Just out of hospital for febrile neutropenia, again

So, I was admitted once again to HUP on Tuesday with a fever to 102.6 and zero (as in none, nil, nada) neutrophils. This was despite getting Neulasta after my #3 dose of CHOP-R. I was surprised since this did not happen after #2 but in the pivotal trial 18% on placebo and 1% on Neulasta had febrile neutropenia (there' s some classic van Saun luck for ya!)
But all went well counts started rising with ANC of 880 on discharge, afebrile and taking today off work to hang out with cousin visiting from Kansas, Pics are from my IV-untethered visit to a delightful patio off the first floor of the Rhoads Pavilion, along Hamilton Walk, and right across the med school library where I last studied in...1974! also my hospital room and me being cheerful! For once ...

This broken great tree and me..

This picture of our tulip poplar, ravaged by winds and rot over the years, but still alive and sprouting new leaves this spring. I definitely identify, we are both hanging on to LIFE!

R-CHOP #3, so far so good

Updating my condition, I got R-CHOP #3 several days ago as Dr Porter was pleased that the lymph node in my neck on the left decreased in size and that my blood counts continue to improve. With a hemoglobin of 11.2 I finally am getting back to normal; it was last at that level in October 2011!  Same with my platelet count up to 190K, it has not been that high probably in 5 years!

Yesterday I got my Neulasta shot, and in corticosteroid induced euphoria I decided to wear my John Lester Red Sox since he was scheduled to pitch last night (he won by the way to go 3-0 and the Sox are leading the AL East as we go into the last week and a half of April)
On the elevator a man my wife thought was a doctor (perhaps by his arrogance) questioned why I was wearing Red Sox jersey, after all this is Philly the home of true sports fanatics.  I explained that Lester was an inspiration to me as a survivor of T cell leukemia, about which said doctor was surprised. See me in my jersey below

Some signs of hope...

So I got my second R-CHOP a week and a half ago, avoided febrile neutropenia so far thanks to Neulasta, and minimal side effects - maybe a little numbing in the feet from vincristine peripheral neuropathy, lower red cells and platelets but not enough to need a transfusion, so far. The only place I could lose hair is with goatee and that is going nowhere (see my mug shot below).

But the really good news is that my quite enlarged lymph nodes are decreased in size, so with a potential 4 more cycles of CHOP-R maybe this presumed transformation can be beaten back.

To sum up the good news, and stealing from Mark Twain, the rumors of my imminent demise (started by knowing too damn much) have been greatly exaggerated....I just freaked out when I saw the Richter's survival curves, but maybe I have the better prognosis large cell lymphoma, the de novo type that is not derived from CLL cells, only time will tell but I feel that I am on a good path!

Why do doctors ignore guidelines

A study presented at the Society of Gynecologic Oncology found that only 37%  of patients with ovarian cancer treated in California from 1999 to 2006 were treated according to guidelines promulgated by the National Comprehensive Cancer Network, a group of 21 academic cancer treatment centers. Showing that the guidelines reflect optimal care, in this study 35% of those who were treated according to the guidelines survived at least 5 years compared to 25% who were not so treated.

There have been other studies showing that doctors do not always follow expert guidelines. In one, a RAND Corporation study found that for a wide variety of medical conditions, only 45% received care consistent with guidelines.

Why do doctors fail to follow guidelines?  As a former practicing pediatrician I believe I can speak to this issue.  Doctors can be stuck in a rut, doing what they always do.  They may not be reading or going to professional meetings to keep up with the latest studies and guidelines. 

The academically based doctors that are real experts in their field may not agree with all the approaches for all of their patients. Since not all guideline recommendations are based on clinical trials but on expert opinion, this is bound to happen .Unfortunately many doctors consider their own experience expertise enough to challenge the guidelines and continue their management the way they have always done it, even if there is good evidence that there are better approaches.

Guidelines regarding management of ear infections in children were promoted in 2004 by the American Academy of Pediatrics that included an option of watchful waiting over immediate antibiotics, a new approach that had I been still in pediatric practice would have been interesting to see how well I myself would have complied to the new recommendations. With parents used to getting antibiotics for their kids' ear infections the observation option with pain control only would be sure to be a hard sell. The guidelines also recommended which antibiotics should be used. A survey of pediatricians in 2006 found that for four common clinical scenarios, based on severity of symptoms and prior antibiotic choice, from 13% to 57% of the respondents agreed with the guidelines.Why such a difference? All these "experts" rejecting the recommendations of the real experts!  One of the treatments was 3 days of an expensive antibiotic shot, sure to be a problem for parents and doctors both. There also was a possibility that the bacteria  that cause ear infections were changing and based on that the antibiotic choices would change.  The authors of the survey also speculate that parental preferences and pharmaceutical company advertising and provision of free antibiotic samples may influence antibiotic choice. 

In a news story on this ovarian cancer study on Boston.com it was noted that another reason patients do not get optimal care is that it only can be given at academic medical centers. Not all patients can afford to travel those distances or have health insurance to cover out of area or network care.  

