Re: CLL experts = longer OS

[Guest guest]

Al, thanks for posting and for the thoughtful comments.

I suppose it should not surprise that we see this difference

- for an indication that is very complex -- therapy for CLL

is guided by patient-specific cytogenetic for example a

major centers, but probably uncommonly elsewhere, and

experience with secondary complications (as noted in the snip

within) associated with CLL in general.

However, one potential bias in this study (perhaps discussed

in the full text) is that fitter/less sick patients are more

likely to seek care at major institutions (are able to)

which might partially account for the better outcomes at

specialty centers. (This issue has been cited with outcomes

from MDACC as well for a treatment of MCL - that was not

replicated in smaller institutions.)

And as we know, eligibility for trials can selects for

younger fitter patients as well.

It would also be good to see how the patients were treated

(local vs. specialist) and if that was also associated with

outcomes. The dicussion snip provides some clues but some of

it seems a bit contradictory. So even though the number of

patients in the analysis is large, that it's an

obersvational study makes intrepretation challenging (as

noted) .. along with the large variation in the patient

population.

It will be interesting to see what independent experts think

about the findings and methods.

Karl

Will try to get access to the full text.

[Guest guest]

Hi Al, Finally got round to reading the paper.

Table 1 of the report shows that the Rai status was not

balanced - the non-CLL MD's having fewer Rai stage patients

(46% vs 59%)

And the non-CLL MDs had more intermediate Rai stage patients

(50% vs. 37%) . Only Rai stage III-IV patients had roughly

equal distribution (4% vs. 3%).

So I wonder if the imbalance in Rai stage could be a

significant factor accounting for the better survival for

patients seen by CLL MDs? If so, I missed the discussion.

On page 3 the authors note: " If a patient was initially seen

by a non-CLL hematologist, but was immediately referred to a

CLL hematologist to assume care, they were classified as

being cared for by a CLL hematologist. " So given the above

uneven distribution by stage, you might speculate that such

referrals took place more often for early stage CLL patients

(who don't require treatment) - a kind of referral bias.

Your thoughts?

Karl

Al Janski wrote:

/message/15865

[Guest guest]

a few thoughts

referred shortly after seeing a NON cll specialist doesn't

necessarily equate with early stage CLL.; could just as

easily been a case that a non cll specialist had doubts

regarding diagnosing and or treatment, or was aware of a

particular option for treatment available at the 'expert's'

disposal. According to one source at Mayo, 10% of patients

seen by their CLL experts, diagnosed with CLL elsewhere, do

not have CLL. So, not sure how that fits into the equation

either. (I was told however they do have something else,

just not cll)

The study is interesting, but we all have to see it for what

it is, as most studies are, retrospective views, rather than

assume the authors advocate a particular position as the

only one. Since it is not possible for all patients

diagnosed with CLL to seek the attention of a CLL expert,

even if that were proven to be a 'best practice' in all

cases, perhaps another conclusion would be that it behooves

the 'experts' to try to keep their colleagues informed of

the latest thinking. It also behooves us as patients to

become and remain involved in our own care and the decision

making processes. We as patients can't always look for the

one pure answer from the one perfect doctor.

but interesting, thought provoking study. beth fillman

[Guest guest]

Hi Beth,

Thank you for commenting. I agree that my comment for a

possible reason for referral bias was speculative.

I have no reason to doubt that there's an advantage to

seeing an expert, truly, but I am skeptical that it makes

that much of a difference: (median OS 10.5 years vs. 8.4

years)

Noting that the p-value of .001 (what everyone reads) was

cited in the abstract; but a p-value of .04 (after

adjustments) was provide in the body of the full text - what

few people read.

copying from the body of the full text: " Physician disease-

specific expertise remained a significant factor for OS

after adjusting for age, sex, stage, ALC at diagnosis, and

whether or not patients were cared for by a fellow (P =

..04). "

I'm not sure that even the .04 p-value will hold up to

expert scrutiny. We'll see.

Further it was stated that: " Patients seen by non-CLL

hematologists were slightly older and more likely to have

intermediate Rai risk but on average had lower ALCs. "

Here the authors elected to leave out the difference in Rai

stage O ... Is 242 - 46% (for MDs) vs. 457 (59%) (for

experts) not signficant?

