PREREGISTRATION (STEP 0): NOTE: Following consent and preregistration to Step 0, peripheral blood must be collected for submission to Fred Hutchinson Cancer Research Center for central assessment of the establishment of BCR/ABL status to confirm patient’s eligibility for registration to Step 1; Fred Hutchinson will typically forward results within 1-2 business days of receipt of the peripheral blood to the submitting institution

PREREGISTRATION (STEP 0): Patient must be >= 18 years of age

PREREGISTRATION (STEP 0): Patient must have pathologically-confirmed chronic phase-CML by one of the following the following criteria:
* Patient has been in CCyR by FISH karyotype or PCR and with detectable BCR/ABL transcript by a standard real-time quantitative polymerase chain reaction RQ-PCR (equal or less than 1% or MR^2) assay for at least 12 months from the first documentation of the CCyr
* Patient has not maintained MR^4.5 (CMR) after initiation of last line TKI therapy; patient can have intermittent values of CMR (at or below MR^4.5); however the patient has to have detectable disease (i.e. cannot be in CMR) in the last one assessment before pre-registration to Step 0
AND
Patient must have a diagnosis of chronic phase-CML and MMR status and BCR/ABL results meets the criteria within 21 days after consenting and pre-registration to Step 0. A bone marrow biopsy prior to enrollment is not required
* NOTE: Please be aware of the required timeframe restrictions; patients are required to enroll on Step 1 within 21 days from the date of consenting (step 0, pre-registration)

PREREGISTRATION (STEP 0): Patients with diagnoses of accelerated or blast phase CML are not eligible

PREREGISTRATION (STEP 0): Patient has been on TKI therapy (first, second, and third line line) for at least 2 years (starting from when first TKI was initiated) prior to step 0 pre-registration
* Allowed TKIs include:
** Dasatinib: 50 – 180 mg per day
** Imatinib: 200 – 800 mg per day
** Nilotinib: 200 – 400 mg every 12-24 hours
** Bosutinib: 200 – 500 mg per day
* Patients must have been on a stable dose of the current TKI for at least 3 months prior to start of EA9171 study therapy

PREREGISTRATION (STEP 0): Patient must not have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

PREREGISTRATION (STEP 0): Patients must not have received a prior allogeneic transplant

REGISTRATION TO TREATMENT (STEP 1): Institution must have received central BCR-ABL test results confirming MRD positive status with detectable level above CMR (0.0032%) but at or below 1% level

REGISTRATION TO TREATMENT (STEP 1): Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

REGISTRATION TO TREATMENT (STEP 1): The BCR/ABL status must meet the criteria within 21 days prior to Step 1 registration. A bone marrow aspirate and/or biopsy prior to registration is not mandatory

REGISTRATION TO TREATMENT (STEP 1): Patient must not have any active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment; patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation

REGISTRATION TO TREATMENT (STEP 1): Patient must not receive any corticosteroids from the time of consent to step 1 registration
* EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g. chronic adrenal insufficiency) is permitted

REGISTRATION TO TREATMENT (STEP 1): Patients must not be pregnant or breastfeeding due to the potential for congenital abnormalities and of harm to nursing infants due to the treatment regimens used; all patients of childbearing potential must have a negative urine or serum pregnancy test within 14 days prior to Step 1 registration to rule out pregnancy; a urine or serum pregnancy test must be repeated within 72 hours prior to receiving the first dose of pembrolizumab if the test done for eligibility/registration to step 1 is done outside of this 72 hour window; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required; a patient of childbearing potential is someone, regardless of whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point; 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential)for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

REGISTRATION TO TREATMENT (STEP 1): Patient must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sex from the time of step 1 registration, while on study treatment, and continue for 120 days after the last dose of study treatment

REGISTRATION TO TREATMENT (STEP 1): Patient may not be currently participating and receiving study therapy or have participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to step 1 registration

REGISTRATION TO TREATMENT (STEP 1): Patient must not have a diagnosis of immunodeficiency or be receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of treatment

REGISTRATION TO TREATMENT (STEP 1): Patient must not have a known history of active TB (Bacillus tuberculosis)

REGISTRATION TO TREATMENT (STEP 1): Patient must not have a history of hypersensitivity to pembrolizumab or any of its excipients

REGISTRATION TO TREATMENT (STEP 1): Patient must not have received a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to step 1 registration or have not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier

REGISTRATION TO TREATMENT (STEP 1): Patient must not have had prior chemotherapy, targeted small molecule therapy (aside from imatinib, dasatinib, bosutinib or nilotinib), or radiation therapy within 2 weeks prior to registration to step 1; patients also must have recovered from all adverse events due to a previously administered agent
* Note: Patients with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study
* NOTE: Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis; a 1-week washout is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system [CNS] disease)

