#6 - Unintuitive treatments for AML
Though AML remains difficult to treat, old-new approaches may unlock new possibilities in service of patients.
Today, April 21st, is world Acute Myeloid Leukemia (AML) awareness day. AML is an aggressive disease of myeloid cells which are critical to proper blood function. Leukemia cells, which get locked into an immature, non-functional and proliferative state, begin to crowd out normal functioning cells, lowering normal red blood and immune cell levels. Patients have difficulty breathing, they get night sweats, they bruise spontaneously, get back pain, and their immune responses against infections become increasingly impaired and ultimately fatal.
Acute Myeloid Leukemia - Treatment Options
AML remains extremely difficult to treat; the disease is often refractory to the armamentarium of medicines, despite their potent toxicity. A frontline (induction) week-long treatment is known as high dose 7+3, an intense chemotherapy regimen that leaves the heart wounded, requires multiple blood transfusions and risk of secondary cancers due to DNA damage. After induction, patients are re-evaluated via biopsy, which requires a hole being drilled through your bone to clip out marrow. The levels of leukemia are then measured and if they’re lucky, they are in complete remission (CR). CR means that the level of leukemic blasts are low enough such that a pathologist is unable to find them. From here patients are typically offered choices:
3-4 additional cycles of consolidation chemotherapy, each the duration of a lunar period with the goal of threading a needle between poisoning the leukemia while the body tolerates.
A complete reset of the blood through a process called an allogeneic, or donor derived, bone marrow transplant (BMT and sometimes known as stem cell transplant). Pioneered by Nobel Laureate, E Donall Thomas, his wife Dottie, and colleagues at the Hutch, BMT also involves intensive chemotherapy, sometimes alongside total body irradiation to eradicate a patient’s hematopoietic stem cell compartment, system required to make all blood cells. A donor stem cell transplant, in the past, would require the donor to suffer through dozens of holes poked into their hip with thick gauge needles, to harvest cores of marrow. Today, following a a dose of filgrastim to mobilize stem cells into the blood, a donor hooked up to an aphereis machine, which takes out the stem cells and returns plasma and other blood back to the donor, over a roughly four hour period. The stem cells are collected in an IV bag and the graft, which looks like a reddish, thick slurry of poorly dissolved tang, is directly infused into the patient without any additional modifications.
Kim’s stem cell transplant, from her sister, infused into her central line.
Despite these bellicose treatments, roughly one in two of patients survive five years past the initial diagnosis. Furthermore, because AML on average tends to impact older patients, who have fragile blood systems, these harsh treatments are not used on them because of the high risk of toxicity and death. Fortunately there are other options, including some novel targeted treatments. But those too are limited to those, whose leukemia, harbors specific genetic targets. We’ll tackle some of those in a future post, especially regarding certain mutations in IDH1 or DNMT3A.
Hope is the thing with feathers
“Hope” is the thing with feathers - That perches in the soul - And sings the tune without the words - And never stops - at all - And sweetest - in the Gale - is heard - And sore must be the storm - That could abash the little Bird That kept so many warm - I’ve heard it in the chillest land - And on the strangest Sea - Yet - never - in Extremity, It asked a crumb - of me. - Emily Dickinson
There have been some recent advances that give hope though. Out of all available treatments, generally, BMT is considered the only curative option. Undergoing BMT is no easy process. It is a harrowing journey with multiple challenges; one must ensure that a donor’s graft is compatible with the patient’s tissues, mediated by cell surface markers called human leukocyte antigens (HLA). Unmatched transplants lead to a deadly toxicity called graft versus host disease (GvHD) where the immune cells from the graft attack the patient’s bodies. The preparatory, or conditioning, treatment regimens, called myeloablation, wipe out the blood compartment and is incredibly painful and debilitating, causing sloughing of the mucosal lining in the mouth, throat and gastrointestinal system. The transplant recipient is suffocated, stripped of oxygen transporting red blood cells, and becomes immune incompetent, increasing the likelihood of a fatal infection. Post transplant, acute and chronic GvHD affects half of patients, even in the context of fully matched transplants where 10 out of 10 HLA molecules are congruent. This occurs even with the use of immunosuppressants, such as steroids and rapamycin-analog molecules, for months or even years to stave off acute and chronic GvHD.
