Myelofibrosis

[Lyall]

Hi everyone

A dear friend of mines father has been diagnosed with myelofibrosis. I'll put the wiki definition here

Myelofibrosis, also known as osteomyelofibrosis, is a relatively rare bone marrow cancer.[1] It is currently classified as a myeloproliferative neoplasm, in which the proliferation of an abnormal clone of hematopoietic stem cells in the bone marrow and other sites results in fibrosis, or the replacement of the marrow with scar tissue.[2][3]

This disease has resulted in an enlarged spleen and liver and compromised immunity due to low blood cell counts. His blood pressure is has also increased pathologically and is being treated with lasix and carvedilol.
He has infrequent attacks of gout which require medicating with colchicine and/or allopurinol. In addition I believe the infection became so bad that kidney function has become compromised with gfr being defined as moderate loss <44.

All these factors combined I'm appealing to anyone with some advice or knowledge they can share. Please I'm very concerned about him.

 

[Lyall]

So what I've been able to piece together so far

• A JAK inhibitor is used in management of myleofibrosis
• Increasing AMPK decreases JAK signaling

Some substances that increase AMPK are

• Caffeine
• Methylene blue
• Aspirin
• Metformin
• Sodium

@haidut Please could I ask your advice if you know of any other substances that are safe in this regard?

 

[haidut]

So what I've been able to piece together so far

• A JAK inhibitor is used in management of myleofibrosis
• Increasing AMPK decreases JAK signaling

Some substances that increase AMPK are

• Caffeine
• Methylene blue
• Aspirin
• Metformin
• Sodium

@haidut Please could I ask your advice if you know of any other substances that are safe in this regard?

I suggest you contact Peat as well, but in addition to the aspirin and methylene blue, I would also consider vitamin K2, vitamin A and cyproheptadine. The first two are commonly used for any type of blood or bone marrow cancers, and the cyproheptadine has recently shown great promise for all myeoloproliferative disorders and is being withdrawn from the market in anticipation of approval for those conditions.

 

[Lyall]

Thank you Haidut for your advice!

I contacted Ray and will put his response here:

Has his serum estrogen been measured? High estrogen, relative to androgens and progesterone, is toxic to the bone marrow, and stimulates fibrocyte growth, and decreases kidney function. Has he used any serotonin-related drugs? Progesterone and thyroid both increase kidney function and improve the balance of androgens and estrogen. Vitamin D and DHEA are other things that might be helpful.

Arkh Anat Gistol Embriol. 1989 Nov;97(11):92-8.
[Interrelation of the osteogenic and hemopoietic tissues of the bone marrow
during the development of estrogenic myelofibrosis].
[Article in Russian]
Ivasenko IN.
By means of estrogenic myelofibrosis, using the method of heterotopic
transplantation of the bone marrow, interrelations of osteogenic and hemopoietic
tissues have been studied. Under estrone effect disorders in stromal
microenvironment take place at the level of stem osteogenic cells of the bone
marrow. Deficiency in cells of monocytic-macrophagal line, inhibiting
proliferation of the bone marrow connective tissue cells, contributes to
development of myelofibrosis. The hormone acts mainly in committed hemopoietic
cells, singly launching them from G0- into S-period of the cycle, and then--into
differentiation, accompanied with an enhanced discharge of cells from the bone
marrow. There is neither direct, nor indirect dependence between the osteogenic
mass and the cellularity of the hemopoietic tissue of the bone marrow. The
changes, that take place in the bone marrow under estrone effect, are reversible.

Toxicol Pathol. 1993;21(2):164-9.
A review of myelofibrosis in dogs.
Reagan WJ(1).
(1)Purdue University, School of Veterinary Medicine, Department of Pathobiology,
West Lafayette, Indiana 47907-1027.
Myelofibrosis is a proliferative response of the bone marrow fibroblasts.
Myelofibrosis can be classified as primary or secondary depending on the
underlying etiology. Primary myelofibrosis is a myeloproliferative disorder in
humans in which there is a clonal proliferation of a pluripotent stem cell.
Hemopathology includes finding nucleated red blood cells and immature
granulocytes in the circulation, extramedullary hematopoiesis, and myelofibrosis.
The proliferation of the bone marrow fibroblasts is not clonal in origin. To the
best of this author's knowledge, this type of myelofibrosis has not been reported
to occur naturally in the dog. Secondary myelofibrosis has been reported in the
dog associated with neoplastic conditions, irradiation, congenital hemolytic
anemias, and a variety of unknown etiologies. It has been shown in some cases of
myelofibrosis that there is often concurrent bone marrow necrosis. Bone marrow
necrosis has been documented in dogs with Ehrlichiosis and septicemia, and
associated with drug treatment, including estrogens and cephalosporins. It is
though that this necrosis is due to the destruction of the bone marrow
microvasculature and/or hematopoietic elements. Release of growth factors by
inflammatory cells may lead to the subsequent fibroblast proliferation. Several
cases of secondary myelofibrosis in female laboratory beagles have been recently
observed. These dogs present with a severe nonregenerative anemia and often a
mild neutropenia with varying degrees of myelofibrosis in the bone marrow. Some
animals have had concurrent bone marrow necrosis. At this time, the exact
etiology is unknown.

