Natural History and Potential for Cure of Patients with Chronic Myeloid Leukemia in Chronic Phase Receiving Frontline Therapy with Recombinant Interferon-Alfa: 30-Year Update From M.D. Anderson Cancer Center
Authors: Quintás-Cardama Alfonso , Kantarjian Hagop M. , O'Brien Susan , Jabbour Elias J. , Garcia-Manero Guillermo , Koller Charles , Pierce Sherry A. , Talpaz Moshe , Cortes Jorge E. 
Published: October 2019

Abstract
Abstract 918

Background:
Prior to the advent of the tyrosine kinase inhibitor (TKI) imatinib, pioneering studies at our institution in the early 1980s established recombinant interferon-alfa (IFN-α) as standard therapy for chronic myeloid leukemia (CML). The use of IFN-α has come to the fore again given its therapeutic properties as an immunomodulatory agent and its putative activity against CML stem cells. We here provide an account of the natural history of patients with early chronic phase CML treated with IFN-α at our institution for the last 30 years.

Methods:
We analyzed 512 patients with early chronic-phase CML who were treated with IFN-α-based therapies between 1981–1995 for the rates of partial (PCyR) and complete cytogenetic response (CCyR), complete molecular response (CMR), major molecular response (MMR), overall survival (OS), transformation-free survival (TFS), and CML cure.

Results:
The median age of the cohort was 42 years (range, 15–76). The distribution of high, intermediate, and low risk patients by Sokal or Hasford was 21%/25%/36% and 10%/27%/44%, respectively. Of the 512 patients, 274 received IFN-α alone or in combination with hydroxyurea or high-dose chemotherapy, 148 received IFN-α and low-dose cytarabine, and 90 were treated with homoharringtonine followed by IFN-α as maintenance. After a median follow-up of 245 months (range, 4–360), the median OS was 82 months. The 5-, 10-, and 20-year survival was 62%, 41%, and 29%, respectively. Overall, 322 patients (63%) achieved a cytogenetic response, including CCyR in 140 (27%), which was obtained after a median of 16 months (range, 3–107 months), and PCyR in 72 (14%) for a major cytogenetic response rate of 41%. The median follow-up for patients who achieved CCyR was 252 months (range, 91–360). The 5-, 10-, and 20-year survival for patients who achieved CCyR was 90%, 79%, and 63%, respectively, with a 20-year TFS of 76%. Serial molecular monitoring by RT-PCR (at least 2 measurements) is available in 46 patients. Of them, 31 achieved CMR that lasted a median of 9 years (range, 1.5–17). Of them, 14 patients remain in CMR off therapy for a median of 9.5 years (range, 1.5–17), 6 remain off therapy with detectable transcripts (5 in MMR) after a median of 10.5 years (range, 4.5–13), 9 remain in CMR after having relapsed and switched to other therapies (5 imatinib, 2 dasatinib, 1 allo-SCT, 1 chemotherapy), and 2 maintained MMR while receiving chemotherapy. Eight of the 31 patients relapsed (including 3 with sudden lymphoid BP). At the time of last follow-up, only 3 of the 31 patients who achieved CMR had died, one after, 1 lymphoid BP, 1 acute myeloid leukemia (with deletion 7), and 1 myeloproliferative disorder (with trisomy 8). All patients eventually discontinued IFN-α therapy (192 resistance, 92 toxicity, 40 resistance/toxicity, BP 37, loss of CCyR 12, 3 death in CCyR, 100 lost to follow-up/other) and received subsequent therapy with TKIs (n=52), allo-SCT (n=68), other therapies (n=74), or unknown (n=314). One hundred twenty-seven patients are still alive and have been followed in our clinics at least once in the last 24 months.

Conclusion:
While currently superseded by imatinib and other TKIs, IFN-α remains an active agent in CML, capable of inducing CCyR in approximately 25% and CMR in 5%-7% of patients in CP. Most patients achieving CMR on IFN-α can safely discontinue therapy and remain in remission with no evidence of residual disease for more than 10 years, suggesting the possibility of CML cure. Some patients relapse molecularly but remain in “non-interventional CCyR” (i.e no therapy and detectable BCR-ABL1 transcripts).

Disclosures:
No relevant conflicts of interest to declare.