REGISTRATION TO TREATMENT (STEP 1): Patients who have received major surgery must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy

REGISTRATION TO TREATMENT (STEP 1): Patient must not have a known primary or additional malignancy that is progressing or requires active treatment or limiting expected survival to =< 2 years; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
* NOTE: If there is a history of prior malignancy, the patient must not be receiving other specific treatment (other than hormonal therapy for their cancer)

REGISTRATION TO TREATMENT (STEP 1): Patient must not have known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of protocol treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to protocol treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability

REGISTRATION TO TREATMENT (STEP 1): Patient must not have active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment

REGISTRATION TO TREATMENT (STEP 1): Patient must not have known history of, or any evidence of active, non-infectious pneumonitis

REGISTRATION TO TREATMENT (STEP 1): Patient must not have an active infection requiring systemic therapy

REGISTRATION TO TREATMENT (STEP 1): Patient must not have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator

REGISTRATION TO TREATMENT (STEP 1): Patient must not have known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study

REGISTRATION TO TREATMENT (STEP 1): Patients who are human immunodeficiency virus (HIV) positive are eligible if they have undetectable HIV viral load and CD4+ T-cell count >= 250/mm^3

REGISTRATION TO TREATMENT (STEP 1): Patients with a known positive test for hepatitis C virus ribonucleic acid (hepatitis C virus [HCV] antibody) indicating acute or chronic infection may be enrolled if the viral load by polymerase chain reaction (PCR) is undetectable with/without active treatment

REGISTRATION TO TREATMENT (STEP 1): Patient must not have a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive)

REGISTRATION TO TREATMENT (STEP 1): Patient must not have received a live vaccine within 30 days prior to step 1 registration
* NOTE: Live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Patients are permitted to receive inactivated vaccines and non-live vaccines including those for the seasonal influenza and COVID-19 (Note: intranasal influenza vaccines, such as Flu-Mist) are live attenuated vaccines, and are not allowed). If possible, it is recommended to separate study drug administration from vaccine administration by about a week (primarily, in order to minimize an overlap of adverse events)

REGISTRATION TO TREATMENT (STEP 1): Absolute neutrophil count (ANC) >= 1,500 /mcL (within 14 days prior registration)

REGISTRATION TO TREATMENT (STEP 1): Platelet count >= 100,000 /mcL (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 1): Hemoglobin (Hgb) >= 9.0 g/dL OR >= 5.6 mmol/L without transfusion of erythropoietin (EPO) dependency (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 1): Serum creatinine =< 1.5 X upper limit of normal (ULN) OR creatinine clearance (per institutional standards) >= 60 mL/min for patients with creatinine levels > 1.5 X ULN (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 1): Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 X ULN (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 1): Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 1): Patients should not be receiving concomitant strong CYP3A4 inducers or inhibitors =< 7 days prior to step 1 registration due to their potential to effect the activity or pharmacokinetics of study agents and/or QT interval prolongation toxicity; should treatment with any of these agents be required, consult with study chair and reference section for TKI dose modifications related to concomitant drugs

REGISTRATION TO TREATMENT (STEP 1): Patients who received prior allogeneic transplant are not eligible

REGISTRATION TO TREATMENT (STEP 2): Institution must have received central BCR-ABL test results confirming MRD positive status at cycle 17 following Step 1 treatment (CCyR or deeper but not in CMR in the last two central lab checks before Step 2)
* NOTE: Pembrolizumab therapy will be delayed if second consecutive BCR-ABL test is performed after end of treatment on Step 1

REGISTRATION TO TREATMENT (STEP 2): Patients must have an ECOG performance status of 0-1

REGISTRATION TO TREATMENT (STEP 2): Patient must have no active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment; patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation

REGISTRATION TO TREATMENT (STEP 2): No current use of corticosteroids at any point of the trial including within 30 days prior to Step 1 registration. EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g., chronic adrenal insufficiency) is permitted

REGISTRATION TO TREATMENT (STEP 2): Patient must not have any other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to =< 2 years; NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy for their cancer)

REGISTRATION TO TREATMENT (STEP 2): Patient must not have a diagnosis of immunodeficiency or be receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of treatment

REGISTRATION TO TREATMENT (STEP 2): Patient must not have a known history of active TB (Bacillus tuberculosis)

REGISTRATION TO TREATMENT (STEP 2): Patient must not have a history of hypersensitivity to pembrolizumab or any of its excipients

