Dear reader, this journal reports the facts faithfully, neither sugar-coating the issues nor looking to sensationalize downturns in Harvey’s journey down this road. On your part, you must realize that these journal entries are not always inspirational or fun stuff, there are rough patches that will be far from soothing bedtime reading. I am not a physician or psychologist, nor am I qualified to give you medical advice. I am an interested layperson reporter − but more than that I am a patient spouse and in that sense I walk in your shoes. I strongly advice you to seek professional help from your own medical team before you make therapy decisions for yourself. CLL Topics and this Journal are a labor of love. We are all volunteers here. None of us have any links to companies or other organizations connected with the health care industry; neither I nor anyone else associated with this effort makes a single dime from it. As for my educational background, you can read about it on our website: Chaya’s Research Credentials.

If you are an existing member of our CLL Topics community, you know what we are all about. If you are a new visitor, we welcome you and hope you find this journal and the parent website www.clltopics.org to your liking. If this journal succeeds in helping even a few transplant patients in their own journey down this complicated and scary road, I will be content.

If you have any comments, please send them to

Be well,

Chaya

1. 2008-02-25 An Introduction to this Journal
2. 2008-02-27 Planning for Success
3. 2008-02-28 Finding that Perfect Match
4. 2008-02-29 “Lite” Stem Cell Transplants
5. 2008-03-01 Three Sources of Stem Cells for Transplants
6. 2008-03-04 Clinical Trial Details
7. 2008-03-06 Making Therapy Decisions With Eyes Wide Open
8. 2008-03-15 Minneapolis, Here We Come
9. 2008-03-17 Revlimid (lenalidomide)
10. 2008-03-20 Easy In, Easy Out
11. 2008-03-22 Bring On the Heavy Guns
12. 2008-03-24 This Too Shall Pass
13. 2008-03-26 Day Zero
14. 2008-03-28 Aftermath
15. 2008-03-29 CMV Viral Reactivation
16. 2008-03-31 Hospitals Learn to Say Sorry
17. 2008-04-02 A Different Kind of Watch & Wait
18. 2008-04-04 A Day in the Transplant Ward
19. 2008-04-05 FUO
20. 2008-04-07 Some Good News to Report
21. 2008-04-10 A New Phase Starts
22. 2008-04-12 Better Living Through Chemicals
23. 2008-04-14 Your Good Deed For The Day
24. 2008-04-15 Mini-Allo Transplant Statistics
25. 2008-04-18 Two Steps Forward, One Step Back
26. 2008-04-23 It Is A Boy!
27. 2008-04-24 Coming Up The Learning Curve
28. 2008-04-28 Scary Times
29. 2008-05-02 We Have a Suspect in Custody
30. 2008-05-03 The Buck Stopped With Him
31. 2008-05-08 Going No Where Fast
32. 2008-05-14 Eat Your Yogurt
33. 2008-05-21 Quickie Update
34. 2008-05-22 Springtime!
35. 2008-05-31 Doldrums
36. 2008-06-09 An Unexpected Left Turn?
37. 2008-06-20 A Very Hard Reality to Face
38. 2008-06-21 Knee Deep In Alligators
39. 2008-06-24 Death In The Family
40. 2008-06-26 P. C. Venkat, 1949-2008

Harvey’s farewell party will be in Sedona, on Saturday, July 5th, starting at 5pm Arizona local time (8pm EDT) continuing till whenever. Please contact farewell@clltopics.org to RSVP and for more information regarding location, driving directions, lodging, etc. If you cannot join us in person, please join us in cyberspace and share your thoughts with us by posting your comments on this blog. Thank you all!

P. C. Venkat, 1949-2008

Palasena Chidambar Venkat, husband, father, brother and patient advocate, died at the University of Minnesota Fairview Hospital on the afternoon of Monday, June 23^rd 2008 from complications of a stem cell transplant to cure his Chronic Lymphocytic Leukemia. He was 59.

He was born in Petaling Jaya, Malaysia, on February 7^th, 1949. He was raised by his paternal grandparents in Bangalore, India. He attended IIT Madras and was awarded his Bachelor’s degree in Electrical Engineering in 1971. There, he met a young Chemistry student named Chaya Rao during his junior year and resolved to follow her to the U.S., where she would be attending graduate school at the University of Michigan.

My parents, Chaya and P. C., were married in The Hague, the Netherlands, on July 12^th, 1971. He received his MBA from the University of Michigan in 1973. He worked for several different banking companies over the next three decades, including Citicorp, First Fidelity, Wachovia and Bank of America. His last job before his retirement was as a turnaround specialist at Sales Support Services. The company was successfully sold in 2001.

They retired when they were 51, in the spring of 2001. In June, my father went to India to bring my maternal grandparents to live with them in their new home in Sedona, Arizona. After he returned he noticed a few swollen lymph nodes, initially treated as a “bug” he had picked up overseas. Further testing and consultation brought a devastating diagnosis: Chronic Lymphocytic Leukemia (CLL).

As his disease progressed over the next several years, he and my mother decided to do everything within their power to battle this cancer, both for themselves and for the broader patient community. They set up CLLTopics.org, a patient education and advocacy web site, in 2002. It quickly became a major force in the patient community. The non-profit was incorporated the next year, and aimed to raise funds to support important clinical trials in CLL research. As of the end of 2007, they had raised over $310,000 and funded four clinical trials with the Mayo Clinic, the Hutch, U. VA and Royal Bournemouth Hospital.

