Abstract
Background:
Survival of children and adolescents with high-risk mature B-cell non-Hodgkin lymphoma (B-NHL) is improved by the addition of rituximab to chemotherapy. The impact of rituximab on immune reconstitution post therapy has not been well described. Herein we report the results of the prespecified, secondary aim of the Inter-B-NHL Ritux study evaluating the immune impacts of the addition of rituximab to intensive chemotherapy.
Methods:
The Inter-B-NHL Ritux 2010 study was an international, randomized, phase 3 trial in children with high-risk, mature B-cell NHL, comparing event free survival between those receiving chemotherapy (chemo) or chemotherapy with rituximab (R-chemo). Measures of immune status were completed at baseline, end of treatment and one year, and yearly thereafter until normalized. The primary endpoints were the rates of low lymphocyte count and immunoglobulin level at one year from the start of therapy. Per protocol analyses compared those randomized to receive R-chemo versus chemo only.
Findings:
From December 2011 to June 2017, a total of 421 patients < 18 years of age with high-risk mature B-cell NHL were enrolled and have immune data at diagnosis and/or during follow-up. At diagnosis, 99/290 (34%) patients (excluding patients with blasts in blood) had lymphopenia and 178/368 (48%) had hypogammaglobulinemia. Post therapy, those randomized to receive R-chemo were more likely to have lymphopenia (86/106 (81%) vs 53/89 (60%), odds ratio (OR) = 2.92 (95%CI 1.53; 5.57), p=0.00091), B-cell lymphopenia (72/75 (96%) vs 36/56 (64%), OR = 13.33 (95%CI 3.71; 47.84), p<0.0001), and hypogammaglobulinemia (67/95 (71%) vs 37/79 (47%), OR = 2.72 (95%CI 1.45; 5.07), p=0.0015). Differences remained at one year for hypogammaglobulinemia only (52/94 (55%) vs 16/63 (25%), OR = 3.64 (95%CI 1.81; 7.31), p=0.00021). Patients in the R-chemo arm were more likely to receive immunoglobulin replacement, mainly due to low immunoglobulin level (26/164 (16%) vs 9/158, (7%), HR=2.63 (95%CI 1.23; 5.62), p=0.010). One patient, in the R-chemo arm, had a life-threatening infection post therapy. Patients in both arms had loss of protective serologies to vaccines.
Interpretation:
Children with high-risk mature B-cell NHL receiving chemotherapy with rituximab are at risk for prolonged hypogammaglobulinemia though severe infections are rare. Strategies for immunoglobulin replacement and revaccination are needed.
Funding:
The Clinical Research Hospital Program of the French Ministry of Health, the Cancer Research UK, the National Institute for Health Research Clinical Research Network, and Children’s Cancer Foundation Hong Kong, the U.S. National Cancer Institute, and by F. Hoffmann-La Roche-Genentech. ClinicalTrials.gov number NCT01516580
INTRODUCTION
Rituximab is a chimeric monoclonal antibody directed at CD20 and is now a standard component of therapy in both adult and pediatric patients with diffuse large B-cell and Burkitt lymphoma. 1–5
The addition of rituximab to chemotherapy has not been associated with an increase in severe infectious toxicity during therapy in studies and meta-analyses of studies in adult lymphoma patients.6,7 In children and adolescents, the randomized Inter-B-NHL-Ritux 2010 trial showed that, during therapy, life threatening (grade ≥ 4) febrile neutropenia occurred in 11.7% of patients in the chemo with rituximab group versus 6.5% of those in the chemo alone group (p=0.11). Grade ≥ 4 infectious events occurred in 18.5% of patients in the chemo with rituximab group versus 11.1% of those in the chemo alone group (p=0.07).1
The longer-term impact of the addition of rituximab to chemotherapy for patients with mature B-cell lymphoma on risks of secondary immunodeficiency is less clear. A study of adult survivors of diffuse large B-cell lymphoma (DLBCL) demonstrated a higher risk of infection, autoimmune diseases and immunodeficiencies compared to adults treated for other cancers.8 In this population of survivors the risk of humoral immunodeficiency was significantly higher in those patients with DLBCL treated in the period of time when rituximab was a standard component of therapy compared to those treated in the prerituximab period.8
Rituximab causes a rapid depletion of CD20 positive B-cells in the peripheral blood with variable but often prolonged time to reconstitution and secondary drug induced hypogammaglobulinemia.9 The kinetics of B-cell recovery in pediatric patients may not be the same as those described in adults given age dependent development of the plasma cell compartment.10 The impact of the addition of rituximab on immune function post completion of intensive lymphoma therapy in children and adolescents has not been well described. A prespecified, secondary aim of Inter-B-NHL-Ritux 2010 was to assess the impact of the addition of rituximab to conventional chemotherapy on laboratory correlates of immune function post completion of active treatment. Herein we describe these results.
METHODS
Study Design and Participants
The primary study was accomplished by two international pediatric oncology cooperative groups, the European Inter-group for Childhood Non-Hodgkin Lymphoma (EICNHL) and the Children’s Oncology Group (COG) and included 12 countries. It was an open-label randomized study that compared an intensive pediatric chemotherapy backbone, modified from the FAB/LMB96-based trial therapy (chemo group) to the same FAB/LMB96-based therapy with rituximab (R-chemo group).1 The study protocol was approved in each participating country by the relevant ethics and regulatory committees. Parents and, if appropriate based on age, patients, signed informed consent and assent forms prior to enrolment. Details of the randomization procedures have been previously reported.1 After a planned interim analysis showed superiority of the event free survival of the R-chemo arm the independent data and safety committee recommended stopping further randomization. A single arm cohort of 120 patients were enrolled and non-randomly assigned to R-chemo in Europe and Hong-Kong to allow for completion of prespecified secondary aims. The 33 patients who were still receiving chemotherapy after the closure of randomization were recommended to receive rituximab regardless of the randomly assigned group (cross-over part of the study). The 14 eligible patients of R-chemo arm of this part of the study with immune data available and the 118 eligible patients of the single arm cohort were included in the immune study as “additional R-chemo” (Figure 1) group.
Figure 1. Patient distribution for the secondary immunity analysis.
N=number of patients eligible for immunity analysis. Ly=number (%) of patients with available data on total lymphocyte counts. Ig=number (%) of patients with available data on IgG, IgA, or IgM.
*Rituximab recommended after patients had started on study treatments. †St Jude staging system. ‡Not included in the randomised chemotherapy alone group to maintain comparability.
Measurement of immune outcomes was a prespecified, secondary aim of the trial and included evaluation at baseline, end of therapy, one year post diagnosis and annually until normalization of both immunoglobulin levels and lymphocytes subsets. In addition, data were collected on immunoglobulin infusions, infections and presence of protective antibody titers for five vaccine preventable diseases.