14. Fortschr Med. 1978 Dec 1;96(45):2273-6.
[Interactions between bones, hematopoiesis and kidney with reference to the sex
hormones. 1. Bones and hematopoiesis, hematopoiesis and kidney--effects of
androgens, androgen deficiency and anemia or estrogen therapy and anemia].
[Article in German]
Schulz W.

15. Clin Haematol. 1975 Jun;4(2):457-78.
Experimental myelofibrosis.
Hunstein W.

16. J Am Geriatr Soc. 1971 Sep;19(9):807-9.
Myeloid metaplasia in a case of estrogen-treated polycythemia vera: association
with myocardial infarction.
Wirth L.

Exotic Animal Hematology and Cytology
https://books.google.com/books?isbn=1118611152
Terry Campbell - 2015 - ‎Medical
Although reversible stem cell injury does not progress to neoplasia, it can lead to myelofibrosis. Estrogen toxicosis is perhaps the most common cause of aplastic anemia (aplastic pancytopenia) in exotic mammals, especially intact female ferrets. Ferrets are induced ovulators and when mating does not occur, the female will ...

October 13, 1962
Effect of Androgenic Hormone in Myelofibrosis
B. J. Kennedy, M.D.
JAMA. 1962;182(2):116-119.
Androgenic hormones have stimulated erythropoiesis in patients with breast cancer and those with refractory anemia, as well as in castrated and in normal experimental animals. Observation of this erythropoietic effect by several investigators has led to use of androgens in treatment of myelofibrosis. Six of 8 such patients treated by the author for prolonged periods with massive doses of androgenic hormone showed improvement. Two women, aged 55 and 75, and 1 man of 64 responded with increased hemoglobin, reticulocytosis, cessation of transfusion requirements, and hypercellular marrow. Three women, aged 56 to 62, required fewer or no transfusions and showed reticulocytosis. Corticosteroids were found to potentiate the effect in some instances. A prolonged remission persisted after cessation of androgen therapy in one case but could not be sustained. Therapeutic levels have in some cases led to polycythemia.

Hematology. 2011 Mar;16(2):90-4.
Danazol therapy combined with intermittent application of chemotherapy induces
lasting remission in myeloproliferative disorder (MPD): an alternative for the
elderly with advanced MPD.
Fontana V(1), Dudkiewicz P, Ahn ER, Horstman L, Ahn YS.
(1)Wallace H Coulter Platelet Laboratory, Division of Hematology/Oncology,
Department of Medicine, University of Miami, Miller School of Medicine, USA.
There is no good alternative therapy available for elderly patients with advanced
myeloproliferative disorders (MPD) who failed on conventional therapies and are
not candidates for bone marrow transplant. We report here an effective therapy
that induced exceptionally long-lasting remissions and improved quality of life.
Eighteen elderly patients (mean age: 70·6 years) (16 myelofibrosis and 2
thrombocythemia) who had failed on conventional therapies were treated. Danazol
was administered daily at 200-800 mg throughout the study. Chemotherapy was
applied intermittently as needed to reduce spleen size and blood counts. Busulfan
(2-4 mg/day) was used most often and 6-mercaptopurine (6-MP) (50-100 mg/day)
and/or cytarabine (100-200 mg/m(2)) if the white blood cell (WBC) count rose
rapidly. When MPD stabilized, chemotherapy was discontinued and dosage of danazol
was reduced. Therapy was well tolerated. Overall, 61% of patients responded with
unexpectedly long-lasting remissions and improved quality of life. Three (17%)
had excellent (E) response, defined by normalization of blood counts and
non-palpable spleen, while eight (44%) had good (G) response, defined by rise of
Hct by ≥7% and ≥50% reduction of spleen. Mean duration of remission was 45 months
(10-78 months) in E responders and 11 months in G responders (2-22 months). This
regimen offers a safe and effective alternative for advanced MPD in the elderly.