In the spring of 2008, he and my mother decided that an elective cord blood stem cell transplant was the best option for a cure to his CLL. They went to the Bone Marrow Transplant center at the University of Minnesota Fairview Hospital. Therapy was initiated on March 20th, and the transplant was given to him on March 26th. He had reached full engraftment, and it appeared that his CLL was in abeyance from the effects of graft-versus-leukemia.

In a devastating reversal, what had started as a cough turned into ‘a touch of pneumonia’, which turned into Acute Respiratory Distress Syndrome (ARDS). He was re-admitted to the hospital on June 14^th, and passed away at 4:30pm on June 23^rd, 2008 after a terrifyingly fast decline.

My Papa was an immense figure in my world. He was intelligent, he was quirky, and he would give you the shirt off his back. His wit could be punishingly wicked and his personal standards were uncompromising.

He had many passions beyond his advocacy. He was an amateur astronomer and served as the webmaster for the Astronomers of Verde Valley. He spent long hours hiking the hills of Sedona, Arizona with his faithful and energetic Australian Shepherd dog, Jasper. He would come home still full of energy, and she would be whupped. He was a classical music buff and Vivaldi was his favorite composer.

He was the first man I ever loved. He brought me roses when I was fifteen and my first boyfriend broke up with me. I will miss him tremendously for the rest of my life.

P. C. is survived by Chaya, his wife of 37 years, his daughter Radha, his brother Raju, his loyal dog Jasper and countless friends all over the world.

Radha Venkat
June 26^th, 2008

Photo taken Prof. Ron Taylor, 2007

If you wish, please make a donation to your local SPCA or animal shelter in P.C.’s memory.

This reporter has lost a husband, best friend, partner and soul mate. The sun is just coming up as I break this news to our extended family - but the world will always be just a little darker and colder for me from now on.

In the days to come we will publish a full length obituary for our fallen hero, both on this Journal as well as CLL Topics website. As he wished, Harvey will be cremated in a private service and for a few days his ashes will drift on the winds around his favorite hiking trails in Sedona.

We will hold a farewell party for Harvey at our home in Sedona, in a week to ten days. Details will be published both here and on www.clltopics.org Please come and share the time with us if you can, electronically if you cannot make it in person. We want to celebrate the life of this gentle and brilliant man - there is much to celebrate about Harvey.

Harvey would not have wanted any pomp or circumstance. If you wish, please make a donation to your local SPCA or animal shelter in his memory. Harvey loved his Aussie Shepherd dog almost as much as he loved any human being.

You would have been proud of your hero - he served your cause right up to the end. His case history has puzzled the experts. No one can quite explain what happened, why a perfectly engrafted transplantee suddenly took a turn for the worse with such devastating consequences. They asked, and I agreed, to a full autopsy. If lessons learned from Harvey’s poor beat-up body can help experts understand things a bit better, if just one transplant patient in the future benefits from it, Harvey would have been proud to be of service.

I do not know what to say, what to feel, what to think as I try to come to grips with this tragedy. I was so sure Harvey was going to beat the odds, and we would soon be heading back home to Sedona. The CLL was defeated - but the dreaded TRM (treatment related mortality) claimed the life of my guy.

Not too many things are in my control right now - I drift in and out of reality, “normal” for a while and a basket case the rest of the time. But I am told this too shall pass. When it does, I will be back. What Harvey and I started by way of patient advocacy is more important than either of us. It will surely not die just because Harvey’s body decided to go AWOL. It will be hard filling his shoes - much of the “soul” of CLL Topics - its look and feel, the gentle tones and soothing art work - all that came from Harvey. Some things may have to change - but with your help we will persevere. So, please be patient, please wait for me.

Chaya

UPDATE: Harvey’s farewell party will be in Sedona, on Saturday, July 5th, starting at 5pm Arizona Standard Time, continuing till whenever. Please contact farewell@clltopics.org to RSVP and for more information regarding location, driving directions, lodging, etc. as well as electronic contact info for those who can’t be there in person. Thank you all!

It is late night as I write this, sitting in Harvey’s ICU room. Harvey is sleeping his induced coma. I think he can still hear me sometimes when I talk to him, but perhaps I am just imagining it for my own consolation. I wonder what dreams he is dreaming as I keep vigil in his room, waiting and worrying about what new crisis the next hour, the next day may bring.

Writing is a form of catharsis for me, a way to clarify my own thoughts. I come from a small family, and both Harvey and I are first generation immigrants with all the emotional loneliness it implies. I want you to know your feedback gives me immense solace. What nature did not do for me, Harvey seems to have corrected by way of our very extended CLL family. I have not met most of you - but we walk down the same paths and that is enough for kinship of the heart.

Dangerous Waters

Harvey is swimming in dangerous waters, alligators to the right of him and alligators to the left of him. Making therapy decisions is very hard when there are so many conflicting needs and risks.