Regarding age, again copying from Table 1 on age: 66.3

(38-95) vs. 63.2 (28-97) - a median difference of 3 years

younger in the patients seeing Experts. Is this truly a

" slight " difference - calling for a minor adjustment in the

analysis?

Also from Table 1 the median ALC was 7.1 (Experts) vs. 9.8

(non-Expert). I don't know enough about ALC to say for sure,

but I thought a composite marker (Rai stage) would be more

predictive of risk than a single biomarker?

As noted, I felt that the authors may have understated the

possible significance of the patient characteristics in the

two groups and I was hunting for possible reasons for the

uneven distribution.

Anyhow, I think a logical place to look for study bias is in

how the patients were assigned to one or the other type of

oncologist - so-called referral bias - so I took a turn at

speculation : )

After you scrutinize also for bias in how the analysis were

done and interpreted it might be fair to speculate about the

practices that may have led to the better results - such as:

the timing of therapy, use of purine nucleoside analogs.

Better, it seems to me, you limit such discussion and

propose or cite studies that may answer those questions,

which fall outside of the scope of this study.

All the best,

Karl

Beth Fillman wrote:

/message/15874

[Guest guest]

Upon first reading the Mayo analysis, I was concerned,

because I had been referred to a hem/onc who was NOT a CLL

specialist (little did I know the difference back in 2005

upon my first diagnosis.) However, upon reading 's

comments, and yours, Karl, I feel a bit more relieved. I

am 5 1/2 years past treatment with Rituxan, which was what

was presented to me at that time as the best action. I

feel great and although I was treated immediately upon

results of many tests, finding that I had 30% bone marrow

involvement, the cancer had been found in the breast via

mammography, I had been extremely tired for over a year,

undergoing several tests involving my heart, as some

symptoms were similar to other I had, before having a

pacemaker placed, etc., I feel it R treatment was the right

thing for me at that time. When this same hem/onc was

ready to treat again with Rituxan due to very high Igm's, I

saw another hem/onc near my home where I was going to be

each summer, and this more conservative hem/onc voted

against treatment at that time. So, the Igm's (I think I'm

correct in this term; the concern is for developing

myeloma), have remained in a similar pattern of up and

down, but no extremes, even though they are much higher than

the normal range. No treatment has been done since 3/2006,

and I can consider myself healthy, and on watch and wait

for future treatment if necessary.

Many patients, upon first diagnosis, don't have the

opportunity to check out all of the possibilities for

treatment, or not. We are referred to someone; we develop

a trusting rapport with that professional, and we either

" get well " , or not. It isn't until we later encounter the

information such as I've received through the LRF, and this

group, that we learn of alternatives. Would I have been

better off to wait for years for treatment? I think not.

Would I have been better off if I had found immediately a

CLL specialist? I am not sure, but feel that probably not.

I am writing this mostly so that newly diagnosed patients

don't panic if they've been treated already and haven't made

the move to see a CLL specialist, because they " didn't know " .

Norma Oxley

dx 12/05; tx 2/06 to 3/06 w/6 weekly Rituxan infusions.

Karl wrote:

/message/15881

[Guest guest]

A couple of embellishments to Beth's excellent comments on

the subject. Beth wrote: " ....Snip.... According to one

source at Mayo, 10% of patients seen by their CLL experts,

diagnosed with CLL elsewhere, do not have CLL. " I was

diagnosed " elsewhere " and when my CLL began behaving

contrary to multiple markers indicating an indolent course

progression, I decided to seek consultation from a CLL

expert (Dr Byrd). I remember him saying that he needed

to repeat various tests I had gotten elsewhere because at

his Clinic, patients who had been diagnosed with CLL from

other Oncologists were sometimes found to be misdiagnosed.

There are literally scores of different leukemias &

lymphomas, many sharing similar markers and clinical

symptoms. One example of potential misdiagnoses involves

mistaking MCL (Mantle Cell Lymphoma) for CLL. Although

there is a much less common indolent MCL the majority of MCL

patients have an aggressive disease needing a different and

more urgent treatment strategy.

