An evolving view of acute leukemia

A few years ago, I came across a provocative case in The New England Journal of Medicine about a 68-year-old man with FLT3/ITD-positive acute myeloid leukemia.

As the story went, this man was enrolled into a phase 2 study using clofarabine (Clolar, Genzyme) for induction therapy and entered a remission.

In first complete remission, he proceeded to a nonmyeloablative matched sibling allogeneic transplant. Unfortunately, he relapsed a few months after his transplant, but he entered another remission with the use of a hypomethylator [decitabine (Dacogen, Eisai)]. This was accompanied by some graft-versus-host disease (GVHD) and, presumably, some accompanying graft-versus-leukemia effect.

Some months later, he relapsed again but entered another remission with additional decitabine and graft-versus-leukemia.

As one consultant noted: “It sounds as though you have turned acute leukemia into a chronic disease, in which you are balancing GVHD against graft-versus-leukemia and giving the patient chemotherapy that is not terribly toxic, which is resulting in a reasonable quality of life despite persistent leukemia a year and a half after diagnosis.”

William Wood

I remember reading this case study and thinking that this concept of acute leukemia as a chronic disease was tantalizing but unrealistic. Now I am not so sure.

In December, I had the privilege of moderating an oral session at the American Society of Hematology annual meeting in San Diego (I should offer special thanks to the ASH CRTI program for providing me with many valuable professional development opportunities during the past few years).

As an acquaintance joked afterward, this particular oral session gave listeners a “healthy dose of [donor lymphocyte infusion (DLI).”

Indeed, many of the presentations were about immune manipulation for relapsing — or imminently relapsing — disease after allogeneic transplant. One study reported on a protocol of sequential courses of azacitidine (Vidaza, Celgene) and DLIs.

Another described “activated DLI” using interferon before and after DLI administration. Still another discussed “modified DLI” consisting of granulocyte colony-stimulating factor-mobilized donor peripheral blood stem cell (G-PBSC) infusions with additional immunosuppression to mitigate GVHD.

In each, a subset of responders enjoyed prolonged survival, and the overall response rates appeared comparable or superior to historical data. Time will tell if these findings hold up after more rigorous testing, but these types of studies are laying a foundation for how we might try to coax, prod and tweak immune responses — with modest toxicity — to control poor-prognosis AML. Whether or not true “cure” was being achieved for these patients, some, at least, were discovering ways to coexist with their diseases.

Trying to stay ahead

In my own practice, I seem to be accumulating patients who are coming in and out of states of active leukemia, as I try to come up with ways to keep their diseases in enough control to allow another few months until the next treatment decisions must be made. One woman has cytogenetically normal, NPM1-mutated AML. I hoped her disease would “follow the rules” and remain in remission after conventional therapy, but it didn’t. After she relapsed, I initiated a donor search and found a well-matched sibling donor but had trouble getting her disease back into remission.

At first, I tried doing this in more conventional ways, with two typical intensive cytotoxic re-induction courses that proved unsuccessful. Her will to persevere persisted, so I changed course to 10 days of decitabine. This didn’t seem to change too much one way or the other, but her functional status was preserved and another month or two had gone by.

Although the possibility of hospice had entered our discussions, we agreed to try something a little different first, and used a course of azacitidine and lenalidomide (Revlimid, Celgene).

It is still a little too early to tell what ultimate success we’ll have with this, but for the first time in quite a while, her platelet count has started to steadily rise, crossing 60,000.

We know the odds are long, but we’ve gained some months and time to think and decide what to do next, without undue organ toxicity, mucositis or overwhelming fatigue. This has been a small win and, hopefully, an indication of more success to come.

Another patient presented symptomatically a year ago with complex cytogenetic AML, likely arising from myelodysplastic syndrome.

He was treated with 10 days of decitabine initially and entered a complete remission. After two cycles, he elected to stop therapy. His quality of life had only improved since initial diagnosis, and he saw no reason to continue, despite my protests to the contrary.