Harvey’s latest medical crisis has been diagnosed as ARDS (acute respiratory distress syndrome). Think of it as your lungs turning into a bloody mess so that it becomes a challenge just to get enough oxygen into your body. Some of you may remember the SARS epidemic scare a few years back. In that case, the viral infection attacked lung tissue and in advanced cases lead to ARDS. But it is not necessary to have a pathogen such as SARS to cause lung damage. It can happen as a result of autoimmune disease as well, the body attacking itself. So far, we have not identified any pathogen causing the lung damage in Harvey, the assumption is that the damage has been caused by sudden and devastating inflammatory cytokine storm that pulped his lung tissue. In otherwise perfectly healthy young people ARDS carries a mortality risk of 30-50%. I am sure you can imagine how much more scary that percentage becomes in the context of a newly transplanted patient.

Plugging the Holes

For a while, Harvey was losing blood so fast that we were not sure we could replace it fast enough to keep his blood pressure from sinking too much. We now seemed to have turned that corner, almost continuous infusions of plasma, platelets and red blood cells have patched most if not all the leaking holes. Hemoglobin, RBC and platelet counts have stabilized. The ventilator with its enriched oxygen content is keeping the oxygenation level in decent shape. But that is just the start. It will take time for the damaged lung tissue to heal. Until that happens, he will have to have ventilator assistance just to breathe. The question boils down to this: will he get that time? Will he be able to dodge all the other alligators in the water long enough for his lungs to heal?

Between The Devil And The Deep Blue Sea

Harvey is on massive doses of methylprednisolone in an attempt to halt the inflammatory spiral that got so dangerous so quickly. What initiated the process? No one knows for sure and there is not much point in speculating right now. Steroids are good at controlling most forms of inflammation. But they are also dangerous in suppressing the body’s ability to fight infections.

That brings us to the second big alligator trolling in the water: uncontrollable infections in a deeply immune compromised host. During times of deep inflammation the body’s first line defenders (neutrophils, macrophages) rush to the site of the inflammation and throw themselves into the fight - often making things worse by shooting off their weapons in random manner, causing even more tissue damage. A close analogy of this process is “keystone cops”, killing friends because they cannot tell the difference between friend and foe.

This misguided zeal of neutrophils is also suicidal - white blood cells die in droves as they exhaust themselves fighting an enemy that they cannot identify. Plugging the holes has stabilized the red blood and platelet parameters. Restoring the white blood counts to healthy levels is not that easy, since it is not possible to give white blood cell transfusions.

GCSF (Neupogen, Neulasta etc) shots are routinely used to goose white blood cell production. But did you know that GCSF (and its sister growth factor GMCSF) are quite inflammatory in themselves? How much GCSF shots can we give Harvey in an attempt to speed up the recovery of white blood cells, before the old inflammatory cascade gets out of control once again? Can we afford not to give him GCSF, if that means longer to neutrophil recovery? Will he survive the inevitable infection that will come by sooner of later, if he has no fighting troops? How much steroidal drugs can we give him to keep a lid on the risk of renewed inflammatory cascade, before we cross over the line in ability to fight infections? We are in a damned-if-we-do-and-damned-if-we-don’t mode here.

“Slim” is Still Alive

We did get one piece of good news. A bone marrow biopsy done earlier in the week shows the graft is still around and doing OK! “Seattle Slim” is one tough kid, he is still 100% in charge in the bone marrow, still trying to produce cell lines in these trying times. Comparison of most recent PET scan with one done a month ago shows GVL happening at a good clip, CLL remnants in full retreat. Way to go kid. May you live long, and may you help bring Harvey back to health.

Crisis Overdose

I oscillate between hope - forlorn though it may be, and unmitigated terror and grief as I contemplate the future. Maybe my best friend will beat the odds, dodge the double alligators of uncontrollable infections / inflammation - along with all the other smaller beasts such as kidney overload, liver toxicity etc. But maybe his lungs won’t get enough time to heal and he won’t ever be woken from the induced coma - what is the point of waking him up, just so he can experience the terror and pain of slow suffocation?

I wanted to spend a life time with my buddy. But on Thursday afternoon I would have settled for even just a couple of minutes together before he had to go into his present long sleep. There were so many people milling around in Harvey’s room in those frantic hours as they tried to intubate him, stabilize the bleeding and get him into ICU. I barely had time to explain to Harvey what needed to be done, and for him to scrawl “Agreed” on a piece of paper - he could not talk - and that was that. Now I sit here watching over him as he dreams away the hours, remote in his coma. Tomorrow will be here soon. Another day, another crisis - I will keep my vigil for as long as it takes, as long as he has a chance.

Be well,

Chaya

I have not written for a while - partly because I have been very busy, and partly because I have not had the heart to write. But I did promise to tell you the truth and nothing but the truth - so here goes. You might want to sit down for this one.

Harvey was readmitted to the hospital on Saturday, June 14th. His “Fevers of Unknown Origin” (which had been simmering for a while) took off again and this time both his blood pressure and oxygen saturation levels headed into unhealthy ranges. Harvey had always had the heart and lung capacity of a much younger man - courtesy of years of regular exercise. Now he was becoming out of breath. I made the decision to take him into the hospital for immediate admission.

