This blog is a way of sharing the information and resources that have helped me to recover my son Roo from an Autism Spectrum Disorder. What I have learned is to view our symptoms as the results of underlying biological cause, which can be identified and healed. I say "our symptoms" because I also have a neuro-immune disorder called Myalgic Encephalomyelitis.

And, of course, I am not a doctor (although I have been known to impersonate one while doing imaginative play with my son)- this is just our story and information that has been helpful or interesting to us. I hope it is helpful and interesting to you!

Wednesday, March 9, 2016

Gleevec (Imatinib)

Gleevec is the brand name for the drug Imatinib ( imatinib mesylate) which is a tyrosine kinase inhibitor (TKI for short).  TKIs are a form of targeted chemotherapy, and Gleevec was originally developed to treat a rare type of leukemia called chronic myelogenous leukemia (CML).  It is now used to treat certain forms of leukemia, a type of intestinal tumor called a stroma, and Mast Cell Disease and sometimes Eosinophilic diseases as well.  For some mast cell patients it is a miracle drug (fro others not so much).  Until this month (February of 2016) it was still under patent so could not be compounded which made it a catch-22 for mast cell patients- it is only considered for very sick patients, but because it could not be compounded these same patients rarely tolerated the drug without serious side effects.  These side effects can be severe enough to require the patient to be hospitalized long term and are often severe enough to make the medicine not an option.  Now that it is not under patent many of us are hoping that this situation will change.

Gleevec is a drug that has a very narrow mode of action, and was developed for a disease other than MCAS, so how does it work in MCAS?  This quote is from a presentation by Dr Afrin and explains what is known about this question "I suspect the reason imatinib can work in some patients with the
D816V mutation is that most of these patients have multiple mutations. We know imatinib can stabilize some of the other mutations, i.e., it doesn’t focus just on the D816V mutation. We don’t exactly know the molecular mechanism yet of how it stabilizes the other mutations or which ones. The fundamental issue with mutations is that although KIT is ordinarily quiescent until it gets activated by stem cell factor, these mutations lead to constitutive activation of KIT. Once KIT is always on, you’ve got to find a way to stabilize it."

KIT is a protein that is expressed on the surface of some types of cells, and once activated by SCF (Stem Cell Factor), it activates pathways in the cell that regulate cellular growth, division, survival, and movement.  Somatic mutations in a gene are mutations that are acquired since birth, not ones that are inherited.  Somatic mutations in KIT can create a signalling protein in the cell that does not need the KIT receptor on the cell's surface to be activated- the mutated protein results in a pathway that is constantly turned "on".  Cells that express KIT (also called CD 117) on their surface include mast cells, melanocytes (cells that produce melanin, then most common pigment of eyes, hair, and skin), reproductive cells (germ cells), and cells in the GI tract called interstitial cells of Cajal (ICCs).  Interestingly ICCs are involved in peristalsis, the movement of food through the GI tract, and many people with MCAS have problems with this.

Whether or not Gleevec actually counts as a chemotherapy drug is a semantic debate.  Chemotherapy drugs are usually thought to be drugs that kill cells, while Gleevec is an example of a drug that works via targeting specific proteins in the cell rather than killing it- called targeted therapy.  It was developed to treat certain forms of cancer which is part of why it is associated with chemotherapy.  It does appear to be safer than the older, non-targeted chemo agents that affected large amounts of body systems and have many side effects.  As a relatively new drug I do not think that the safety profile has been fully understood yet.  Similar drugs include Dasatinib and Sunitinib (which targets and inhibits vascular endothelial growth factor).

