Molecular Tests Discriminate Prognosis in Normal Karyotype AML
Abstract & commentary
By Andrew S. Artz, MD, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationships relevant to this field of study.
Synopsis: Acute myeloid leukemia in the elderly has a poor prognosis using standard therapy. Lenalidomide is a thalidomide analogue with activity at low doses for low-risk MDS harboring a 5q-. Two institutions using different protocols evaluated high-dose lenalidomide induction (35-50 mg daily for 14-21 days, 14-30 days of rest) followed by lower dose maintenance (10 mg daily). Out of 33 patients, four patients had a complete response. Interestingly, the two evaluable patients with AML and a trisomy 13 both achieved a complete cytogenetic remission lasting 8-9 months. Lenalidomide has activity in AML. Further study will be needed to confirm if certain cytogenetic subsets of AML have higher response rates to lenalidomide.
Source: Fehniger T, et al. Single-agent lenalidomide induces complete remission of acute myeloid leukemia in patients with isolated trisomy 13. Blood. 2009;113: 1002-1005.
Acute myeloid leukemia (AML), particularly in older adults, has dismal long-term outcomes.1 These poor results relate to worse disease features such as multi-drug resistance, a tendency to arise from myelodysplastic syndromes (MDS), and adverse karyotypes. Further, worse performance status of older adults diminishes tolerance to chemotherapy. While outcomes have improved for younger adults with AML, the poor survival among older AML patients remains unchanged. Novel approaches are sorely needed that have a different mechanism of action than standard chemotherapy and/or have improved tolerability.
Lenalidomide is an oral thalidomide analogue that shows considerable activity in multiple myeloma and low-risk MDS accompanied by the 5q- cytogenetic abnormality.2 Lenalidomide-related myelosuppression has limited the dose to 10 mg per day for MDS. These lower doses result in plasma concentrations much lower than that achieved from the higher doses for multiple myeloma.3 Fehniger et al report two cases from separate institutions and protocols of AML harboring a trisomy of lenalidomide-induced complete remissions.
The first case was a 71-year-old man who presented with de novo AML without known MDS treated at Washington University. Metaphase cytogenetics only revealed a trisomy 13. He received lenalidomide at 50 mg per day for 14 days, with 30 days of rest followed by cycle 2 of 50 mg per day for 21 days. The peripheral blood blasts improved, and the marrow showed aplasia and residual blasts. After one month of rest following cycle 2, low-dose therapy at 10 mg daily for 28-day cycles was begun. At the end of the first cycle of consolidation (124 days from initial treatment), blood counts normalized and a bone marrow demonstrated a complete cytogenetic response with 60% cellularity, less than 5% blasts, and no cytogenetic abnormalities (CRc). CRc was confirmed six and 16 weeks after this. He remained on maintenance lenalidomide but relapsed nine months after the initial CRc.
In a second case, a 68-year-old man treated at Ohio State University had AML arising from MDS in first relapse after 3.5 years. While a normal karyotype was present at diagnosis, a trisomy 13 was detected at relapse. Lenalidomide was started at 35 mg/day for 21 days followed by seven days of rest. After cycle 1, he remained pancytopenic, transfusion dependent, and the marrow had residual disease and persistence of the trisomy 13. After four days of cycle 2, an infection required holding therapy. After four weeks, the counts recovered while therapy remained on hold. A bone marrow showed a CRc. The patient was consolidated with two cycles of lenalidomide at 35 mg per day, but was later reduced to 10 mg per day for 21 of 28 days because of myelosuppression; he relapsed nine months after the initial CRc.
Importantly, among other patients treated at Washington University with lenalidomide, none of the 13 non-trisomy 13 AML patients achieved CR. One patient had a trisomy 13 with additional cytogenetic abnormalities; lenalidomide was only given for six days because of infection. At Ohio State University, two of 18 non-trisomy 13 AML patients had responses. One 74-year-old patient with AML and a normal karyotype in second relapse with skin involvement at relapse achieved a third CR lasting eight months. In another case, a 61-year-old male with AML and a monosomy 7 received an allogeneic hematopoietic transplant in CR2 from an unrelated donor. Relapse followed nine months later, and he achieved CRc after three cycles of lenalidomide and continues on therapy.
Commentary
Fehniger et al report two complete cytogenetic remissions among older adults with AML and a trisomy 13 using high-dose lenalidomide. The patients maintained the remissions 8-9 months with low-dose consolidation lenalidomide. The data are intriguing in that older adults with AML generally have a poor prognosis even using induction chemotherapy. Moreover, rare karyotypic abnormalities such as trisomy 13 usually predict a poor prognosis.4 Finally, many older adults are not eligible for intensive therapy due to co-existent health limitations.
The results must be put in perspective. Essentially, four of 33 (12%) patients achieved a complete remission. While lenalidomide could be viewed as non-intensive therapy, the high doses used for induction likely lead to considerable myelosuppression and may result in other serious toxicities. Further therapies such as hypomethylating agents or clofarabine probably have more activity. At a minimum, high-dose lenalidomide, followed by lower-dose consolidation, has some activity in AML and certainly warrants continued study.
The largest question these data raise is whether the responses in two patients with AML and trisomy 13 are coincidence or a unique biology. While Fehniger et al postulated the association of mutation in the RUNX1 gene and increased expression of the FLT-3 tyrosine kinase gene (which is located on chromosome 13), the exact reason that lenalidomide would inhibit these specific targets is not addressed. Because the mechanism of lenalidomide is not well appreciated, and may relate to multiple pathways, a uniform hypothesis, or target, is unlikely. Lenalidomide has activity in MDS, including non-5q minus, so it is not surprising to see some activity in AML, especially since AML in older adults often arises from MDS. Further investigation of high-dose lenalidomide, particularly in AML with rare cytogenetic abnormalities, is of great interest.
References
1. Appelbaum FR, et al. Age and acute myeloid leukemia. Blood. 2006;107: 3481-3485.
2. List A, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005;352: 549-557.
3. Richardson PG, et al: A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108: 3458-3464.
4. Farag SS, et al. Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461. Blood. 2006;108: 63-73.