Patients aged 6 months to 18 years with newly diagnosed high-grade, mature B-cell neoplasms (Burkitt, DLBCL or high-grade mature B-cell NHL not otherwise specified) and St Jude stage III disease with an LDH > twice the adult institutional upper limit of the normal value, or with stage IV disease and/or leukemic presentation were eligible. Patients with primary mediastinal (thymic) large B-cell lymphoma were not eligible. 1 Of note, patients with known congenital immunodeficiency, HIV infection, or who were identified as hepatitis B carriers and patients with prior exposure to rituximab were ineligible as were patients who had received anti-cancer treatment except corticosteroids of less than 7 days duration in total. Patients who were pregnant or lactating were excluded based on the toxicities of the chemotherapy regimen. There were no exclusions based on performance status or laboratory based measurements of organ function.
Disease response evaluation criteria were defined in the protocol, with disease progression or relapse being any increase of more than 25% in the product of the two largest diameters of any measurable lesion, the appearance of new lesions or the appearance or reappearance of Burkitt cells or tumoral large cells in bone marrow or CSF.
Procedures
The details of the treatment protocol have been published previously.1 After a pre-phase of low-dose cyclophosphamide, vincristine, and prednisone, patients received 4 to 6 courses (according to disease stage) of intensive polychemotherapy. Rituximab was given as an IV infusion (375 mg/m2) on day two prior (day −2) and day 1 of each of the two induction chemotherapy courses and on day 1 of each of the two consolidation courses, for a total of 6 doses.
Baseline, prior to treatment initiation, assessment of immune status included total peripheral blood lymphocyte count and CD19+CD20+ B-cell enumeration by flow cytometry, serum IgG, IgA and IgM levels and measurement of serum antibodies to specific vaccines (Polioviruses, Tetanus, Diphtheria toxoids, Pneumococcus and Haemophilus influenzae). Peripheral blood count evaluation of other lymphocyte subsets (CD3+, CD3+CD4+, CD3+CD8+, as well as CD3−CD16+ (or CD3-CD56+, or CD3-CD16+CD56+) NK cells) using flow cytometry was optional. These tests were performed in the institutional clinical laboratories. Normative age-related cell count and immunoglobulin values were used according to reference standards 11,12 (appendix p 1-2). For IgG and IgA, three levels of decrease (mildly, moderately and severely) were defined by the following thresholds: for IgG, if age ≤ 10 years, lower limit of the normal range (LLN), 4 g/L and 2 g/L, if age > 10 years, LLN, 5 g/L and 2 g/L; for IgA, if age ≤ 10 years, LLN, 0.2 g/L and 0.1 g/L, if age > 10 years, LLN, 0.4 g/L and 0.2 g/L. For IgM, two levels of decrease (mildly and severely) were defined by the following thresholds: if age ≤ 10 years, LLN and 0.1 g/L, if age > 10 years, LLN and 0.2 g/L. For CD19+CD20+ B-cells, severely low was defined as an absolute value of < 100 count/mm3, and for CD3+ CD4+ T-cells severely low was defined as an absolute value of < 200 count/mm3.
The same panel of immune assessments was collected at the end of therapy (2 months after the start of the last course of chemotherapy) and at one year from study entry. The protocol specified collection of these studies at one year from study entry and then yearly if not normalized. For those patients with abnormal immunoglobulin and lymphocyte subset values at the one-year timepoint, follow up was requested annually up to 5 years post diagnosis or until values normalized.
Serum antibodies to vaccine preventable infections were considered positive if they were classified as being in the protective range by the respective clinical laboratory’s reference specifications. The protocol did not prescribe revaccination though suggested live vaccines not be administered until recovery of B-cells and that non-live vaccines could proceed according to institutional standards.
The protocol recommended that not only a significant low level of immunoglobulins but the occurrence of severe or recurrent infections should be considered for decision making regarding use of immunoglobulin replacement therapy, in addition to referring investigators to their respective national guidelines, if available.
All CTCAE version 4 grade 3 and higher non-haematologic toxicities, including infectious toxicities were captured during each cycle of chemotherapy and in prespecified post therapy time periods. Evaluations for autoimmune conditions were not a prespecified outcome and specific data were not collected. Amongst European patients only, for those with at least one clinically relevant low immunoglobulin level reported after therapy, additional data were collected for infectious events of any grade to identify those who may have experienced clinically important but lower grade infectious adverse events. Additionally the case report form was amended (16/5/2014) to capture neutrophil counts in follow up in European patients to assess post treatment neutropenia.
Outcomes
The primary endpoint of the Inter-B-NHL Ritux 2010 study, the event free survival of patients who received rituximab in addition to LMB chemotherapy regimen versus LMB chemotherapy alone, has been reported previously.1 Secondary endpoints were 1) the complete remission rate and the overall survival between randomized arms, 2) safety of therapy including grade 3 and higher non-haematologic adverse events and 3) the immune impacts of therapy including the rate of patients with low immunoglobulin levels and lymphocyte counts at one year from study entry. Sample size was estimated for the primary endpoint analysis. Herein we report the immune impact outcomes of lymphocyte enumeration (total and subset) and immunoglobulin levels at baseline, end of therapy and one year from study entry. Additional outcomes reported are the prevalence of vaccine preventable infection protective serology and the exposure to immunoglobulin replacement therapy and indications for use of this treatment.
Statistical Analysis
Comparisons between the R-chemo arm and chemo arm were restricted to the randomized part of the study. Patients in the crossover group (n=15) who received different rituximab doses were not included in the analyses in order to perform the analyses among patients with the same schedule of rituximab administration, as per the original trial protocol. Comparisons were performed using chi-square test or Fisher exact test. Odds-ratios for R-chemo group versus chemo group were estimated in logistic regression models. In addition, a descriptive analysis of all patients who received R-chemo was performed to improve estimation accuracy in these patients. Patients with bone marrow involvement and blasts in the peripheral blood were removed from peripheral blood count analyses at the baseline. Patients with events, defined as relapse, progressive disease, second cancer, detection of residual viable tumor cells after the second consolidation course (ie primary refractory disease) or death from any cause were included only in the analyses of baseline data of cell counts and immunoglobulin levels in order to avoid disturbing the study of rituximab effect on immunity parameters by the effect of second line chemotherapy on immunity.
A post hoc analysis of the associations between initial patient and disease characteristics and IgG level at one-year was performed using logistic regression. In case of missing data, the analyses were performed only in patients with available data. Data availability is presented in appendix (appendix, pages 8,9). In the comparative randomized part of the study, sensitivity analyses using multiple imputation were done for the three main endpoints (total lymphocyte count, B-cell count and IgG level) at the completion of therapy and at one year from study entry.
Analyses were done with SAS (version 9.4).
The data cut-off for this analysis was March 23, 2022 for EICNHL patients and September 30, 2019 for those from COG.
This study is registered with Clinicaltrials.gov NCT01516580.
Role of the funding source
The funders of the study had no roles in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
RESULTS
Between December 19, 2011 and June 13, 2017 there were 482 total patients enrolled at 176 participating centers (Fig 1). In the randomized portion (n=289) the median follow up was 58.3 months (IQR 43–65 months) and in the additional non randomized R-chemo portion (n=132) the median follow up was 49.9 months (IQR 36–59 months). In the randomized portion, sixteen eligible patients initially assigned to the chemotherapy only arm were, following the interim analysis, assigned to receive rituximab. Fifteen of them received rituximab but these patients were not included in this analysis because they initiated rituximab at variable points during therapy and received a range of total doses. Ten additional patients were not included in this analysis, seven were deemed ineligible based on histology or disease stage, two who were in the chemo arm but received rituximab and one consent withdrawal. Additionally, 35 patients had no lymphocyte or immunoglobulin data submitted. Hence there were 421 total patients included in this analysis.
