haddad at umontreal.ca

> >

> >

> >

> >

> > Le 2011-07-22 à 17:38, David Rawlings a écrit :

> >

> >> As Jack and I have discussed previously, our group in Seattle would be

> keen

> >> to participate in a trial- I suggest designing a 2 arm protocol eg Ritux

> >> with or without Aza.

> >> David

> >>

> >> -----Original Message-----

> >> From: pagid-bounces at list.clinimmsoc.org

> >> [mailto:pagid-bounces at list.clinimmsoc.org<pagid-bounces at list.clinimmsoc.org>]

> On Behalf Of Nelson, Robert P Jr

> >> Sent: Friday, July 22, 2011 11:15 AM

> >> To: pagid at list.clinimmsoc.org

> >> Subject: Re: [CIS-PAGID] CVID + LIP

> >>

> >> What about considering a mutlicenter clinical trial so we could

> contibute

> >> our patients to an organized effort?  Bob

> >> ________________________________________

> >> From: pagid-bounces at list.clinimmsoc.org [

> pagid-bounces at list.clinimmsoc.org]

> >> on behalf of Fleisher, Thomas (NIH/CC/DLM) [E] [TFleishe at cc.nih.gov]

> >> Sent: Friday, July 22, 2011 10:32 AM

> >> To: Routes, John; pagid at list.clinimmsoc.org

> >> Subject: Re: [CIS-PAGID] CVID + LIP

> >>

> >> Sorry for copying all on a simple question to Jack.

> >>

> >> Thomas A. Fleisher, M.D.

> >> Chief, Department of Laboratory Medicine

> >> NIH Clinical Center

> >> 301 496-5668 (T)

> >> 301 402-1612 (F)

> >>

> >> -----Original Message-----

> >> From: Routes, John [mailto:jroutes at mcw.edu <jroutes at mcw.edu>]

> >> Sent: Friday, July 22, 2011 8:32 AM

> >> To: pagid at list.clinimmsoc.org

> >> Subject: Re: [CIS-PAGID] CVID + LIP

> >>

> >> We have treated over ten patients with combination chemotherapy

> consisting

> >> of rituxin and azathioprine with outstanding results no infections and

> in

> >> many cased complete or near complete clearing.

> >>

> >> Sent from my Verizon Wireless BlackBerry

> >>

> >> ________________________________

> >> From: Terri Tarrant <tarra002 at gmail.com>

> >> Sender: "pagid-bounces at list.clinimmsoc.org"

> >> <pagid-bounces at list.clinimmsoc.org>

> >> Date: Fri, 22 Jul 2011 06:16:47 -0500

> >> To: pagid at list.clinimmsoc.org<pagid at list.clinimmsoc.org>

> >> ReplyTo: "pagid at list.clinimmsoc.org" <pagid at list.clinimmsoc.org>

> >> Subject: Re: [CIS-PAGID] CVID + LIP

> >>

> >> Yes, we have 3 cases that responded well (2 with CVID and 1 idiopathic

> LIP).

> >> We used the Eisenberg protocol of 1 g IV day 0 and day 14 with 100 mg IV

> >> solumedrol pre-med.  We did not use in combination with other drugs.  We

> did

> >> not see an increase in infections.  All patients needed redosing at 9-12

> >> month intervals.

> >>

> >> Terri Tarrant

> >>

> >> On Thu, Jul 21, 2011 at 10:07 PM, Church, Joseph

> >> <JChurch at chla.usc.edu<mailto:JChurch at chla.usc.edu>> wrote:

> >> Colleagues:

> >>

> >> A 60yo female with long term CVID has had lymphoid interstitial

> pneumonitis

> >> that was biopsy documented in 2005.

> >>

> >> She had developed worsening of symptoms over the past 6 months.

> >>

> >> She is trying to avoid increasing her prednisone, currently at 10mg/d,

> >> because of coronary artery disease and hypertension; she could not

> tolerate

> >> CellCept.

> >>

> >> Has anyone tried Rituximab in this setting?

> >>

> >> Joe Church, MD

> >> Children's Hospital Los Angeles

> >>

> >>

> >>

> >> ---------------------------------------------------------------------

> >> CONFIDENTIALITY NOTICE: This e-mail message, including any attachments,

> >> is for the sole use of the intended recipient(s) and may contain

> >> confidential

> >> or legally privileged information. Any unauthorized review, use,

> disclosure

> >> or distribution is prohibited. If you are not the intended recipient,

> please

> >> contact the sender by reply e-mail and destroy all copies of this

> original

> >> message.

> >> ---------------------------------------------------------------------

> >>

> >>

> >>

> >> --

> >> Terri Tarrant, MD

> >> Assistant Professor of Medicine

> >> Thurston Arthritis Research Center

> >> Lineberger Cancer Center Member

> >> CB # 7280, 3300 Manning Dr.

> >> Chapel Hill, NC 27599

> >> (919) 843-4727

> >> http://tarc.med.unc.edu/tarrant_welcome.php

> >>

> >>

> >>

> >>

> >

>

>

>



--
-------------- next part --------------
An HTML attachment was scrubbed...
URL: <http://seven.pairlist.net/mailman/private/pagid/attachments/20110726/c270c507/attachment-0001.html>