Background: Patients with hematologic malignancies have a lower vaccine response and higher rates for SARS CoV-2 morbidity and mortality. We present preliminary data focusing on humoral vaccine responses and correlates with disease subtype and treatment exposure. Methods: We analyzed data from 332 patients with a hematologic malignancy from May 1, 2021 – Jan 31, 2022 who received SARS-CoV-2 vaccination and performed a prospective cohort serologic study with the Elecsys® Anti-SARS-CoV-2-S test. Patients received homologous or heterologous vaccine combination of BNT162b2, mRNA1273, ChAdOx1 nCoV-19, and/or Ad26.COV2.S. Blood samples were obtained before any vaccination, 2-6 weeks after the second vaccine (2V), before third vaccine (3V), and 2-6 weeks after 3V. Results: The median age was 67 years (range 18-91years) with 41.9% female. At 2V, 11.5% and at 3V, 23.8% received heterologous vaccines. Treatment status at first vaccine dose significantly affected peak 2V antibody response (p < 0.05). Seropositive rate and median antibody titer after 2V for previously untreated patients were higher compared to patients on active therapy or had previously been treated. Treatment naïve (n = 60; seropositivity 85.1%; median titer 1306 U/mL; [Q1-Q3:11.4- > 2499]); first-line (1L) active therapy (n = 127;65.4%; 41.25 U/mL; [ < 0.8-592.5]); second-line and beyond (2L+) active therapy (n = 56; 60.7%; 2.6U/mL; [ < 0.8-154]); previous treatment with 1L (n = 66;64.8%; 118 U/mL; [ < 0.8- > 2499]); previous treatment with 2L+ (n = 23; 59.1%; 4U/mL; [ < 0.8-229.5]). Of 61 patients that were seronegative at 2V, 17 (27.9%) seroconverted after 3V. Anti-CD20 monoclonal antibody (mAb) containing therapy as the most recent treatment from 2V had the greatest impact on humoral response. Exposure to anti-CD20 mAb based regimens or as monotherapy revealed low antibody responses (n = 84; seropositivity 22.6%; median titer < 0.8 U/mL; Q1-Q3 [ < 0.8- < 0.8]). On analysis of indolent B-cell Non-Hodgkin Lymphomas whereby antiCD-20 mAb are often incorporated, treatment proximity to 2V impacted responses: < 3 months (n = 33; 22%; < 0.8 U/mL; [ < 0.8- < 0.8]) vs. 12-24 months (n = 4; 60%; 228 U/mL; [ < 0.8-232]). In contrast, tyrosine kinase inhibitor (n = 38; 100%; 858 U/mL; [221- > 2499]), proteosome inhibitor monotherapy (n = 4;100%; median titer 1520 U/mL; [462- > 2499]) were among the subgroups with the highest numerical responses, however, the addition of corticosteroids impacted vaccine response as seen in proteosome inhibitor with corticosteroids (n = 7; 85.7%; 6.6 U/mL; [1.8-115.2]). Conclusions: The humoral response from our single institution cohort identifies diminished responses depending on treatment status and the type of treatment including the proximity of treatment exposure to receipt of vaccination. Furthermore, vaccine boosters can induce antibody responses in patients who were previously seronegative.