Hydroxychloroquine and Ivermectin show promise as anti-cancer drugs, but are unlikely to be allowed in clinical practice for cancer treatment
Preface
Pharmaceutical companies and their captured regulatory agencies do not allow the use cheap generic drugs that are safer and more effective in treating cancer than expensive patented medications. Repurposed drugs for cancer have no chance of getting approved by the FDA. Insurance companies have been paying $10,000 for a monthly supply of a BTK and / or a BCL2 inhibitor used in treatment of Chronic Lymphocytic Leukemia. The FDA approval process requires a huge investment. And there is no way to recoup the investment if a drug is already approved for other indications and can be prescribed “off-label”. For the foregoing reasons, in the fields of oncology and hematology, off-label prescribing of repurposed drugs is generally not allowed for cancer treatment.
Old school chemotherapy agents are toxins that kill cells in a dose dependent fashion, with lethal doses being lower for the more metabolically active cells, such as Acute Leukemia, which take up more of the toxins than cells that are less active metabolically. These chemo agents often do more harm than good when used against chronic, slowly proliferating cancers.
By the 1990s new types of anti-cancer agents came into use, such as monoclonal antibodies that directly kill or assist one’s immune system to kill cancer cells while doing little-to-no-harm to normal cells. This type of immunological therapy was combined with chemotherapy agents, or utilized as stand alone treatments, then combined with a new generation of molecules that target (inhibit or activate) chemical signaling / pathways which lead to cell death. Cancer cells are generally more sensative than normal cells to the moleules selected as anticancer agents.
Repurposing Ivermectin and Hydroxychloroquine for cancer treatment
For more than a decade, both Hydroxychloroquine (HCQ) and Ivermectin have been under investigations as anticancer agents. I found references to “in vitro” studies utilizing normal and malignant human cell lines and to clinical trials which enrolled human cancer patients. But I could not find any references to in vitro studies and human clinical trials about the combination of HCQ and Ivermectin for treatment of cancer. I have encountered some acedotes related in support grops by patients about combining HCQ and Ivermectin to treat cancers, but not many so far.
Some medical journal articles about hydroxychloroquine and Ivermectin as cancer fighting agents report common mechanisms of action, ie, inhibition of BCL2 and activation of Capsase3. See footnotes 1, 2 and 3.
”Ivermectin has powerful antitumor effects, including the inhibition of proliferation, metastasis, and angiogenic activity, in a variety of cancer cells. This may be related to the regulation of multiple signaling pathways by ivermectin through PAK1 kinase. . . “ [footnote 1].
”Key Points: Targeting of PAK1 inhibits primary AML and MDS patients' cells including leukemia stem cells but spares healthy stem and progenitor cells. Inhibition of PAK1 induces differentiation and apoptosis of AML cells through downregulation of MYC and a core network of MYC target genes.” [Footnote 4]
One of the wonder drugs approved in recent years for at least several hematological cancers, and on track for approval for others is Venetoclax, a very potent BCL2 inhibitor. BCL2 is a family of molecules involved in chemical signaling that is essential to preserving the impermeability of mitochondial membranes. Mitochondria are energy producing organelles found in nearly all human cells. Inhibition of BCL2 chemical signaling / pathways can result in mitochondial membranes becoming permeable, which in turn allows emzymes which reside in the cytoplasm to invade and destroy the mitochondria.
Venetoclax has also been studied as a stand alone treatment and in combination with Hydroxychloroquine or Ivermectin, with better patient outcomes seen with these combinations compared to Venetoclax by itself.
One draw back of Venetoclax is that its action as a BCL2 inhibitor leads to the death of some normal cells. In clinical trials of Venetoclax for Chronic Lymphocytic Leukemia about 30 to 35% of those enrolled in the trials developed grade 3 or 4 cytopenias (very serious reductions in the number of various blood cells and / or platelets) which are often less than fully reversible or are non-reversable. Liver and Kidney function are carefully monitored for elevation of enzyme levels that correlate to cell damage. While taking Venetoclax, the drug manufacturer also recommends administration of an anti-gout drug that reduces uric acid levels, eg Allopurinol in order to protect the kidneys.
The FDA has approved Venetoclax for CLL, some other lymphomas and myeloid leukemias. The Myeloid blood line includes red cells, neutrophiles and platelets. Venetoclax is also on a fast track for approval in combination with another drug to treat MyeloDysplastic Syndrome, of which there are many variants. Dysplastic is medical jargon for the abnormal form / construction of a cell, which can change its function. MyeloDysplastic Syndrome MDS involves some genetic mutations which alter the form and function of cells, progressing at various tempos and eventually causing severe disease and death in many cases. MDS was generally considered to be only a possible pre-cancer, but is now recognized as a type of cancer itself, which usually begins with a single cell which reproduces via cloning, grows faster than normal cells and is usually dysfunctional to some degree.
