Venetoclax Added to Fludarabine + Busulfan Prior to Transplant for AML, MDS, and MDS/MPN

- This research study is a Phase I clinical trial, which tests the safety of an
investigational drug and tries to define the appropriate dose and schedule of the
investigational drug to use for further studies. "Investigational" means that the drug
is being studied.

- In this research study, investigators are trying to determine a safe dose of the study
drug, Venetoclax, when given in combination with a standard chemotherapy.

- There are two phases in this research study:

- The first phase of the study is called the Dose-Escalation phase where venetoclax
will be given in different doses until the safest maximum dose has been identified.

- The second phase of the study is call the Dose-Expansion phase where more
participants will be treated at this dose level to obtain additional information on
safety. For both the Dose-Escalation or Dose-Expansion phase of this study, there
will be a screening period, a pre-transplant period, a transplant period, and a
post-transplant follow up period.

- In this research study, participants will receive venetoclax plus chemotherapy. This
chemotherapy is called the "conditioning regimen", which is treatment required to
prepare the body for bone marrow transplantation). The conditioning regimen chemotherapy
will suppress the immune system and may help to destroy cancer cells. During this
process normal bone marrow cells are destroyed as well, thus making way for donor stem
cells.

-- Fludarabine and busulfan (FluBu2) are both chemotherapies that will be given as a
part of the conditioning regimen.

- The FDA (U.S. Food and Drug Administration) has not approved Venetoclax for this
specific disease, but it is approved for other uses. Venetoclax is an oral drug that
selectively inhibits Bcl-2, which is critical for keeping cancer cells alive.

Inclusion Criteria:

- Age 18 years and older.

- Patients must have a prior diagnosis of one of the following:

- (Note: Mutational and cytogenetic studies performed at sites other than
Dana-Farber Cancer Institute or Brigham and Women's Hospital will require review
of the outside cytogenetic and/or molecular pathology reports by the overall PI.)

- High-risk MDS, which is defined as IPSS Intermediate-2, IPSS High, or the
presence of a mutation in TP53, JAK2, or those in the RAS pathway including
NRAS, KRAS, PTPN11, CBL, NF1, RIT1, FLT3, and KIT

- High-risk AML, which is defined as one of the following subsets:

- AML with adverse risk disease according to ELN guidelines including one
of the following features:

- a history of mutation in TP53, RUNX1, or ASXL1

- t(6;9)(p23;q34.1); DEK-NUP214

- t(v;11q23.3); KMT2A rearranged

- t(9;22)(q34.1;q11.2); BCR-ABL1

- inv(3)(q21.3q26.2) or t(3;3)(q21.3;26.2); GATA2,MECOM(EVI1)

- -5 or del(5q)

- -7

- -17/abn(17p)

- Complex karyotype

- Monosomal karyotype

- Wild-type NPM1 and FLT3-ITDhigh

- Secondary AML, which is defined as a history of antecedent hematologic
disorder (an MPN or MDS), a diagnosis of therapy-related myeloid
neoplasm including t-MDS and t-AML, or AML with myelodysplasia-related
changes, OR

- "Secondary-type" AML, which is defined by the presence of a mutation in
any of the following eight genes including SRSF2, SF3B1, U2AF1, ZRSR2,
ASXL1, EZH2, BCOR, or STAG2

- High-risk chronic myelomonocytic leukemia (CMML) or MDS/MPN unclassifiable
(MDS/MPN-U), which is defined by the presence of trisomy 8, chromosome 7
abnormalities or complex karyotype (3 or more abnormalities); or by the
presence of a mutation in ASXL1

- Measurable disease is not required for eligibility.

- Patient is determined to be a suitable candidate for an allo-HCT using a reduced
intensity conditioning (RIC) regimen using peripheral blood stem cell as stem
cell source.

- Patient must have a matched related or an 8/8 unrelated donor option for his/her
allo-HCT.

- Patient must have an ECOG performance status ≤ 2

- There are no limitations or minimum on the amount of prior therapy for patient's
advanced myeloid malignancy. Prior exposure to venetoclax is allowed.

- Patient must have normal organ function as defined below:

- Total bilirubin ≤ 2.0 x institutional upper limit of normal (In patients
with Gilbert's Syndrome, Total Bilirubin ≥ 2.0 is permitted.)

- AST(SGOT)/ALT(SGPT) ≤ 3 × institutional upper limit of normal

- Creatinine ≤ 2 mg/dL

- The effects of venetoclax on the developing human fetus are unknown. For this
reason, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in
this study, she should inform her treating physician immediately. Men treated or
enrolled on this protocol must also agree to use adequate contraception prior to
the study, for the duration of study participation, and 4 months after completion
of venetoclax administration. For women who are of child-bearing potential, they
must have a negative serum beta-HCG (human chorionic gonadotropin) test to be
eligible.

- Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

- Patients with > 10% blasts on bone marrow biopsy.

- Patients recommended to receive a myeloablative conditioning regimen prior to
transplantation (since there is a known survival advantage for AML using higher
intensity).

- Patients who have a history of prior allogeneic stem cell transplantation.

- Patients who have had chemotherapy (with the exception of hydroxyurea and/or
dexamethasone) or radiotherapy or investigational therapy within 14 days prior to
starting treatment on study. Exception: Patients on FLT3 small molecule inhibitors can
stay on this treatment up until 7 days prior to first treatment dose on study.

- Symptomatic or untreated known CNS involvement of disease

- Patients with active heart disease (New York Heart Association class 3-4 as assessed
by history and physical exam, or a critical event including unstable
angina/stroke/myocardial infarction within the last 6 months prior to first dose on
study).

- Patients who receive a medication that is a strong or moderate CYP3A inhibitor or
inducer within 7 days prior to the first dose of study drug. Note: Patients may
receive these CYP3A agents starting 3 days after the last dose of venetoclax on study
if clinically necessary.

- Malabsorption syndrome or other clinically significant condition that would preclude
enteral administration.

- Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that in the opinion of the investigator may increase the risk associated
with study participation or investigational product administration or may interfere
with the interpretation of study results and/or would make the patient inappropriate
for enrollment into this study.

- Patients with known active hepatitis B virus (HBV) infection should be excluded
because of potential effects on immune function and/or drug interactions. However, if
a patient has HBV history with an undetectable HBV load by polymerase chain reaction
(PCR), no liver-related complications, and is on definitive HBV therapy that is not
contraindicated on this study, then he/she would be eligible for study.

- Patients with known active hepatitis C virus (HCV) infection. However, if a patient
with a history of HCV infection has received definitive therapy (and is now HCV viral
load negative), or if a patient has a reactive HCV antibody test but has an
undetectable viral load by PCR, then he/she would be eligible.

- Patients with known active HIV infection out of concern for the drug-drug interaction
with venetoclax and HAART therapy.