At least what we’re seeing here is nothing out of the ordinary: during a Vidaza cycle, all of Beth’s blood levels get eaten up. Note that her White Blood Cells level on 9/26 is listed as a “critical result” – and the platelets are not far behind, I’m sure.
The good news is that her “blasts” level has been at 0% for a while. That’s fantastic. Also, her neutrophils are back up, and in conjunction with some things called “Bands” (which I have not been showing all along), things could be better but they are still ok.
I wrote to Dr. Rossetti: “Beth has been feeling some of the symptoms of low hemoglobin – tired, body aches, light headed. We thought this might be some of the effects of the Vidaza, (she had her last injections yesterday), but maybe not. All in all, she had a pretty good weekend, despite that she was in the middle of a Vidaza cycle. But we can tell when she’s getting ‘low’ because it’s a big effort for her just to get through taking a shower in the morning.”
He noted that “these types of disorders can be exceedingly difficult to cope with…especially in younger patients”. He also reminded me of both “the magnitude of the disease” and also “the curative goal of transplant.”
That is, she’s going to feel crappy. She’s got leukemia which is eating up her blood. But on the positive side, there is great hope that she can be cured of all this. We just need to sit tight.
We have an appointment at 1:45 today with Dr. Rossetti, our usual monthly appointment with him. My hope is that we’ll hear some good news about a donor, and possibly a schedule for the transplant. So today I’ll go in and work from about 6 am till 10 am, and then take Beth to her Vidaza treatment at 11:30, and then out to West Penn.
One of the women I work with has a mother-in-law who has had a mild, chronic version of leukemia since 1988. Over the years, she had no treatment at all for it; now she is in her 70’s and it has increased a bit and so now they’re bringing her in for chemo.
The danger always is that these “pre-leukemias” (MDS, CMML, etc.) will progress to AML (“acute myeloid leukemia”). That’s when it’s really aggressive.
Beth has gone the other way. They’ve beaten down her leukemia function, but in the process they’ve seemingly hollowed her out as well. She had some difficulty walking up the three steps to our bridge last night. She has 20% bone marrow, instead of the usual 50%. And all her other blood levels are just bumping along at a very low rate.
When I first started reading about Vidaza, I was under the impression that “The expectation is that the Vidaza will reduce her overall ‘risk level’ and strengthen her body for ‘conditioning’, which will kill most if not all of the cancer-causing function”, as I wrote at the time.
In a randomized controlled trial comparing azacitidine to supportive treatment of MDS, around 16% of people receiving the drug had a complete or partial response—blood cell counts and bone marrow morphology returning to normal—and 2/3 patients who required blood transfusions before the study no longer needed them after receiving azacitidine (emphasis added).
So Beth is not among those who has not needed the transfusions. She’s needed them. The Vidaza is killing the cancer-causing function, but on the other hand, it doesn’t seem to be strengthening her at all.
We learned a few things in our appointment with Dr. Jalil yesterday, though I’m not certain I understand it all. Dr. Jalil’s is where Bethany has been getting her Vidaza treatments. He had received a copy of Bethany’s bone marrow biopsy results, but he hadn’t had a chance to read them closely yet.
We did learn a few things. Large, trendy things, I guess you could say.
First is that the treatment seems to be working effectively. “As expected”. That is, while we have been watching Bethany’s blood levels go up and down, the general trend is that almost everything is going down.
Early bone marrow biopsies showed her being “hypercellular” – that is, her bone marrow was marked by extra tissue, and even some scar tissue. Now she is at about a 20% level of bone marrow. That is, yes, very low. Explanation: “the medication is controlling the disease”. (Blasts and monocytes, in aggressive leukemia, would tend to build up. That Bethany’s is so well cleared out is seen to be a good thing.)
For example, in an early biopsy, her blast counts were 10-15%; now they are 4%. Normal folks are at 5% blasts in their bone marrow (blasts are “baby blood cells” that grow up and differentiate. In aggressive leukemia, the blast number tends to exceed 20% to 30%, and they really “gum up the works”. So this level is good).
Beth’s monocytes are still hovering around the 10% level. That they have not gone higher is a positive thing. (They could have moved from 10% to 20%, but they didn’t.)
In short, the treatment kills both bad cells and good cells. And we have seen some good cell production in this.