Lucky I made that call when I did, even though I had to struggle past rather uncooperative doctors and “fellows” manning the weekend shift. A chest X-ray showed slight infiltration in his lungs, not enough to be classified as full blown pneumonia, but nevertheless worrisome. They suggested Harvey use oxygen overnight, just to be comfortable. By next morning, oxygen supply via the cannula (little plastic tubes at the tip of one’s nostrils) was no longer sufficient and we had to move to a full mask covering his mouth and nose.

The rapidity of events after this was truly breathtaking, I am still reeling from shock. We went from mild opacity in one corner of the lungs on X-ray to full blown total “ground glass opacity” of entire volume of both the lungs in a matter if 24 hours. A pressure assist oxygen delivery system (”Bi-Pap”) was suggested as a way of keeping Harvey well oxygenated, a way of avoiding full intubation and ventilation (machine controlled breathing). That lasted less than 12 hours. The “prudent and pre-emptive” intubation rapidly became a crisis management procedure. Harvey’s lungs gushed a whole lot of blood as they were trying to intubate him, he was bleeding and losing blood faster than they could replace with transfusions.

Since last night Harvey was on the intensive care section of the transplant wing, listed as critically ill. He is in a medically assisted coma, to keep him fully sedated as they tried to stabilize him. It was a touch and go last evening. I was told to call the family in, none of the many docs milling around gave me any assurance he was going to make it overnight. As one expert put it, he is as sick as a person can be and still be in the land of the living.

Harvey made it overnight, much to everyone’s surprise. Right now he is resting easy. We have a better control on the internal bleeding (we think), blood pressure and heart rate have stabilized. But he still needs almost continuous transfusions of red blood cells and platelets, just to keep him going. His blood counts have all crashed, he is in full blown pancytopenia with WBC hitting a scary 0.1K this morning. We are fighting multiple wars here. During all this trauma he had an episode of atrial fibrillation, which seems to have caused damage to his heart. His lungs are a bloody mess, any one’s guess whether they will be able to recover, ever. His kidneys are struggling.

What caused this devastating cascade of inflammation that made mincemeat of his lungs, implicated his heart, and overloaded his kidneys? No one is quite sure. But this much is sure. Harvey’s life is hanging by a very slender thread and the odds are not good at all that the frayed thread will hold. I am pretty much in shell shock, after have been up for three nights in a row. I would have crashed completely but for the strong shoulder of our daughter. And now our son-in-law is here as well to lend support. A very special thank you to “Lisa”, a true friend in need.

Will Harvey make it? I don’t know. I wish I could tell you that I am optimistic. Every time I try to read the tea-leaves and suggest an optimistic outcome, I am cautioned against false hope by the experts. Their consensus is uniformally bleak.

My heart and soul are aching with grief and tension. I will try and update you again in a couple of days. Right now the world is a dark and scary place and I do not know whether either of us will make it alive out of this nightmare. I am forcing my self to write, mostly because it is what Harvey would have wanted. This Journal is his legacy to the CLL patient community he loves - I hope against hope that he will be around for a long time to continue his crusade.

Please forgive me for not replying in person to all the caring and worried emails you have sent me for the past week or so. I hope this Journal entry will help keep you in the loop. You deserve no less.

Love,

Chaya

Back when Harvey had his mysterious and quickly-resolved rash on his hands and legs, the transplant team referred him to the Dermatology Department. They examined the rash, did a punch biopsy and later opined that the rash could be consistent with GVHD. Not exactly a strong finding of GVHD, just that it could be GVHD.

Since I am not one to miss an opportunity, I pointed out a small dark patch of skin that Harvey has sported on his right cheek for more than a decade. It had an uneven shape, was darker in some places than in others, with irregular borders. I thought these were sufficient reasons to be concerned, but what do I know, I am only a layperson, an over anxious spouse. We have asked a series of dermatologists to look at it over the last seven years. Each time we were told it was nothing to worry about. Since we were now in the presence of a real expert in oncological dermatology, I brought the “spot” to the attention of the attending physician.

Once again, we were told this is probably nothing more than keratosis, a case of hyper-pigmentation and of no medical consequence. But since it is something that is causing us concern, we were offered the option of having the offending patch frozen off.

I am sure many of you have had moles and the like frozen off with liquid nitrogen. It takes but a few minutes, they do not even use any local anesthesia. The doctor was obviously a senior guy who has done this a million times before and it took less than a minute to douse the patch (about 3mm by 6mm in size) with super cold liquid nitrogen.

Post-Freeze Guidance

We were told the area would blister, weep, and then the sore would form a crust and heal over. No need for any dressing or special handling. Not even a scheduled follow-up appointment. It was all pretty much a routine thing. I felt a little silly about insisting on this consultation and procedure, a long string of dermatologists had pronounced it of no medical consequence. Harvey rolled his eyes at my excessive caution, but went along with the procedure because of all the times I have preached the risk of squamous cell carcinoma in immune compromised CLL patients.

Now They Tell Us

The big freeze was 6 days ago. Sure enough, the site produced a most impressive blister that produced copious amounts of “weeping”. Then the blistered skin sloughed off, leaving behind a round, red, angry looking sore. No problem, the darn thing did not hurt at all and we were calmly waiting for it to crust over and begin healing.

