Acute Biphenotypic Leukemia, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Hematopoietic Cell Transplantation Recipient
Conditions
Brief summary
This phase II trial studies how well ibrutinib works in preventing acute leukemia in patients after reduced-intensity conditioning and stem cell transplant. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES: I. To reduce the incidence of relapse at 18 months after reduced-intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) in blast crisis from a historical baseline of 45% to 25%, using ibrutinib maintenance therapy. SECONDARY OBJECTIVES: I. To study the incidence and severity of post-transplant complications in subjects receiving ibrutinib maintenance after allogeneic HCT. II. To study the incidence of infectious complications in subjects receiving maintenance ibrutinib after allogeneic HCT. III. To study the impact of ibrutinib maintenance on minimal residual disease after RIC and allogeneic HCT. IV. To study the impact of maintenance ibrutinib on immune reconstitution and alloreactivity after allogeneic HCT, specifically on Th1/ Th2 polarization, T follicular cell number, T and B cell repertoire, serum immunoglobulin levels, and alloantibody formation. OUTLINE: Beginning 60-90 days after allogeneic HCT, patients receive ibrutinib orally (PO) once daily (QD) for up to 18 months post-transplant in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 2 years.
Interventions
DRUGIbrutinib
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
Sponsors
National Institutes of Health (NIH)
Pharmacyclics LLC.
Andrew Rezvani
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA FOR ENROLLMENT (PRE-TRANSPLANT) * Diagnosis of acute myeloid leukemia (AML), acute biphenotypic leukemia, or acute lymphoblastic leukemia (ALL); CML transformed to blast crisis is eligible * Planned allogeneic HCT using fludarabine phosphate (FLU)/melphalan hydrochloride (MEL) or FLU/busulfan (BU) conditioning * Planned graft versus host disease (GVHD) prophylaxis consisting of tacrolimus (TAC)/methotrexate (MTX) or TAC/sirolimus (SRL) * Human leukocyte antigen (HLA) identical sibling donor, HLA matched unrelated donor, or donor mismatched at 1 HLA allele or antigen * Less than or equal to 5% blasts on bone marrow examination within 60 days of starting conditioning * Age \>= 18 years and =\< 70 years * Able to give informed consent * Subjects will be eligible if their planned conditioning regimen for allogeneic HCT consists of one of the two following standard reduced intensity conditioning regimens: * FLU/MEL: fludarabine phosphate (fludarabine) 120 to 180 mg/m\^2; melphalan hydrochloride (melphalan) =\< 150 mg/m\^2 * FLU/BU: fludarabine 120 to 180 mg/m\^2; busulfan =\< 8 mg/kg orally or =\< 6.4 mg/kg intravenously * Subjects will be eligible if their planned post grafting immunosuppression consists of one of the two following regimens: * TAC/MTX: tacrolimus (oral or intravenous) and intravenous methotrexate administered according to institutional standard practice. * TAC/SRL: tacrolimus (oral or intravenous) and oral sirolimus, administered according to institutional standards of care * INCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION) * Age \>= 18 years * Eastern Cooperative Oncology Group (ECOG) performance status of =\< 2 * Absolute neutrophil count (ANC) \> 0.75 x 10\^9/L * Platelet count \> 50 x 10\^9/L * Hemoglobin \> 8.0 g/dL without transfusion or growth factor support for at least 7 days prior to screening (with the exception of pegylated granulocyte-colony stimulating factor \[G-CSF\] and darbopoietin, which require at least 14 days of abstinence prior to screening) * Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 3.0 x upper limit of normal * Estimated creatinine clearance \>= 30 mL/min via Cockroft-Gault formula * Bilirubin =\< 1.5 x upper limit of normal (unless elevated bilirubin is due to Gilbert's syndrome or of non-hepatic origin) * Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) (activated partial thromboplastin time \[aPTT\]) =\< 1.5 x upper limit of normal * Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no menses for \>= 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy); female subjects of childbearing potential must have a negative serum pregnancy test upon screening * Male and female subjects who agree to use both a highly effective method of birth control (eg, implants, injectables, combined oral contraceptives, some intrauterine devices \[IUDs\], sexual abstinence, or sterilized partner) and a barrier method (eg, condoms, vaginal ring, sponge, etc) during the period of therapy and for 30 days after the last dose of study drug for females and 90 days after the last dose of the study drug for males * Between day +60 and day +90 after allogeneic HCT
Exclusion criteria
*
