Safety and efficacy of intrathecal rituximab in children with B cell lymphoid CD20+ malignancies: An international retrospective study
Conflict of interest: The authors have no conflicts of interest or funding to disclose.
Abstract
Central nervous system (CNS) involvement in patients with mature B non-Hodgkin lymphoma, post-transplantation proliferative disorder and acute lymphoblastic leukemia confers a significantly inferior prognosis as compared to patients without CNS disease. Intrathecal (IT) or intraventricular administration of rituximab is an option for this group of patients. We report 25 children with CNS involvement of CD20+ B lymphoid malignancies who received in total 163 IT/intraventricular rituximab doses. The median number of doses received by each patient was 6, with a median dose of 25 mg. The most common adverse events were Grades 1 and 2 peripheral neuropathies in five patients (20%), allergy in two patients, and headache in two patients. These events were self-limited, occurring in the 48 hours after treatment and resolving within 24 hr. Three patients presented with more severe though transient side effects, one with a Grade III neuropathy and two with seizure. Eighteen patients (72%) of those treated with IT/intraventricular rituximab, with or without other CNS directed treatment, achieved a CNS remission. This case series suggests that IT/intraventricular rituximab has therapeutic efficacy and relatively limited toxicity. Prospective trials of IT/intraventricular rituximab for patients with CNS involvement of CD20 + B lymphoid malignancies are warranted. Am. J. Hematol. 91:486–491, 2016. © 2016 Wiley Periodicals, Inc.
Introduction
Primary or recurrent B cell lymphoid malignancies involving the central nervous system (CNS) remain a therapeutic challenge, irrespective of the subtype. Despite the favorable outcomes in children with mature B non-Hodgkin lymphoma (NHL) 1-3, for those with recurrent disease the prognosis is dismal 4-7. Patients with CNS involvement at the time of recurrence have a particularly poor outcome 4, 6, 7.
CNS involvement in patients with B cell post-transplantation proliferative disorder (PTLD) also confers a significantly inferior prognosis compared to patients without CNS disease 8, 9, as does CNS involvement refractory to conventional therapies in patients with precursor B acute lymphoblastic leukaemia (ALL) 10, 11.
Intensive conventional chemotherapy, intravenous rituximab and hematopoietic stem cell transplantation (HSCT) are limited in efficacy in the treatment of CNS disease, partly because of the drug/antibody penetration of the blood brain barrier 5, 12. In contrast, regional delivery of drugs directly into the CSF is pharmacologically advantageous, with small doses producing high CSF concentrations with minimal systemic exposure 13. Unfortunately, only a limited number of drugs, primarily methotrexate, steroids and cytarabine, have been found to be both safe and efficacious when administered by the intrathecal (IT) route.
Rituximab is a chimeric murine/human monoclonal anti CD20 antibody, with a human IgG1-antibody and a variable region isolated from a murine anti-CD20 monoclonal antibody 12, 14. The mechanism of action of rituximab comprises complement-mediated lyses of B cells and involves antibody-dependent cellular cytotoxicity 14. There is extensive experience with using rituximab alone and in combination with chemotherapy regimens used to treat B-cell malignancies in adult patients 14. When used in combination with chemotherapy it has been demonstrated to increase disease free survival and overall survival in adults with diffuse large B cell lymphoma 15, 16. Data is more limited in children with B cell malignancies both the in relapsed and up-front treatment settings 6, 17-20. A large international randomized trial designed to evaluate the efficacy and safety of rituximab in combination with intensive conventional chemotherapy in children and adolescents with newly diagnosed higher risk B-NHL is currently open for accrual (EudraCT N°: 2010-019224-31, COG ANHL1131).
Systemically administered rituximab has limited efficacy in treating CNS disease 21, 22 likely due to poor CNS penetration. After intravenous administration of rituximab CSF concentration remains very low, ranging from 0.1 to 0.2% of systemic rituximab concentration 23. Results in patients with B cell lymphoid malignancies with leptomeningeal infiltration suggest that IT or intraventricular rituximab may have a therapeutic effect 9, 24-29. IT or intraventricular administration of rituximab could be a useful addition to therapy of patients with B-cell malignancies involving the CNS and possibly also could be considered for prophylaxis for malignancies with risks of CNS recurrence. However, clinical experience with this route of administration is very limited, especially in children 9, 28, 29 Table 1.