See: http://clltopics.org/PI/MCLWolf.htm for details.

Some patients can share more than one " species " of

leukemia/lymphoma supporting the idea that having a CLL

expert on your team may lead to a longer and better QoL.

This is doubly true when treatment is considered. Even when

a correct diagnosis of CLL is made, a general oncologist can

misdiagnose a patient's stage (been there - had that happen)

and require unnecessary CT-scans. I asked the 4th

oncologist, in as many months at my local clinic, what he

recommended for my frontline treatment and his answer was

CVP-R. I politely asked if he could provide a paper showing

CVP-R as an appropriate TX for CLL and to his credit he

owned up to his lack of knowledge about CLL. This doc

claimed to be a friend of Dr. Kanti Rai and that is how I

ended up with a consultation with Dr. Rai. Does this make

the doc who misdiagnosed both my stage of disease and an

inferior TX a bad doc? Not necessarily, because in that

clinic there were folks with highly aggressive metastatic

cancers compared to my CLL and given the number and variety

of Leukemias & Lymphomas for which many of the same drugs

will work but not cure, his sloppiness is, if not

forgivable, understandable. CVP-R in my case would have

" worked " to some degree but what about the patient with a

17p del., unmutated IgVH status with a rapidly progressing

course of disease? The wrong TX protocol using a purine

analog like Fludarabine could easily put a patient's life in

danger and be ineffective for the CLL. I have known one

such unfortunate soul who was put on Fludarabine by an Older

Onc who had not kept up with research. That patient died. A

CLL expert would never have made that error.

Life being what it is to include the difficulties of

obtaining access to a CLL expert, it is well to remember

that CLL is the focus of a CLL expert and CLL patients come

with a variety of co-morbidities. If a patient is lucky

enough to be otherwise healthy when diagnosed, the chances

of co-morbidities increases when treatment is needed, during

TX and after TX. If my experience is that of other patients,

the lack of attention to my efforts of alerting doctors to

my developing kidney issues, it points toward a pervasive

flaw shared among CLL experts and heme/onc generalists which

is the focus on CLL to the exclusion of a need to address

all medical issues in any given patient as a whole.

From attending two Blood Cancer Symposiums hosted by the

Mayo Clinic I have come away with a feeling that the culture

at the Mayo Clinic puts more emphasis on treating not just

the primary disease, e.g. CLL, but the varied ancillary

conditions that arise from having CLL.

One interesting and potential benefit for patient

participation in experimental drug Clinical Trials is that

it mandates attention on all side effects and overall health

issues of the patient.

WWW - nearing 5yr anniversary of DX - currently in Clinical

Trial for PCI-32765 monotherapy doing well.

[Guest guest]

As I learned, SMZL can also be mistaken for CLL.

SMZL, rare as it is, also has several varieties (IgVH

mutation status, different abnormalities of q3 or q7), and

perhaps 30% of cases are more aggressive than the typical

indolent cases.

Another close relative is HCL (there are a few variations

that are more complex to treat). I've read that there's a

new classification for lymphomas that have some similarities

of both HCL and SMZL. I have also read of cases where one

" transformed into the other " , though transformation being

much less aggressive than Richter's.

B-PLL can probably also be mistaken for either CLL or mantle

cell.

The challenge is the infinite number of characteristics that

these disorders can consist of...

Mike

Wayne Wells wrote:

/message/15885

[Guest guest]

How true this is, Mike. Back in 11/05 when I first presented

with a high WBC I had some initial studies (Fish etc) that

puzzled the local heme/onc who sent me to a major cancer

center, Sloan Kettering in NYC. The local was sure I had

Mantle Cell Lymphoma and that was soon ruled out. At Sloan

they had to figure out whether I had SMZL or CLL and their

further testing indicated I had atypical CLL. I have Trisomy

12 and a 13q del at stage 0. I remain at stage 0 today with

no symptoms and am truly grateful for that. Wouldn't we love

to know what makes us acquire and accumulate these

chromosome damages? we will probably never know so the best

we can do is live as best we can with the deck we are dealt.

A tall order.