Finally, I saw something I had noted in all of my poking around to learn things about CMML. I emailed Dr. Rossetti about it:
I believe I saw that Beth’s condition, once “dysplastic”, now more exhibited the “myeloproliferative” characteristics. Without knowing exactly what that means, I want to point you to this recent study (again, with the low number of patients from CMML), in a school of thought that may or may not be well accepted, that the shift from myelodysplastic to myeloproliferative properties is really a progression of the disease.
I realize that we are dealing with some pretty nasty stuff — it’s not quite AML, and the low numbers of blasts and other numbers are good. But I hope you can put this into context for us.
And he responded:
The two variants remain largely distinguished by the height of the white count. Beth’s white count is well controlled and her marrow is actually exhibiting lower cellularity than before. Thus, on a clinical basis, I do not think she is transforming.
While there are emerging data suggesting a continuum, this does not seem to be universal. At her young age, I would be inclined to the same treatment either way: first an MTI [methyltransferase inhibitor – Vidaza], then transplant. If at anytime we see evidence of progression, we may consider chemo. At present, I like where we are headed.
The good thing, then: there is no “progression”. Dr. Jalil summed it up: “We want to see the least number of bad cells.” That, he suggested, was the definition of healthy marrow. Even if it’s only at a 20% level.
In a recent review of 50 allogeneic transplantations for CMML (i.e., median age 44, age range 19–61 years) from related (n = 43) or unrelated (n = 7) donors, the 5-year-estimated overall survival was 21%. The 5-year estimated probability of relapse was 49%. The data showed a trend for a lower relapse probability of acute graft versus host disease grade II through grade IV and for a higher relapse rate in patients with T cell-depleted grafts, suggesting a graft-versus-CMML effect. This latter series represents the largest cohort of patients with adult CMML and allogeneic stem cell transplantation to date.
The clinical course of chronic myelomonocytic leukemia (CMML) is extremely variable, and disease progression can occur at any time from diagnosis. Median survival is about 20 months. About 20% of patients develop acute myeloid leukaemia (AML). Multivariate analyses performed by several groups showed that elevated medullary blast count, low haemoglobin, elevated serum lactate dehydrogenase (LDH), and perhaps an increased lymphocyte count, are the most important independent prognostic parameters
CMML is an uncommon clonal disorder of the bone marrow that has been classified as a myelodysplastic/myeloproliferative (MDS/MPS) according to WHO classification given its heterogeneous clinical, hematological and morphologic features.2 The median survival in CMML is 18 to 20 months from diagnosis. Subset analysis on patients diagnosed with CMML from existing decitabine [similar to Vidaza] trials has offered invaluable insight on the management of a disease that is difficult to treat as there are few studies to date that study CMML alone. The experience with decitabine in CMML was demonstrated in three open-label and single-arm multicenter Phase II studies and a multicenter Phase III study retrospectively reviewed by Wijermans et al. Overall, results from those 4 studies demonstrated an ORR of 26% (10% CR + 16% PR), a HI of 19%, a median of 15-month survival from initial decitabine treatment (95% CI, 8 to 22 months), and a 2-year survival of 25%. In the trial conducted by Aribi et al to evaluate the activity of decitabine in patients diagnosed with CMML, 19 patients with CMML were given 1 of 3 schedules of decitabine with total dose per course of 100 mg/m2.34 The study design dictated repeated courses every 4 weeks for a minimum of 3 courses without dose escalations. Results demonstrated an ORR of 68%, a CR of 58%, a HI of 11%, and a 2-year survival rate of 48%. Patients were exposed to a median of 9 courses of decitabine. Larger randomized trials featuring patients with CMML are needed to further establish the potential of decitabine for this difficult to treat disease.
Today Beth has another bone marrow biopsy. Dr. Rossetti says this is just simply a matter of routine. The timing of it leads me to believe also that it will provide information that will help in some way as they select a marrow donor. We should know more about the donor selection, too.
In all, things should be moving into the next phase quickly, I would think. The most difficult thing about all this is the waiting. But of course, it is going to be a long haul, and we’re going to end up doing a lot of waiting.
We are due to be at West Penn at 8:00 am, which means leaving here around 7:00 am. “Nothing by mouth past midnight”. They are going to do this in the recovery room of the West Penn short stay unit, and instead of having the biopsy with just a local anesthetic, which did not seem to help her much with the pain last time, she’ll be under “conscious sedation”. Beth will be taken in at 10:00 am for the biopsy. I will probably miss a whole day at work.