Currently there is no approved treatment for MDS besides a stem cell transplant after reaching an advaced stage, at least for the variant of MDS which I have.
My experience as a patient diagnosed with CLL and MDS
I was diagnosed as having Chronic Lymphocytic Leukemia in 2014 as a result of trying to find an explanation for frequent and chronic infections resistant to anti-biotics and drenching, full body night sweats. I met criteria for curative treatment at time of diagnosis, but no treatment was offered for almost 2 years. Only grudgingly was treatment offered after the onset of symptoms consistent with spleen ischemia, including severe pain in the upper left abdominal that could not be explained otherwise. Treatment with a monoclonal antibody not only eliminated the spleen pain, but also eliminatted night sweats and need for antibiotics for about 6 months.
I consulted almost a dozen hematologists who were certain that “b-grade symptoms” associated with advanced lymphoma, such as drenching night sweats and frequent infections had nothing to do with CLL, a form of lymphoma. A diagnosis of Common Variable Immune Deficiency was made without any supporting evidence in order to explain away a “b-grade” symptoms. I went to many hematologists for a second opinion who were unwilling to second guess a colleague and who stated that they did not agree with guidelines for diagnosis and treatment of CLL followed by specialists at academic centers such as Mayo Clinic in Rochester MN.
I transferred care to Mayo Clinic just before I experienced a complete remission of b-grade symptoms for about 6 months. Following a relapse of symptoms, I was treated with a BTK inhibitor, then a combination of a monoclonal antibody and Venetoclax.
I stopped the BTK inhibitor, then Venetoclax because of unacceptable side effects. However, immediately after stopping Venetoclax, no CLL could be found in the blood, and only 2 of 10,000 lymphocytes in the bone marrow were identified as CLL. A long, deep remission was expected without further treatment.
The BTK inhibitor is a immunosuppressive agent approved for treatment of host versus graft disease that was repurposed and patented for CLL. I developed chronic, multi-organism infections, Postural Orthostatic Tachycardia Syndrome and symtomatic heart dysrhythmias from the BTK inhibitor, then multiple cytopenias from Venetoclax, a BCL2 inhibitor. The adverse effects of these drugs diminished over time.
About one year after terminating CLL reatment in 2019, my hemaglobin increased to more than 14 million per microliter of blood, and consistently stayed at that level for about 8 months (checked monthly), then dropped below 14 million during the summer of 2021, then below 13 million in May 2022. This was preceded by heavy night sweats and symptomatic spleen enlargement. That triggered an investigation by a CLL speccialist to determine the cause, and maybe some form of treatment.
I began to take ivermectin on a daily basis in early June 2022 to treat a respiratory virus, possibly the omicron variant of SARS cov2. Night sweats became lighter and less frequent until I reduced the dose to 0.12 mg / kg in line with a plan to discontinue the ivermectin. The night sweats immediately improved with a daily dose of 0.24 mg / kg. However there was not much improvement with the hemaglobin. Spleen symptoms got worse, with pain with sitting down which I rated as a “3.” I could live with that for a while, but not indefinitely if the pain got to be a lot worse. Symptomatic spleen ischemia can lead to necrosis with life threatening complications.
A CLL specialist ran tests to rule out likely causes of anemia, spleen enlargement and night sweats, other than CLL and couldn’t find anything. Suspecting a bone marrow disease, the specialist ordered tests for MDS and other diseases. There were reasons to suspect MDS, including malformed neutrophils and red blood cells seen on a periperal blood smear. Another clue pointing to bone marrow involvement, neutrophil counts dropping below normal limits during treatment with Venetoclax, and subsequently running on the low end of the normal range, even with severe, systemic bacterial infections.
The testing of samples from a bone marrow biopsy, including the analysis of 20 cells at metaphase (a phase of cell division) led to a diagnosis of MDS with a deletion and trasposition of genes associated with an intermediate prognosis (between poor and relatively good). The lab ran out of samples before it could do further genetic testing for prognostic purposes. However, because there were not an abundance of blast cells in the bone marrow, I wouldn’t qualify for treatment, and if I did qualify for treatment in the near future, the anemia and other symptoms would be much worse then they are. No urgent need to get another bone marrow biopsy because the results would not likely give me any treatment options, and I am not inclined to choose any of the available treatment options.