Characteristics of the 421 patients are described in Table 1.
Table 1:
Patient clinical and laboratory characteristics at baseline
| Randomized chemo (n=142) | Randomized R-chemo (n=147) | Additional R-chemo* (n=132) | All R-chemo** (n=279) | All patients (n=421) | |
|---|---|---|---|---|---|
| Patient and disease features | |||||
|
| |||||
| Biologic sex | |||||
| Male | 120 (85%) | 122 (83%) | 102 (77%) | 224 (80%) | 344 (82%) |
| Female | 22 (15%) | 25 (17%) | 30 (23%) | 55 (20%) | 77 (18%) |
| Age (years), mean (std dev),[range] | 8.4 (4.3) [2; 17] | 9.1 (4.0) [2; 17] | 8.9 (4.1) [2; 17] | 9.0 (4.0) [2; 17] | 8.8 (4.1) [2; 17] |
| < 6 years | 51 (36%) | 40 (27%) | 39 (30%) | 79 (28%) | 130 (31%) |
| 6-< 12 years | 59 (42%) | 67 (46%) | 59 (45%) | 126 (45%) | 185 (44%) |
| ≥ 12 years | 32 (23%) | 40 (27%) | 34 (26%) | 74 (27%) | 106 (25%) |
| Pathological diagnosis | |||||
| Burkitt lymphoma | 125 (88%) | 127 (86%) | 121 (92%) | 248 (89%) | 373 (89%) |
| DLBCL | 12 (8%) | 17 (12%) | 10 (8%) | 27 (10%) | 39 (9%) |
| High grade B-cell lymphoma, NOS | 5 (4%) | 3 (2%) | 1 (1%) | 4 (1%) | 9 (2%) |
| Prognosis group | |||||
| Group B high-risk | 74 (52%) | 72 (49%) | 61 (46%) | 133 (48%) | 207 (49%) |
| Group C without CSF blasts (C1) | 55 (39%) | 60 (41%) | 53 (40%) | 113 (41%) | 168 (40%) |
| Group C with CSF blasts (C3) | 13 (9%) | 15 (10%) | 18 (14%) | 33 (12%) | 46 (11%) |
| Stage (Murphy Stage) | |||||
| Stage III | 66 (46%) | 64 (44%) | 53 (40%) | 117 (42%) | 183 (43%) |
| Stage IV | 28 (20%) | 28 (19%) | 35 (27%) | 63 (23%) | 91 (22%) |
| Leukemic disease (B-AL) | 48 (34%) | 55 (37%) | 44 (33%) | 99 (35%) | 147 (35%) |
| Bone marrow involvement | |||||
| No | 79 (56%) | 81 (55%) | 70 (53%) | 151 (54%) | 230 (55%) |
| Yes | 63 (44%) | 66 (45%) | 62 (47%) | 128 (46%) | 191 (45%) |
|
| |||||
| Lymphocyte$ and immunoglobulin values | |||||
|
| |||||
| Total lymphocytes, N | 104 | 105 | 81 | 186 | 290 |
| Low, N (%) | 33 (32%) | 37 (35%) | 29 (36%) | 66 (35%) | 99 (34%) |
| CD19+CD20+ B-cells, N | 73 | 71 | 44 | 115 | 188 |
| Mildly Low, N (%) | 16 (22%) | 21 (30%) | 6 (14%) | 27 (23%) | 43 (23%) |
| Severely low, N (%) | 11 (15%) | 9 (13%) | 4 (9%) | 13 (11%) | 24 (13%) |
| CD3+ T-cells, N | 49 | 57 | 38 | 95 | 144 |
| Low, N (%) | 31 (63%) | 37 (65%) | 27 (71%) | 64 (67%) | 95 (66%) |
| CD3+CD4+ T-cells, N | 40 | 49 | 36 | 85 | 125 |
| Mildly Low, N (%) | 18 (45%) | 21 (43%) | 17 (47%) | 38 (45%) | 56 (45%) |
| Severely low, N (%) | 6 (15%) | 8 (16%) | 5 (14%) | 13 (15%) | 19 (15%) |
| CD3+CD8+ T-cells, N | 40 | 49 | 36 | 85 | 125 |
| Low, N (%) | 26 (65%) | 34 (69%) | 20 (56%) | 54 (64%) | 80 (64%) |
| NK-cells, N | 32 | 38 | 35 | 73 | 105 |
| Low, N (%) | 20 (62%) | 19 (50%) | 17 (49%) | 36 (49%) | 56 (53%) |
| Immunoglobulin IgG, N | 124 | 132 | 112 | 244 | 368 |
| Mildly Low, N (%) | 32 (26%) | 30 (23%) | 35 (31%) | 65 (27%) | 97 (26%) |
| Moderately low, N (%) | 21 (17%) | 29 (22%) | 19 (17%) | 48 (20%) | 69 (19%) |
| Severely low, N (%) | 3 (2%) | 7 (5%) | 2 (2%) | 9 (4%) | 12 (3%) |
| IgA, N | 121 | 133 | 110 | 243 | 364 |
| Mildly Low N (%) | 5 (4%) | 15 (11%) | 6 (5%) | 21 (9%) | 26 (7%) |
| Moderately low N (%) | 6 (5%) | 3 (2%) | 5 (5%) | 8 (3%) | 14 (4%) |
| Severely low N (%) | 0 (0%) | 2 (2%) | 2 (2%) | 4 (2%) | 4 (1%) |
| IgM, N | 123 | 133 | 111 | 244 | 367 |
| Mildly Low N (%) | 10 (8%) | 18 (14%) | 19 (17%) | 37 (15%) | 47 (13%) |
| Severely low, N (%) | 1 (1%) | 5 (4%) | 1 (1%) | 6 (2%) | 7 (2%) |
Non-comparative R-chemo group: patients of the cross-over and single arm parts;
All R-chemo group includes patients of the randomized R-chemo and Non-comparative R-chemo groups;
Excluding patients with bone marrow disease with peripheral blasts at the time of diagnosis for lymphocyte counts.