Not long after I sent out my news release, we were contacted by Bill Zlatos, a reporter from the Pittsburgh Tribune Review. Bill has been talking with Beth quite extensively over the last couple of weeks, and he’s planning to do a fairly significant story on her, her military experience, and of course, the notorious burn pits.
Beth had a good weekend – she seemed to be feeling pretty good and even energetic, although we limited our activities to TV, reading, and church. We’re noticing a pattern. On the weeks when Beth is getting her Vidaza treatment, and the following week, she is tired, wrung-out, achy, and her blood levels seem to go down. We don’t have any blood numbers for the most recent week (week 3 of the cycle), but she seemed to feel better this past weekend.
Wednesday we’re going to go down to the VA to get a photograph for Beth’s ID card, and then we’ll head out to West Penn hospital for another bone marrow biopsy. We’ve been told by the doctor that it is “a matter of routine” to have one of these after three or four rounds of Vidaza. “This way we have a better sense of how things are progressing.” He also says, “Based on the counts, I suspect we are in a good place.”
Beth has had two such operations, and both have been painful for her. After all, they are breaking into a bone. The doctor also says she will be able to do this procedure “under conscious sedation” – which will help ease the pain for her, moreso than just the local anesthesia she received the last two times.
Over the last couple of days, I’ve been going in to work from 5:00 am till 9:00 am, to get in four hours, before leaving to take Beth to her Vidaza treatments and doctor’s appointments. Wednesday and Thursday she will only have Vidaza treatments, so I’m going to continue go in and work very early in the morning, then leave to take her to her treatments, and then drop her off at home and go back to work for the afternoon, to get full days in. We’ve had to do it this way because all of the older guys started school this week, and I’m trying to take off as little time as possible.
One of my greatest fears is the prospect of taking unpaid time off of work, and thus not having an income during the critical time when Beth is most heavily involved in her transplant process. We learned quite a bit about the transplant procedure and schedule yesterday.
First, there are at least five potential donors who matched on 10 of 10 HLA (DNA) categories. Not all of these are ideal simply because of their age (in their 50’s), but they are continuing to search and there may be more of these folks, as well as some 9 of 10 matches that may be more well suited physically. And again, there needs to be some further testing for all of them. (Apparently in one of the more important categories, Beth has a somewhat rare combination of markers).
Here’s the rough transplant schedule when that occurs:
Daily Outpatient treatment (3 days, -9 to -6, treatment with Kepivance)
Inpatient chemo and radiation, (6 days, -6 to -1, Fludarabine, Busulfan and Thymoglobulin, and two days of total body irradiation).
TRANSPLANT (Day zero)
Daily Outpatient – from approximately days +1 to +30. Daily monitoring (five- to 10-hour stays) at <a href=”http://www.wpaci.org/index.cfm”>West Penn Hospital’s</a>Medical Short Stay (MSS) unit. There is also a 75% chance of an infection that will require a readmission.
Days +31 to +100 – twice-weekly office monitoring.
If there is going to be a relapse, it will most likely occur during the first year after transplant. Two years out from the procedure, the chance of a relapse is minimal (just 1% To 2%). And five years out, that risk is almost nonexistent.
Beth has a roughly 15-20% chance of mortality during this process. In the <a href=”https://johnbugay.wordpress.com/2011/08/23/back-home-from-the-intake-meeting/”> mortality chart provided below</a>, the “immediate complications” include all kinds of infections, as well as acute Graft vs Host (GvH) complications, some of which can be fatal. Some chronic GvH complications can also be fatal, but most are treatable with medications.
The ideal outcome will of course be that Beth can live out a long and healthy life span, with minimal requirements for medications to control GvH symptoms (which can also fade over time).
Early on I told Beth that this was not a disease that she’s temperamentally suited to have. She’s always been more of a person of action: “tell me what to do, and I’ll go and do it.” But there are many uncertainties with this process. Those uncertainties are hard to deal with, but the meetings we had yesterday helped to clear up many questions we’d been having.
Interestingly, Dr. Rossetti is a former Roman Catholic and a convert to Eastern Orthodoxy. We had a bit of a conversation yesterday about church fathers and ancient Rome and T.F. Torrance. Pretty cool.
