Precursor Cell Lymphoblastic Leukemia-Lymphoma, Vitamin D Deficiency
Conditions
Keywords
Leukemia, ALL, Vitamin D, Bone Density, Body Fat, Obesity, Adipose
Brief summary
Many adolescents with acute lymphoblastic leukemia (ALL) have been found to have low bone density by the end of treatment. This can lead to long-term suffering in survivors due to poor bone health. Vitamin D is known to be associated with bone health and previous research has established that Vitamin D insufficiency is very common at diagnosis of ALL and worsens over the course of treatment. Researchers have also learned that a relationship exists between both Vitamin D and fat tissue and ALL and fat tissue. In adolescents being treated for ALL as well as in early survivors, this randomized study will therefore examine the effect of Vitamin D and calcium supplementation on correcting Vitamin D insufficiency and on improving bone density in the context of changes in body composition and body fat. Bone density will be measured by a radiology exam called qCT (quantitative computed tomography) while body composition and body fat will be measured by a different radiology exam called a DXA (dual energy x-ray absorptiometry scan) . The study will also examine in depth the relationship between these three elements - Vitamin D insufficiency, obesity, and ALL - and their impact on bone density.
Interventions
DIETARY_SUPPLEMENTVitamin D and Calcium Citrate
Vitamin D (10,000 int.units/ml) 100,000 int. units (10ml) by mouth once every two months x 3 times (total treatment period approximately 6-7 months) Calcium Carbonate (1,000 mg/tab = 400 mg elemental calcium/tab) 2,000 mg (2 chewable tabs) by mouth every day for approximately 6-7 months
Sponsors
The Leukemia and Lymphoma Society
Children's Hospital Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
10 Years to 29 Years
Healthy volunteers
Yes
Inclusion criteria
GROUP A: Patients with newly diagnosed ALL * Are greater than or equal to 10 years of age and less than or equal to 21 years of age at diagnosis of ALL * Have a new diagnosis of untreated ALL classified as high risk per NCI criteria (due to being greater than 10 years of age) * Are beginning treatment with a Children's Cancer Group/Children's Oncology Group high risk protocol with a 4-drug induction including steroids * Are not pregnant GROUP B: Early survivors of ALL * Were treated for ALL and remain in first CR1 (complete remission) * Were equal to or greater than 10 years of age and less than or equal to 21 years of age at diagnosis of ALL * Have completed treatment on or as per a Children's Cancer Group/Children's Oncology Group high risk protocol between 12 and 48 months prior to enrollment in this study (consisting of a plan for a 4-drug induction including steroids in Induction, Delayed Intensification, and steroid pulses in Maintenance. Steroids are allowed to have been discontinued due to toxicity). * Are not pregnant GROUP C: Siblings of Group A * Are either a full-sibling or a half-sibling of a patient in Group A * Are living at the same residence as the sibling/half-sibling from Group A * Are greater than or equal to 10 years of age and less than or equal to 21 years of age at the time of study entry, and within 3 years of the age diagnosis of ALL in the sibling/half-sibling from Group A * Are on the same Vitamin D supplementation regimen (if any) as the sibling from Group A at the time of his or her diagnosis
Exclusion criteria
(All Groups): * Have a diagnosis of Down syndrome (Trisomy 21) or any genetic disease associated with abnormal bone development * Are undergoing treatment with other medicines that affect bones including chronic use of of steroids, bisphosphonate therapy, or Vitamin D at average dose greater than 400 international units (IU)/day * Have an underlying diseases altering body structure (i.e. missing a limb, severe dysmorphism) or severely affecting mobility (i.e. total or hemiparesis) * Have a history of chemotherapy or radiation for other cancers * Cannot complete the radiology exams/radiology exams uninterpretable (i.e. people with a hip replacement or prosthesis)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Vitamin D Level (Group A) | +6 months | Change in Vitamin D levels from baseline to study end (Group A: Consolidation through end of Delayed Intensification) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bone Mineral Density by Quantitative Computed Tomography (QCT) at Study End (Group A) | +6 months | Bone mineral density (vBMD) at end of study period (Group A: end of Delayed Intensification) |
| Change in Vitamin D Level (Group B) | +6 months | Change in serum vitamin D level was assessed in survivors at baseline and after 6 months of supplementation |