Today our ever so observant PA (Physician’s Assistant) decided she did not like the way the site looked. She then went the extra mile and got us in to see someone at the Dermatology Department right away (Thank you, Emily!). In walked a doctor and his 3 interns under training. They looked at the site, touched it, hemmed and frowned, and finally opined it looked “odd”. Great. Please define odd, I asked humbly.

Well, they said, it could be nothing, just a case of inflamed skin tissue. Or, on the other hand, it could be squamous cell carcinoma, basal cell carcinoma etc. They then proceeded to tell me that skin cancer can be quite dangerous in CLL patients and immune compromised patients, especially when they are under immune suppressants like cyclosporine as part of their post transplant care. Yeah, I really needed this lecture about the dangers of skin cancer in CLL patients.

Meanwhile, We Wait

The medical consensus is to use a topical steroid cream on the spot, to see if that will take care of the potential inflammation. One week later, the site will be evaluated again. If it still looks “odd”, the next step is a biopsy to see if it is indeed squamous cell carcinoma or some other type of skin cancer. Surgery looms, if the biopsy comes back positive for some form of skin cancer.

I am fit to be tied. It is not as if I have been careless or remiss in addressing a potential problem. I brought it to the attention of countless oncologists and dermatologists. None of them suggested any action other than ignoring it. I am tempted to think they looked at Harvey’s brown skin and assumed he would have a low risk of skin cancer. Now, right when we are going through a complex cord blood transplant, we may have to wage a war on a second front.

I almost did not write about this latest development, it is such a depressing report. But then I remembered I promised to tell the whole truth about Harvey’s journey - and this is very much part of that experience. We hope for the best at our next meeting with the dermatologists, we hope the steroid cream does what it is supposed to do. But even if they pronounce satisfaction and that it was, after all, only inflammation that caused the site to look “odd”, I think this time I am going to insist on a full biopsy.

Be well, stay out of the sun!

Chaya

I had very different expectations for this Journal when I got started. It was going to be a terrific educational tool for our patient community, with lots of useful links, reviews and literature references. Harvey’s personal story was going to be used only to illustrate points that I wanted to make about the technology of stem cell transplants.

As it turned out, this has become much more of personal record of our transplant journey - mostly because I have not had much time or tranquility of mind to do a lot of reading of the latest articles in “Blood” etc. But I must also confess that the human warmth expressed in so many of your feedback emails has also seduced me into writing more about Harvey and less about the technology. This is an omission that I hope to correct at the earliest opportunity.

When the Adrenaline Rush is Gone

I have not written for a few days because there is nothing new to report. The pesky fevers are gradually coming under control, but not as quickly as I and Harvey would wish. Latest CMV viral count in the blood has come back “negative”. There is no trace of the virus in Harvey’s blood. It has been more than a month since Harvey needed platelet transfusion and more than several weeks since the last red blood cell transfusion. I doubt he will need either of these transfusions in the future, Seattle Slim seems to be up to the job of making his own platelets and red blood cells. Harvey has now been weaned off of all the intravenous drugs, even the intravenous ganciclovir has been changed to valganciclovir, the oral version of the drug. Harvey will be on this anti-viral for another six weeks, that is how seriously they take CMV infection and therefore their desire to make sure the virus is fully and totally nuked.

Which brings us to the important question: what are we still doing here? Why are we not going home to Sedona tomorrow?

Prudence is the Better Part of Valor

Several good reasons for sticking around here a little longer, I am afraid. Harvey has yet to defeat the daily fevers completely. They no longer get to the spectacular highs of a few weeks back, but he does still get a fever once in a while - especially right after he has had a GCSF (Neupogen) shot to boost neutrophil counts. He still needs daily prednisone to keep a steady keel. They still do not know what is causing the fevers, now that they have totally ruled out every possible infection known to medicine. Is it GVHD? Is it some funky version of “engraftment syndrome”? Until the experts feel more comfortable that they have a handle on what is going on, they are reluctant to let us out of their sight. Frankly, I am just as happy to have access to their expertise for a little while longer. I am told most transplant patients and their caregivers develop “separation anxiety” when told to go home.

Harvey is still on pretty high dose of Gengraf (cyclosporine). According to the clinical trial protocol this will continue for 100 days post transplant (we are now at Day +67 since the transplant) and then gradually decreased for another three months - provided there is no GVHD. If all goes well, Harvey will be off of cyclosporine at the end of 6 months. As we know, GVHD is one of the most perilous and nasty side effects of stem cell transplants. Gengraf is the major defense against GVHD getting established in any big way. This immune suppressant keeps the new immune system under strict curfew as it were, waiting until we are reasonably sure Slim is past his unruly teenage angst and not likely to go on a vandalism rampage. Other institutions use other drugs to do the same thing - tacrolimus (”Prograf”) is popular at M. D. Anderson I understand.

Full dose Gengraf as well as the high dose valganciclovir because of Harvey’s short flirtation with CMV infection means there is still significant drug load on Harvey’s liver and kidneys. We are fortunate that Harvey came into the transplant in the pink of health where liver and kidney function are concerned. But all the drugs he has had to tolerate has put a strain on his kidneys (slightly elevated creatinine level) and they they want to be sure this is a transient phenomenon. Let me hasten to assure you, the elevation is just over the healthy range and most often drops right down to a normal level when Harvey pays attention to staying very well hydrated (or he gets a bag of saline through the spanking new PICC line in his upper arm). Liver function parameters (AST, ALT) blip up when the docs change one or more of drug dosages, then recover a couple of days later. Bilirubin, another much watched parameter, has stayed rock steady.

