This article is more than 5 years old. Information may no longer be current.
Toxicity, tradeoffs in the treatment of AML
Click Here to Manage Email Alerts
I’d like to use this column as an opportunity to revisit an earlier discussion about the tradeoffs between anti-leukemic efficacy and treatment-related toxicity when considering conditioning regimen intensity for acute myeloid leukemia. This dilemma came to mind again with one of my new transplant consults from last week. A previously quite healthy man with hypertension as his only comorbid illness, Mr. D is a man in his mid to late 50s who felt mildly fatigued in early August while traveling abroad. He eventually pursued a medical evaluation for this and was found to be pancytopenic. A typical diagnostic work-up ensued, and he was eventually diagnosed with acute myeloid leukemia with complex, high-risk cytogenetic abnormalities. He had never had previously abnormal blood counts, and there was no morphologic suggestion that his disease had arisen in a background of myelodysplasia.
Mr. D was hospitalized and treated with standard 7+3 induction chemotherapy. He did fairly well with this, up and active throughout treatment, with the exception of a likely line infection towards the end of his hospitalization. This was treated with line removal and replacement followed by a course of vancomycin.
|
|
When I saw Mr. D in clinic, he looked and felt well and I estimated his ECOG performance status to be a 1. He had a recovery bone marrow biopsy that demonstrated morphologic remission, with cytogenetic data pending. Previously noted FISH abnormalities for monosomy 7 and EGR1 had resolved. Unfortunately, his creatinine had increased from a normal baseline to a level around 2, and he had a recently obtained supratherapeutic vancomycin level. I suspected that the two were related. An 8/8 sibling match was likely to be available, pending donor confirmation.
A patient’s options for treatment
This case raised several familiar questions. The first was easy to answer – given the poor-risk cytogenetic abnormalities, an allogeniec transplant, particularly one with an 8/8 matched sibling donor, appeared to be a superior strategy to standard chemotherapy. I had this conversation with my patient in detail, including estimated risks of treatment-related mortality, graft versus host disease, other complications, and functional disability. By the end of the conversation, he appeared to have a clear grasp of the risks and benefits and wished to proceed.
The next question was a little more complicated – whether to condition with myeloablative or reduced intensity conditioning, and with which regimen. On the one hand, this patient had high-risk disease and would benefit from as much anti-leukemic effect as he could tolerate. On the other hand, he was over 55 years of age and might have had some underlying subclinical renal dysfunction based on his recent creatinine elevation. Though I was hoping for improvement back to a normal baseline creatinine after resolution of the acute renal insult, I did wonder if the patient’s long-standing hypertension might have had some cumulative (previously subclinical) effects on his kidneys over time.
At our center, we tend to use busulfan- and fludarabine-based regimens for both myeloablative and reduced intensity approaches in our AML patients. Published data with myeloablative Bu/Flu generally suggests NRM rates of 20% to 30% in the first 2 years after transplantation, though NRM rates may be lower than this with myeloablative targeted IV Busulfan. On the other hand, reduced intensity Bu/Flu regimens are feasible with acceptable NRM rates in older patients. In comparing the two, a retrospective analysis at the Dana Farber Institute looked at outcomes in patients over the age of 50 years treated with myelobalative or nonmyeloablative conditioning for AML or MDS. NRM rates in the RIC group were 26% vs 33% in the myeloablative group, with higher relapse in the RIC group (61%) than the myeloablative group (38%). There was no difference in overall survival between the two groups. A retrospective EBMT analysis in patients with AML over the age of 50 years also showed less treatment-related mortality, more relapse, and similar overall survival between reduced intensity and myeloablative regimens. These results were confirmed in a prospective study, albeit one with limitations in study design. Other investigators have looked at health-related quality of life, though in general this is relatively understudied in comparing RIC and myeloablative regimens.
The opinions of colleagues
When I presented my case to my colleagues, the general recommendation was to offer the patient a myeloablative regimen if his kidneys recovered and if I felt that he could tolerate higher intensity chemotherapy, based on his poor risk cytogenetic disease. However, given the ambiguity in the optimal treatment approach, there was also sentiment to consider this patient for a very interesting Blood and Marrow Transplant Clinical Trials Network (BMT CTN) multicenter phase 3 study (0901) that randomizes patients 18 to 65 years of age with a diagnosis of AML or MDS to reduced intensity or myeloablative conditioning. RIC regimens can either utilize busulfan and fludarabine or fludarabine and melphalan, while patients receiving myeloablative conditioning can receive busulfan and cyclophosphamide, or busulfan and fludarabine, or cyclophosphamide and total body irradiation (>1200-1420cGy). Hopefully, this prospective study will eventually help to answer some of these questions.
My question to you today: what are your feelings about reduced intensity versus myeloablative conditioning regimens for patients over the age of 50 years with AML? Do you always prefer one versus the other? How do you factor comorbidities and functional status into your decision making – and is this a formal consideration that you entertain or one that is done by your overall gestalt? Are you enrolling patients onto BMT CTN 0901, and why or why not? As always, I am grateful for your thoughts.
William Wood, MD, is assistant professor of medicine, division of hematology/oncology, at the University of North Carolina, Chapel Hill. Dr. Wood may be reached at william_wood@med.unc.edu. Disclosure: Dr. Wood reports no relevant financial disclosures.
For more information:
- Alyea EP. Biol Blood Marrow Transplant. 2006 Oct;12(10):1047-55.
- Aoudjhane M, Leukemia. 2005 Dec;19(12):2304-12.
- de Lima M, Blood. Aug 1;104(3):857-64. Epub 2004 Apr 8.
- Martino R, Bone Marrow Transplant. 2008 Jan;41(1):33-8. Epub 2007 Nov 5.
- Mohty M, Blood. 2003 Jul 15;102(2):470-6. Epub 2003 Mar 20.