| Bone Mineral Density by QCT in Survivors at Study End (Group B) | +6 months | Bone mineral density (vBMD) at end of study period (Group B: after 6 months) |
| Prevalence of Obesity and Vitamin D Insufficiency in Adolescents With Newly Diagnosed ALL and in Their Siblings | 1 timepoint | Insufficiency defined as 25(OH)D \< 30 ng/ml |
Countries
United States
Participant flow
Pre-assignment details
Group A: 2 participants enrolled but did not reach time of randomization (1 induction death, 1 severe toxicity/change in treatment plan) Group B: 2 subjects enrolled but did not reach time of randomization or undergo any study procedures (2 lost to follow-up)
Participants by arm
| Arm | Count |
|---|---|
| On Therapy Intervention (Group A) Subjects randomized following Induction to receive education plus:
Vitamin D and Calcium Citrate: Vitamin D (10,000 int.units/ml) 100,000 int. units (10ml) by mouth once every two months x 3 times (total treatment period approximately 6-7 months) Calcium Carbonate (1,000 mg/tab = 400 mg elemental calcium/tab) 2,000 mg (2 chewable tabs) by mouth every day through study period (total treatment period approximately 6-7 months)P | 19 |
| On Therapy Standard of Care (Group A) Subjects randomized following Induction to receive standard of care with education alone | 10 |
| On Therapy Natural History (Group A) Subjects surviving to end of Induction but ineligible for randomization for any reason | 20 |
| Survivorship Intervention (Group B) Survivors to receive education plus:
Vitamin D and Calcium Citrate: Vitamin D (10,000 int.units/ml) 100,000 int. units (10ml) by mouth once every two months x 3 times (total treatment period approximately 6 months) Calcium Carbonate (1,000 mg/tab = 400 mg elemental calcium/tab) 2,000 mg (2 chewable tabs) by mouth every day through study period (total treatment period approximately 6 months) | 6 |
| Survivorship Standard of Care (Group B) Survivors either randomized to received standard of care with education alone OR vitamin D sufficient and continued for follow-up only. | 13 |
| Siblings (Group C) Healthy siblings of subjects in Group A | 4 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Change in therapy plan | 0 | 0 | 3 | 0 | 0 | 0 |
| Overall Study | Death | 1 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | On Therapy Intervention (Group A) | On Therapy Standard of Care (Group A) | On Therapy Natural History (Group A) | Survivorship Intervention (Group B) | Survivorship Standard of Care (Group B) | Siblings (Group C) | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 15 years | 15 years | 14 years | 19 years | 18 years | 15 years | 15 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 8 Participants | 16 Participants | 5 Participants | 5 Participants | 3 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 2 Participants | 4 Participants | 1 Participants | 3 Participants | 0 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 1 Participants | 6 Participants |
| Region of Enrollment United States | 19 participants | 10 participants | 20 participants | 6 participants | 13 participants | 4 participants | 72 participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 9 Participants | 3 Participants | 3 Participants | 4 Participants | 29 Participants |
| Sex: Female, Male Male | 13 Participants | 6 Participants | 11 Participants | 3 Participants | 10 Participants | 0 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 19 | 0 / 10 | 0 / 6 | 0 / 13 | 0 / 0 |
| other Total, other adverse events | 0 / 19 | 0 / 10 | 0 / 6 | 0 / 13 | 0 / 0 |
| serious Total, serious adverse events | 0 / 19 | 0 / 10 | 0 / 6 | 0 / 13 | 0 / 0 |
Outcome results
Primary
Change in Serum Vitamin D Level (Group A)
Change in Vitamin D levels from baseline to study end (Group A: Consolidation through end of Delayed Intensification)
Time frame: +6 months
Population: Includes subjects in each group evaluable for vitamin D endpoint. Calculation of change = Vitamin D level at study end (end of DI, \~+6 months)/Vitamin D level at baseline (start of consolidation).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| On-Therapy Intervention (Group A) | Change in Serum Vitamin D Level (Group A) | Change in serum Vitamin 25(OH)D level | 5.5 ng/ml | Standard Error 1.7 |
| On-Therapy Intervention (Group A) | Change in Serum Vitamin D Level (Group A) | Post-intervention serum Vitamin 25(OH)D level | 26.5 ng/ml | Standard Error 12.4 |
| On Therapy Standard of Care (Group A) | Change in Serum Vitamin D Level (Group A) | Change in serum Vitamin 25(OH)D level | -0.30 ng/ml | Standard Error 2.2 |
| On Therapy Standard of Care (Group A) | Change in Serum Vitamin D Level (Group A) | Post-intervention serum Vitamin 25(OH)D level | 19.0 ng/ml | Standard Error 7.4 |