For total lymphocytes, CD3+ T cells, CD3+CD8+ T-cells and NK cells low is less than the lower limit of the normal (LLN) range for age; for CD19+20+ B-cells mildly low is <LLN and ≥ 100 / mm3, and severely low is < 100 / mm3 ;
for CD3+CD4+ T-cells mildly low is < LLN and ≥ 200 / mm3 and severely very low is < 200 / mm3 ;
for IgG mildly low is < LLN and (≥ 4 g/L if age ≤ 10y or ≥ 5 g/L if age >10y), moderately low is ≥ 2 g/L and (< 4 g/L if age ≤ 10y or < 5 g/L if age >10y), severely low is < 2 g/L;
for IgA mildly low is < LLN and (≥ 0.2 g/L if age ≤ 10y or ≥ 0.4 g/L if age >10y), moderately low is ≥ 0.1 g/L and < 0.2 g/L if age ≤ 10y or ≥ 0.2 g/L and < 0.4 g/L if age >10y and severely low is < 0.1 g/L if age ≤ 10y or < 0.2 g/L if age>10y;
for IgM mildly low is < LLN and (≥ 0.1 g/L if age ≤ 10y or ≥ 0.2 g/L if age >10y) and severely low is< 0.1 g/L if age ≤ 10y or < 0.2 g/L if age >10y,
NK cells are identified as those that are CD3−CD16+ or CD3−CD56+
At baseline the R-chemo and chemo randomized patient groups were similar in percentages of patients with low total lymphocytes, B-cells, T-cells or NK-cells in the peripheral blood (Table 1). Excluding patients with bone marrow disease with peripheral blasts at the time of diagnosis, 34% (99/290) patients had lymphopenia with 13% (24/188) with severely low CD19+20+ B-cells (< 100/mm3) and 15% (19/125) with severely low CD3+CD4+ T-cells (<200/mm3).
The randomized R-chemo and chemo groups were similar in terms of the percentage of patients with low immunoglobulin levels with 48% (178/368) of all patients having IgG levels less than the lower limit of normal for age (Table 1). Of these patients, a small subset (N=12) had severely low immunoglobulin (IgG levels of < 2g/L) including 3/124 (2%) in the chemo group and 7/132 (5%) in the R-chemo group and 2/122 (2%) in the additional R-chemo cohort. A very small number across all groups had severely low IgA (n=4) and/or IgM (n=7) levels at baseline. Blood cell counts and Ig levels at inclusion according to bone marrow (BM) involvement and presence of blasts in blood are presented in the appendix (appendix page 10).
At one month after the end of therapy, those randomized to receive R-chemo versus chemo alone were more likely to have lymphopenia, B-cell lymphopenia and severely low B-cell lymphopenia (Table 2). At one-year post start of therapy these differences between the two groups were no longer apparent. The percentage of patients with low T-cells and/or NK-cells were not different between randomized groups at either timepoint. Among all patients receiving rituximab, the values of these outcomes were similar between patients in randomized R-chemo group and those in additional non-randomized R-chemo group (Table S11). Of note, there were no patients in the R-chemo group identified as having severe neutropenia in the follow up time periods
Table 2:
Lymphocyte and immunoglobulin levels at the end of chemotherapy and one year after start of therapy
| One month after the end of chemotherapy | One year after inclusion | |||||||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| Randomized chemo | Randomized R-chemo | p-value* OR** (95%CI) | All R-chemo | Randomized chemo | Randomized R-chemo | p-value* OR** (95%CI) | All R-chemo | |
| Total lymphocytes, N | 89 | 106 | p=0.00091 | 208 | 81 | 104 | p=0.82 | 195 |
| Low, N (%) | 53 (60%) | 86 (81%) | OR 2.92 (1.53–5.57) | 168 (81%) | 13 (16%) | 18 (17%) | OR 1.09 (0.50–2.39) | 33 (17%) |
| CD19+CD20+ B-cells, N | 56 | 75 | p<0.0001 | 138 | 47 | 67 | p=0.34 | 124 |
| Mildly low, N (%) | 5 (9%) | 3 (4%) | (64% vs 96%) | 7 (5%) | 3 (6%) | 10 (15%) | (19% vs 27%) | 18 (15%) |
| Severely low, N (%) | 31 (55%) | 69 (92%) | OR 13.33 (3.71–47.84) | 126 (91%) | 6 (13%) | 8 (12%) | OR 1.55 (0.63–3.84) | 13 (10%) |
| CD3+ T-cells, N | 41 | 67 | p=0.30 | 135 | 40 | 61 | p=0.55 | 120 |
| Low, N (%) | 36 (88%) | 63 (94%) | OR 2.88 (0.55–8.67) | 124 (92%) | 14 (35%) | 25 (41%) | OR 1.29 (0.56–2.95) | 49 (41%) |
| CD3+CD4+ T-cells, N | 38 | 64 | p=0.53 | 124 | 37 | 58 | p=0.82 | 110 |
| Mildly low, N (%) | 23 (61%) | 34 (53%) | (100% vs 97%) | 62 (50%) | 14 (38%) | 24 (41%) | (46% vs 48%) | 48 (44%) |
| Severely low, N (%) | 15 (39%) | 28 (44%) | Not estimable | 58 (47%) | 3 (8%) | 4 (7%) | OR 1.10 (0.48–2.51) | 4 (4%) |
| CD3+CD8+ T-cells, N | 37 | 63 | p=0.11 | 123 | 37 | 58 | p=0.68 | 110 |
| Low, N (%) | 22 (59%) | 47 (75%) | OR 2.00 (0.84–4.77) | 89 (72%) | 10 (27%) | 18 (31%) | OR 1.22 (0.49–3.03) | 33 (30%) |
| NK cells, N | 32 | 51 | p=0.98 | 106 | 33 | 51 | p=0.074 | 99 |
| Low, N (%) | 12 (37%) | 19 (37%) | OR 0.99 (0.40–2.47) | 39 (37%) | 8 (24%) | 5 (10%) | OR 0.34 (0.10–1.15) | 12 (12%) |
| Immunoglobulin | ||||||||
| IgG, N | 79 | 95 | p=0.0015 | 184 | 63 | 94 | p=0.00021 | 174 |
| Mildly low, N (%) | 23 (29%) | 33 (35%) | (47% vs 71%) | 65 (35%) | 12 (19%) | 32 (24%) | (25% vs 55%) | 64 (37%) |
| Moderately low, N (%) | 14 (18%) | 30 (32%) | OR 2.72 (1.45–5.07) | 56 (30%) | 4 (6%) | 18 (19%) | OR 3.64 (1.81–7.31) | 34 (20%) |
| Severely low, N (%) | 0 (0%) | 4 (4%) | 8 (4%) | 0 (0%) | 2 (2%) | 3 (2%) | ||
| IgA, N | 78 | 95 | p=0.0060 | 181 | 64 | 92 | p=0.017 | 170 |
| Mildly low, N (%) | 9 (12%) | 21 (22%) | (15% vs 34%) | 47 (26%) | 2 (3%) | 11 (12%) | (5% vs 17%) | 20 (12%) |
| Moderately low, N (%) | 3 (4%) | 8 (8%) | OR 2.79 (1.32–5.90) | 13 (7%) | 0 (0%) | 5 (5%) | OR 4.28 (1.19–15.37) | 8 (5%) |
| Severely low, N (%) | 0 (0%) | 3 (3%) | 4 (2%) | 1 (2%) | 0 (0%) | 1 (1%) | ||
| IgM, N | 78 | 95 | p=0.00020 | 180 | 64 | 92 | p=0.013 | 170 |
| Mildly low, N (%) | 30 (38%) | 52 (55%) | (44% vs 72%) | 102 (57%) | 4 (6%) | 21 (23%) | (8% vs 23%) | 35 (21%) |
| Severely low, N (%) | 4 (5%) | 16 (17%) | OR 3.26 (1.73–6.13) | 26 (14%) | 1 (2%) | 0 (0%) | OR 3.49 (1.24–9.82) | 1 (1%) |
p-value of comparison of < all patients below the lower limit of the normal (LLN) range between randomized chemo and randomized R-chemo.
