vit. D levels vs. tumor burden or lysis

[Guest guest]

Re: Vitamin D insufficiency and prognosis in chronic

lymphocytic leukemia (CLL)

At 01:09 PM 11/4/2010, Gach wrote:

>As my CLL progressed and my WBC gradually increased from 15,000 to

>285,000, another test showed very low vitamin D levels, even though

>I had maintained the 2,000 IU daily supplementation all along. My

>conclusion is that it was CLL progression that interfered with the

>absorption of vitamin D..

Similarly, my blood levels of vitamin D have moderately decreased as

my WBC counts have moderately increased.

I have thought that a possible explanation for decreasing blood

levels of vitamin D with increasing WBC counts might be because CLL

cells have been observed (2003, C.Pepper et al.) to have high

expression of vitamin D receptors, which might reach a level high

enough, as WBC counts rise, such that blood levels of vitamin D might

be significantly decreased because of binding to these

receptors. One could do some calculations to assess whether that

might be at least a theoretical possibility.

However, the authors (Shanafelt et al.) of the current Blood paper,

observed no relationship between serum blood levels of vitamin D and

indicators of tumor burden (e.g. Rai stage). See the " SNIP " s from

their " Discussion " below.

These observations of Shanafelt et al. do not absolutely exclude the

possibility of CLL being involved (in some patients) in lower blood

levels of vitamin D, but it may not be a simple relationship with CLL

cell burden.

For example, several years ago, it was theorized that when 'sickled'

red blood cells (in patients with sickle cell anemia) are broken down

( " lyse " ) and their hemoglobin is leaked into the blood (hemolysis),

that 'free' hemoglobin can bind and remove an important vasodilator

(nitric oxide), locally depleting nitric oxide in blood vessels,

causing local vasoconstriction and resultant pain.

Likewise, maybe it isn't the level of vitamin D receptors on intact

CLL cells that is important. Maybe what is important is the amount

of free vitamin D receptors leaked into blood when CLL cells are

broken down (e.g. via apoptosis). As such, it would be interesting

to measure in CLL patients the rate of CLL cell apoptosis (and/or

'free' vitamin D receptors) vs. serum vitamin D levels. Again, one

could do some calculations to assess whether that might be at least a

theoretical possibility.

Al Janski

Blood First Edition Paper, prepublished online November 3, 2010; DOI

10.1182/blood-2010-07-2956; Tait D. Shanafelt et al.

http://bloodjournal.hematologylibrary.org/cgi/content/abstract/blood-2010-07-295\

683v1

Vitamin D insufficiency and prognosis in chronic lymphocytic leukemia (CLL)

DISCUSSION:

SNIP......

The vitamin D receptor is highly expressed by CLL B-cells relative to

normal B and T-cells and pharmacologic doses of vitamin D derivatives

developed as therapeutic compounds have been shown to induce caspase

3 and 9 dependent apoptosis (e.g. mitochondrial pathway) of CLL

B-cells in vitro.

[Ref. #33: C. Pepper et al., Blood, 1 April 2003, Vol. 101, No. 7,

pp. 2454-2459]

SNIP..........

One question that arises is whether serum vitamin D levels could be

influenced by tumor burden (e.g. higher ALC or greater nodal disease

could lead to vitamin D binding and lower serum levels). [Ref.

37-40] In this regard, serum vitamin D levels had no relationship

with Rai stage in either the discovery cohort or the confirmation

cohort and also had no correlation with ALC in the 229 patients in

the discovery cohort who had an ALC measured within 2 months of the

vitamin D measurement. Furthermore, serum vitamin D levels remained a

predictor for TTT among both Rai 0 patients and patients with stage

Rai >1 when these groups were evaluated separately and on the MV

analysis controlling for disease stage. Thus, while an important

aspect for future investigations, it does not appear that the

observed relationship between serum vitamin D levels and clinical

outcome is related to an interaction between vitamin D levels and tumor burden.

[Guest guest]

hi everyone -

Yes, , it would be interesting to do our own little informal study.

I'm 52 and according to a recent bone scan, I'm so osteopenic that I'm a

hair's breadth away from having osteoporosis. Never had prednisone for

any real period of time; though pretty sunlight deprived. Parathyroid

was functioning. Have had CLL for at least 8 years (dx stage 4). D3

levels were 22; on 5,000 IU daily and being rechecked in about a month.