One of the more vexing issues for us has been the notion (a) that Beth’s levels needed to be under control before the transplant to maximize her chances for success, and (b) the key number that we were watching, the hemoglobin level, was continuing to go down through these treatments.
Yesterday’s intake meeting was an important milestone for us, not least because I accidentally stumbled upon a chart that contained all of Beth’s blood numbers, not just one day at a time, but in chart form. Dr. Jalil had one of these charts for roughly the period in July and early August, and Dr. Rossetti graciously had one printed for me with the most current numbers.
These charts had some numbers that I had simply not seen before, because I was asking the various office staffs to send the individual blood numbers, and I wasn’t always receiving them.
I’ve updated and reproduced the chart here, using some of the missing numbers and there are some really important things to note. First, look at the Blasts level. In July, they went way up, after the first cycle of Vidaza. We hadn’t seen this. And after the second cycle of Vidaza they went down to zero. That’s a critical level, because these are the cancer cells. Note also, the Blasts level went up a bit later in August as well. But after this cycle of Vidaza, I think we can expect to see some more zeroes.
Note too, the Hemoglobin levels went up just a bit between August 11 and August 15. That small rise was attributable not to a transfusion, but just to her own system raising her hemoglobin level. In fact, she may not have required a transfusion after August 11 (on August 18), given that level of 8.7 on August 15, but she got one anyway.
Her White Blood Cells, Platelets, and Neutrophils (especially these) are seeming to moderate, closer to the normal range over time. This is exclusively a function of the Vidaza.
So while we had been looking at just one number, Hemoglobin, and not seeing much progress there, the doctors had been looking at some of the other numbers, and that whole picture was a much more hopeful one.
Beth immediately responded to the Vidaza today, in a negative way. After two transfusions in recent weeks, she has been feeling about as well as she has felt in months, over the last few days. However, the Vidaza treatment reminds her that it really is a kind of “chemotherapy,” and the “cytotoxic” effect just knocks her on her butt. Back again are the diarrhea and the body aches and the desire to sleep all the time.
Yet the other thing that Vidaza does is to “change the genes” in the blood cells. Enables the blasts — “baby” undifferentiated blood cells — to differentiate and become normal healthy cells.
There are three major cell lines in your blood: red (hemoglobin), white, and platelets. Beth’s red blood cells are consistently low and they don’t seem to be responding. White counts and platelet counts are low but holding steady. This is one of the good effects of the Vidaza. Neutrophils (white cells) are low but holding steady. Monocytes (another white cell) are high. That’s one of the reasons why this is “chronic myelomonocytic leukemia” (CMML).
The intention is to have her bone marrow in as good a shape as possible in preparation for the transplant. Dr. Jalil said yesterday he wishes her hemoglobin would have shown some signs of recovery by now. But, he says, “after only two treatments, things look good.” If her hemoglobin still was not responding after three, four, five treatments, “we would be a little worried”.
What if it doesn’t respond this time? He says they’ll still go ahead with the transplant. My sense is that it’s the only real option. If she were 75 years old, they’d continue with the Vidaza and blood transfusions so long as they made her comfortable. But the prognosis for this disease is not a good one. They’ll want to do the transplant, to wipe the slate clean anyway.
We’ll find out more about that at the intake meeting today.
It’s going to be a busy week for us. Beth has a doctor’s appointment today and our big “intake meeting” with the transplant folks tomorrow. I expect that we’ll learn what treatment is going to be like for the coming months, the status or our donor search, maybe get some clarifications on the diagnosis and prognosis, and a lot more. Meanwhile, Beth begins Vidaza, Cycle 3 this week as well.
Beth had a pretty good weekend; we visited my cousin Walt, who is also a veteran; he recently had heart bypass surgery, and he gave us a pretty good report about how to navigate the VA system. There’s one difference: he’s a Vietnam veteran, and much of what the VA will cover from that conflict is settled; we are still waiting on a study by the VA on the topic of the “Long-term Health Consequences of Exposure to Burn Pits in Iraq and Afghanistan”. Stay tuned.
The car situation is going to be much complicated from here out, as the older guys start school today; two of them will begin the CCAC Nursing School program, and a third is starting general studies there as well. There are five of us going different places, and three cars. The younger kids start school next week. Fortunately, recent changes in the school bus schedules don’t seem to have affected us.