Context: Patients with hematologic malignancies have an increased risk of SARS-CoV-2 infection, severe COVID-19, and higher mortality rates. Objective: We investigated the immunological response to SARS-CoV-2 after infection and/or vaccination and explored the impact of treatment response on antibody levels. Design: We added a cohort of CML patients to the ongoing study SPARTA. We collected saliva and peripheral blood to measure levels of SARS-CoV-2 antigen and antibodies. Results: From 10-1-2021 to 3-31-2022, we prospectively enrolled 69 participants (32 with CML, 37 non-cancer) with similar sociodemographic characteristics. There was a significant difference in the frequency of previous SARS-CoV-2 infections, where the control group had a higher percentage of patients previously diagnosed with COVID-19 (18.8% vs. 84%). Nevertheless, there was no difference in the detection of SARS-CoV-2 at the time of enrollment (0% vs. 5.6%). SARS-CoV-2 antibodies, either IgG or neutralizing (nAB), were detected in most of the participants regardless of cancer status (IgG, 84.4% in the CML cohort and 91.7% in the non-cancer cohort; nAB, 84.4% vs. 88.9%). The two groups had comparable IgG (mean 160.8 vs. 157.5 Ru/mL) and nAB (mean 1,473 vs. 1,509 ng/ml) levels. Overall, IgG and nAB levels were significantly higher in subjects who received the last vaccine dose within 6 months compared to those who received it ≥6 months previously (IgG, CML, mean 177.7 vs. 113.2, control 190.5 vs. 134.4; nAB, CML 1,784 vs. 951.9, control 2,066 vs. 1,335). Both groups had comparable mean antibody levels according to the time since the last dose (IgG, ≤6 months, 177.7 vs. 190.5, ≥6 months, 113.2 vs. 134.4; nAB, ≤6 months, 1,784 vs. 2,066, ≥6 months 951.9 vs. 1,335). There was no difference in the detection and levels of antibodies according to therapy with TKIs (IgG, mean 158.8 vs. 185.2; nAB, 1,515 vs. 1,883) or achieving MMR (IgG, mean 152.4 vs. 177.5; nAB, 1,447 vs. 1,686). Conclusions: The immunological response to SARS-CoV-2 among CML patients is comparable to that in non-CML subjects. TKI therapy and the response to treatment did not impact the development of antibodies. Moreover, antibody levels decreased over time, with the most significant drop after 6 months since the last immunization dose.