| n° pts | Disease | Age (years) | Dose | Neurotoxicity | Efficacy | Reference |
|---|---|---|---|---|---|---|
| 7 | ALL | 4−21 | 10 mg | No toxicity | 5/7 CNS CR | Jaime-Perez et al 2004 29 |
| 6 | B-NHL | 30−70 | 10−40 mg | Neuropathy grade III (1/6 patients) | 4/6 CNS CR | Schulz et al 2004 24 |
| 10 | PCNSL | 29−84 | 10−50 mg | Hypertension 2/10, diplopia 1/10 | 3/10 CNS CR | Rubenstein et al 2007 25 |
| 14 | PCNSL | 37−75 | 10−25 mg | Neuropathy grade III (1/10), muscle weakness (1/10) | 6/14 CNS CR | Rubenstein et al 2013 26 |
| 8 | PTLD | 5−19 | 10−30 mg | Seizure 1/8 | 5/8 CNS CR | Czyzewski et al 2013 9 |
- IT, intrathecal; CNS, central nervous system; PCNSL, Primary CNS lymphoma; ALL, acute lymphoblastic leukemia; CR, complete response, NHL, non-Hodgkin lymphoma; PTLD, post-transplant lymphoproliferative disease.
Optimal therapy for relapsed/refractory CNS disease in mature B-cell NHL, B-lineage ALL, and B-cell PTLD has not been established. The major goal of this study was to review in depth the experience with the use of IT or intraventricular rituximab in children and young adults with CNS involvement of CD20+ B lymphoid malignancies.
Methods
Study population and setting
Eligibility criteria included children and young adults aged 0–21 years with CD20+ mature B-NHL, mature B and B precursor-ALL or B cell PTLD, treated with IT or intraventricular rituximab between January 1st, 2000 and March 1st, 2015. Eligible patients were identified by direct communication with clinicians and researchers involved in the care of these patients in Europe, North America, Australia, and Asia.
Data
Survey documents were developed and distributed to investigators from centers that identified eligible patients. Data was extracted from medical charts for all eligible patients. Data collected included patient demographics, disease-related features, including stage, CNS status, and bone marrow disease and data on treatment protocol(s). Information was collected regarding IT and intraventricular rituximab, including administration (dose, number of doses, method of administration), documented side effects, and evidence of response. Toxicities of IT and intraventricular rituximab were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 scale. In addition data regarding overall patient outcome was collected. The treating clinician determined the cause of death as well as the response to therapy.
Participating countries included Canada, United States, Germany, Austria, Australia, Belgium, Spain, Russia, Sweden, Saudi Arabia, and Portugal.
Statistical analysis
Descriptive statistics were used to characterize cases. Median and range (minimum/maximum) or frequency and percentage were collected for all variables. Statistical analyses were performed using SAS-PC software (version 9.4; SAS Institute, Cary, NC).
The study was approved by the Research Ethics Board at The Hospital for Sick Children, Toronto, Canada.
Results
Patients’ characteristics
Twenty-five patients were included in the study. Baseline characteristics are summarized in Table 2. The median age was 12.8 years (range, 1.6−20.4 years). Fifteen patients (60%) had CNS positive, CD20+ B mature (all Burkitt) NHL or leukemia, 3 patients (12%) had relapsed CD20+ precursor-B ALL with CSF involvement, and 7 patients (28%) had CNS+ B cell PTLD. Details of patient treatment, outcome, and adverse events are shown in Table 3. A total of 163 doses of IT or intraventricular rituximab were given to the 25 patients. The median number of doses received by each patient was 6 (range, 1–20 doses). Median dose administered was 25 mg (range, 10−40 mg). Route of administration included IT in 17 patients (68%) and intraventricular in 8 (32%). Eighteen patients (72%) received IT or intraventricular rituximab in combination with other IT chemotherapies. In the majority of patients (19 patients, 76%) IT or intraventricular rituximab was administered with a frequency of twice a week, in the others weekly.
| Frequency (%) | |
|---|---|
| SEX | |
| Male | 19 (76%) |
| Female | 6 (24%) |
| Disease status | |
| 1st diagnosis | 9 (36%) |
| 1st relapse | 9 (36%) |
| Multiple relapses | 4 (16%) |
| Refractory | 3 (12%) |
| Type of CNS disease | |
| CSF + | 10 (40%) |
| IPM | 10 (40%) |
| CSF+ and IPM | 5 (20%) |
| Pathology | |
| B precursor ALL | 3 (12%) |
| B mature NHL | 15 (60%) |
| PTLD | 7 (28%) |
- CSF, cerebrospinal fluid; IPM, intraparenchymal mass; ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin lymphoma; PTLD, post-transplant lymphoproliferative disease.