What Do the Experts Look For in Diagnosing GVHD?

The University of Minnesota protocol has pretty strict definition of what constitutes GVHD. Typically, graft-versus-host-disease shows its ugly self in either the skin, liver or GI tract. Below are the expected symptoms / clinical lab results for GVHD at these three locations, graded from I (easy) through IV (really tough).

Lets see how Harvey’s experience stacks up on this basis.

• Yes, he had a bit of red rash on the backs of his hands, arms, and legs. The rash looked pretty good for a few days, then quietly disappeared. A punch biopsy of the skin at the site of the rash was not quite conclusive, even though the pathology report said it could be consistent with GVHD. The rash certainly did not cover anywhere close to 25% of Harvey’s body - I would guess it was not more than 5% of his body. Is this enough to classify this as Grade I skin GVHD? The experts do not think so.
• Liver GVHD is out of the question. Harvey’s total bilirubin counts have stayed stubbornly in the healthy range.
• As for GI tract GVHD, the main symptom of this is substantial and sustained diarrhea. Possibly because Harvey has been very good about getting his probiotics via daily yogurt snack, he has not had any diarrhea to speak of, certainly not on a daily basis. In fact, the magnesium pills he has to take daily are just enough to counterbalance a touch of constipation courtesy of cyclosporine. What can I say, the man has a healthy gut.

I guess we should be grateful for small mercies - GVHD is not a fun thing to have. Bottom line, there has been precious little going on besides the mystery fevers and it is hard to write when there is no ‘hot’ news to report.

Next week Harvey gets a PET scan to fully stage his CLL (or lack thereof!). I am keeping my fingers crossed that Slim has been doing his job and killing each and every CLL cell that he can find in Harvey’s body. Soon as I hear the results, I will be sure to let you know. After all, that is the point of going through all the pain and hassle of a stem cell transplant - to CURE this ‘incurable’ cancer - right?

Be well,

Chaya

Spring is my favorite season of the year. After a cold and dank winter, it is wonderful to see the land and creatures blossoming once again under the golden warmth of sunshine. Mind you, spring can be a fickle season. The warm sunlight of today can easily turn into blustery winds chilling the unwary T-shirt wearer to his very bones. But if you are like me, I am sure you take pleasure in the warmth of springtime today, who can tell what tomorrow will bring?

The Dark Days

Harvey had been struggling with daily fevers for several weeks now. We are not talking about the 100.5F fevers for which neutropenic CLL patients are told to go to the hospital. We are talking about mind-bending fevers that reached as high as 104.5 to 105F at their peak. Everyday, the morning would start out mild. No fever, no chills, no problems. By midday, the picture would begin to change. The fever would increase gradually, totally resistant to maximum safe doses of Tylenol and Advil. By mid afternoon it would hit its peak. On some days the fever would break by late evening. On other days it would continue into the night, making it impossible for Harvey or me to get any sleep. Often the fever would be accompanied by bone rattling chills / shivering, followed by drenching sweats that required change of pyjamas and sheets. I have never done so much laundry in my life.

The docs looked for any pathogens that could be causing the fevers. They looked for the common ones, they looked for the uncommon ones, they looked for the downright bizarre tropical ones ones because Harvey had spent a significant chunk of his life in Malaysia and India. With the sole exceptions of HHV6 (reported on earlier) that was soon resolved and a stubborn CMV infection (more on that nasty critter below), they could find no infections in Harvey. Samples from the Hickman port Harvey was fitted with were tested again and again. Nothing. Nada. In desperation, just in case the port was harboring some pathogen that was refusing to come out into the samples collected and tested, the decision was made to pull the Hickman port. I was sorry to see it go, it was working so beautifully and made all the intravenous infusions so much easier for Harvey.

The hope was that if the port was the guilty party, removing it would solve the problem. No such luck. Two days after they yanked out the Hickman, Harvey put on his best fever performance yet, hitting his career high note of 105F. I would be lying if I said I was as cool then as I am now, writing about it after the fact. Fortunately for Harvey and me, an old school friend of ours was visiting and so we had some one to freak out with us. Misery loves company. Oh yes, they did try to culture the removed port itself, to see if any bugs could be encouraged to grow. Once again, the results were a resounding zero.

One of the experts in charge of the protocol decided to do a little experiment. Harvey was given an intravenous dose of 60mg of prednisone, along with the rest of his antibiotic and antiviral medications. Something amazing happened. For the first time in weeks, Harvey had no fever that day. He stayed cool as a cucumber for the whole day, he felt like himself again. We went for a walk, had a relaxed lunch, watched TV, felt human again.

After much back and forth, it finally became clear to me (and most of the attending physicians) that the only agent that controlled Harvey’s fevers was prednisone, carefully calibrated down to 40mg/day. There was some concern about doing this for any length of time, since Harvey still had that pesky CMV infection and it is not safe to prescribe immune suppressive steroidal drugs to patients with live infections. But frankly we were running out of options and I could not see how my friend was going to be able to tolerate these massive fevers any longer.

