Dear Dr. Chee,
Thank you so much for sharing your life's battle with us in your amazing book. I downloaded it yesterday and am now all the way to chapter 9. Ever since January of this year, I had begun to hope and believe that my 7 yr-old daughter's immune system would one day eradicate her biphenotypic leukemia (ALL+AML expressed in each blast). Your book quickly confirmed and helped solidify this assertion. I am confident that her cure will come through immunotherapy. (The clinical advice is to achieve remission and head straight for a second bone marrow transplant.)
I have a connection at BMS that is working to help get us either Yervoy or Opdivo. Until then, we need to "buy some time." We recently finished a course of medium intensity Mylotarg w/Cytarabine and there's now only one very small lung nodule left and her bone marrow has 0.09% blasts. (She used to be "chock full" of tumors with 40% blasts in the peripheral blood.) By Friday of this week, we need to decide whether to repeat Mylotarg, this time with a hi intensity backbone of fludarabine and cytarabine, or to give Venetoclax a try, which is a BCL-2 inhibitor.
If all roads (hopefully) lead to PD-1 inhibitor or CTLA-4 inhibitor, or even Notch-1 inhibitor (our daughter has the Notch-1 mutation), I'm wondering what you would recommend between these two current options. Or, do you have any other recommendation?
Our problem with high intensity Mylotarg is that it would cripple her immune system and leave her vulnerable to infection - a 60% likelihood. I feel that this is dangerous because if we do get past that round and end up receiving immunotherapy, we want her immune function to be strong rather than traumatized, right? The upside to high intensity chemo is that it should keep the disease at bay and prevent relapse in the CNS and skin. (Ava originally relapsed after transplant in the skin, and just more recently in the CNS. But all of it has cleared after total skin electron therapy and further chemo.)
Our concern with Venetoclax is that she would be only the 2nd child to have received it, and we are uncertain of the efficacy since there is no pediatric data. Clinical trials are set to begin in the 4th quarter. I understand from mouse models that Venetoclax does not cross the blood brain barrier. So if it the treatment is ineffective, she might be vulnerable to CNS or even skin relapse, both of which have been very difficult to deal with.
The compromise to either option would be to use Mylotarg with a lighter backbone such as Azacitidine, or if we go with Venetoclax, then to give her a dose of intrathecal chemo during the round.
I hope to finish your book by tomorrow, which will give me so many more insights. In the meantime, thank you so much for creating this forum for us!
So blessed by your unstoppable courage and impeccable work,
Mike
Hi Mike,
We’re so sorry that Ava has had a difficult battle.
If your goal is to get PD1 or CTLA4, and your treatment decision is at hand, “buying time” for paperwork may not be necessary.
Checkpoint inhibitors can be gotten immediately, off-label, from any physician willing to prescribe it. (Since these immunotherapies are already FDA-approved for other cancers.) As we describe in the book, many larger clinics charge an exorbitant markup (400%). But there are doctors who will provide the drug at cost—no wait for paperwork from companies necessary. The cost price for PD-1 inhibitors ranges around $5-12K per treatment the last time we checked (it’s been a while). Expensive, but doable.
The ability of Mylotarg/Cytarabine to shrink those “chock full” of tumors is not to be taken lightly. Sounds like Ava’s doctor sees an opportunity to hit the disease with a 2nd BMT while the tumor load is at a minimum.
A thought: If they are looking to follow with a 2nd BMT, it suggests Mylotarg/Cytarabine is non-curative? Secondly, what is the evidence that a 2nd BMT can cure?
Ava’s situation sounds somewhat similar to Mary’s (the lymphoma patient we discuss in the book). Mary’s disease was refractory to multiple regimens including a first BMT. Those foretold the likelihood of failure of her 2nd BMT.
The decision to choose PD1/CTLA4 versus BMT+other cytoreductive drugs is challenging, especially when the data is unclear. As you’ve seen from our book, we strive to be as data driven as possible, leveraging whatever imperfect data that may exist.
For example, is there any data on the curative potential of refractory ALL+AML? If such data suggests a low potential, we might choose immunotherapy instead.
Another thought: We, too, would tread carefully with Venetoclax, especially if they haven’t used it in pediatric patients much. Again, the question we’d focus on is what is the evidence of curative potential? If there is strong evidence it can cure—perhaps combined with mylotarg/BMT, then we might consider it. But if the evidence is weak, we might be inclined to take the immunotherapy route.