R

Adks NY and AZ

Mike Abrams wrote:

As I learned, SMZL can also be mistaken for CLL.

[Guest guest]

As I understand it CD5 by flow cytometry in

SMZL is negative and positive in CLL.

~chris

Mike Abrams wrote:

> As I learned, SMZL can also be mistaken for CLL.

[Guest guest]

I think that in most cases CLL and Mantle Cell are CD5+.

I believe that follicular is usually CD10+ and mutated IGvH.

I believe Waldenstrom's is also mutated? Mine is strong on

CD20, but CD5-, CD10-, CD-30-, cyclin D1-, ZAP-70- and

CD38-...... but unmutated. I also do not have some of the

typical markers for Hairy Cell Leukemia, though I did have

the typical symptoms for HCL (massive spleen, autoimmune

blood issues). Waldenstrom's would have abnormal IgM

antibody, but my issues were with IgG.

This puzzle seems to add up to SMZL (or one of its

varieties) by process of elimination, though I can't say how

accurate that is.

wrote:

As I understand it CD5 by flow cytometry in

SMZL is negative and positive in CLL.

[Guest guest]

On Sept. 5, Dr. Hamblin wrote a commentary about this subject at:

http://mutated-unmuated.blogspot.com/2011/09/why-experts-do-better.html

At 09:46 AM 9/5/2011, karlamonyc wrote:

>I have no reason to doubt that there's an advantage to seeing an

>expert, truly, but I am skeptical that it makes that much of a

>difference: (median OS 10.5 years vs. 8.4 years)

Dr. Hamblin concluded:

" ....I find the paper believable. It is not necessary to be treated

by an expert - their fellows do even better than they do, but make

use of an experts expertise. "

Thus, as the paper indicated (SNIP below), if a treating non-expert

consults with a CLL expert, on average, better outcomes can be

expected than if an expert is not consulted.

DISCUSSION SNIP from T. D. Shanafelt et al. (complete reference below):

" Collaborative management between a local hematologist/oncologist and

CLL expert may also be a good model as the data on patients cared for

by fellows at our center suggest it is not necessary patients be

managed directly by a disease expert provided the expert can provide

counsel to the treating physician. In this regard, the physician

charge for a second opinion by a disease expert is a relatively low

cost intervention($600), roughly 1% of the average wholesale price of

6 cycles of first-line CLL therapy. "

At 09:46 AM 9/5/2011, karlamonyc wrote:

>Also from Table 1 the median ALC was 7.1 (Experts) vs. 9.8 (non-Expert).

Actually, the values are reversed. Mean ALC for patients treated by

experts was 9.8 and 7.1 for non-experts.

At 09:46 AM 9/5/2011, karlamonyc wrote:

>I don't know enough about ALC to say for sure, but I thought a

>composite marker (Rai stage) would be more predictive of risk than a

>single biomarker?

>After you scrutinize also for bias in how the analysis were done and

>interpreted it might be fair to speculate about the practices that

>may have led to the better results - such as: the timing of therapy...

In apparent agreement on the importance of ALC versus the importance

of timing of initial treatment, Dr. Hamblin indicated:

" The most striking difference between the two groups was that the

experts kept the patients on watch and wait longer. Once treatment

starts then hazards are introduced. The patient is more likely to

develop infections, autoimmunity, extra chromosomal abnormalities,

pancytopenia, Richter's transformation and MDS. The commonest mistake

I see made by general oncologists is to treat just because of a high

white count - not an indication in the international guidelines. "

Al Janski

REFERENCE:

" Hematologist/oncologist disease-specific expertise and survival:

Lessons from chronic lymphocytic leukemia (CLL)/small lymphocytic

lymphoma (SLL) " ; Tait D. Shanafelt MD et al.; Article first published

online: 26 AUG 2011; DOI: 10.1002/cncr.26474

ABSTRACT:

<http://onlinelibrary.wiley.com/doi/10.1002/cncr.26474/abstract>http://onlinelib\

rary.wiley.com/doi/10.1002/cncr.26474/abstract

or http://tinyurl.com/6z8c47k

[Guest guest]

Hi Al,

I agree with the authors and Dr. Hamblin that the big

difference in OS is challenging to account for by an

imbalance in risk factors alone.