In a recent article in the Atlantic, Sarah Zhang documents the new use of an old chemotherapy, cyclophosphamide, in a post-BMT setting. Cyclophosphamide, a mustard-like agent, is a chemotherapy widely used in many contexts including in the treatment of cancer and autoimmune diseases, which acts to eliminate certain immune cell subsets, CD8+ killer T-cells, that are responsible for GvHD. For reasons, not completely understood, cyclophosphamide spares other immune cells, including a population of wound healing immune cells, called regulatory T-cells, which aid in the establishment of tolerance between graft and host. Use of cyclophosphamide seemed like a strong candidate as an additional tool to mediate GvHD. But the use of chemotherapy after donor cells were infused seemed counterintuitive and ridiculous; why would one use a cell killing chemical right after introducing a precious life saving graft? For some reason it works, and works well. And after decades of research, initiated by researchers at Johns Hopkins, Post Transplant Cyclophosphamide (PTCy) has become a de rigeur treatment in BMT settings.
PTCy shows nearly a 50% improvement in relapse-free survival
Unexpected benefits and unlocking new opportunities
While patients are benefiting from this use case of cyclophosphamide, there are add-on benefits that were further unexpected. In the past, partial HLA matches between donors and recipients, or haploidentical BMTs, were rarely used due to the fear of more frequent and more intense GvHD. Thus BMT wasn’t extremely common because full matches were rare, even among siblings, and the premier BMT donor registry, had trouble finding matches for non-Caucasian patients. With researchers demonstrating “that haploBMT with PTCy after myeloablative conditioning is safe and efficacious for adult and pediatric patients with hematologic malignancies,” researchers greatly expanded the patient population for BMT including:
Pediatric patients: parents are always haploidentical and can now act as transplant donors to their children
Patients without full matches: the odds of finding a haploidentical donor is significantly higher, especially for patients whose ethnicities are under-represented in the donor registries.
Older patients: though there are still challenges in treating patients over 70, lower risk of GvHD makes this an option
There is one more potential advantage. The rationale behind BMT is that another person’s immune system recognizes the patient’s leukemia as foreign and attacks the cancer in a process known as Graft vs Leukemia (GvL). While the data is still inconclusive, haploidentical BMT, in theory, can induce stronger GvL, potentially preventing relapses and driving better outcomes. More research will be required to validate this, or optimize this, but with relapse rates from BMT at roughly 50%, improvements in efficacy are still needed. My friend, and Chimera co-founder, Gus remains in remission from MDS after 11 years, following BMT, with PTCy incidentally, thanks to Bart Scott. And Kim, who relapsed in less than 100 days post-BMT, is no longer here. This is the stark arithmetic of leukemia and what limitations BMT still faces today.
The story of PTCy is hopeful, innovative and counterintuitive. Who would’ve thought that the repurposing of an old chemotherapy could democratize BMT as a treatment, and in doing so, improve outcomes and dignity for patients, by ameliorating the side effects of GvHD? Years ago, when I asked Carl June, godfather of CAR-T, what he was most excited about in the field of medicine, it wasn’t new T-cell therapies, or CRISPR, or other advanced therapeutic technologies. He simply stated “PTCy, post transplant cyclophosphamide.” I was floored; but as a trained transplanter he could anticipate the panoply of positive benefits if you could dramatically reduced the impact of GvHD.
As I reflect on the treatment options for AML, today, I am cautiously optimistic about options for patients. My friend, and former SAMO high school wrestling captain, Brian Garrison, has concentrated his development efforts in cell therapies against AML. Gus and I have focused our efforts on CAR-T against AML targeting novel, blast restricted glycotopes, as opposed to the typical CD33, CD123 or WT-1 targets. But PTCy is already here and it’s making a huge difference. And looking forward, I expect it to help unlock these new therapeutic modalities that many of us are working on, with a chemical that is almost a century old.
Post Script on BMT - Orca Bio “supergrafts”
My friend Ivan Dimov runs Orca Bio, which applies a proprietary cell sorting technology, to achieve something similar to PTCy. They create, what they used to call “supergrafts," now called Designer Immune Systems. Using their technology, they can take a BMT graft, and use their tech to eliminate, or add, certain cell subsets to optimize GvL and limit GvHD. The results have been amazing: high overall survival, reduced intensity conditioning regimens, low incidents of GvHD without PTCy and applicability to haploidentical matched recipients and older patients. Their take on engineering BMT, while different from the use of PTCy, is an elegant and customizable one that promises to give alternatives to patients. And I am hopeful that as they continue to learn more about designing immune systems, they can engineer BMTs to be safer, more effective and ultimately dignifying.