My MD believes that vitamin D plays a role in immunogenicity and would

like to see my levels >55.

I'm a little confused: does the disease itself cause Vitamin D

deficiency or does Vitamin D deficiency play a role in CLL? Do other

medications (besides prednisone) contribute to Vitamin D deficiency

and/or hypercalcemia?

Can anyone comment?

Best,Marietta

>

> Friends,

>

> I need to take between 12,000-15,000 unit of Vit. D3 to maintain a

> level around 50 and I live in sunny southern Californian

>

> I wonder if others have found that they need very high doses of Vit D

> to raise their blood level to the upper half of normal

>

> Let me know. Might make an interesting study: Increased Vit D needs in

> CLL?

>

> I am osteopenic, but then I was on steroids for > 6 months for ITP so

> I doubt the low Vit D was much of a factor.

>

> Be well

>

>

>

[Guest guest]

We do not know whether vitamin D deficiency plays a role in the development of

CLL or whether CLL results in a vitamin D deficiency.

What we do know is that over 30% of adults in the US are vitamin D deficient.

We have seen reports of patients with adequate vitman D levels doing better with

their disease than those who are deficient. What is VERY IMPORTANT to remember,

and a very important teaching point that we always have to clarify, is the issue

of cauality. Patients with CLL who have more aggressive disease might ingest

lower amounts of vitamin due to poor appetite or less interest due to the

aggressive of the disease. Right now, we only know that they are associated,

and there are many ways they could be associated.

The important question will only be answered if we can take one-half of the

patients that we would expect to do poorly and replete their vitamin D level,

and then see if they do better than those not repleted. This study will

obviously never get done given the ethical implications of leaving patients

vitamin D deficient.

One other aspect that is worthy of emphasis is that we have no information

regarding repleting to a particular level. Right now, the only data suggests

repletion to adequecy. Any claims of pushing to the dose into the middle or

high end of normal are without data. The FDA is examining target ranges for

vitamin D at this time, but we do not yet have those data.

Rick Furman, MD

> >

> > Friends,

> >

> > I need to take between 12,000-15,000 unit of Vit. D3 to maintain a

> > level around 50 and I live in sunny southern Californian

> >

> > I wonder if others have found that they need very high doses of Vit D

> > to raise their blood level to the upper half of normal

> >

> > Let me know. Might make an interesting study: Increased Vit D needs in

> > CLL?

> >

> > I am osteopenic, but then I was on steroids for > 6 months for ITP so

> > I doubt the low Vit D was much of a factor.

> >

> > Be well

> >

> >

> >

>

>

>

>

[Guest guest]

At 07:44 AM 11/10/2010, Rick Furman, MD wrote:

>Patients with CLL who have more aggressive disease might ingest

>lower amounts of vitamin due to poor appetite or less interest due

>to the aggressive of the disease.

One of concerns I have about the recently reported Mayo study

(Shanafelt et al.) is that vit.D levels were (apparently) only

measured once (within 12 months of the time of diagnosis), yet

follow-up analyses (e.g. of TTT and OS) were reported out to a

" median followup " of 3 years and 9.9 years later.

Dietary intake of vit.D is just one of many variables, over time,

that could alter the vit.D status (sufficient vs. deficient) of a

given patient.

As such, ideally, it would have been desirable to have multiple

measurements of vit.D levels on patients throughout the study, e.g.

to know whether patients who were vit.D deficient at diagnosis

remained deficient throughout the period of analysis. For example,

maybe OS did not reach statistical significance because some of the

patients in the vit.D deficient group, and/or patients in the vit.D

sufficient group, did not maintain their respective status throughout

the majority of the period of analysis.

Given these data reported by Shanafelt et al. are derived from a

" discovery cohort study " , which was apparently designed for a variety

of analyses other than, or in addition to, vit.D dependent

observations, multiple measurements of blood vit.D may not have been an option.

However, it seems that for more definitive assessments of the

importance of vit.D in the prognosis of CLL, multiple measures of

blood vit.D would be an important component of the experiment design.

Al Janski