My point is that the study is a comparison of apples to

oranges - the study method being inadequate to answer the

question in a definitive (= sign) way.

I did not think the authors gave enough time to discussing

the limitations of the study methods and gave too much time

to the factors that might explain their conclusion.

But would I see an expert in CLL if it was feasible for me?

You bet! But I had that view before this study was

published.

Cheers,

Karl

[Guest guest]

At 07:55 AM 9/14/2011, " karlamonyc " wrote:

>- the study method being inadequate to answer the question in a

>definitive (= sign) way. I did not think the authors gave enough

>time to discussing the limitations of the study methods

END OF QUOTE.....

For reference, below my signature, are the limitations identified in

the Discussion by the authors, some of which have been discussed on

this thread. Some of the issues related to patient bias, mentioned

by Karl, are not included.

At 07:55 AM 9/14/2011, " karlamonyc " wrote:

>But would I see an expert in CLL if it was feasible for me? You

>bet! But I had that view before this study was published.

END OF QUOTE.....

I expect most CLL patients also would prefer to be cared for by a CLL

specialist than a hem/onc generalist, because they believe that, on

average, they'd receive better care from a specialist. This begs the

question as to the motivation(s) for the Mayo Clinic conducting this

retrospective analysis of a value that most people might consider obvious.

One incentive is that the existence of solid evidence for improved

clinical endpoints (e.g. OS), as a result of treatment by a CLL

specialist, might be useful for arguing for increased insurance

coverage of extra costs associated with using a CLL specialist vs. a

patient using only a hem/onc generalist or hem/oncs specializing in

care of other blood cancers. This is indirectly inferred by the

following SNIPS from the paper's Introduction and

Discussion. However, whether the evidence is rigorous enough to

achieve that goal, may be questionable.

INTRODUCTION SNIP.......

" The care of patients with cancer is becoming increasingly complex.

Previous studies have demonstrated that the cancer outcomes of

patients undergoing tumor resection may differ based on hospital

volume and surgeon experience. Although less data are available

regarding the outcome of cancers treated nonsurgically, studies from

both the United States and Europe suggest a survival advantage for

patients with these cancers when cared for at high-volume

centers. Despite these trends, insurance companies are pursing

physician cost profiling as part of strategies to drive patients to

the lowest cost provider rather than the most expert.

DISCUSSION SNIP.....

" ....the physician charge for a second opinion by a disease expert is

a relatively low cost intervention($600), roughly 1% of the average

wholesale price of 6 cycles of first-line CLL therapy. "

END OF QUOTES.....

Al Janski

DISCUSSION SNIP......

" Our study is subject to a number of limitations. First, the study

was restricted to patients with CLL/SLL, and our results are not

necessarily applicable to patients

with other malignancies. Although some aspects of CLL management are

different than most other cancers (eg, observation for asymptomatic

early-stage patients), we doubt the importance of physician

disease-specific expertise is unique to CLL. Second, although the

survival differences we observed persisted on multivariate analysis

controlling for age, stage, sex, and ALC, other unmeasured

confounding variables could exist. For example, we could not control

for differences in biologic prognostic variables (eg, ZAP70

expression, IGHV gene mutation status, genetic defects detected by

FISH) because many patients did not have these tests performed, they

were markedly less likely to be performed by non-CLL hematologists,

and they were not missing at random among patients seen by non-CLL

hematologists. These tests were not used to make treatment decisions

during the study interval and, because they were not considered in patient

scheduling, it is believed they were evenly distributed among

patients cared for by CLL and non-CLL hematologists. Third, we

classified patient's treating provider at the time of

diagnosis/initial consultation and at initiation of first therapy,

which are 2 of the most objectively defined time points in the CLL

disease course but which cannot completely account for complex

patterns of shifting care and referrals. We attempted to minimize the

influence of any referral bias by limiting the analysis to patients

seen within 1 year of diagnosis. Fourth, we used physician's primary

disease group to designate disease specific expertise, an imperfect

classification because some physicians outside the disease group

cultivate expertise. "