| Rituximab IT/I.vent. | Additional CNS directed therapy | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ID | Country | Age (years) | Sex | Disease status | Type of CNS disease | Dose (mg) | Doses n° | Before IT/I. vent R | With IT/I. vent R | After IT/I. vent R | Toxicity (Grade I–IV AE)with Rituximab | CNSRemission | Status | Cause of Death |
| Pre-B ALL patients (CD20+) | ||||||||||||||
| 1 | ESP | 16.8 | M | m. relapses | CSF + | 25 | 4 |
Systemic chemotherapy TIT Allo-HSCT |
− | − | Allergy (I-II) | No | Dead | PD |
| 2 | ESP | 6 | F | m. relapses | CSF + | 10 | 3 |
Systemic chemotherapy TIT IT-Liposomal Ara-C |
− |
Allo-HSCT Cranial Radiation |
− | Yes | Alive | − |
| 17 | AUT | 14.2 | F | m. relapses | CSF + | 40 | 4 |
Systemic chemotherapy TIT Allo-HSCT |
− | − | − | No | Dead | PD |
| B mature NHL and leukaemia (all Burkitt) | ||||||||||||||
| 3 | CAN | 8.3 | M | 1st relapse | CSF + | 10 | 8 | − |
R-ICE IT-MTX and Ara-C |
Allo-HSCT | − | Yes | Dead | PD, CNS negative |
| 4 | USA | 14.5 | M | 1st relapse | IPM, CSF+ | 10–25 | 6 | − |
R-ICE IT MTX |
Cranial Radiation Allo-HSCT |
P. Neuropathy (I-II) | Yes | Dead | PD |
| 5 | SAU | 5.5 | M | 1st relapse | IPM | 10 | 9 | – |
ICE TIT |
Auto-HSCT | Seizure (IV) | Yes | Dead | Other |
| 6 | AUS | 16.3 | M | 1st relapse | IPM, CSF+ | 25 | 10 | − |
R-ICE IT-MTX |
− | − | Yes | Dead | PD |
| 8 | RUS | 4.6 | M | 1st diagnosis | IPM | 25 | 3 | − |
NHL-BFM2004 + R TIT |
Auto-HSCT | − | Yes | Alive | – |
| 9 | RUS | 4.3 | M | 1st diagnosis | IPM | 25 | 5 | − |
NHL-BFM2004 + R TIT |
Auto-HSCT | − | Yes | Alive | – |
| 10 | RUS | 2.4 | F | 1st diagnosis | IPM | 10 | 4 | − |
NHL-BFM2004 + R TIT |
Auto-HSCT | − | Yes | Alive | − |
| 11 | RUS | 7.7 | M | 1st diagnosis | IPM | 15 | 3 | − |
NHL-BFM2004 + R TIT |
− | − | Yes | Alive | − |
| 12 | RUS | 15.7 | M | 1st diagnosis | IPM | 25 | 3 | − |
NHL-BFM2004 + R TIT |
− | − | Yes | Alive | − |
| 13 | SWE | 17.7 | M | refractory | CSF+ | 25 | 6 |
NHL-BFM2004 TIT |
– |
Allo-HSCT Cranial radiotherapy |
− | Yes | Dead | PD |
| 15 | SWE | 3.9 | M | refractory | IPM, CSF+ | 40 | 10 | – |
R-ICM R-ICE TIT, IT-Liposomal Ara-C |
Allo-HSCT Cranial radiotherapy Surgery |
P. Neuropathy (I-II) Headache (I-II) |
Yes | Alive | − |
| 16 | PRT | 15 | M | m. relapses | CSF+ | 10 | 4 |
Systemic chemotherapy R-ICE TIT Allo-HSCT Cranio-spinal Radiation |
– | TIT | − | No | Dead | PD |
| 18 | AUT | 13.7 | M | 1st relapse | CSF+ | 40 | 1 | − |
CC bloc BFM R-CHOP R-BM IT MTX |
Auto-HSCT | Seizure (II) | Yes | Dead | TRM |
| 23 | GER | 16.3 | F | 1st relapse | CSF+ | 25 | 6 | − |
R-VICI R-ICIT TIT |
Allo-HSCT | P. Neuropathy (II-III) | Yes | Alive | − |
| 24 | GER | 11.5 | M | 1st relapse | CSF+ | 25 | 6 | − |
R-VICI R-ICIT TIT |
Allo-HSCT | P. Neuropathy (I-II) | Yes | Alive | − |
| Post-transplant lymphoproliferative disease (CD20+) | ||||||||||||||
| 7 | BEL | 20.4 | F | 1st relapse | CSF+ | 25 | 10 | − |
CC bloc BFM M1 bloc of LMB IT MTX |
− | P. Neuropathy (I-II) | Yes | Alive | − |
| 14 | SWE | 17.2 | M | refractory | IPM | 20–35 | 9 | − |
Systemic chemotherapy R I.v. TIT |
− |
P. Neuropathy (I-II) Headache (I-II) Allergy(I-II) |
Yes | Alive | − |
| 19 | AUT | 15.8 | M | 1st diagnosis | IPM, CSF+ | 20 | 4 | − | R i.v. | − | − | No | Dead | TRM, PD |
| 20 | AUT | 12.1 | F | 1st diagnosis | IPM, CSF+ | 40 | 4 | − | R i.v. | − | − | PR | Dead | TRM |
| 21 | USA | 15.3 | M | 1st relapse | IPM | 25 | 14 | − |
R i.v. (4 doses) I. Vent MTX (5 doses) |
− | − | Yes | Alive | − |
| 22a | GER | 1.6 | M | 1st diagnosis | IPM | 15 | 2 | − | R i.v. | − | − | No | Alive | − |
| 22b | GER | 1.7 | M | 1st relapse | IPM | 20 | 7 | − |
R i.v. TIT |
− | − | Yes | Alive | − |
| 22c | GER | 2.1 | M | 2st relapse | IPM | 10 | 11 | − |
R i.v. TIT |
Allo-HSCT | − | Yes | Alive | − |
| 25 | GER | 5.3 | M | 1st diagnosis | IPM | 20 | 8 | − |
Systemic chemotherapy TIT |
− | − | Yes | Alive | − |
