I received this letter from Dr. Michael Snyderman, the Director of Clinical Oncology for the WPI, this morning. I am posting it with permission. He is hoping to lend some balance to the discussion. This is what one doctor did with early testing, even before the scientific process had run its course, since he would have been dead before ever starting treatment had he been unable to connect the dots.
Dear Dr. Deckoff-Jones:
It is a shame that the WPI has lost time from having to be on the defensive. I am a believer in MLRVs causing human disease. The supporting data actually goes back to the 1970s. Three different research labs including Robert Gallo’s the co-discoverer of HIV found MLRVs in many different types of lymphoma and leukemia. I believed in “XMRV” enough that when Dr. Mikovits told me that my blood sample was positive, I put myself on AZT and raltegravir for my chronic lymphocytic leukemia and CFS. At the time I started treatment (5/27/10) both were getting worse quickly. I had no treatment for cancer or CFS prior to ARV’s.
I have been a hematologist/oncologist for 40 years. I am tired and am not cured but I am improved at 11 months on treatment. Both the leukemia and the CFS improved coincident with disappearance of infectious virus from my plasma.
I am plotting total lymphocyte count, total B-cells (CD19) and an unfavorable clone of CLL cells (trisomy12). As you can see, my counts were going up rapidly and now are slowly improving. To my eye it looks convincing that there has been a definite biological change in the leukemia. I also feel somewhat less fatigued and my neuropathic pain is gone. Attached are my lymphocyte count, CD19 (leukemia cells) and trisomy 12 cells (the worst group of cells of my leukemia), as well as my original cytokine profile, vs. 9 months of treatment.
There is no other reasonable explanation than that XMRV, or another retrovirus, was at least making things worse, and subtracting its influence has improved my disorders. This is proof of principle in my opinion. Obviously, an enormous amount of work needs to be done. For example, we don’t have a protease inhibitor, and ARVs are not going to be the only answer. My perspectives are mine, but I believe there is a scientific basis.
I have B-cell CLL with unfavorable prognostic factors: doubling time < 1 year and trisomy 12. I also had the characteristic elevations of cytokines, fatigue and pain seen with CFS. I started AZT and raltegravir May 2010, because I felt things were deteriorating and I had little to lose. More importantly, if I was successful, it could translate into a treatment option for cancer patients that otherwise could not be helped.
The use of ARVs for treatment of cancer is not new; it was used in the 1990s for treatment of HTLV-1 associated lymphoma and did help. I knew then that if I used it on patients I would be vulnerable to censure from my fellow oncologists. I look at the fact that I got CLL as the opportunity of a lifetime to do some good. I am a one person project. I hope sharing my data will encourage people that we will prevail. I will be submitting this data to an online Hematology Oncology journal soon. Some excerpts from the paper are included below.
Michael Snyderman, MD
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Review of murine leukemia virus-related viruses and malignancy and outcomes of anti-retroviral drug therapy in a Xenotropic Murine Leukemia Virus Related Virus XMRV positive patient with Chronic Fatigue Syndrome and chronic lymphocytic leukemia.
Background: Xenotropic Murine Leukemia Virus-Related Virus (XMRV) was identified in 2006 in some patients with prostate cancer and first isolated in 2009 from most patients with the Chronic Fatigue Syndrome (CFS). Of a cohort of 300 patients with CFS from the 1984 Nevada outbreak, 13 developed B-cell malignancies. The 13 patients were positive for XMRV and a gd T-cell clonal expansion. Causality of XMRV associated CFS and malignancy can be addressed by treatment with anti-retroviral drugs. A patient with both CFS and CLL was available for study. Materials and Methods: Peripheral blood mononuclear cells were isolated. XMRV infection was detected by RT-PCR for gag and env expression; isolation of infectious virus and seroreactivity to XMRV antigens. Cytokine profiles were determined by multiplex analysis of 30 cytokines chemokines and growth factors on a Luminex platform. T-cell clonal expansion was determined by testing for clonal T-cell receptor gamma gene rearrangement (TCRg) by assays available from commercial clinical laboratories. Results: A patient with CFS and B-cell chronic lymphocytic leukemia (CLL) was positive for XMRV and clonal TCRg. He showed improvement in his cytokines, CFS symptoms and hematological parameters simultaneous with disappearance of infectious XMRV in plasma after treatment with AZT and raltegravir. Conclusions: Improvement of both the CFS and CLL simultaneous with disappearance of infectious XMRV from plasma after anti-retroviral therapy suggests that XMRV was etiological for both. Anti-retroviral therapy might have a positive impact on CFS and XMRV associated malignancy in other patients.