OR: Odds ratio of low level for R-Chemo group compared to Chemo group; CI: confidence interval
For total lymphocytes, CD3+ T-cells, CD3+CD8+ T-cells and NK cells low is less than the LLN range for age;
for CD19+20+ B-cells mildly low is <LLN and ≥ 100 / mm3, and severely low is < 100 / mm3;
for CD3+CD4+ T-cells mildly low is < LLN and ≥ 200 / mm3 and severely very low is < 200 / mm3;
for IgG mildly low is < LLN and (≥ 4 g/L if age ≤ 10y or ≥ 5 g/L if age >10y), moderately low ≥ 2 g/L and (< 4 g/L if age ≤ 10y or < 5 g/L if age >10y), severely low is < 2 g/L;
for IgA mildly low is < LLN and (≥ 0.2 g/L if age ≤ 10y or ≥ 0.4 g/L if age >10y), moderately low is low ≥ 0.1 g/L and < 0.2 g/L if age ≤ 10y or ≥ 0.2 g/L and < 0.4 g/L if age >10y and severely low is < 0.1 g/L if age ≤ 10y or < 0.2 g/L if age>10y;
for IgM mildly low is < LLN and (≥ 0.1 g/L if age ≤ 10y or ≥ 0.2 g/L if age >10y) and severely low is< 0.1 g/L if age ≤ 10y or < 0.2 g/L if age >10y, NK cells are identified as those that are CD3-CD16+ or CD3-CD56+
At one month after the end of therapy and persisting at one year after the start of therapy, patients in the R-chemo arm were significantly more likely to have low IgG, IgA and IgM levels (Table 2). Specifically, IgG hypogammaglobulinemia was present in 67/95 (71%) versus 37/79 (47%), OR = 2.72 (95%CI 1.45; 5.07), p=0.0015, at end of therapy and 52/94 (55%) vs 16/63 (25%), OR = 3.64 (95% CI 1.81; 7.31), p=0.00021 at one year post therapy in patients who received R-chemo versus chemo respectively. No patient (0/79 0% (95%CI 0%−4.6%)) in the chemo group had severely low IgG (IgG < 2g/L) levels post therapy, whereas in all patients in the R-chemo group there were 8/184 (4% (95%CI 2%−8%)) and 3/174 (2% (95%CI 0.4%−5%)) patients with severely low IgG levels at the end of therapy and the one-year timepoints, respectively.
Amongst patients in the randomized chemo and R-chemo groups, a sensitivity analysis with multiple imputation of missing data for total lymphocytes, B-cells and IgG showed slightly less impact of rituximab on these three parameters than in the crude analyses of observed cases but the statistically significant differences remained. (appendix page 12). Statistically significant differences also remained in analysis of lymphopenia and low immunoglobulin levels based in biologic sex, with the exception of the one month post therapy timepoint where no differece in lymphopenia between randomized groups was identified in females (appendix page 13-16). Analysis by biologic sex is limited by the number of females enrolled.
Beyond the one-year post diagnosis timepoint, analysis is limited by small numbers of patients with available data. At 2 years post inclusion there was one patient in the chemo group and one patient in the R-chemo group who had severely low CD19+/CD20+ B cells. At this timepoint there were no patients identified with moderately or severely low IgG in the chemo group whereas there were 9 patients identified as having moderately low (n=7) or severely low (n=2) IgG levels amongst patients who received R-chemo.
Of all patients who received R-chemo, age less than or equal to 15 years, receiving group C versus group B therapy and low IgG level at baseline were associated with low IgG level at one year post therapy in multivariable analyses (Table 3).
Table 3:
Patient and disease features associated with IgG level below lower limit of the normal range at the one-year time point in those treated with R-chemo therapy
| Normal IgG level N=73 | IgG < LLN N=101 | Univariate p-value | Multivariate* p-value | OR (95%CI) | |
|---|---|---|---|---|---|
| Male | 61 (43%) | 80 (57%) | |||
| Female | 12 (36%) | 21 (64%) | 0.47 | ||
| Age (years) mean (std) | 9.5 (4.5) | 8.1 (3.6) | |||
| < 15 years | 57 (37%) | 97 (63%) | 9.13 (2.39–34.80) | ||
| ≥ 15 years | 16 (80%) | 4 (20%) | 0.00025 | 0.0012 | Reference |
| Burkitt | 66 (42%) | 93 (58%) | |||
| DLBCL | 7 (54%) | 6 (46%) | 0.39** | ||
| Other | 0 (0%) | 2 (100%) | |||
| Group B | 36 (51%) | 35 (49%) | Reference | ||
| Group C1 | 31 (38%) | 51 (62%) | 3.48 (1.51–8.06) | ||
| Group C3 | 6 (29%) | 15 (71%) | 0.11 | 0.0087 | 3.08 (0.87–10.92) |
| Stage III | 30 (48%) | 33 (52%) | |||
| Stage IV | 18 (46%) | 21 (54%) | |||
| B-AL | 25 (35%) | 47 (65%) | 0.26 | ||
| BM involvement < 25% | 48 (47%) | 54 (53%) | |||
| BM involvement ≥ 25% | 25 (35%) | 47 (65%) | 0.10 | ||
| No CNS involvement | 54 (45%) | 67 (55%) | |||
| CNS involvement | 19 (36%) | 34 (64%) | 0.28 | ||
| LDH ≤ 2 ULN | 12 (55%) | 10 (45%) | Reference | ||
| LDH > 2 ULN | 61 (40%) | 91 (60%) | 0.20 | 0.091 | 2.52 (0.86–7.40) |
| IgG ≥ LLN at baseline | 39 (48%) | 42 (52%) | Reference | ||
| IgG < LLN at baseline | 21 (28%) | 53 (72%) | 0.012 | 0.017 | 2.51 (1.18–5.34) |
LLN: lower limit of the normal range; DLBCL: diffuse large B-cell lymphoma; B-AL: B-cell acute leukemia; BM: bone marrow; CNS: central nervous system; ULN: upper limit of the normal range
Model based on 155 patients due to missing data on IgG level at baseline for 19 patients. Variables with p-value < 0.10 was kept in the model. OR: Odds ratio of IgG < LLN; CI: confidence interval
Burkitt versus DLBCL
During therapy and in post-therapy follow up, more patients in the R-chemo versus chemo arm received one or more immunoglobulin infusions (26/164 vs 9/158, 5-year incidence rate 16% (95%CI 11%−22%) vs 7% (95%CI 3%−12%), HR=2.63 (95%CI 1.23; 5.62) (appendix 19, 20). The median number of doses per patient was 3 (range 1–50, interquartile range 2–7) in the chemo group and 2 (range 1–18, interquartile range 1–3) in the R-chemo group. The most common indication stated was hypogammaglobulinemia alone followed by frequent infections. There was geographic variability in the use of immunoglobulin replacement. Amongst those randomized to therapy including rituximab, and limited to countries that enrolled at least 30 patients, the percentage of patients who received immunoglobulin replacement varied from 0 to 30%.
