Inclusion Criteria: 

PREREGISTRATION (STEP 0)

• Age ≥ 18 years.
• Patient has pathologically-confirmed chronic phase-CML one of the following the following criteria:
  • Patient has been in MMR (i.e. MR3) with detectable BCR/ABL transcript by a standard RQ-PCR assay for at least 12 months from the first documentation of the MMR;
  • Has been in MMR (i.e. MR3) but still has detectable BCR/ABL transcript by a standard RQ-PCR assay for at least 12 months from the first documentation of the MMR;
  • Up to two values above MMR (0.1%) are allowed in the last 12 months long as there was no change in the type or dose of TKI in last 6 months, none of the lab values were higher than CCR (1% or more) in the last 12 months, and all values in the last 6 months were at MMR or deeper;
  • Patient has not maintained MR4.5 (CMR) within the time of initiation of TKI therapy and pre-registration. Patient can have intermittent values of CMR (at or below MR4.5). However the patient has to have detectable disease (i.e. cannot be in CMR) in the last 2 assessments before pre-registration; AND 
  • Patient must have a diagnosis of chronic phase-CML has been confirmed by a bone marrow aspirate and/or biopsy with ≤ 10 % myeloid blasts (i.e., no accelerated or blast phase) within 21after consenting and pre -registration to step 0 and MMR status and BCR/ABL results meets the criteria outlined above.
    • 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)
• Patients with diagnoses of accelerated or blast phase CML are not eligible.
• Patient has been on TKI therapy (first and/or second line) for at least 2 years (starting from when first TKI was initiated) prior to 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.
• Patients must have been on a stable dose of the current TKI for the last 3 months prior to pre-registration. For patients with two values of above MMR (0.1%) within the last 12 months, patient must have been on stable dose of the current TKI for the last 6 months prior to pre-registration.
• For patients who are on second line TKI, patient has been on second line TKI for at least a year from start date of second line TKI.
• Patient must not have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Patients must not have received a prior allogeneic transplant.

REGISTRATION TO TREATMENT (STEP 1)

• Institution has received central BCR-ABL test results confirming MRD positive status and bone marrow aspirate and/or biopsy has confirmed chronic phase CML (i.e. no accelerated or blast phase CML) Bone marrow showing morphologic remission is acceptable.
• Patients have an ECOG Performance Status of 0-2.
• Diagnosis of chronic phase-CML must had been confirmed by a bone marrow aspirate and/or biopsy with ≤ 10 % myeloid blasts (i.e., no accelerated or blast phase) within 21 days prior to registration to step 1. Bone marrow aspirate and/or biopsy showing morphologic remission is acceptable. MMR and BCR/ABL status meets the criteria defined above.
• 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
• No current use of corticosteroids from time of consent to 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.
• No 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).
• Women 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. Patients must also not expect to conceive or father children from the time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment
  • All females of childbearing potential must have a negative urine or serum pregnancy test conducted within 14 days prior to 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 female of childbearing potential is any woman, regardless of sexual orientation or 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).
  • Female of child bearing potential? ______ (Yes or No)
    • Date of urine/serum study: ___________
• Women of childbearing potential and sexually active males must use accepted and effective method(s) of contraception or to abstain from sex from time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment. 
• 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 of registration.
• 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.
• Patient must not have a known history of active TB (Bacillus Tuberculosis).
• Patient must not have a history of hypersensitivity to pembrolizumab or any of its excipients.
• Patient must not have received a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to registration or have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Patient must not have had prior chemotherapy, targeted small molecule therapy (aside from imatinib, dasatinib, 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-CNS disease).
• Patients who have received major surgery must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Patient must not have a known additional malignancy that is progressing or requires active treatment. 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.
• 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.
• 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
• Patient must not have known history of, or any evidence of active, non-infectious pneumonitis.
• Patient must not have an active infection requiring systemic therapy.
• 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.
• Patient must not have known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• 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.
• Patients with a known positive test for Hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection may be be enrolled if the viral load by PCR is undetectable with/without active treatment.
• Patients must not have a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive).
• Patient must not have received a live vaccine within 30 days of registration.
  • NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
• Patients must meet the following criteria with all screening labs performed within 14 days prior to registration:
  • Absolute neutrophil count (ANC) ≥ 1,500 /mcL
    • ANC: _________ Date of Test: _________
  • Platelet count ≥ 100,000 /mcL
    • Platelet:_______ Date of Test: _________
  • Hgb ≥ 9.0 g/dL OR ≥ 5.6 mmol/L without transfusion of EPO dependency
    • Hgb:__________ Date of Test:__________
  • Serum creatinine ≤ 1.5 X upper limit of normal (ULN) OR Creatinine clearance (per institutional standards) ≥ 60 mL/min for patient with creatinine levels > 1.5 X ULN
    • Serum creatinine ______________Date of Test: ________
  • or
    • Creatinine clearance: __________ Date of Test: ________
  • Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 X ULN
    • Bilirubin: __________ Institutional ULN: _________ Date of Test: __________
  • AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
    • ALT: _______ Institutional ULN: _________ Date of Test: _______
    • AST:_______  Institutional ULN:_________ Date of Test: _______
• Patients should not be receiving concomitant strong CYP3A4 inducers or inhibitors ≤ 7 days prior to 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 5.5 for TKI dose modifications related to concomitant drugs.
• Patients who received prior allogeneic transplant are not eligible.

