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Two cases of relapse after allogeneic stem cell transplantation
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Mr. B was a gregarious man in his 60s who had been diagnosed with Burkitt’s lymphoma several years ago. He was well known to my colleagues in the hematologic malignancies group. I met him for an unfortunate reason — despite the successful cure of his lymphoma, he had developed a treatment-related myelodysplastic syndrome with unfavorable cytogenetic features. He was referred to me for consideration of allogeneic stem cell transplantation.
At first, things went fairly well. Mr. B received four cycles of therapy with 5-azacytidine, and both his bone marrow and peripheral blood counts markedly improved. In the meantime, we had found an unrelated donor and identified a transplant date.
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Mr. B’s transplant was uneventful until engraftment, when he developed a systemic inflammatory response syndrome-like reaction that resulted in a brief ICU stay. With successful resuscitation, he recovered — though edematous and battle-worn — and was discharged. Unfortunately, just 2 months after transplant, his disease rapidly relapsed and was now frank acute myeloid leukemia. Mr. B, his wife and some of the other providers who had been involved in his care previously talked extensively about his options. None were particularly promising. Understanding fully that the chance of success would be limited, Mr. B opted to proceed with leukemia re-induction treatment using traditional cytotoxic chemotherapy.
Re-induction successful
From a disease standpoint, re-induction was a modest success, with a complete remission demonstrated on bone marrow biopsy. Unfortunately, with count recovery came severe lower gastrointestinal graft-versus-host disease (GVHD). Mr. B’s GVHD treatment escalated fairly rapidly during the next weeks, with only limited effectiveness. His disease remained in remission and his GVHD was coming under control. Despite this, he developed acyclovir-resistant herpes simplex virus viremia, and despite treatment doses of foscarnet, he succumbed to herpes simplex virus encephalitis.
Disease relapse after allogeneic transplant is crushing. Our patients have gone into this high-risk, high-intensity procedure having invested the greatest possible hopes. Instead of a cure, they must now confront a set of impossible choices and a host of potential complications. Mr. B’s case was a reminder that disease control, in this setting, is only part of the picture.
When another patient’s disease then relapsed after transplant, I found myself in a familiar situation. Similar to Mr. B, Mr. M’s disease had come roaring back, and in Mr. M’s case, there was also skin GVHD that was only just coming under control. Unlike Mr. B, though, Mr. M had a disease with a “targetable” abnormality — his AML was marked by a FLT3 internal tandem duplication mutation.
FLT3 inhibitors
To date, the success rates of FLT3 inhibitors in AML have been fairly modest. Sorafenib (Nexavar, Bayer), a tyrosine kinase inhibitor used more often in renal cell carcinoma, has FLT3 inhibiting properties and has been studied as part of upfront treatment for newly diagnosed AML. Its efficacy in this setting has been marginal. Currently, there are other, more potent FLT3 inhibitors that are being investigated combined with cytotoxic chemotherapy for the initial treatment of AML. Some of these are giving reason for optimism, but it is too early to accurately gauge the overall benefits of this approach.
Nonetheless, a series of reports have emerged that suggest some encouraging results when sorafenib is used to treat relapsed FLT3-positive AML after allogeneic transplant, in contrast to the upfront setting. The reasons for this are not entirely clear; they may be artefactual (ie, small numbers and reporting bias) or biologic (some commentators have observed that post-transplant relapsed AML may be more “addicted” to FLT3 and thus more responsive to FLT3 inhibition). In any case, the possibility of incorporating a less toxic approach into the treatment of Mr. M’s relapsed disease was appealing. I had a detailed discussion with Mr. M and his family about available options, and we ultimately decided to proceed with a trial of single-agent sorafenib.
Remarkably, within a week, Mr. M’s peripheral blasts cleared, and a follow-up bone marrow aspirate and biopsy a few weeks later showed normocellular, trilineage hematopoiesis with less than 5% blasts. This was very encouraging. Unfortunately, molecular testing showed persistence of the FLT3 mutation, and Mr. M’s blood counts remained pancytopenic. This is where we are today. I am hoping that Mr. M’s positive response continues, and that perhaps we can eventually consolidate these gains with other treatment strategies.
William Wood, MD, is assistant professor of medicine, division of hematology/oncology, at the University of North Carolina, Chapel Hill. He may be reached at william_wood@med.unc.edu.
Disclosure: Dr. Wood reports no relevant financial disclosures.
For more information:
- Metzelder S. Blood. 2009;113:6567-6571.