Toxicity during the treatment period has been reported previously.1 Among the 279 patients who received rituximab, 16 (6%) did not receive the planned 6 doses (2, 3, 6 and 5 patients received 1, 2, 4 and 5 doses, respectively, with toxicity being identified as the reason for failure to complete the planned number of infusions in 9 patients. Among the 279 patients of the R-chemo group there were 4 treatment-related deaths and among the 142 patients of the chemo group there were 2 treatment-related deaths. After the one-month post completion of therapy timepoint there were no deaths in patients who remained in remission. In the follow up period grade 3 and higher adverse events were rare (table 4). One patient in the R-chemo arm with severely low IgG at one month post completion of therapy had a grade 4 infectious event 2 months post the final chemotherapy administration with a polymicrobial bacterial sepsis. Additionally, there were 5 patients, all treated with rituximab, including 4 in the randomized arm, with grade 3 infections between 1- and 29-months post completion of therapy including EBV (n=1), herpes zoster, (n=1), bacterial infection (n=1) and pneumonia (n=2). Amongst these 6 patients with grade 3 and higher infectious complications post therapy, two patients received immunoglobulin replacement following the infectious event. In the 43 European patients identified as having low IgG in the follow up period, with focused queries, an additional 5 patients were also identified with lower grade infectious events, including sinusitis, lung infection, impetigo, pharyngitis and viral infections. All were in the R-chemo groups.
Table 4:
Adverse events of grade 3 or higher during the follow-up period
| Randomized Chemo | Randomized R-chemo | Additional R-chemo | |
|---|---|---|---|
| Infection grade ≥ 3 | 0 | 5 | 1 |
| Epstein Barr virus infection (grade 3) | 1 | 0 | |
| Herpes zoster virus infection (grade 3) | 0 | 1 | |
| Bacterial infection (grade 3) | 3 | 0 | |
| Bacterial infection (grade 4) | 1 | 0 | |
| Neurotoxicity grade ≥ 3 | 0 | 0 | 2 |
| Tremors, dystonia (grade 3) | 1 | ||
| Heel pain and lossof reflexes (grade 3) | 1 |
At baseline, in all patients with available serology data, there were 74/126 (59%) with protective serologies to Poliovirus, 162/220 (74%) to Tetanus, 128/182 (70%) to Diphtheria, 88/139 (63%) for Pneumococcus and 72/129 (56%) for Haemophilus influenzae(Appendix, pages 21). Vaccine serology data was obtained on a limited number of patients at follow up timepoints. Patients were identified with documented positive titers at baseline and subsequent negative titers post completion of therapy in both the R-chemo and chemo treatment groups, including 4/47 (9%) for polio, 24/99 (24%) for Tetanus, 18/79 (23%) for Diphtheria, 21/50 (42%) for Pneumococcus and 14/40 (35%) for Haemophilus influenzae (Appendix, pages 21). Conversely a small number of patients with negative serologies, either at baseline or post therapy were documented to have protective antibodies post vaccination, though several of these patients had received intercurrent immunoglobulin replacement therapy ((Appendix, pages 22).
Whilst patients with known immunodeficiency were excluded from the trial, B-cell NHL can be the presenting feature of primary immunodeficiency. We therefore sought to understand individual immune trajectories with a view to identifying patients with greater risk of underlying immunodeficiency. Twenty-four patients out of 188 (13%) had severely low CD19+20+ B-cells (<100/mm3) at baseline. Three of these patients continued to have severely low B-cells at the last time point evaluated, two at 1-year post enrolment (one each in the R-chemo and chemo groups) and one at 2-years post enrolment (chemo group). Similarly, there were 19 patients out of 125 (15%) with severely low CD3+CD4+ T-cells (<200mm/3) at baseline. Three patients continued to have severely low CD3+CD4+ T-cells at the last timepoint evaluated, at 7 months, one year and 3 years post enrolment.
There were 12 patients out of 368 (3%) with severely low levels of IgG (< 2g/l) at baseline, 5 of whom had concurrent severely low CD19+20+ B-cells. None of these patients had severely low IgG levels at the one-year timepoint. Conversely there were three patients identified as having severely low IgG levels at the one-year time point, all who received R-chemotherapy. All three of these patients had had normal IgG levels at the time of enrolment.
In total, there were 47 patients out of 378 (12%) who had severely low CD19+20+ B-cells and/or CD3+CD4+ T-cells and/or severely low levels of IgG at baseline. Follow up on immune parameters is available for 28 of these patients. Among them, 19 patients (68%) had normal immune parameters at last evaluation and six patients (32%) continued to have abnormal immune tests at or greater than one year post inclusion. Only one of these patients was identified as having an acute infection in the follow up period, which was an episode of grade 4, life threatening sepsis.
DISCUSSION
This study showed that, whereas differences in B-cell lymphopenia and profound B-cell lymphopenia between the group who received R-chemo and chemo resolved by one year post diagnosis, patients receiving R-chemo were more likely to have persistently low immunoglobulin levels. Compliance with follow up data submission post the 1-year time point was sub-optimal making extended analyses limited and based on small numbers.
Rituximab depletes CD20 positive B-cells. All B lineage hematopoietic cells are CD20 positive except earliest precursor cells, pro-B cells and the terminally differentiated antibody producing plasma cells. 13 Exposure to rituximab causes predictable transient B-cell depletion in blood and, although plasma cells are not directly affected by the CD20 B-cell depletion, is associated with prolonged hypogammaglobulinemia in some patients.
In a large cohort study of adult patients treated with rituximab for various indications, of those who had normal immunoglobulin levels at baseline, 19% had mild to severe deficiency at 18 months.14 Similar results have been described in other patient groups.15 Rituximab related hypogammaglobulinemia is more common in children than in adults, potentially related to age dependent development of the immune system and a lower percentage of memory B-cells/plasma cells in children.16 In our study, 55% (52/94) of patients who received rituximab and chemotherapy and were tested at one year from start of therapy had low immunoglobulin levels, compared to 25% (16/63) of those who received chemotherapy alone. In those exposed to rituximab, younger age, worse prognostic group and low IgG level at baseline were predictive of low IgG at one year post therapy.
Hypogammaglobulinemia is associated with risks of bacterial infections. Additionally, exposure to rituximab has been associated with very rare cases, primarily in adult patients, of progressive multifocal leukoencephalopathy, chronic enteric viral infections and viral reactivation syndromes, most notably hepatitis B. 17,18 In this study there were no fatal infections in the follow-up period however there were a small number of patients with severe infections, all of whom had received rituximab. Severe infections in the post therapy period are expected to be rare events and therefore registry data capturing large patient numbers may be required to accurately quantify this risk.