In summary, the main focus in this situation is get as much data about the curative potential of these powerful cytotoxics/BMT. Lack of such evidence would tilt us towards immunotherapy, especially given the strong success of PD-1/CAR-T in blood cancers.
Have you or doctor discussed PD-1 or CAR-T clinical trials? You can look up clinicaltrials.gov and contact the trial coordinator even if the trial doesn’t seem to be a perfect fit. Sometimes they can make exceptions for patients even if the inclusion/exclusion criteria don’t perfectly match.
Also, CRI’s website is a great resource:
http://www.cancerresearch.org/cancer-immunotherapy/impacting-all-cancers...
We’ll continue to think about Ava’s situation, what we’d do if it were our own daughter. But we wanted to reply to your post quickly as it sounds like a decision is impending.
Hang in there,
Eddy and Rene
Hi Eddy and Rene,
We are about to ask Ava's doctor about prescribing PD-1. Since we do not know what he will say, we want to be prepared to look elsewhere. Do you have any recommendations for doctors who will prescribe? Do we face further issues because it's for pediatric? Getting the inhibitor off label immediately sounds amazing otherwise. Thank you for the per dose price range from awhile back. How many doses are typically needed for a 17kg 7-yr-old?
Regarding Mylotarg/Cytarabine as being non-curative, you are correct. For Ava's physicians, all hope for cure rests in the 2nd BMT. The prognoses, however, has decreased by more than half. So we're down to less than 20% statistically for success.
I asked our doctor about the clinical trial https://clinicaltrials.gov/ct2/show/NCT02275533 and he said it was open to ages 18+. He also said there that there is no pediatric data for Opdivo, and that " the drug is not available at the current time. It would take a great deal of time to find out if we could get it." This makes me wonder if getting PD-1 with his help will be problematic.
Thank you so much for such a quick reply. We'll keep you posted!
Mike
One more thought/question:
Biphenotypic seems to be a rare cancer, at 5% of ALL cases.
For rare cancers, second, third or even fourth opinions are important, given the lack of data.
Is Ava being currently seen at an academic center? Hopefully she is. Even so, it is valuable to consider consulting at one of the major blood cancer centers in the country for additional opinions. (MD Anderson, Memorial Sloan, Dana Farber, Fred Hutchinson.
Yes, we are at Fred Hutchinson. We've also consulted with Dana Farber, St. Jude's, and a little with Memorial Sloan. All have recommended 2nd BMT. But I really want to pursue immunotherapy. For pediatrics, there still seem to be many hurdles due to the rarity of Biphenotypic.
On the one hand, having 3 different centers recommend a second BMT bears careful consideration. If they all asserted a chance of with the second BMT, and they had data to back it up, then we'd seriously consider it.
You mention a 20% chance. Although lowish, that number would offer hope, assuming it is based on solid data.
In Rene's case, we were told 20% curative potential with surgery. However, upon careful examination, we found that the 20 percent odds could not be corroborated. The leading surgeon at MSKCC said my disease was incurable, going to great lengths to explain the details. Likewise, the survival curve (in chapter 3) implied all patients in my situation would die.
So, again, it boils down to getting as clear a picture of the data—a clear understanding of what these 3 centers have advised, and whether these were recommendations made based on the idea that "there really isn't anything else, so why not" as opposed to "there is clear and verifiable data" that strongly shows a cure is indeed possible with a second BMT.
As for clinical trials for pediatric patients, it's good to focus on pediatric centers such as CHOP (Children's hospital of Philadelphia).
CRI's website lists various pediatric immunotherapy trials:
http://www.cancerresearch.org/cancer-immunotherapy/impacting-all-cancers...
Seattle Children’s Hospital is enrolling pediatric patients with CD19-positive leukemia (NCT02028455).
Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute are enrolling pediatric and young adult patients with relapsed ALL (NCT01860937, NCT01430390).
Baylor College of Medicine is enrolling both adult and pediatric patients with CLL and ALL (NCT01853631, NCT02050347).
University College London is enrolling pediatric and young adult patients with ALL (NCT02443831, NCT02808442).
Children’s Hospital of Philadelphia is enrolling pediatric and young adult patients with ALL (NCT02650414).
City of Hope, Children’s Hospital Los Angeles, Children’s Hospital of Orange County, and Children’s Hospital Colorado are enrolling pediatric and adolescents with ALL (NCT02625480).
The University of Texas MD Anderson Cancer Center is enrolling adult and pediatric patients with ALL or CLL (NCT02529813).
Also, how about CAR-T? Has Ava's cancer been tested for CD-19?
