Acute Lymphoblastic Leukemia
Conditions
Brief summary
This multi-center open label clinical trial aims to identify predictors of low antibody titers to vaccine antigens in children with ALL who completed chemotherapy in the prior 6 months, and to determine the immunogenicity and safety of diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis-Haemophilus influenzae type b (DTaP-IPV-Hib) and 13-valent pneumococcal conjugate vaccine (PCV13) booster immunization administered 6 months post-chemotherapy, followed by 23-valent pneumococcal polysaccharide vaccination (PPV23) 2 months later. The results will support the development of clinical practice guidelines for this population.
Detailed description
Rationale and Aims: Children with acute lymphoblastic leukemia (ALL) have evidence of persistent immunosuppression following chemotherapy and may experience waning of immunity to vaccines received prior to treatment. There is no standard of care in Canada regarding immunologic evaluation or booster immunization of children with ALL after chemotherapy. This study aims to identify predictors of low baseline immunity to vaccine antigens in children with ALL and to evaluate the immunogenicity and safety of a standard immunization regimen: DTaP-IPV-Hib and PCV13 booster immunization administered 6 months post-chemotherapy, followed by PPV23. Study Design: This will be a multi-center open-label clinical trial in which children who were diagnosed with ALL at ≥1 year of age, and have not received immunizations other than influenza since completing chemotherapy will undergo immunologic evaluation and serologic testing for pneumococcus, tetanus, pertussis and varicella. They will then be immunized with PCV13, DTaP-IPV-Hib, regardless of immunization history \[unless PPV23 was received within the prior 12 months\]. Other routine vaccines required as per provincial and centre-specific immunization policies will also be administered. PPV23 will be administered 8 weeks after PCV13. Repeat serologic testing will be conducted at 2 months and 12-15 months after DTaP-IPV-Hib and PCV13 immunization to assess short and long-term immune responses. Adverse events following immunization (AEFI) will be captured through standardized telephone interviews on days 8-10 and 30-33 post-immunization that will capture local and systemic AEFI.
Interventions
BIOLOGICALPrevnar®13
A single dose of Prevnar®13 will be administered to subjects with ALL who are 6-12 months post-completion of chemotherapy.
BIOLOGICALPneumovax® 23
A single dose of Pneumovax® 23 will be administered to subjects approximately 2 months after Prevnar®13
BIOLOGICALPediacel®
A single dose of Pediacel® will be administered to subjects with ALL who are 6-12 months post-completion of chemotherapy.
Sponsors
Canadian Immunization Research Network
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 18 Years
Healthy volunteers
Yes
Inclusion criteria
Cases with ALL: Inclusion Criteria: * Diagnosed with standard, high-risk or very-high risk ALL * Age at diagnosis: ≥1 year of age (age at enrollment: ≥3 years) * Completed chemotherapy 3 to 12 months prior to enrollment * No evidence of ALL relapse or secondary malignancy * No known primary immunodeficiency * No receipt of pneumococcal or tetanus-containing vaccines since completing chemotherapy * No history of allergy to any component of PCV13 * Caregiver and/or participant is English or French-speaking and able to provide written informed consent
Exclusion criteria
* Infantile ALL * Evidence of disease relapse or secondary malignancy * History of underlying primary immunodeficiency * Transplant recipient * Received intravenous immunoglobulin (IVIG) within past 9 months or other blood products within the prior 3 months.Children who received PPV23 within 12 months of enrollment will not be eligible to receive PCV13 or PPV23. These children can still participate in the baseline evaluation, receive DTaP-Hib-IPV vaccine, and have tetanus and pertussis serology measured at 2 and 12-15 months post-immunization. Controls: Inclusion criteria * Children 3-18 years of age, age-matched to cases * Caregiver and/or participant is English or French-speaking and able to provide written informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Protective Titres to PCV13 Serotypes Post-immunization With PCV13+PPV23 | Pre-vaccination Baseline, 2 months and 12-15 months | The percentage of participants with protective titres (with protective level defined as ≥0.35 ug/ml, as per World Health Organization criteria) to PCV13 serotypes will be assessed at 2 months and 12-15 months post PCV13+PPV23 and compared to baseline levels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Protective Titres to PCV7 Serotypes at Baseline | Day 0 | The number of participants with protective titres (≥0.35 ug/ml) to PCV7 serotypes at baseline will be compared to age-matched controls. |
| Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Day 0 | Baseline geometric mean titers (GMT) and percentage of subjects with protective titres to pneumococcal serotypes in children with ALL versus age-matched controls. |
| Immune Responses to Pertussis Toxin Following DTaP-IPV-Hib Booster Vaccination | Prevaccination baseline, 2 months, 12-15 months | Baseline, Short-term (baseline - 2 months after vaccination) and long-term (baseline - 12-15 months) vaccine responses to DTaP-IPV-Hib will be measured using GMT ratios. |
| Baseline Pertussis Toxin Titers in Children With ALL Versus Healthy Controls | Day 0 | Baseline geometric mean titers (95% confidence intervals) reported as IU/ml in children with ALL versus controls |
| Baseline Varicella Titers in Children With ALL Versus Controls. | Day 0 | Geometric mean titers (95% confidence interval) in AI (antibody index) |
| Immune Responses to Tetanus Toxoid Following DTaP-IPV-Hib Immunization | baseline, 2 months, 12-15 months | Baseline, short-term (baseline to 2 months after vaccination) and long-term (baseline to 12-15 months) vaccine responses to DTaP-IPV-Hib will be measured using GMTs with 95% confidence intervals |
| Baseline Tetanus Toxoid Antibody Titers in Children With ALL Versus Controls | Day 0 | Baseline geometric mean titers (95% confidence intervals) reported as IU/ml in children with ALL versus controls |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events Following Immunization Requiring Healthcare Visit or Leading to >=1 Day of Disability | days 8-10 and 30-33 | Adverse Events Following Immunization requiring healthcare visit or leading to \>=1 day of disability will be captured through structured telephone interviews on days 8-10 and 30-33 after each immunization |
Countries
Canada
Participant flow
Recruitment details
Participants were recruited based on physician referral across 10 pediatric centres. Controls were recruited at 3 centres. Participants were enrolled between November 2015 to September 2017.
Pre-assignment details
155 of the 156 participants recruited met inclusion criteria. Of the 78 participants with ALL recruited, 1 did not meet inclusion criteria and 3 withdrew consent prior to study start. All of the 78 control participants met inclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Experimental Children who were diagnosed with ALL at ≥1 year of age, and are within 6-8 months of completing chemotherapy will receive 1 dose each of: Prevnar®13 and Pediacel® vaccines, followed by 1 dose of Pneumovax® 23 given 2 months after PCV13.
Prevnar®13: A single dose of Prevnar®13 will be administered to subjects with ALL who are 6-12 months post-completion of chemotherapy.
Pneumovax® 23: A single dose of Pneumovax® 23 will be administered to subjects approximately 2 months after Prevnar®13
Pediacel®: A single dose of Pediacel® will be administered to subjects with ALL who are 6-12 months post-completion of chemotherapy. | 74 |
| Healthy Control Children 3-18 years of age who are not immunocompromised age-matched to cases from Group 1. | 78 |
| Total | 152 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 8 | 0 |
| Overall Study | Screen Failure | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Total | Healthy Control | Experimental |
|---|---|---|---|
| Age, Continuous | 8.2 years | 8.3 years | 8.1 years |
| ALL disease risk category High risk | 27 Participants | — | 27 Participants |
| ALL disease risk category Standard risk | 40 Participants | — | 40 Participants |
| ALL disease risk category Unknown | 1 Participants | — | 1 Participants |
| ALL disease risk category Very high risk | 6 Participants | — | 6 Participants |
| Interval from last chemotherapy to serology | 6 months | — | 6 months |
| Interval from last vaccine to baseline blood draw DTaP/Tdap-containing vaccine | 4.85 years STANDARD_DEVIATION 2.6 | 3.7 years STANDARD_DEVIATION 2.5 | 6.0 years STANDARD_DEVIATION 2.7 |
| Interval from last vaccine to baseline blood draw PCV | 6.3 years STANDARD_DEVIATION 2.85 | 7.2 years STANDARD_DEVIATION 3.4 | 5.4 years STANDARD_DEVIATION 2.3 |