General guidance for revaccination in children following cancer therapy is variable, with some guidelines suggesting revaccination starting at 6 months. 19 20 Data to inform vaccination post rituximab exposure are extremely limited. In adult patients, prior exposure to rituximab is a risk factor for poor vaccine response to a number of vaccines including influenza, tetanus, Haemophilus and pneumococcus and SARS-Cov-2, with variability based on timing related to rituximab administration and with a suggestion of need for repeated vaccinations.21–24 The data available for loss of vaccine protective antibodies in this study is limited, however many patients with documented protective antibodies prior to therapy had loss of protective titers in follow up. Identifying the utility of post-treatment serological testing serologies, or other measures of immunity, and effectiveness of revaccination is a significant research gap within pediatric oncology. These data will be critically important in informing national organizations in the development and optimization of guidance for immunization for children post immune therapies for cancer, including rituximab.
Primary immunodeficiency (PID) is a known risk factor for development of lymphomas in children.25,26 The true prevalence of PID at the point of lymphoma diagnosis is unknown.27 While pre-existing immunodeficiency was an exclusion criterion within the Inter-B-NHL-Ritux 2010 trial, it is likely that a small number of patients in our study had undiagnosed PID. As most children in this study with markedly abnormal lymphocyte/immunoglobulin levels at baseline normalized those parameters following treatment, immunological investigations at the time of diagnosis with lymphoma do not offer a specific approach to screening for PID. Conversely, children with prolonged hypogammaglobulinemia following rituximab therapy for autoimmune cytopenias were more likely to have PID diagnosed than those whose immunoglobulin levels recovered within 12 months of completing therapy.28 In our study, there were ~ 3% of children with persisting hypogammaglobulinemia and/or lymphopenia one year after therapy. Further investigation of children experiencing prolonged hypogammaglobulinemia and/or lymphopenia following treatment for lymphoma may help to identify those with an immunological predisposition. Additionally, the increasing use of either targeted or genome wide sequencing approaches is likely to identify children with previously undiagnosed PID in a more precise and timely manner and may inform treatment approaches.
This study has several limitations. First, in the follow up period only infectious events meeting criteria for a serious (grade 3 or higher) adverse event required reporting. The incidence and nature of lower grade infectious toxicities, such as those treated as an outpatient, were captured in only a subset of patients identified as having hypogammaglobulinemia. Second, laboratory evaluations were not completed at a centralized facility which may have led to some variability in reporting. Third not all laboratory evaluations were completed on all patients at all timepoints and hence data is available only on a subset of patients and data is primarily limited to two timepoints - end of therapy and one year after trial inclusion. For lymphocyte counts (total lymphocytes and B-cells), the only factor related to missing data was the cooperative groups (data not shown). For immunoglobulins, cooperative group was also associated with missing data and at the one-year monitoring, physicians checked more frequently IgG level in patients treated with rituximab than in patients treated without rituximab and in patients with prognostic groups C than B (data not shown). This differential IgG monitoring in the groups with and without rituximab could create a bias in the estimation of the rituximab effect on IgG. However, as IgG assessment was performed less frequently in patients who had not received rituximab, we can assume that, if there is a bias, it would rather go in the direction of an overestimation of the negative effect of rituximab on IgG, thus our results would be rather conservative and cautious. Fourth, vaccination records prediagnosis were not available. Fifth, the laboratory studies included were quantitative measures and not functional immunologic studies. Finally, the potential confounding impact of immunoglobulin replacement therapy on serological evaluation for vaccine preventable infections was not accounted for in the analysis.
In summary, the addition of rituximab has measurable impact on laboratory measures of immune function post therapy in children receiving intensive therapy for mature B-cell lymphoma, including a risk for prolonged hypogammaglobulinemia, warranting monitoring during the post therapy period. Identification of those children and adolescents most likely to benefit from immunoglobulin replacement therapy and revaccination is a significant research gap as is a structured approach to identification of the subset of patients with possible underlying primary immunodeficiencies.
Supplementary Material
Research in context.
Evidence before this study:
We considered the evidence from studies in patients with lymphoma and rituximab exposure and pediatric patients treated with rituximab for other indications. In preparation of this manuscript, we searched PubMed with no date or language restrictions using the search terms “rituximab”, “hypogammaglobulinemia” and “lymphoma”. Existing pediatric cancer data suggested that the addition of rituximab to chemotherapy did not significantly increase risks of infectious toxicity during the period of active therapy. Population-based data has shown that exposure to rituximab in the treatment of lymphoma is associated with increased risks of hypogammaglobulinemia and infections in adult lymphoma patients in long term follow up. Very limited data existed on immune status and infection risk after therapy in pediatric patients treated with rituximab for a lymphoma. The Inter-B-NHL Ritux 2010 study was an international, randomized, phase 3 trial in children with mature B-NHL, comparing event free survival between those receiving intensive chemotherapy or intensive chemotherapy with rituximab.1 A prespecified, secondary aim of this study was an evaluation of the immune impacts of rituximab therapy in pediatric patients post completion of intensive therapy.
Added value of this study.
The Inter-B-NHL Ritux 2010 established the use of rituximab in addition to intensive chemotherapy as standard treatment for children with high-risk mature B cell lymphoma, and rituximab for this indication has been recently approved by both FDA and EMA. This trial adds value to the existing literature through demonstration of the risks associated with the use of rituximab in this context, specifically the risk of prolonged hypogammaglobulinemia. The study provides some reassurance that despite prolonged hypogammaglobulinemia, severe infections post completion of therapy are very rare. This study also provides data on the clinical use of immunoglobulin replacement therapy in this setting and in a subset of children the rates of protective vaccine serologies at baseline and post therapy. It provides the first large data set describing parameters of immune function in this patient group at the time of diagnosis. Lastly, data from this study suggest that a small proportion of patients may have undiagnosed primary immunodeficiency but that baseline immunological parameters alone do not identify these patients.
Implications of all the available evidence
This study provides data that informs the need for awareness and monitoring for hypogammaglobulinemia post completion of therapy in pediatric patients with B-NHL. All of the available evidence, including that provided in this study, suggests that patients with lymphoma treated with rituximab require careful immune follow up care post therapy. The data from this study highlight existing research gaps, including the need for data to inform the optimal use of immunoglobulin replacement therapy and vaccination strategies as well as systems to identify children with B-NHL who may have primary immunodeficiency.
Acknowledgement of funders:
Supported by a grant (PHRC2010) from the Clinical Research Hospital Program of the French Ministry of Health, by Cancer Research UK, the National Institute for Health Research Clinical Research Network, and Children’s Cancer Foundation Hong Kong, by grants (U10CA180886 and U10CA180899) from the U.S. National Cancer Institute, and by F. Hoffmann–La Roche–Genentech. This study was in part funded by the NIH, none of the authors are employed by the NIH or received NIH grant support for this work.