A patient with CFS and B-cell CLL tested positive for XMRV in both plasma and leukemia cells. His virus was sequenced and was closely related to the previously sequenced XMRV strains in our laboratory. He had antibodies to XMRV proteins. He was also positive for a clonal TCRg by both quantitative and qualitative assays. He had unfavorable prognostic factors including a trisomy 12 clone and a doubling time of less than one year and had no prior therapy. He started treatment with AZT and raltegravir 571 days after diagnosis. By day 56 of treatment, infectious XMRV was no longer detectable in plasma and his cytokine levels had improved. This coincided with improvement in symptoms of CFS which included fatigue, difficulty in concentration and neuropathic pain. He continues on treatment for eight months with good tolerance of drugs and works full time. His previously increasing absolute lymphocyte count (ALC), CD 19 cells and trisomy 12 cells are trending downward. At start of treatment, his ALC was 16,348/cu mm and CD 19 cells 11,658/cu mm up from 3,303 at diagnosis. His trisomy 12 cells peaked at 8,490/cu mm day 117 of treatment up from 1,550 at diagnosis. After 285 days of treatment his ALC was down to 10,600/cu mm, CD 19 cells down to 6,015 and trisomy 12 down to 4,558.
We have previously reported that most CFS patients are positive for XMRV if multiple detection methods are used. The development of lymphoid malignancies in 13 of 300 CFS patients suggests that CFS patients are at a several hundred fold increased risk for malignancy compared to generally quoted incidences in the general population. Of these 13 patients, all that were tested were positive for both XMRV and a clonal gd T-cell expansion. The greatly increased risk for B-cell malignancy in an XMRV infected population may be due to infection of the B-cell line by XMRV. Cancers have mutated genes and changes in gene expression that could make them permissive to infection by retroviruses. Retroviruses have been thought to cause cancer by insertional mutagenisis. This mechanism requires that the retrovirus proviral DNA be integrated into host cell DNA next to a proto-oncogene thereby inducing activation of the proto-oncogene. A more important mechanism with XMRV may be the ability of viral proteins to change gene expression. Several independent groups have found that shortly after a permissive cell line is infected with XMRV, multiple genes are expressed and that these genes could be involved in production of the malignant phenotype. Spadafaro has shown that reverse transcriptase can cause gene activation and lead to the malignant phenotype. In some cancers env and gag may also be important in malignant transformation.
A complementary hypothesis is that T-cells are also infected by XMRV resulting in a clonal T-cell expansion. The clonal T-cells produce elevated cytokine levels which may be partially responsible for the CFS. Furthermore these cytokines may have a paracrine activity that stimulates a simultaneous neoplasm to behave in a more aggressive fashion.
One objection to considering XMRV a pathogenic virus is that there was previously no explanation as how a murine leukemia virus could have entered the human population. However, early vaccines were prepared by passaging human virus through mice for the purposes of viral isolation and for attenuation. This would have allowed for contamination of vaccines with murine leukemia viruses. The original Yellow Fever Vaccine was made in the early 1930’s by culturing the virus in mouse cerebral tissue. Some patients received both the Yellow Fever virus and infected mouse cerebral tissue.
The YF17D strain was used to immunize over 400 million people world-wide over the next 65 years. It was the policy of the U.S. Armed Forces to vaccinate service men for Yellow Fever from the 1940’s through the 1970’s. The polio vaccination trials in the United States started in 1952. The polio virus was passaged through mice, cotton rats and primates to achieve attenuation. Although the Salk vaccine was treated with formalin, many patients received the live oral attenuated polio virus. Indeed, the patient studied here, received the live oral polio vaccine in the early 1950s, fifteen years later developed symptoms of CFS and fifty-five years later developed CLL. He also received the Yellow Fever vaccine in the early 1970’s on entering the Armed Services.
In summary, a new patient with both CFS and B-cell CLL was identified. Both his leukemia cells and plasma were positive for XMRV and he had antibodies to viral proteins. He also was positive for a clonal TCRg and had elevated cytokine levels. With anti-retroviral therapy he showed improvement in his cytokine levels, CFS symptoms and hematological parameters simultaneous with the disappearance of infectious XMRV from his plasma. Presumably his improvement was related to the anti-retroviral effects of treatment.
Alternative explanations for the therapeutic effect of his anti-retroviral therapy have been offered. One of these is “selective toxicity” which has never before been seen with the hundreds of agents use as cancer therapeutics and seems an unlikely explanation for his improvement. Anti-telemorase activity of the AZT has also been considered, but the rapid response to treatment does not fit the kinetics of depletion of telomers.
There is nothing unique about this patient’s clinical presentation to suggest that his case is any way unrepresentative. His response to anti-retroviral therapy suggests that XMRV was etiological for both his CFS and CLL and that anti-retroviral therapy might help other patients with CFS and XMRV associated malignancy. Many more patients need to be studied. Ultimately questions that should be answered are what neoplasms are associated with XMRV, will existing anti-retrovirals have activity in these neoplasms and what would be the optimal combination of anti-retrovirals.