REGISTRATION TO TREATMENT (STEP 2): Patients must not be pregnant or breastfeeding due to the potential for congenital abnormalities and of harm to nursing infants due to the treatment regimens used; all patients of childbearing potential must have a negative urine or serum pregnancy within 14 days prior to registration on step 2 to rule out pregnancy; a urine or serum pregnancy test must be repeated within 72 hours prior to receiving the first dose of pembrolizumab on step 2 if the test done for eligibility/registration to Step 2 is done outside of this 72 hour window; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required; a patient of childbearing potential is someone, regardless of whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

REGISTRATION TO TREATMENT (STEP 2): Patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sex from the time of step 2 registration, while on study treatment, and continue for 120 days after the last dose of study treatment

REGISTRATION TO TREATMENT (STEP 2): Patient must not have known history of, or any evidence of active, non-infectious pneumonitis

REGISTRATION TO TREATMENT (STEP 2): Patient must not have an active infection requiring systemic therapy

REGISTRATION TO TREATMENT (STEP 2): Patient must not have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patients’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator

REGISTRATION TO TREATMENT (STEP 2): Patients who are human immunodeficiency virus (HIV) positive are eligible if they have undetectable HIV viral load and CD4+ T-cell count >= 250/mm^3

REGISTRATION TO TREATMENT (STEP 2): Patient with a known positive test for hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection might be enrolled if the viral load by PCR is undetectable with/without active treatment

REGISTRATION TO TREATMENT (STEP 2): Patients must not have a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive)

REGISTRATION TO TREATMENT (STEP 2): Patient must not have received a live vaccine within 30 days of planned start of study therapy; NOTE: Live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Patients are permitted to receive inactivated vaccines and any non-live vaccines including those for the seasonal influenza and COVID-19 (Note: intranasal influenza vaccines, such as Flu-Mist are live attenuated vaccines and are not allowed). If possible, it is recommended to separate study drug administration from vaccine administration by about a week (primarily, in order to minimize an overlap of adverse events)

REGISTRATION TO TREATMENT (STEP 2): Absolute neutrophil count (ANC) >= 1,500 /mcL (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 2): Platelet count >= 100,000 /mcL (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 2): Hgb >= 9.0 g/dL OR >= 5.6 mmol/L without transfusion of EPO dependency (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 2): Serum creatinine =< 1.5 X upper limit of normal (ULN) OR creatinine clearance (per institutional standards) >= 60 mL/min for patients with creatinine levels > 1.5 X ULN (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 2): Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 X ULN (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 2): AST (SGOT) and ALT (SGPT) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 2): Patients should not be receiving concomitant strong CYP3A4 inducers or inhibitors =< 7 days prior to step 2 registration due to their potential to effect the activity or pharmacokinetics of study agents and/or QT interval prolongation toxicity; should treatment with any of these agents be required, consult with study chair and reference section for TKI dose modifications related to concomitant drugs

PRIMARY OBJECTIVE:
I. Assess the proportion of chronic myelogenous leukemia (CML) patients on stable-dose tyrosine kinase inhibitor (TKI) who convert to undetectable minimal residual disease (UMRD) (molecular response [MR]^4.5) during or within 2 years of initiating pembrolizumab therapy.

SECONDARY OBJECTIVES:
I. Among patients who have converted to UMRD (MR^4.5), assess the proportion of CML patients who maintain UMRD for 6 months and 12 months.
II. Among patients who have converted to UMRD (MR^4.5), assess the proportion of CML patients who discontinue their TKI.
III. Among patients who have converted to UMRD (MR^4.5), assess the proportion of CML patients who are UMRD and/or TKI-free at 2 years from first determined UMRD.
IV. Assess the proportion of CML patients who develop grade 3 or 4 immune related adverse events related to pembrolizumab treatment during the first 2 years after registration (not including grade 3 events that respond to corticosteroids and improve to grade 1 or less within 4 weeks).

OUTLINE:
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and dasatinib orally (PO) once daily (QD), imatinib mesylate PO QD, nilotinib PO twice daily (BID), or bosutinib PO QD on days 1-21 as clinically indicated per the treating physician. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients with detectable MRD after cycle 18 continue pembrolizumab and dasatinib, imatinib mesylate, nilotinib, or bosutinib every 21 days for up to an additional 18 cycles in the absence of disease progression or unacceptable toxicity. Patients with UMRD at any time before cycle 18 discontinue pembrolizumab after cycle 18 and continue dasatinib, imatinib mesylate, nilotinib, or bosutinib every 21 days for 48 weeks after UMRD first determined in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection and may undergo bone marrow biopsies or bone marrow aspirates throughout the study.

After completion of study treatment, patients are followed up every 6 months for 6 years from the date of registration.