Control of Residual Disease in Imatinib Treated Chronic Myeloid Leukemia Patients with Peptide Vaccinations: 2 Years Follow up of CMLVAX100 Trial.
Authors: Bocchia Monica , Abruzzese Elisabetta , Ippoliti Micaela , Pirrotta Maria Teresa , Trawinska Malgorzata M. , Amabile Marilina , Martinelli Giovanni , Forconi Francesco , Gozzetti Alessandro , Carella Angelo M. , Raspadori Donatella , Lauria Francesco 
Published: April 2020

Abstract
In the past five years, the body of data concerning imatinib mesylate had certainly defined the role of this drug as very effective first line debulking therapy for CML patients. However, both the persistence of molecular disease in most of patients together with the evidence that discontinuation of imatinib inevitably exerts on a rapid loss of response, suggest that with imatinib alone the cure of CML is unlikely. CMLVAX100 is a peptide-based vaccine that specifically targets p210-b3a2 in CML cells through the induction of a peptide-specific T cell response in b3a2-CML vaccinated patients. We recently published the preliminary results of a pilot study testing the immunological response and antitumor activity of vaccinations with CMLVAX100 in 10 patients showing persistent residual disease during treatment with imatinib. We here report the results on a larger cohort of patients and with a longer follow up. Up to date 21 patients were enrolled in this study. After a median time of 24 months (range 12–50) of imatinib treatment, patients started vaccinations with CMLVAX100 showing different degrees of persistent residual disease: 8/21 patients presented with molecular disease, 10/21 showed residual cytogenetic disease (range 2–45% of Ph+ metaphases), while 3/21 presented only an hematological response (100% of Ph+ metaphases). No improvement of their residual disease was documented for a median of 12 months (range 6–24) before starting vaccinations. Vaccine treatment plan included 6 vaccinations at 2 weeks interval (immunization) and for responder patients additional boosts of vaccine every 4–6 months. So far 18/21 patients completed the immunization and are evaluable for response; in addition 8/18 received 4 further boosts of vaccine. After immunization, CMLVAX100 induced a prompt immunological response in most of the patients as 17/18 patients showed peptide specific T cell response in vitro and 12/18 developed a positive delayed type hypersensitivity response in vivo. After 6 vaccinations 6/10 patients with persisting cytogenetic disease reached a complete cytogenetic response (CCR), with 3 of them achieving an undetectable level of bcr-abl transcript. In addition, 3/5 evaluable patients starting vaccinations with persistent molecular disease, further reduced their bcr-abl level, wth one reaching molecular negativity. None of the 3 patients vaccinated in hematological remission had cytogenetic response. Of the 8 patients who underwent 4 additional boosts of vaccine, one reached a complete molecular response, 5 maintained the response obtained after immunization, while 2 patients who previously achieved an undetectable level of bcr-abl transcript, lost the complete molecular response, while maintaining CCR, thus suggesting that a 6 months interval between boosts could be too long to maintain an efficient immune control on residual leukemic cells. In conclusion, we confirm that CMLVAX100 has a synergistic antitumor effect with imatinib in CML patients with persistent minimal residual disease. However, follow-up data recommend that closer boosts of vaccine are necessary in order to maintain an optimal level of response.