Int J Hematol. 2007 May;85(4):338-43.
The effect of anabolic steroids on anemia in myelofibrosis with myeloid
metaplasia: retrospective analysis of 39 patients in Japan.
Shimoda K(1), Shide K, Kamezaki K, Okamura T, Harada N, Kinukawa N, Ohyashiki K,
Niho Y, Mizoguchi H, Omine M, Ozawa K, Haradaa M.
(1)Medicine and Biosystemic Science, Kyushu University Graduate School of Medical
Sciences, Fukuoka, Japan. [email protected]
Between 1999 and 2005, 285 patients received new diagnoses of myelofibrosis with
myeloid metaplasia (MMM) in Japan. Anemic symptoms were present in 162 patients,
and hemoglobin (Hb) concentrations were <10 g/dL in 197 patients. Fifty-five MMM
patients were treated with anabolic steroids, and their effect on anemia during
MMM was evaluated in 39 patients. A "good" response was defined as an Hb increase
of >or=1.5 g/dL, cessation of transfusion dependence, and an Hb concentration of
>10 g/dL maintained for at least 8 weeks. A "minimum" response was defined as an
Hb increase of >or=1.5 g/dL and transfusion independence for at least 8 weeks.
Both good and minimum responses were considered "favorable." Favorable responses
were achieved in 17 patients (44%, 8 good and 9 minimum responses). None of the
pretreatment variables, such as the lack of transfusion dependence, a higher Hb
concentration at the start of treatment, or the absence of cytogenetic
abnormalities, were associated with a response to anabolic steroid therapy.
Adverse events associated with anabolic steroid therapy were moderate and
transient. Two patients required definitive withdrawal of treatment. Thus,
anabolic steroids are well tolerated and effective for the treatment of anemia in
a subset of MMM patients.


Eur J Haematol. 2002 Apr;68(4):233-5.

Remission of transformed myelodysplastic syndrome with fibrosis after danazol
therapy.
Damaj G(1), Lefrère F, Canioni D, Rubio MT, Radford-Weiss I, Valensi F, Varet B,
Hermine O.
(1)Department of Clinical Hematology, Hôpital Necker Enfants-Malades, Paris,
France. [email protected]
Danazol has been used with success in some hematological diseases, but there is
no report of this treatment in acute leukemia. We report here a case of remission
of myelodysplastic syndrome with myelofibrosis in transformation after danazol
therapy in a 72-yr-old man. The role of danazol in remission induction is briefly
discussed.

Vet Rec. 2002 Aug 24;151(8):244-5.
Prevention of oestradiol-associated toxicosis in a dalmatian by early
intervention with granulocyte colony-stimulating factor.
Suttorp M(1), Hoffmann B, Sippell WG.
(1)Department of Paediatric Haematology and Oncology, University Children's
Hospital, Dresden, Germany.

J Am Vet Med Assoc. 1992 Mar 15;200(6):814-6.
Use of lithium for treatment of estrogen-induced bone marrow hypoplasia in a dog.
Hall EJ(1).
(1)Veterinary Hospital, University of Pennsylvania, Philadelphia 19104.
Marrow hypoplasia and consequent pancytopenia caused by simultaneous
administration of estradiol cyclopentylpropionate and diethylstilbestrol were
diagnosed in a 6-year-old Old English Sheep-dog. The dog was treated with lithium
carbonate (11 mg/kg of body weight, PO, q 12 h) for 6 weeks. Despite the
generally grave prognosis associated with estrogen toxicosis, lithium treatment
was apparently successful in inducing regeneration of the bone marrow. Side
effects of lithium treatment were not noticed.

Medicina (B Aires). 1982;42(5):581-2.
[Effect of progesterone in anemia of idiopathic myelofibrosis].
[Article in Spanish]
Quiroga Vergara ER, Quiroga Micheo E.