Sources and Further Reading:

Gleevec: the Breakthrough in Cancer Treatment

How Gleevec Works

Gleevec information sheet from Novartis


Clinical Pharmacokinetics of Imatinib Mesylate

Side Effects:

Patients Taking Imatinib for CML Have Similar Risk of Death as General Population

Endocrine side effects of broad-acting kinase inhibitors

Principal long-term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase
"IM is associated with toxicity, though most of the adverse effects attributed occur within the first 2 years of starting therapy and some reverse with continued treatment at the same dose. Toxicity appears mild to moderate in most instances and appears easily manageable and potentially reversible. Some patients may experience lethargy and develop different types of rashes; others gain weight from fluid retention, especially infraorbital edema but occasionally much more generalized, which responds in some cases to diuretics. Other effects include bone pain, which can sometimes be debilitating. Liver chemistry can be abnormal, and this may, on rare occasions, progress to liver failure. Rare incidences of prolongation of the QTc interval on the electrocardiograph have been reported. A small proportion of patients in CP who start IM at 400 mg/day experience cytopenias within the first year of therapy. They typically develop neutropenia and/or thrombocytopenia and sometimes anemia."

Case Histories of Severe Depression With Imatinib and Dasatinib

In Mast Cell Disease:

This is a presentation given by Dr Afrin in which he discusses a number of cases in which Gleevec was given and resulted in dramatic improvement.  The presentation itself if very long (153 pages) and covers a lot of ground, but the case histories are interesting.

This is a blog post from another MCAD patient whose disease is very far progressed.  In this post she discusses her choice to begin the medication, how she and her medical team have gone about administering it, and what the results have been.

Imatinib Mesylate in the Treatment of Systemic Mastocytosis: a phase ll trial
"Mastocytosis is characterized by the abnormal proliferation of mast cells in 1 or more organs. In most patients, a mutation is present in the gene for C-KIT, resulting in deregulation of the c-kit receptor. Imatinib mesylate is a potent inhibitor of c-kit receptor tyrosine kinase activity. Therefore, the authors evaluated the efficacy and safety of imatinib mesylate as treatment for patients with systemic mastocytosis.  

Patients with systemic mastocytosis received imatinib mesylate orally at a dose of 400 mg once daily for 3 to 6 months. Low doses of prednisone were added during the first 2 weeks. Endpoints were reductions in serum tryptase, urinary N-methylhistamine excretion, skin lesions, the number of mast cells in bone marrow sections, hepatomegaly and/or splenomegaly, and symptoms.

Of 14 patients who were included in the study, 11 patients had the D816V mutation. One patient expressed the FIP1L1-PDGFR-alpha rearrangement gene. In 2 patients, no mutation was found. In 10 patients, serum tryptase levels decreased >20%. In all patients, urinary N-methylhistamine excretion was reduced. In 8 of 13 evaluable patients, the number of mast cells in the bone marrow decreased. Skin symptoms diminished in 5 of 9 patients. Hepatosplenomegaly improved in 3 of 6 patients. Symptoms decreased in 8 of 13 patients. In all patients who had the D816V mutation, reductions in > or =2 endpoints were achieved. In the patient who expressed the FIP1L1-PDGFR-alpha rearrangement gene, a complete response was attained. In general, imatinib mesylate was tolerated well."

bcr-abl-Induced Cell Lines Can Switch From Mast Cell to Erythroid or Myeloid Differentiation In Vitro
" Engraftment of mice with bone marrow cells infected with a bcr-ab1 retrovirus has been shown to elicit multiple hematopoietic disorders, including a clonal but nontransplantable hyperproliferation
of erythroid and/or mast cells. Culture of spleen and bone marrow cells from such mice usually yielded mast cell lines, even when erythroid disease dominated the primary animal. The mast cells, which carried the same proviral insert as the primary disease, generally grew slowly and were neither transplantable nor clonogenic in agar until they had been cultured for several months. Unexpectedly, several bcr-ab/-induced lines switched in vitro from mast cell to megakaryocytic and/or erythroid character, and one became myeloid. The dramatic phenotypic shifts seem likely to involve changes occurring within progenitor cells maintaining the clone, rather than mutation of mature mast cells. The variant lines exhibited substantial spontaneous differentiation, despite being readily ransplantable and therefore fully transformed. The production of hematopoietic growth factors by the mast cell lines and their phenotypic variants may implicate an autocrine loop in their evolution."

Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia.
"We examined the in vitro- and in vivo effects of the KIT-targeting drug imatinib on growth and development of human MC. Imatinib was found to inhibit stem cell factor (SCF)-induced differentiation of MC in long-term suspension cultures (IC50: 0.01 µM). Correspondingly, long-term treatment of chronic myeloid leukemia (CML) patients with imatinib (400 mg/day) resulted in a marked decrease in MC. In patients with continuous complete molecular response during therapy, bone marrow MC decreased to less than 5% of pre-treatment values, and also serum tryptase concentrations decreased significantly (pre-treatment: 32.0 ± 11.1 ng/ml; post-therapy: 3.4 ± 1.8, p<0 .01="" a="" accompanied="" adverse="" affected="" also="" and="" are="" assumed="" attributable="" by="" clinical="" cml="" decrease="" depletion="" develop="" drug-induced="" events="" far.="" healthy="" homeostasis="" however="" i="" imatinib-therapy.="" imatinib="" in="" independently="" is="" kit="" known="" less="" lineages="" mc-deficiency="" mc-development="" mc="" mice.="" myeloid="" no="" not="" of="" other="" our="" patients.="" produced="" production="" recorded="" relevant="" so="" substantial="" suggesting="" suppresses="" syndrome="" than="" that="" tissues="" to="" together="" vitro="" vivo.="" was="" we="" were="">

The tyrosine kinase network regulating mast cell activation.
"Mast cell mediator release represents a pivotal event in the initiation of inflammatory reactions associated with allergic disorders. These responses follow antigen-mediated aggregation of immunoglobulin E (IgE)-occupied high-affinity receptors for IgE (Fc epsilon RI) on the mast cell surface, a response which can be further enhanced following stem cell factor-induced ligation of the mast cell growth factor receptor KIT (CD117). Activation of tyrosine kinases is central to the ability of both Fc epsilon RI and KIT to transmit downstream signaling events required for the regulation of mast cell activation. Whereas KIT possesses inherent tyrosine kinase activity, Fc epsilon RI requires the recruitment of Src family tyrosine kinases and Syk to control the early receptor-proximal signaling events. The signaling pathways propagated by these tyrosine kinases can be further upregulated by the Tec kinase Bruton's tyrosine kinase and downregulated by the actions of the tyrosine Src homology 2 domain-containing phosphatase 1 (SHP-1) and SHP-2. In this review, we discuss the regulation and role of specific members of this tyrosine kinase network in KIT and Fc epsilon RI-mediated mast cell activation."

Successful treatment of mast cell activation syndrome with sunitinib
"Mast cell (MC) activation syndrome (MCAS) is a recently recognized, likely prevalent collection of heterogeneous illnesses of inappropriate MC activation with little to no MC neoplasia likely driven by heterogeneous patterns of constitutively activating mutations in MC regulatory elements including various tyrosine kinases (TKs, dominantly KIT). MCAS typically presents as chronic multisystem polymorbidity of generally inflammatory ± allergic theme. As with indolent systemic mastocytosis (SM), treatment of MCAS focuses more against MC mediators than MC neoplasia, but some cases prove refractory even to the TK inhibitor (TKI) imatinib reported useful both in uncommon SM cases not bearing SM's usual imatinib-resistant KIT-D816V mutation and in some cases of MCAS (which rarely bears KIT-D816V). Most allergy is principally a MC activation phenomenon and sunitinib is a multitargeted TKI shown helpful in controlling a murine model of oral allergy syndrome. We present the first report of use of sunitinib in life-threatening MCAS refractory to multiple agents including imatinib achieving immediate, complete, sustained, non-toxic remission suggesting a new option for treatment of aggressive MC disease."

Complete Response After Imatinib Mesylate Therapy in a Patient With Well-Differentiated Systemic Mastocytosis