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Relapsed Leukemia | Up to 18 months | Relapsed leukemia is defined as \> 5% leukemic blasts detected in bone marrow or peripheral blood. Participants were also be considered to have relapsed leukemia if they receive any active treatment for progressive leukemia after allogeneic HCT, even if they have \< 5% leukemic blasts. Withdrawal of immunosuppression alone is not considered an active treatment for progressive disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Acute Graft-versus-host Disease (GVHD) (Any Grade) | At 180 days | Acute GVHD grades II-IV and III-IV was evaluated according to the following criteria. Stage of Acute GvHD was assessed as follows. * Stage 1: Skin: rash \< 25% of skin. Liver: bilirubin 2 to 3 mg/dL. Gut: diarrhea \>500 mL/day or upper-gut symptoms with positive histology * Stage 2: Skin: rash 25 to 50% of skin. Liver: bilirubin 3 to 6 mg/dL. Gut: diarrhea \>1000 mL/day. * Stage 3: Skin: rash \> 50% of skin. Liver: bilirubin 6 to 15 mg/dL. Gut: diarrhea \> 1500 mL/day. * Stage 4: Skin: generalized erythroderma with bulla formation. Liver: bilirubin \> 15 mg/dL. Gut: diarrhea \> 2500 mL/day or severe abdominal pain with or without ileus Grade of Acute GvHD was determined as follows. * Grade 1: Stage 1-2 Skin + No Liver stage + No Gut stage * Grade 2: Stage 3 Skin OR Stage 1 Liver or Stage 1 Gut * Grade 3: No Skin stage + Stage 2 to 3 Liver Stage 2 to 4 Gut * Grade 4: Stage 4 Skin + or Stage 2 to 3 Liver + No Gut stage |
| Number of Participants With Chronic GVHD | At 18 months | Assessment of chronic GvHD was performed using the 2015 NIH consensus criteria. |
| Number of Participants Negative for Detectable Minimal Residual Disease | day +90, day +180, 1 year, 1.5 years | Detectable minimal residual disease was assessed using high-throughput sequencing (ClonoSEQ) and high-sensitivity flow cytometry. Minimal residual disease was considered present if \> 1 x 10\^-6 leukemic clones are detected by ClonoSEQ, or if any aberrant blasts matching the original leukemic immunophenotype are detected by high-sensitivity flow cytometry. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Prevention (Ibrutinib) Beginning 60-90 days after allogeneic HCT, patients receive ibrutinib PO QD for up to 18 months post-transplant in the absence of disease progression or unacceptable toxicity. | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | Prevention (Ibrutinib) |
|---|---|
| Age, Customized 50-59 | 2 Participants |
| Age, Customized 60-69 | 6 Participants |
| Diagnosis Acute leukemia | 4 Participants |
| Diagnosis Acute myeloid leukemia | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment United States | 8 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 8 |
| other Total, other adverse events | 7 / 8 |
| serious Total, serious adverse events | 3 / 8 |
Outcome results
Primary
Number of Participants With Relapsed Leukemia
Relapsed leukemia is defined as \> 5% leukemic blasts detected in bone marrow or peripheral blood. Participants were also be considered to have relapsed leukemia if they receive any active treatment for progressive leukemia after allogeneic HCT, even if they have \< 5% leukemic blasts. Withdrawal of immunosuppression alone is not considered an active treatment for progressive disease.
Time frame: Up to 18 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Prevention (Ibrutinib) | Number of Participants With Relapsed Leukemia | Relapsed | 3 Participants |
| Prevention (Ibrutinib) | Number of Participants With Relapsed Leukemia | Not relapsed | 5 Participants |
Secondary
Number of Participants Negative for Detectable Minimal Residual Disease
Detectable minimal residual disease was assessed using high-throughput sequencing (ClonoSEQ) and high-sensitivity flow cytometry. Minimal residual disease was considered present if \> 1 x 10\^-6 leukemic clones are detected by ClonoSEQ, or if any aberrant blasts matching the original leukemic immunophenotype are detected by high-sensitivity flow cytometry.
Time frame: day +90, day +180, 1 year, 1.5 years
Population: Participants who had minimal residual disease testing at the respective time point.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Prevention (Ibrutinib) | Number of Participants Negative for Detectable Minimal Residual Disease | day +90 | 8 Participants |
| Prevention (Ibrutinib) | Number of Participants Negative for Detectable Minimal Residual Disease | day +180 | 7 Participants |
| Prevention (Ibrutinib) | Number of Participants Negative for Detectable Minimal Residual Disease | 1 year | 5 Participants |
| Prevention (Ibrutinib) | Number of Participants Negative for Detectable Minimal Residual Disease | 1.5 years | 5 Participants |
Secondary
Number of Participants With Acute Graft-versus-host Disease (GVHD) (Any Grade)
Acute GVHD grades II-IV and III-IV was evaluated according to the following criteria. Stage of Acute GvHD was assessed as follows. * Stage 1: Skin: rash \< 25% of skin. Liver: bilirubin 2 to 3 mg/dL. Gut: diarrhea \>500 mL/day or upper-gut symptoms with positive histology * Stage 2: Skin: rash 25 to 50% of skin. Liver: bilirubin 3 to 6 mg/dL. Gut: diarrhea \>1000 mL/day. * Stage 3: Skin: rash \> 50% of skin. Liver: bilirubin 6 to 15 mg/dL. Gut: diarrhea \> 1500 mL/day. * Stage 4: Skin: generalized erythroderma with bulla formation. Liver: bilirubin \> 15 mg/dL. Gut: diarrhea \> 2500 mL/day or severe abdominal pain with or without ileus Grade of Acute GvHD was determined as follows. * Grade 1: Stage 1-2 Skin + No Liver stage + No Gut stage * Grade 2: Stage 3 Skin OR Stage 1 Liver or Stage 1 Gut * Grade 3: No Skin stage + Stage 2 to 3 Liver Stage 2 to 4 Gut * Grade 4: Stage 4 Skin + or Stage 2 to 3 Liver + No Gut stage
Time frame: At 180 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prevention (Ibrutinib) | Number of Participants With Acute Graft-versus-host Disease (GVHD) (Any Grade) | 4 Participants |
Secondary
Number of Participants With Chronic GVHD
Assessment of chronic GvHD was performed using the 2015 NIH consensus criteria.
Time frame: At 18 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prevention (Ibrutinib) | Number of Participants With Chronic GVHD | 3 Participants |