| Interval from last vaccine to baseline blood draw Varicella | 5.85 years STANDARD_DEVIATION 3.7 | 5.2 years STANDARD_DEVIATION 4.2 | 6.5 years STANDARD_DEVIATION 3.2 |
| Lymphocyte subsets at enrollment CD19+ B cells | 0.6 cells x10^9/l | — | 0.6 cells x10^9/l |
| Lymphocyte subsets at enrollment CD3+ T cells | 1.4 cells x10^9/l | — | 1.4 cells x10^9/l |
| Lymphocyte subsets at enrollment CD4+ T cells | 0.8 cells x10^9/l | — | 0.8 cells x10^9/l |
| Lymphocyte subsets at enrollment CD8+ T cells | 0.5 cells x10^9/l | — | 0.5 cells x10^9/l |
| Lymphocyte subsets at enrollment NK cells (CD56+/CD16+) | 0.2 cells x10^9/l | — | 0.2 cells x10^9/l |
| Previous doses of DTaP or Tdap 0 | 2 Participants | 0 Participants | 2 Participants |
| Previous doses of DTaP or Tdap 1-3 | 13 Participants | 1 Participants | 12 Participants |
| Previous doses of DTaP or Tdap 4 | 53 Participants | 17 Participants | 36 Participants |
| Previous doses of DTaP or Tdap ≥5 | 84 Participants | 60 Participants | 24 Participants |
| Previous doses of PCV 0 | 28 Participants | 9 Participants | 19 Participants |
| Previous doses of PCV 1-2 | 12 Participants | 2 Participants | 10 Participants |
| Previous doses of PCV ≥3 | 111 Participants | 66 Participants | 45 Participants |
| Previous doses of PCV Received more than ≥1 dose at ≥12 months of age | 106 Participants | 62 Participants | 44 Participants |
| Previous doses of PCV Received more than ≥1 dose PCV13 | 72 Participants | 38 Participants | 34 Participants |
| Previous doses of PCV Unknown | 1 Participants | 1 Participants | 0 Participants |
| Previous doses of varicella vaccine 0 | 28 Participants | 11 Participants | 17 Participants |
| Previous doses of varicella vaccine 1 | 74 Participants | 26 Participants | 48 Participants |
| Previous doses of varicella vaccine ≥2 | 49 Participants | 40 Participants | 9 Participants |
| Previous doses of varicella vaccine Unknown | 1 Participants | 1 Participants | 0 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Region of Enrollment Canada | 152 Participants | 78 Participants | 74 Participants |
| Sex: Female, Male Female | 75 Participants | 38 Participants | 37 Participants |
| Sex: Female, Male Male | 77 Participants | 40 Participants | 37 Participants |
| Total lymphocyte count at enrollment | 2.3 cells x10^9/l | — | 2.3 cells x10^9/l |
| Total serum IgG at enrollment | 8.5 g/l | — | 8.5 g/l |
| Total white blood cell count at enrollment | 6.5 cells x10^9/l | — | 6.5 cells x10^9/l |
| Treatment Protocol Children's Oncology Group | 49 Participants | — | 49 Participants |
| Treatment Protocol Dana Farber Cancer Institute | 25 Participants | — | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 74 | 0 / 73 |
| other Total, other adverse events | 56 / 74 | 46 / 73 |
| serious Total, serious adverse events | 0 / 74 | 0 / 73 |
Outcome results
Primary
Percentage of Participants With Protective Titres to PCV13 Serotypes Post-immunization With PCV13+PPV23
The percentage of participants with protective titres (with protective level defined as ≥0.35 ug/ml, as per World Health Organization criteria) to PCV13 serotypes will be assessed at 2 months and 12-15 months post PCV13+PPV23 and compared to baseline levels.
Time frame: Pre-vaccination Baseline, 2 months and 12-15 months
Population: Participants analyzed equaled the overall number of ALL participants that completed the study and had analyzable serology collected at 2 months and 12-15 months post-vaccination.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Experimental | Percentage of Participants With Protective Titres to PCV13 Serotypes Post-immunization With PCV13+PPV23 | 2 months post-PCV13 | 40 Participants |
| Experimental | Percentage of Participants With Protective Titres to PCV13 Serotypes Post-immunization With PCV13+PPV23 | 12-15 months post-PCV13 | 22 Participants |
Secondary
Baseline Pertussis Toxin Titers in Children With ALL Versus Healthy Controls
Baseline geometric mean titers (95% confidence intervals) reported as IU/ml in children with ALL versus controls
Time frame: Day 0
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Experimental | Baseline Pertussis Toxin Titers in Children With ALL Versus Healthy Controls | 4.10 EU/ml |
| Healthy Control | Baseline Pertussis Toxin Titers in Children With ALL Versus Healthy Controls | 10.35 EU/ml |
Secondary
Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls
Baseline geometric mean titers (GMT) and percentage of subjects with protective titres to pneumococcal serotypes in children with ALL versus age-matched controls.