It is particularly ironic that the news about this ovarian cancer study came out this week as I developed fever and neutropenia due to  CHOP-R and had to be admitted to hospital for IV antibiotics after multiple cultures.  Since I have had febrile neutropenia at least 3 times in the past, after fludarabine, I was not surprised.  Perhaps I should have been surprised that I was not given a granulocyte-colony stimulating factor (G-CSF) like Neulasta or Neupogen after that first day of  chemo. I did get Neulasta after bendamustine treatments in the past.  Having my laptop with me in hospital I looked up the American Society of Clinical Oncology guidelines for using G-CSFs.  This document, published in 2006, recommends using a G-CSF when the risk for febrile neutropenia is over 20%.  The study of  CHOP-R in lymphoma patients found a febrile neutropenia rate of only 18% so my oncology team was not amiss in forgoing using Neulasta on the first cycle. But wait the guidelines also say this:

Certain clinical factors predispose to increased complications from prolonged neutropenia, including: patient age greater than 65 years; poor performance status; previous episodes of FN; extensive prior treatment including large radiation ports; administration of combined chemoradiotherapy; cytopenias due to bone marrow involvement by tumor; poor nutritional status; the presence of open wounds or active infections; more advanced cancer, as well as other serious comorbidities. In such situations, primary prophylaxis with CSF is often appropriate even with regimens with FN rates less than 20%. This was the consensus opinion of the expert committee. Such high-risk patients are most often excluded from clinical trials, and this is not a situation likely to have additional clinical data.

So maybe my past history should have led the team to use Neulasta as I have had febrile neutropenia before but maybe that was not in my record at Penn.Maybe the poor status of my marrow with the prolonged anemia and low platelets, but that was actually improving at the time. So  I am confident my oncology team had the right judgement, but ask myself whether I should have reminded them of my history. If I had received the very expensive Neulasta - $2000-6000 for a single dose(depending on what your oncologist can charge your insurance)  - it would have prevented a much more expensive hospitalization. Oh well, water under the bridge.

How I plan to cope with my new prognosis...

See this entry in my less-used blog, the Friendly Curmudgeon, my random thoughts on my spirtiual path, primarily Quaker (Religious Society of Friends).

Richter's syndrome (My luck may just be running out)

I say this because my oncology team acknowledged that I do probably have Richter's transformation, based on the clinical presentation of a rapidly growing local node area while the leukemia seems to be under control elsewhere (other nodes OK, marrow improving) and increased blood levels of LDH (I finally stopped denying this possibility and actually inquired as to my blood levels of said biomarker).

For friends and family who don't want to wade through a lot of the technical stuff I posted below, see this excellent summary for layfolk of the condition by a CLL expert, Dr Sharman. This summary does not however tell the story like the following dismal graphic (click to enlarge fo easier viewing) from a large series of Richter's patients:

(note very little differences between whole group and those treated in fall off of survival)

What follows in this post is more science for those interested; I do it to keep my head straight. But I may not have much time left on this planet now and need to get right spiritually and emotionally. I plan a future post on this as have given this much thought of late....

Most all of the transformations in Richter's are to diffuse large B-cell lymphoma (DLBCL). Rarely there can be Hodgkin's lymphoma, accelerated CLL or prolymphocytic transformation.  For me there is no evidence for the latter 2 conditions, and I guess biopsy is the only way to rule out the odd Hodgkin's, probably also the response to chemo selected.

Looking over recent reviews on this condition, my future is definitely uncertain, the survival rate is not good for most of those who develop Richter's, the 80% of that come from what is called clonal evolution of one's CLL cells, by repeated mutation, a very bad one being a mutated p53, which is a tumor suppressor (read more here, warning quite technical) when it is normal, otherwise, with many types of mutations, the tumors go wild...

In the other 20% the DLBCL develops de novo as a secondary cancer. See an image which explains the different types (ignore the verbiage re mutated IgG status, too technical for this discussion, but if you are game this image is from this article)

The difference in prognosis between these two types of transformation is significant. In one recent article the median survival for those with de novo lymphoma was reported to be 62.5 months vs 14.2 months in those with clonal transformation. Unfortunately there is no commonly used clinically available test to differentiate the two types.

So what about treatment, then? Standard of care seems to be CHOP=R which if reasonably successful can be followed by stem cell transplant. Here is a summary from a state of the art article on CLL:

Management of Richter’s  syndrome  therefore  remains  unsatisfactory with overall response rates of around 34% using CHOP or platinum containing chemotherapy, and 47% using rituximab-containing regimen. The mean overall survival is around 8 months from end of treatment

Here are more survival curves from a large MD Anderson series:

Using a score derived from patient and tumor characteristics, from what I can tell I score a 3, see this dismal curve:

A little  better prognosis in Richter's was reported at ASH 2011 by a European group, with 15 patients treated with CHOP-R in a Phase 2 truak, there was a 67% overall response rate, a 15 month median progression-free survival and a 27 month  median overall survival


and this one looks better for those who respond to chemo and get transplant, albeit just 7 patients:

So time will tell, issues to be discussed with my onco team in the coming weeks include the following: do I need a biopsy to definitely prove diagnosis, how many cycles of CHOP-R, should we continue to pursue the viability of transplant with the two possible unrelated donors that were found on the registry match t.and again what about my trying CAR-T if the cells can be found to express CD19 and they can grow sufficient T cells?

Some links to pdfs of key Richter's articles, including a recent review and an earlier publication of  the MD Anderson experience:

Jain, O'Brien, 2012. Richter's Transformation in Chronic Lymphocytic Leukemia [most current review]

Tsimberidou, et al 2006.  Clinical Outcomes and Prognostic Factors in Patients
With Richter’s Syndrome Treated With Chemotherapy or Chemoimmunotherapy With or Without Stem-Cell Transplantation [MD Anderson experience]


Rossi et al , 2011. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation [all about p53 and survival differences]

Probably more to come when I find them....need to do this medical-intellectual exercise as I put off really thinking about my demise....