Blood Cells Mol Dis. 2015 Mar;54(3):234-41. doi: 10.1016/j.bcmd.2014.12.005. Epub 2015 Jan 15.
Activation of non-canonical TGF-β1 signaling indicates an autoimmune mechanism for bone marrow fibrosis in primary myelofibrosis.
Ciaffoni F1, Cassella E2, Varricchio L2, Massa M3, Barosi G4, Migliaccio AR5.
Primary myelofibrosis (PMF) is characterized by megakaryocyte hyperplasia, dysplasia and death with progressive reticulin/collagen fibrosis in marrow and hematopoiesis in extramedullary sites. The mechanism of fibrosis was investigated by comparing TGF-β1 signaling of marrow and spleen of patients with PMF and of non-diseased individuals. Expression of 39 (23 up-regulated and 16 down-regulated) and 38 (8 up-regulated and 30 down-regulated) TGF-β1 signaling genes was altered in the marrow and spleen of PMF patients, respectively. Abnormalities included genes of TGF-β1 signaling, cell cycling and abnormal in chronic myeloid leukemia (EVI1 and p21(CIP)) (both marrow and spleen) and Hedgehog (marrow only) and p53 (spleen only) signaling. Pathway analyses of these alterations predict an increased osteoblast differentiation, ineffective hematopoiesis and fibrosis driven by non-canonical TGF-β1 signaling in marrow and increased proliferation and defective DNA repair in spleen. Since activation of non-canonical TGF-β1 signaling is associated with fibrosis in autoimmune diseases, the hypothesis that fibrosis in PMF results from an autoimmune process triggered by dead megakaryocytes was tested by determining that PMF patients expressed plasma levels of mitochondrial DNA and anti-mitochondrial antibodies greater than normal controls. These data identify autoimmunity as a possible cause of marrow fibrosis in PMF.

J Clin Endocrinol Metab. 2015 Nov;100(11):4307-14. doi: 10.1210/jc.2015-2580. Epub 2015 Oct 20.
Vitamin D Supplementation Decreases TGF-β1 Bioavailability in PCOS: A Randomized Placebo-Controlled Trial.
Irani M1, Seifer DB1, Grazi RV1, Julka N1, Bhatt D1, Kalgi B1, Irani S1, Tal O1, Lambert-Messerlian G1, Tal R1.
CONTEXT:
There is an abnormal increase in TGF-β1 bioavailability in women with polycystic ovary syndrome (PCOS), which might play a role in the pathophysiology of this syndrome. Vitamin D (VD) supplementation improves various clinical manifestations of PCOS and decreases TGF-β1 levels in several diseases including myelofibrosis.
OBJECTIVE:
The objective of the study was to determine the effect of VD supplementation on TGF-β1 bioavailability in VD-deficient women with PCOS and assess whether changes in TGF-β1/soluble endoglin (sENG) levels correlate with an improvement in PCOS clinical manifestations.
DESIGN:
This was a prospective, randomized, placebo-controlled trial.
SETTING:
The study was conducted at an academic-affiliated medical center.
PARTICIPANTS:
Sixty-eight VD-deficient women with PCOS who were not pregnant or taking any exogenous hormones were recruited between October 2013 and January 2015.
INTERVENTIONS:
Forty-five women received 50 000 IU of oral vitamin D3 and 23 women received oral placebo once weekly for 8 weeks.
MAIN OUTCOMES MEASURES:
Serum TGF-β1, sENG, lipid profile, testosterone, dehydroepiandrosterone sulfate, and insulin resistance were measured. The clinical parameters were evaluated before and 2 months after treatment.
RESULTS:
The VD level significantly increased and normalized after VD supplementation (16.3 ± 0.9 [SEM] to 43.2 ± 2.4 ng/mL; P < .01), whereas it did not significantly change after placebo. After the VD supplementation, there was a significant decrease in the following: the interval between menstrual periods (80 ± 9 to 60 ± 6 d; P = .04), Ferriman-Gallwey score (9.8 ± 1.5 to 8.1 ± 1.5; P < .01), triglycerides (138 ± 22 to 117 ± 20 mg/dL; P = .03), and TGF-β1 to sENG ratio (6.7 ± 0.4 to 5.9 ± 0.4; P = .04). In addition, the ΔTGF-β1 to sENG ratio was positively correlated with Δtriglycerides (r = 0.59; P = .03).
CONCLUSIONS:
VD supplementation in VD-deficient women with PCOS significantly decreases the bioavailability of TGF-β1, which correlates with an improvement in some abnormal clinical parameters associated with PCOS. This is a novel mechanism that could explain the beneficial effects of VD supplementation in women with PCOS. These findings may support new treatment modalities for PCOS, such as the development of anti-TGF-β drugs.
TRIAL REGISTRATION:
ClinicalTrials.gov NCT02460380.