One Less Thing to Worry About

The CMV infection was the big roadblock in giving Harvey the prednisone dose he needed to control the fevers. Yesterday, for the first time, we saw the CMV viral counts go down. They had been hanging tough at the 2K - 2.7K range ever since CMV was diagnosed several weeks ago. Yesterday the counts went down to 0.2K. Anything less than 0.1K is considered inconsequential. Harvey will stay on intravenous gancyclovir for a week longer, followed by several more weeks of oral version of the same drug (valagancyclovir), just to make sure the CMV is destroyed completely. The fact that the antiviral therapy is proving effective and the viral counts have come down sharply demonstrated that the 40mg prednisone he had been getting for the past 4 days has not gummed up the works.

A Mystery For The Experts

I keep telling Harvey it is OK to be a somewhat boring person at times like this, but he just does not seem to get it. He has become an interesting puzzle for the doctors, as they try to explain what is causing his high fevers. One by one, all the known pathogens have been ruled out, as well as the poor blameless Hickman port. As Sherlock Holmes would say, once you have ruled out all the probable causes, what remains must be the cause, however unlikely it may sound. Among the less likely culprits are (1) drug induced hyper immune reaction (and Harvey has been on drugs enough to sink several good sized boats) (2) Something called an “engraftment syndrome” where the newly minted donor neutrophils go on a rampage, tricking the body into thinking there is an infection of some sort and therefore jacking up the body temperature (3) good old fashioned GVHD. The jury is still out and we do not yet have a consensus on what may have triggered the high temperatures. The fact that Harvey also had a transient but pretty impressive rash on his arms and legs at one point may be a clue.

My money is on some weird and unconventional presentation of GVHD. I have one totally unrelated bit of information for making this bet. Harvey had these “shoddy nodes” along the side of his neck, sort of pebbly nodes I could feel with my fingers, even after going through all the preconditioning and the transplant itself. Over the last couple of weeks these and every other node we could feel all over his body have disappeared. Is this the much longed for graft-versus-leukemia (GVL) effect, clearing his body of the last traces of CLL? If he is experiencing GVL, were the fevers the other side of the coin, the evil twin GVHD? The experts are not convinced. But that is my story and I am sticking to it - for now.

When it rains it pours

Let’s see: we got a handle on how to control Harvey’s fevers with prednisone, CMV viral loads decreased dramatically, Harvey seems to have shaken off the last remaining traces of any unnaturally enlarged lymph nodes - pretty good news you say? Well, you have not heard the last bit yet. Today was got the latest results of molecular studies to check on the status of the two cord blood units Harvey received back on March 26th. As of today, Seattle Slim is 100% in charge and Harvey is fully chimeric and engrafted. There is no trace of the second cord blood unit, or Harvey’s own prior cancerous immune system. Slim is getting pretty good at making red blood cells, platelets and neutrophils (the last need a little coaxing once in a while with a Neupogen shot because of all the immune suppressive drugs Harvey is getting), which means Harvey needs very few transfusions.

Don’t let me get too euphoric. There are still bridges to cross. The experts are still scratching their heads on what caused the fevers in the first place and what would happen if we discontinue the prednisone. Would the fevers return with a vengeance, or would we have succeeded in changing the pattern once and for all? Is the shoe yet to drop on the subject of GVHD? How long will it take Harvey to recover his lost weight and strength? It breaks my heart to see him so scrawny, barely able to keep up with me when we go on our very short walks. But his spirit is doing well, especially since he won his bet with me - contrary to predictions, he managed to keep most of the hair on his head (what there was of it to begin with) as well as his beloved goatee.

It has been a turbulent and oftentimes very scary couple of weeks. Today, I can feel the spring sunshine in my bones, I am holding on to my sense that Harvey has turned the corner and we will soon be heading back home to our beloved Sedona. I can’t wait to get our dog back, our life back. Thanks for keeping the vigil with us, it means a great deal to Harvey and me.

Be well,

Chaya

Harvey’s CMV infection is finally under control. The viral titer has come down from more than 2,000 to a mere 200. He will continue with the intravenous gancyclovir for a while longer, just to be on the safe side.

The fevers were spectacular for a while. But now we seem to have a handle on how to control them - good old prednisone. More on that later.

Spring has sprung in Minneapolis and it is a wonderful time of the year. For all of you who have stuck with us through thick and thin, my heartfelt thanks. You know that old saying, friends in need etc? We have been blessed in the number of people who chose to keep in touch with us during the dark days.

Be well,

Chaya

I wish I had new stuff to report. Harvey continues to have fevers, some of them alarmingly high and accompanied with shivering and chills - what is affectionately known as “Shake & Bake” by cancer patients. The graft continues to do well. As of today the platelet count is 45K! Long way up from when it used to be 10K with help from platelet infusions and not that far from 50K when he is considered to be officially “platelet engrafted”. The worrisome thing is that the latest CMV viral count has not budged much, it is still hanging tough at ~ 2K. They increased the ganciclovir dose as of today and if that does not work the plans are to switch to Foscarnet on Monday of next week. Local guidelines call for administration of foscarnet only as a hospital in-patient procedure and Harvey would very much prefer not to have to go back into the slammer. Hopefully, the higher ganciclovir dose will have kicked CMV butt by next week and we don’t have to consider Foscarnet.