Footnotes
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Data Sharing
De-identified, individual participant data collected during the trial will be made available for individual particpant data for the purposes of meta-analysis. Proposals should be submitted to https://redcap.gustaveroussy.fr/redcap/surveys/?s=DYDTLPE4AM. A document indicating the objective of the research, the methodology, the statistical analysis plan and the variables within the database required for the research must be submitted. A scientific board will review and approve the request. A specific agreement between the sponsor and the researcher is requested for data transfer. This data transfer agreement details both parts responsibilities to ensure the required level of data integrity and legal and ethical obligations.
Declaration of Interest:
G.A.A.B provides consultancy to Roche, Novartis, Merck and Janssen. All other authors have no competing interests to disclose. AA, CP and VMC received grant support, paid to her institution, from F. Hoffmann–La Roche.
Clinicaltrials.gov Trial Number: NCT01516580
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
REFERENCES
- 1.Minard-Colin V, Auperin A, Pillon M, et al. Rituximab for High-Risk, Mature B-Cell Non-Hodgkin’s Lymphoma in Children. N Engl J Med 2020; 382(23): 2207–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Ribrag V, Koscielny S, Bosq J, et al. Rituximab and dose-dense chemotherapy for adults with Burkitt’s lymphoma: a randomised, controlled, open-label, phase 3 trial. Lancet 2016; 387(10036): 2402–11. [DOI] [PubMed] [Google Scholar]
- 3.Roschewski M, Dunleavy K, Abramson JS, et al. Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma. J Clin Oncol 2020; 38(22): 2519–29. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Sehn LH, Salles G. Diffuse Large B-Cell Lymphoma. N Engl J Med 2021; 384(9): 842–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Zhu KY, Song KW, Connors JM, et al. Excellent real-world outcomes of adults with Burkitt lymphoma treated with CODOX-M/IVAC plus or minus rituximab. Br J Haematol 2018; 181(6): 782–90. [DOI] [PubMed] [Google Scholar]
- 6.Hua Q, Zhu Y, Liu H. Severe and fatal adverse events risk associated with rituximab addition to B-cell non-Hodgkin’s lymphoma (B-NHL) chemotherapy: a meta-analysis. J Chemother 2015; 27(6): 365–70. [DOI] [PubMed] [Google Scholar]
- 7.Lanini S, Molloy AC, Fine PE, Prentice AG, Ippolito G, Kibbler CC. Risk of infection in patients with lymphoma receiving rituximab: systematic review and meta-analysis. BMC Med 2011; 9: 36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Shree T, Li Q, Glaser SL, et al. Impaired Immune Health in Survivors of Diffuse Large B-Cell Lymphoma. J Clin Oncol 2020; 38(15): 1664–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Kado R, Sanders G, McCune WJ. Suppression of normal immune responses after treatment with rituximab. Curr Opin Rheumatol 2016; 28(3): 251–8. [DOI] [PubMed] [Google Scholar]
- 10.Blanco E, Pérez-Andrés M, Arriba-Méndez S, et al. Age-associated distribution of normal B-cell and plasma cell subsets in peripheral blood. J Allergy Clin Immunol 2018; 141(6): 2208–19.e16. [DOI] [PubMed] [Google Scholar]
- 11.Shearer WT, Rosenblatt HM, Gelman RS, et al. Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol 2003; 112(5): 973–80. [DOI] [PubMed] [Google Scholar]
- 12.Orkin SH. Nathan and Oski’s hematology and oncology of infancy and childhood. Eighth edition. ed. Philadelphia, PA: Elsevier/Saunders; 2015. [Google Scholar]
- 13.Leandro MJ. B-cell subpopulations in humans and their differential susceptibility to depletion with anti-CD20 monoclonal antibodies. Arthritis Res Ther 2013; 15 Suppl 1: S3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Barmettler S, Ong MS, Farmer JR, Choi H, Walter J. Association of Immunoglobulin Levels, Infectious Risk, and Mortality With Rituximab and Hypogammaglobulinemia. JAMA Netw Open 2018; 1(7): e184169. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Mikulska M, Lanini S, Gudiol C, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid cells surface antigens [I]: CD19, CD20 and CD52). Clin Microbiol Infect 2018; 24 Suppl 2: S71–S82. [DOI] [PubMed] [Google Scholar]
- 16.Khojah AM, Miller ML, Klein-Gitelman MS, et al. Rituximab-associated Hypogammaglobulinemia in pediatric patients with autoimmune diseases. Pediatr Rheumatol Online J 2019; 17(1): 61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Bennett CL, Focosi D, Socal MP, et al. Progressive multifocal leukoencephalopathy in patients treated with rituximab: a 20-year review from the Southern Network on Adverse Reactions. Lancet Haematol 2021; 8(8): e593–e604. [DOI] [PubMed] [Google Scholar]
- 18.Seto WK, Chan TS, Hwang YY, et al. Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study. J Clin Oncol 2014; 32(33): 3736–43. [DOI] [PubMed] [Google Scholar]
- 19.Cesaro S, Giacchino M, Fioredda F, et al. Guidelines on vaccinations in paediatric haematology and oncology patients. Biomed Res Int 2014; 2014: 707691. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Zhang L, Martin AM, Ruble K. Postchemotherapy Immunization Practices for Non-HSCT Pediatric Oncology Patients. J Pediatr Hematol Oncol 2019; 41(4): 289–93. [DOI] [PubMed] [Google Scholar]
- 21.Bonelli MM, Mrak D, Perkmann T, Haslacher H, Aletaha D. SARS-CoV-2 vaccination in rituximab-treated patients: evidence for impaired humoral but inducible cellular immune response. Ann Rheum Dis 2021; 80(10): 1355–6. [DOI] [PubMed] [Google Scholar]
- 22.Nazi I, Kelton JG, Larché M, et al. The effect of rituximab on vaccine responses in patients with immune thrombocytopenia. Blood 2013; 122(11): 1946–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.de Lavallade H, Garland P, Sekine T, et al. Repeated vaccination is required to optimize seroprotection against H1N1 in the immunocompromised host. Haematologica 2011; 96(2): 307–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Cheng DR, Barton R, Greenway A, Crawford NW. Rituximab and protection from vaccine preventable diseases: applying the evidence to pediatric patients. Expert Rev Vaccines 2016; 15(12): 1567–74. [DOI] [PubMed] [Google Scholar]
- 25.Kebudi R, Kiykim A, Sahin MK. Primary Immunodeficiency and Cancer in Children; A Review of the Literature. Curr Pediatr Rev 2019; 15(4): 245–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Sandlund JT, Shurtleff SA, Onciu M, et al. Frequent mutations in SH2D1A (XLP) in males presenting with high-grade mature B-cell neoplasms. Pediatr Blood Cancer 2013; 60(9): E85–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Bomken S, van der Werff Ten Bosch J, Attarbaschi A, et al. Current Understanding and Future Research Priorities in Malignancy Associated With Inborn Errors of Immunity and DNA Repair Disorders: The Perspective of an Interdisciplinary Working Group. Front Immunol 2018; 9: 2912. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Ottaviano G, Marinoni M, Graziani S, et al. Rituximab Unveils Hypogammaglobulinemia and Immunodeficiency in Children with Autoimmune Cytopenia. J Allergy Clin Immunol Pract 2020; 8(1): 273–82. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.