There are active orders for another bone marrow biopsy to further evaluate the MDS. However, even in the unlikely event that I meet criteria for treatment, the only curative treatment option is a bone marrow transplant, which is not an appealing option to me.
Whether and to what degree spleen symptoms are caused by CLL cannot be determined wihout removing the spleen to examine some of the tissues, according to a CLL specialist (off the record). However, if the objective is to treat the underlying causee and avoid splenectomy, that would not do. In theory one could treat the CLL and see if that resolves the spleen symptoms. That is how diagnoses are sometimes confirmed when there are no available diagnostic tests, but not in this case.
When confronted with the need for treatment, but with no hope of getting a diangosis and treatment, I began to consider the possibility that I might have access to a viable treatment in the form of repurposed drugs already approved by the FDA for other indications. The symptomatic improvement which I experienced with ivermectin led me to search for answers on the internent to the question, does ivermectin show promise as an anticancer agent? The answer was yes. It showed promise as a treatment for CLL, MDS and Acute Myeloid Leukemia. I also encountered references to hydroxychloroquine as a treatment for CLL, MDS and AML.
I started hydroxychloroquine at a daily dose of 200mg daily on August 1, 2022 and continued ivermectin at 0.24 mg / kg. Within 4 days the spleen pain was gone, and within 6 weeks the red cell count and hematocrit were normal and the hemaglobin was just short of being normal for men at 13.4 million per microliter. I don’t know what these changes signify. However, I should be able to get the CLL and MDS re-evaluated soon.
If the populations of cancer cells are diminishing, it is likely that ivermectin and hydroxychloroquine are functioning well as anticancer agents for me. That would not necessarily mean that they would work well for anyone else with one or both of the same cancers. Other medications and diet could be interacting wtih HCQ and Ivermectin. The cancers and complications from it could be more responsive to those HCQ and Ivermectin than other cancers or variants of the same cancers.
There have no no adverse effects from taking ivermectin and hydroxychloroquiine so far. I am keeping my primary doctor and two Mayo Clinic specialists informed, and have yet to be advised to stop nor to continue. These doctors are constrained from practicing medicine by protocols, the lack of guidelines for diagnosis and treatment for two cancers whose symptoms and treatments overlap. The rules they follow, dictated by pharmaceutical companies with support from the FDA and their employers amounts to mandatory medical malpractice in some situations.
1) Ivermectin, a potential anticancer drug derived from an antiparasitic drug
https://www.sciencedirect.com/science/article/pii/S1043661820315152
2) Hydroxychloroquine (Hcq) Induces apoptosis in b-chronic lymphocytic leukemia cells (B-cll) Via activation of CASPASE-3 and down-regulation of BCL-2
3) Early induction of apoptosis in B-chronic lymphocytic leukaemia cells by hydroxychloroquine: activation of caspase-3 and no protection by survival factors
4) PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome
PAK 1 blockers: Potential Therapeutics against Covid 19
In my most recent test for Minimal Residual Disease, my CLL couunt per 10k gated lymphocyte events has dropped by 50% compared to May 2022. It is probable that colonized CLL in the lymphatic system and other hiding places is being killed off faster than it can proliferate. It had been rising by more than 6 fold per year with no treatment. The MDS is also going into remission as evidenced by normalized and improving blood counts. This is just anecdotal evidence and the only evidence that is published anywhere, so far as a know. about the effectiveness of combining hydroxychloroquine and ivermectin to treat and kind of cancer. Also mo night sweats, no revival of spleen ischemia symptoms that I experienced before combining treatment. Plus, both drugs slow down the breakdown of insulin in cells in different ways, thus improving glucose tolerance. HCQ is prescribed for diabetes in India as a second or third line of treatment, prior to injecting insulin, leading to better glucose tolerance and better control of blood glucose levels. I don't know what the protocol for HCQ as a diabetes treatment is. I am not on a very high dose of HCQ, just 200 mg daily and about 40 micrograms per kilometet of ivermectin, which is fairly high, but well below toxic levels. I have adjusted doses up and dose, checked the effects on lab tests, and adjusted some more. I suspect that I am on an optimal dose of both drugs for the cancer treatment
Hi Doug. I really appreciate your write-up on this. I have CLL too and I know you from some of the online CLL groups we are both in. I have used IVM for Covid - as both a treatment and prophylactically throughout 2021 when I was also on venetoclax. I have HCQ on hand but have not used it yet. I too have read some literature on both IVM & HCQ having relevance for cancer treatment. Your spleen results are a very good sign. Keep up the good work and keep sharing your discoveries, please.