Time frame: Day 0
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Experimental | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 1 | 0.19 mg/L |
| Experimental | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 3 | 0.17 mg/L |
| Experimental | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 4 | 0.19 mg/L |
| Experimental | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 6B | 0.38 mg/L |
| Experimental | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 7F | 0.26 mg/L |
| Experimental | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 9V | 0.45 mg/L |
| Experimental | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 14 | 0.46 mg/L |
| Experimental | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 18C | 0.21 mg/L |
| Experimental | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 19F | 0.99 mg/L |
| Experimental | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 23F | 0.29 mg/L |
| Healthy Control | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 18C | 0.49 mg/L |
| Healthy Control | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 1 | 0.52 mg/L |
| Healthy Control | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 9V | 0.92 mg/L |
| Healthy Control | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 3 | 1.01 mg/L |
| Healthy Control | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 23F | 1.15 mg/L |
| Healthy Control | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 4 | 0.54 mg/L |
| Healthy Control | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 14 | 1.76 mg/L |
| Healthy Control | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 6B | 1.20 mg/L |
| Healthy Control | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 19F | 3.21 mg/L |
| Healthy Control | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Pneumococcal Serotype 7F | 0.7 mg/L |
Secondary
Baseline Tetanus Toxoid Antibody Titers in Children With ALL Versus Controls
Baseline geometric mean titers (95% confidence intervals) reported as IU/ml in children with ALL versus controls
Time frame: Day 0
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Experimental | Baseline Tetanus Toxoid Antibody Titers in Children With ALL Versus Controls | 0.16 IU/ml |
| Healthy Control | Baseline Tetanus Toxoid Antibody Titers in Children With ALL Versus Controls | 1.73 IU/ml |
Secondary
Baseline Varicella Titers in Children With ALL Versus Controls.
Geometric mean titers (95% confidence interval) in AI (antibody index)
Time frame: Day 0
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Experimental | Baseline Varicella Titers in Children With ALL Versus Controls. | 0.33 Antibody index |
| Healthy Control | Baseline Varicella Titers in Children With ALL Versus Controls. | 1.00 Antibody index |
Secondary
Immune Responses to Pertussis Toxin Following DTaP-IPV-Hib Booster Vaccination
Baseline, Short-term (baseline - 2 months after vaccination) and long-term (baseline - 12-15 months) vaccine responses to DTaP-IPV-Hib will be measured using GMT ratios.
Time frame: Prevaccination baseline, 2 months, 12-15 months
Population: A total of 73 participants received DTaP-IPV-Hib, 67 provided a follow up sample at 2 months post-vaccination and 66 provided a follow up sample at 12 months post-vaccination.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Experimental | Immune Responses to Pertussis Toxin Following DTaP-IPV-Hib Booster Vaccination | Pre-vaccination Baseline | 4.10 EU/ml |
| Experimental | Immune Responses to Pertussis Toxin Following DTaP-IPV-Hib Booster Vaccination | Baseline - 2 months post-vaccination | 30.67 EU/ml |
| Experimental | Immune Responses to Pertussis Toxin Following DTaP-IPV-Hib Booster Vaccination | Baseline - 12-15 months post-vaccination | 10.39 EU/ml |
Secondary
Immune Responses to Tetanus Toxoid Following DTaP-IPV-Hib Immunization
Baseline, short-term (baseline to 2 months after vaccination) and long-term (baseline to 12-15 months) vaccine responses to DTaP-IPV-Hib will be measured using GMTs with 95% confidence intervals
Time frame: baseline, 2 months, 12-15 months
Population: Participants with analyzable data at each timepoint were included
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Experimental | Immune Responses to Tetanus Toxoid Following DTaP-IPV-Hib Immunization | Pre-vaccination Baseline | 0.16 IU/ml |
| Experimental | Immune Responses to Tetanus Toxoid Following DTaP-IPV-Hib Immunization | Baseline - 2 months post-vaccination | 4.00 IU/ml |
| Experimental | Immune Responses to Tetanus Toxoid Following DTaP-IPV-Hib Immunization | Baseline - 12-15 months post-vaccination | 1.08 IU/ml |
Secondary
Number of Participants With Protective Titres to PCV7 Serotypes at Baseline
The number of participants with protective titres (≥0.35 ug/ml) to PCV7 serotypes at baseline will be compared to age-matched controls.
Time frame: Day 0
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental | Number of Participants With Protective Titres to PCV7 Serotypes at Baseline | 4 Participants |
| Healthy Control | Number of Participants With Protective Titres to PCV7 Serotypes at Baseline | 30 Participants |
Other Pre-specified
Number of Participants With Adverse Events Following Immunization Requiring Healthcare Visit or Leading to >=1 Day of Disability
Adverse Events Following Immunization requiring healthcare visit or leading to \>=1 day of disability will be captured through structured telephone interviews on days 8-10 and 30-33 after each immunization
Time frame: days 8-10 and 30-33
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Experimental | Number of Participants With Adverse Events Following Immunization Requiring Healthcare Visit or Leading to >=1 Day of Disability | Possibly related to vaccination | 3 Participants |
| Experimental | Number of Participants With Adverse Events Following Immunization Requiring Healthcare Visit or Leading to >=1 Day of Disability | Unrelated to vaccination | 7 Participants |
| Experimental | Number of Participants With Adverse Events Following Immunization Requiring Healthcare Visit or Leading to >=1 Day of Disability | No AEFI requiring healthcare visit or leading to >=1 day of disability | 64 Participants |