For example, Seattle Children's has this clinical trial:
https://clinicaltrials.gov/show/NCT02028455
Your doctor would probably have tested for this but we never assume so.
I think the 20% curative potential isn't accurate for Ava. While no transplant specialist has told us that her disease is incurable, there is just not enough data on 2nd BMTs for biphenotypic patients. For example, in a subset of around 50 who relapsed after 1st transplant and who went on to attempt a 2nd BMT, only one had this disease type. But with those 50, there was no survival curve I could find. So we have a hard time factoring in all these variables. As BMTs treat various types of blood disorders, perhaps that is the way immunotherapy broadly covers many cancers? There's some hope in that, given the FDA approval even if it's just for one particular type.
But as we consider 2nd BMT, we hope it would be curative but we want to prepare for relapse and hope that by then, immunotherapy would be better understood and available. This is where we wonder about the importance of the graft and its resulting effect on Ava's immune system. Her first transplant was a cord blood transplant, which is considered naive compared to a live donor, whose borrowed immune system is robust after it has taken a few months to properly engraft. For Ava's current immune system, it's now between 2-3 years old and it pains me to wipe it all away. (In fact, it was THE cure for all her life threatening food allergies, and she can now eat ALL the foods she previously could never even touch.)
The other option is haploidentical bone marrow transplant, which is to use a parent as the donor. Recent studies have shown these to be just as effective, from a GVHD (graft vs. host disease) and relapse standpoint, as a matched unrelated donor (which was not available for Ava because no matched donor could be found). Of the haploidentical transplant methods, these are the three most common: t-cell depletion w/CD34+, GCSF w/immunosuppression, and post-transplant cyclophosphamide. To even consider these options would require us to consult outside of Fred Hutch, which we've begun to do. But my concern is how important post-transplant immune function is when it comes to effective immunotherapy. Do we sacrifice relapse potential for immune function? How likely is GVHD to get in the way of qualifying for immunotherapies?
At the present time, here at Seattle we would go for a cord blood transplant that is more mismatched than the first, so as to stimulate more graft vs. leukemia effect. I believe we are in the best care here. I just am not sure whether we should also be trying to lay the groundwork for immunotherapy if/when it becomes available.
Thank you for all those clinical trial links. I will pour through those and ask our doctor about them. Ava didn't qualify for CAR-T on the CD-19 when it came out. I will have to check and see if anything has changed since then.
We hear you about the lack of data. It'll be interesting to know what the success/morbidity/mortality rates for the 50 patients in the study you mentioned, as well as other similar studies. Even though there's no data for biphenotypic, perhaps the data for single-phenotype refractory leukemias may still give a general idea of what to expect.
Yes, we think autoimmune type side effects such as GVHD can complicate/preclude immunotherapy trials or even off-label immunotherapy. That would definitely be something we'd be wary of.
On the other hand, we probably wouldn't worry too much about "wiping away" her existing immune system. We don't have a whole lot of experience with blood cancers. But at a cursory level, we would think that as long as the second BMT engrafts, Ava would have a functioning immune system amenable to immunotherapy.
Furthermore, if pursuing brute-force CAR-T therapies, the "wiping away" could actually be helpful, in theory. There'd be fewer existing T cells to compete for inflammatory cytokines, and also lower probability that her existing immune system will oppose/reject the genetically-modified T cells.
Whether you choose to do immunotherapy right now, or after a second BMT, she would need anti-leukemic T cells for successful PD-1. For that, we would choose to combine PD-1 with a small amount of radiation to an existing tumor (if she has any). This combination was what patient Mary and former president Jimmy Carter received (described in the Introduction and chapter 7). The radiation will help ensure presence of anti-leukemic T cells, without which PD-1 is thought to be impotent.
Finally, one thought to consider in your decision making is the mortality and morbidity rate of the second BMT. Immunotherapies like PD-1 also have their own share of side effects, but the side-effects profile is well documented and generally low. (You can verify this for yourself for peace of mind.)
Overall you seem to be well informed of the various factors and pros/cons of choosing the immunotherapy versus a second BMT. So, whatever path you choose, know that you've made the best possible decision, given the limited data.
How large is the lung nodule? If it's not too large (between 0.5cm to 3cm), the lung nodule can be cryoablated, usually an out-patient procedure. Since the dead tumor is left in the body, it can act as a broad cancer vaccine, generating T cells against all the possible tumor antigens. After the cryoablation, the administration of PD-1 could make the other tumor cells visible to the immune system, causing a systemic immune response against the cancer.