1. Br J Haematol. 2004 Oct;127(1):34-9.
Platelet-rich plasma serotonin levels in chronic myeloproliferative disorders:
evaluation of diagnostic use and comparison with the neutrophil PRV-1 assay.
Koch CA(1), Lasho TL, Tefferi A.
(1)Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
In a prospective study of 109 subjects, an enzyme-linked immunosorbent assay
(ELISA) was used to measure platelet-rich plasma (PRP) serotonin levels in
patients with polycythaemia vera (PV; n = 27), essential thrombocythaemia (ET; n
= 14), myelofibrosis with myeloid metaplasia (MMM; n = 30), secondary or spurious
polycythaemia (SP; n = 22) and controls (n = 16). Nine study subjects who were
taking a selective serotonin reuptake inhibitor (SSRI) all displayed a markedly
decreased PRP serotonin level (median, 24.2 ng/10(9) platelets; range, 0-49.3)
and were therefore excluded from further analysis. Among the remaining 100
subjects, the median and range of PRP serotonin levels, in ng/10(9) platelets,
was significantly lower in MMM (89.5; 0-278.3), PV (204.8; 0-496.0) and ET
(385.3; 136.8-1025.7) compared with both SP (608.8; 369.0-1780.1) and controls
(567.2; 359.9-1071.1). Neutrophil polycythaemia rubra vera-1 (PRV-1) expression
was concurrently assayed by real-time polymerase chain reaction in 69 patients
(23 PV, 17 SP, 12 ET, seven MMM, 10 controls). PRP serotonin measurement
performed as well as the PRV-1 assay in distinguishing PV from SP (93% vs. 86%
test accuracy). The current study suggests that PRP serotonin concentration might
be considered as one of the several biological markers that complement each other
for the diagnosis of PV.

2. Scand J Haematol. 1985 Feb;34(2):146-51.
Platelet 5-hydroxytryptamine transport and storage in myeloproliferative
disorders.
Cortellazzo S, Viero P, Buczko W, Barbui T, de Gaetano G.
Platelets of patients with myeloproliferative disorders (MD) such as
polycythaemia vera (PV), chronic myelogenous leukaemia (CML), idiopathic
myelofibrosis (IM) and essential thrombocythaemia (ET) have been found to have
low 5HT levels measured both by a fluorimetric and a liquid chromatographic
assay. Km and Vmax for platelet active uptake of 3H-5HT were not significantly
different in controls and patients. Inhibition of 5HT reuptake by imipramine or
induction of moderate release by fenfluramine were not sufficient to distinguish
the group of MD platelets from controls, although some patients had less of a
tendency to retain intraplatelet amine. The low platelet 5HT content found in our
patients seems not to be the consequence of disturbed active transport of 5HT
across platelet membrane. Although defective storage of this amine within the
cell is probable, the results of the present study do not rule out the
possibility that platelets from MD patients undergo in vivo activation by
endogenous stimuli not inhibited by aspirin. 10 d treatment with aspirin did not
result in any significant rise in intraplatelet 5HT concentration.

3. Thromb Haemost. 1982 Oct 29;48(2):125-6.
Effect of aspirin on platelet 5-hydroxytryptamine and beta-thromboglobulin plasma
levels in patients with myeloproliferative diseases.
Viero P, Cortelazzo S, Bassan R, Barbui T.
14 patients with myeloproliferative diseases (MD) showed low 5-hydroxytryptamine
(5-HT) platelet content and high beta-thromboglobulin (beta-TG) plasma levels.
This pattern could support the view that MD platelets undergo "in vivo"
degranulation. A single dose of aspirin was unable to induce modifications of
platelet 5-HT and plasma beta-TG, whereas 6 out of 14 patients treated over 7
days period with the drug showed a decrease but not normalization in their
beta-TG levels. No modification of platelet 5-HT was obtained suggesting that the
cause of dense bodies deficiency may lie in the production of abnormal platelets
and not be related to "in vivo" degranulation.

 

[Lyall]

@haidut Do you think estrone sulphate is a good blood marker to test for estrogen burden in this context?
Ray says it's only indirectly related to the active estradiol.