He continued to enjoy his usual life during the next several months, until his counts started to drift downward and he again become severely pancytopenic. He became convinced, unsurprisingly, that his assessment of his disease had been inaccurate, and this time he agreed to further therapy and began to inquire about a reduced-intensity allogeneic transplant.

Although not optimistic about re-capturing his AML, I restarted decitabine and he again has entered a complete remission with normal peripheral blood counts. We are proceeding with a donor search and are planning to move in this direction if successful. A year has now elapsed since his original diagnosis with high-risk AML, and he has yet to feel much in the way of effects of his disease.

Preserving quality of life

A third patient unfortunately succumbed to this disease after a courageous fight. Among these three patients, his story is probably the most similar to the story referenced in NEJM article.

He was a man in his mid-60s who had been diagnosed with FLT3-positive AML more than 16 months ago and underwent standard induction chemotherapy. This produced typical toxicities, and he developed pulmonary aspergillosis, from which he recovered.

After a course of cytarabine consolidation, he proceeded a year ago to reduced-intensity conditioning allogeneic transplant from an unrelated donor. He tolerated this extremely well, walking more than 70 miles around the bone marrow transplantation unit during his reduced-intensity conditioning transplant.

Unfortunately, just after day 100, he developed frank relapse, with simultaneously falling chimerism and high and rising peripheral blast counts. I treated him with sorafenib (Nexavar, Bayer), which cleared his blasts and restored donor chimerism but left him pancytopenic.

Throughout this, his FLT3-positive clone remained molecularly detectable in the blood and marrow. Nonetheless, he continued to live at home, and although his quality of life was diminished — due in part to some adrenal insufficiency, which improved along with his functional status after daily replacement — he remained out of the hospital.

This persisted for many months while we explored and pursued other potential treatment options, including repeat PBSC infusion. Unfortunately, blasts reappeared in the periphery. This time, we elected for hypomethylator treatment, which again promptly cleared the circulating and marrow blasts, although pancytopenia persisted. We prepared for a G-PBSC infusion, but before additional donor cells could be collected, infection intervened. He was re-admitted to the hospital, where he eventually passed away.

Before he did, though, we were able to bring his infection under control for a period of time. He enjoyed Christmas and New Year’s with family. He made peace with his illness and had further conversations of closure with people he loved. I had hoped things would turn out differently, but in the end, the outcome was peaceful and not unexpected.

I offered hospice and supportive care at many steps along the way. He was clear to me at each of these points that, as long as there were non-futile disease-directed interventions available, he was not ready to abandon active therapy. I told him I would push hard for whatever it was that he wanted, so long as I felt that this would not cause undue toxicity, harm or suffering.

Throughout his course, that is what we did together, and although we were never able to bring his AML under control for more than a few months at a time, he did live 16 months from his diagnosis with FLT3-positive AML, much of it with some preserved quality of life and the continued presence of those he cared about most.

I don’t know that I’m ready yet to call acute leukemia a chronic disease, but the way I am thinking about it is increasingly changing. I am not entirely sure any more what the goals of treatment are in each case and how management strategies should be arranged to achieve these goals.

Is conventional therapy — re-induction after re-induction, escalating doses of highly toxic drugs, re-conditioned second transplants, and using increasingly bigger guns to beat back increasingly stubborn diseases — necessarily the right way to think about AML?

Certainly it may be, for the right patients under the right circumstances. For many, though, perhaps the goal of long-term, continuous complete remission is unlikely — but the careful arrangement of less intensive, targeted or immune-based therapies might prolong life, improve quality and create some chronicity for this acute disease.

William Wood, MD, is assistant professor of medicine in the division of hematology/oncology at the University of North Carolina in Chapel Hill. He may be reached at william_wood@med.unc.edu. Disclosure: Dr. Wood reports no relevant financial disclosures.

For more information:

• Dey BR. N Engl J Med. 2009;361:1099-1106.