“Let Them Eat Yogurt”

Since I do not have much news to report on Harvey, I will address some of the issues raised by our reader’s comments on the previous post.

Probiotics are an important part of keeping the gut healthy. These are ‘good bacteria’ that have learned to live in harmony with their human hosts. When their colonies get wiped out for whatever reason, most people get a bad case of diarrhea. One of the major causes of wholesale death of gut bacterial colonies is use of broad spectrum antibiotics. Think back to all the times you had heavy doses of antibiotics, for whatever reason. As the days of antibiotic therapy went on, I am willing to bet most of you got a case of “the runs”.

A simple way of helping your gut maintain a healthy ecosystem of good bacteria is to use foods that are a good source of probiotics such as yogurt. In recent months yogurt companies have come out with a bewildering array of “probiotic” yogurts. Harvey and I have become fans of “Danactive” and “Activia”. (No, I do not own stock in Dannon - and you are welcome to try other brands that you might find better tasting). The trick is to make sure the yogurt you do eat has “live” bacteria. A decade ago almost none of the national brands had live bacteria and you could get the live bacteria variety only in health food stores. If like me you are willing to go the extra step, you can make your own yogurt. It is not at all hard to do and you can get a good yogurt maker and starter for less than the cost of a family meal at the local McDonald. There are also probiotic capsules you can buy, I think the brand name is “Culturelle”.

Keeping your gut well populated with good bacteria is good for another reason. It is a jungle out there. If there are no good guys occupying all the eco niches available, bad guys can get a toe hold and start capturing more of the available real estate. As anyone who has gone through an infection of C. Diff can vouch, this is one nasty stomach bug that you do not want to encourage. Most of us are infected with C. Diff at some point in our lives (it is transmitted by poor hygiene, water contaminated with human waste etc) and our guts retain a sample of the bacteria. Take away the protective effects of good probiotic bacteria and C. Diff may grab the window of opportunity and flourish. C. Diff infection during stem cell transplant carries a still penalty - it is one of the first bugs that they tested Harvey for. I am happy to report Harvey’s gut is well populated with good bacteria and negative for any nasty C. Diff.

Graft-versus-Host-Disease (GVHD) is one of the most important and negative aspects of stem cell transplants. It is the evil twin of much desired Graft-versus-Leukemia (GVL) that is so important in eradicating remaining traces of cancer. GVHD can take place in many different organs: skin, gut, liver, even the eyes. Typically, gut centered GVHD is the most common, along with skin GVHD. There are many theories about what precipitates GVHD - this is an intensely researched area of research as you can imagine. One of the theories goes like this. During the preconditioning chemotherapy / radiation regimen of the transplant, the gut is stripped clean of its protective probiotic bacterial colonies. This in turn leads to inflammation of the lining of the gut.

Step two, the new graft gets settled down and starts making effector cells such as T-cells. These new T-cells look around, sense the massive danger signals coming in from the inflamed lining of the gut and rush to join the “battle” they think is going on. Problem is, these newly minted T-cells from the newly engrafted stem cells do not quite know how to tell friend from foe. Net result, we have a situation similar to the infamous keystone cops, T-cells firing their ammunition all around without necessarily hitting any bad pathogens. This over-the-top and poorly targeted immune response of the newly minted effector cells (T-cells, NK cells, macrophages etc) causes significant damage to the tissues of the gut, killing many of the cells lining the gut and precipitating gut GVHD. The worse the damage to the cellular lining, the more the inflammatory signals getting out and calling even more troops to the “party”. You get the picture, this is one cascade of events you do not want to trigger.

Since there is not a whole lot you can do about avoiding chemo and radiation prior to transplant, the next best thing you can do is soothe down your gut and resolve any inflammation as early as you can, before the ever so efficient (not!) T-cells decide they need to get involved in the process. Probiotics are an excellent solution. Believe it or not, a recent article and editorial in the ever so professional and ’starchy’ journal “Blood” addressed this very issue in a articles titled “Graft versus Yogurt” and “Let them eat Yogurt”. I believe I reviewed these articles earlier on our website www.clltopics.org , you can look it up by searching for the key word “yogurt” in the search box at the top of the home page.

Making “Raita”

Most Americans are used to eating yogurt that has been sweetened with sugar, fruit or sweeteners. Purists in India would shudder at the concept. Most Indians eat yogurt as a regular part of their diet and kids are fed yogurt even before they become toddlers. I have eaten yogurt all my life, most often just plain. On more special occasions or when I have the time, I make a popular Indian dish called “Raita”. It is very easy to make and I thought I would share the recipe with you.

• Peel, core, de-seed and dice fine a couple of medium sized cucumbers.
• Blend in a quart of yogurt (whole milk variety tastes better, but you can use low fat or fat free if you must).
• Add finely chopped green chili peppers - make it as hot or mild as you wish. I use Jalapeno peppers.
• A generous dash of lemon juice, salt & coarsely ground black pepper to taste, half-cup of chopped fresh cilantro - and you are done.
• Serve chilled. If you wish to make it more festive looking, you can also add grated baby carrots, finely minced sweet onion, finely chopped red bell peppers.

Be well,

Chaya