| On-Therapy Natural History (Group A) | Change in Serum Vitamin D Level (Group A) | Change in serum Vitamin 25(OH)D level | 1.0 ng/ml | Standard Error 2.6 |
| On-Therapy Natural History (Group A) | Change in Serum Vitamin D Level (Group A) | Post-intervention serum Vitamin 25(OH)D level | 23.3 ng/ml | Standard Error 2.8 |
Secondary
Bone Mineral Density by QCT in Survivors at Study End (Group B)
Bone mineral density (vBMD) at end of study period (Group B: after 6 months)
Time frame: +6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| On-Therapy Intervention (Group A) | Bone Mineral Density by QCT in Survivors at Study End (Group B) | Cortical bone mineral density | 2087.4 cm3 | Standard Deviation 39.3 |
| On-Therapy Intervention (Group A) | Bone Mineral Density by QCT in Survivors at Study End (Group B) | Cancellous bone mineral density | 243.6 cm3 | Standard Deviation 28.7 |
| On Therapy Standard of Care (Group A) | Bone Mineral Density by QCT in Survivors at Study End (Group B) | Cortical bone mineral density | 2049.3 cm3 | Standard Deviation 73 |
| On Therapy Standard of Care (Group A) | Bone Mineral Density by QCT in Survivors at Study End (Group B) | Cancellous bone mineral density | 269.3 cm3 | Standard Deviation 80 |
Secondary
Bone Mineral Density by Quantitative Computed Tomography (QCT) at Study End (Group A)
Bone mineral density (vBMD) at end of study period (Group A: end of Delayed Intensification)
Time frame: +6 months
Population: Subjects enrolled following the change to the open-label randomization were imaged for cortical bone density at the femur, subjects enrolled prior to this in the Natural History group were imaged at the tibia. The change was made for later subjects due to technical reasons to provide a better estimate of cortical density.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| On-Therapy Intervention (Group A) | Bone Mineral Density by Quantitative Computed Tomography (QCT) at Study End (Group A) | Cortical BMD | 2093.1 cm3 | Standard Deviation 62.5 |
| On-Therapy Intervention (Group A) | Bone Mineral Density by Quantitative Computed Tomography (QCT) at Study End (Group A) | Cancellous BMD | 203.8 cm3 | Standard Deviation 77.1 |
| On Therapy Standard of Care (Group A) | Bone Mineral Density by Quantitative Computed Tomography (QCT) at Study End (Group A) | Cortical BMD | 2090.9 cm3 | Standard Deviation 26.7 |
| On Therapy Standard of Care (Group A) | Bone Mineral Density by Quantitative Computed Tomography (QCT) at Study End (Group A) | Cancellous BMD | 201.4 cm3 | Standard Deviation 66.4 |
| On-Therapy Natural History (Group A) | Bone Mineral Density by Quantitative Computed Tomography (QCT) at Study End (Group A) | Cortical BMD | 927.5 cm3 | Standard Deviation 65.3 |
| On-Therapy Natural History (Group A) | Bone Mineral Density by Quantitative Computed Tomography (QCT) at Study End (Group A) | Cancellous BMD | 159.1 cm3 | Standard Deviation 54.9 |
Secondary
Change in Vitamin D Level (Group B)
Change in serum vitamin D level was assessed in survivors at baseline and after 6 months of supplementation
Time frame: +6 months
Population: Change in Vitamin D = Vitamin D at +6months/Vitamin D at baseline
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| On-Therapy Intervention (Group A) | Change in Vitamin D Level (Group B) | Change in serum Vitamin 25(OH)D level | 1.0 ng/ml | Standard Error 2.2 |
| On-Therapy Intervention (Group A) | Change in Vitamin D Level (Group B) | Post-intervention serum Vitamin 25(OH)D level | 26.0 ng/ml | Standard Error 2 |
| On Therapy Standard of Care (Group A) | Change in Vitamin D Level (Group B) | Change in serum Vitamin 25(OH)D level | -1.0 ng/ml | Standard Error 2.1 |
| On Therapy Standard of Care (Group A) | Change in Vitamin D Level (Group B) | Post-intervention serum Vitamin 25(OH)D level | 29.0 ng/ml | Standard Error 2.9 |
Secondary
Prevalence of Obesity and Vitamin D Insufficiency in Adolescents With Newly Diagnosed ALL and in Their Siblings
Insufficiency defined as 25(OH)D \< 30 ng/ml
Time frame: 1 timepoint
Population: Group C: Only four siblings enrolled and arm closed early due to poor accrual. Specimens from this group were not analyzed so no results are available.~Group A: 39 subjects enrolled at diagnosis had Vitamin D testing performed at diagnosis and had results available.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| On-Therapy Intervention (Group A) | Prevalence of Obesity and Vitamin D Insufficiency in Adolescents With Newly Diagnosed ALL and in Their Siblings | 0 Participants |
| On Therapy Standard of Care (Group A) | Prevalence of Obesity and Vitamin D Insufficiency in Adolescents With Newly Diagnosed ALL and in Their Siblings | 36 Participants |