REGISTRATION TO TREATMENT (STEP 2)

• Institution has received central BCR-ABL test results confirming MRD positive status at Cycle 16 or 17 or 18 following Step 1 treatment (MMR or deeper but not in CMR in the last two central lab checks before Step 2).
• Patients have an ECOG Performance Status of 0-2.
• 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.
• No current use of corticosteroids. 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.
• No 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).
• 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.
• Patient must not have a known history of active TB (Bacillus Tuberculosis).
• Patient must not have a history of hypersensitivity to pembrolizumab or any of its excipients.
• Women 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. Patients must also not expect to conceive or father children from the time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment
• All females of childbearing potential must have a negative urine or serum pregnancy within 14 days prior to registration on step 2 to rule out a 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 female of childbearing potential is any woman, regardless of sexual orientation or 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; or3) 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).
• Female of child bearing potential? ______ (Yes or No)
  • Date of urine/serum study: ___________
• Women of childbearing potential and sexually active males must use accepted and effective method(s)of contraception or to abstain from sex from time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment. (Refer to Section 5.6.2 for detailed information on contraception requirements while on this study).
• Patient must not have known history of, or any evidence of active, non-infectious pneumonitis.
• Patient must not have an active infection requiring systemic therapy.
• 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.
• 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.
• 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.
• Patients must not have a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive).
• Patient must not have received a live vaccine within 30 days of planned start of study therapy.
  • NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
• Patients must meet the following criteria with all screening labs performed within 14 days prior to registration:
• Absolute neutrophil count (ANC) ≥ 1,500 /mcL
  • ANC:__________ Date of Test:__________
• Platelet count ≥ 100,000 /mcL
  • Platelet:__________ Date of Test:__________
• Hgb ≥ 9.0 g/dL OR ≥ 5.6 mmol/L without transfusion of EPO dependency
  • Hgb:__________ Date of Test:__________
• Serum creatinine ≤ 1.5 X upper limit of normal (ULN) OR Creatinine clearance (per institutional standards) ≥ 60 mL/min for patient with creatinine levels > 1.5 X ULN
  • Serum creatinine ______________Date of Test:________
• or
  • Creatinine clearance:__________ Date of Test:_________
• Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 X ULN
  • Bilirubin:__________ Institutional ULN:_________ Date of Test:__________
• AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
  • ALT: _______ Institutional ULN:_________ Date of Test: _______
  • AST: _______ Institutional ULN:_________ Date of Test: _______
• Patients should not be receiving concomitant strong CYP3A4 inducers or inhibitors ≤ 7 days prior to 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 5.5 for TKI dose modifications related to concomitant drugs.