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....

The wild ride continues

As you can see below, the group of nodes on the left side of my neck (on the right by the photo taken with iPhone), there has been rapid growth, with some pain, and my oncology team is now planning on major chemotherapy for this.

There has yet to be any labeling of this a transformation, and maybe that would necessitate a biopsy, but I am to start a course of CHOP-R, which is commonly used in several types of non-Hodgkins lymphoma (NHL) as well as in Richter's transformation of CLL (to diffuse large B cell lymphoma usually). CHOP is

• Cyclophosphamide, an alkylating agent which damages DNA by binding to it and causing cross-links
• Hydroxydaunorubicin (also called doxorubicin or Adriamycin), an intercalating agent which damages DNA by inserting itself between DNA bases
• Oncovin (vincristine), which prevents cells from duplicating by binding to the protein tubulin
• Prednisone or prednisolone, which are corticosteroids. 

R is for rituximab.Here is a further discussion of the CHOP-R regimen, which includes side effects. And here highlighted in yellow are the results of a phase II German study of R-CHOP showing for those fludarabine-resistant (that would be me) about a 50% response and a 27 month median survival.

My morning bus driver had NHL - now probably "cured" as he is more than 5 years out. Today he noted that he lost all his hair including beard and eyebrows with the same regimen. So in discussion with my wife Cynthia I am going to the barber and going back to my bald look (which I daily maintained by shaving before low platelets made me stop) as well as shave the beard patiently grew on the sides, but keep my goatee until the drugs take it away Here are some photos of my curly locks, soon to be gone:

Look for my projected picture (from a year or more ago) of the return of the shaved old man below, hopefully celebrating success with this next therapeutic adventure . But I am nervous about this therapy yet it seems like the best approach for now....and then on to a clinical trial, perhaps with one or more of the new TKIs (see prior post) or the CART pilot if can clear this node. The one assumed inaccuracy in the pic below is I maintained my goatee....only time will tell....

All these tyrosine kinase inhibitors...

....could there be one for me?

Oral drugs that inhibit the tyrosine kinase enzymes that are part of signalling molecules in various cancer cells (as well as normal cells in some cases) are the current rage in oncology drug development. In chronic myelogenous leukemia (CML) treatment has been revolutionized with this approach to inhibiting an abnormal signalling protein that occurs in this type of leukemia. First, the tyrosine kinase inhibitor (TKI) imatinib (Gleevec) was approved in 2001 and then at least 4 more approved in following years, the most recent being ponatinib approved in December 2012.

In CLL there are signalling pathways within the B cell that also have tyrosine kinase proteins for which there have been oral drugs developed. Two are in phase III trials, ibrutinib and idelasib, both of  inhibit signalling proteins in B cell receptor network. The B cell receptor or BCR is an antibody like molecule that when stimulated leads to B cell multiplication, OK for normal B cells, bad when leukemia cells do so. Here is  a very complex diagram of the BCR pathway:

ibrutinib inhibits the BTK protein and idelasib the P13K (see black boxes in diagram above).  
See a video of interview by Dr Brian Koffman, a fellow MD and CLL survivor, of Dr Thomas Kipps about drugs that effect BCR in development for CLL.

Not as far in development is GS-9973 which inhibits the protein SYK (also boxed in above).  There is an intriguing phase II trial that will evaluate the combination of idelasib and GS-9973 that is not yet recruiting patients. The idea of using two inhibitors is clearly aiming for a synergistic effect or perhaps bypassing any mutations in the proteins that would develop during therapy and lead to proteins resistant to one of the drugs.

Another signalling protein network involves apoptosis, or cell death.  The family of proteins to which Bcl-2 belongs inhibit the sequence of signals that lead to apoptosis. See the diagram below, the boxed areas are where Bcl-2 is thought to work on mitochondria, inhibiting the signal that leads to cell death.:

By inhibiting Bcl-2, apoptosis of leukemic cells could proceed. The drug furthest in development is ABT-199 which has had a temporary setback with a suspension of recruitment for early phase trials due to several deaths from tumor lysis syndrome. The company developing the drug, Abbvie, has stated 

"Previous and current trials have shown that dose escalation methods can control tumor lysis syndrome and we have every expectation that the trials will come off of clinical hold and that we will be able to initiate Phase 3 trials in 2013, as planned."

 See the video interview of Dr Kipps on Bcl-2 in CLL. 

So how might one of these drugs help me? Well I am clearly not in remission, the rituximab-high dose methylprednisone only shrinking my quite large left cervical node temporarily. Although I don't have peripheral lymphocytosis and my marrow is recovering with reg(ard to platelets and RBC (see prior posts on this blog), see the ginormous node which continues to increase now only about 9 days after finishing the last cycle of HDMP:

Since my other palpable nodes are not as rapidly growing, I of course worry about Richter's transformation, but I always worry about that. Am getting a CT scan in several weeks to see how nodes are doing internally but if I don't have Richter's  I clearly need more treatment. I am quite interested in the phase II trial of the agents in combination noted above. I plan to email the investigator to inquire as to where the trial is being done, hopefully one will be reasonably close to home. I think since my other option, the CAR T cell study has not been formally offered to me, I have to keep my options open......

My marrow continues to recover!

Great news, Wayne-followers! I saw Dr Porter this week and again my blood counts are improving, with a hemoglobin over 10 for the first time since over a year ago (Halloween 2011) and platelets are stable at 87K. Total white count 2.7 low but at least neither neutropenia nor high lymphocyte counts.

The large lymph node on the left side of my neck did not decrease in size as dramatically as with the last HDMP-Rituxan cycle, but Porter is encouraged that my marrow seems to be coming back even though I still have bulky lymphadenopathy. The balance for future treatment now swings back to the CAR Tcell project, over the transplant option. It would depend on further tests - CT scan and repeat marrow - and if they can harvest adequate T cells from me.

So no transfusions or treatment for now, to get CT scans to check nodes burden internally in a few weeks, and then we'll see...