- CSF, cerebrospinal fluid; CNS, central nervous system; IPM, intraparenchymal mass; IT, intrathechal; I. Vent, intraventricular; i.v., intravenous; R, rituximab; ICE, ifosfamide, carboplatine, etoposide; VICI, dexamethasone, vincristine, idarubicine, carboplatin, ifosfamid; ICIT, idarubicine, carboplatin, ifosfamid, paclitaxel; TIT, triple intrathecal therapy; Allo-HSCT, allogeneic hematopoietic stem cell transplantation; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; Auto-HSCT, autologous hematopoietic stem cell transplantation; MTX, methotrexate; Ara-C, Cytarabine; ICM, Ifosfamide, carboplatin, methotrexate; PR, partial response, PD, progression disease; TRM, treatment related mortality; AE, adverse events; m. relapses, multiple relapses; ESP, Spain; AUT, Austria; AUS, Australia; GER, Germany; SWE, Sweden; BEL, Belgium; PRT, Portugal; RUS, Russia; SAU, Saudi Arabia; CAN, Canada.
Adverse events
Overall, intraventricular or IT rituximab with or without systemic chemotherapy was well tolerated (Table 3). The most common adverse events were Grades 1 and 2 neuropathies with paresthesia and pain in five patients (20%), allergy (mild itchiness, Grade 1/2) in two patients, and headache Grade 1/2 in two patients. These events were self-limited, occurring in the 48 hr after IT or intraventricular rituximab and resolving within 24 hr. One patient presented with a Grade 3 neuropathy, with severe lower back pain immediately after IT rituximab administration and required narcotic analgesia. He recovered completely and was able to resume the treatment. Two patients presented with seizures. Patient one had a brief (less than 5 min) seizure (Grade 2) in the 24 hr post-IT rituximab, described by the clinician as possibly related to rituximab. Patient two had a prolonged seizure Grade 4 a few hours after rituximab injection; the impression of the clinical team was that the cause of the seizure was likely related to the primary disease (a very large intraparenchymal mass) and less likely to rituximab. In the first case IT rituximab was not resumed, in the second case it was resumed without further neurologic toxicities. Patient ID 22 with PTLD and CNS infiltration received IT rituximab in the first line treatment, at the first relapse and at the second relapse, with a total of 20 IT rituximab doses without evidence of toxicity.
Response to therapy
Eighteen patients (72%) of those treated with intraventricular or IT rituximab, with or without other CNS directed treatment, achieved a CNS remission.
Of the patients with precursor-B ALL, one of the three patients achieved a CNS remission with only IT rituximab. This patient is still alive 5 years later after consolidation with allogeneic HSCT and cranial irradiation. In the other two patients a remission was not obtained. Among the 15 patients with CNS Burkitt NHL or leukemia, the five cases with intraparenchymal mass that received intraventricular rituximab as first line treatment (three with an autologous HSCT consolidation) are all alive in remission with a follow-up longer than 3 years. Nine of the 10 patients with relapsed or refractory CNS Burkitt NHL or leukaemia obtained a CNS remission with IT rituximab; eight in combination with other CNS directed therapy and one with rituximab alone. Three patients are long-term survivors, all after consolidation with allo-HSCT. Among the 7 patients with PTLD, three patients received IT rituximab as first line treatment: Complete, partial, and no remission were obtained, respectively. The four patients who received IT rituximab for relapsed or refractory PTLD in combination with IT and/or systemic therapy all obtained CNS remission and are alive. In five patients (three Pre-B ALL and two Burkitt NHL/leukemia with CNS relapse) IT/intraventricular rituximab was applied as monotherapy, and CNS remission was achieved in 40% of the cases.
Discussion
Although case reports and small case series describing the use of IT/intraventricular rituximab have been previously published, this is the largest case series to date of pediatric patients.
This study demonstrates that IT or intraventricular administration of rituximab can be done with limited associated toxicity in the majority of children with CD20+ CNS Burkitt NHL, mature B and CD20+ B precursor-ALL or B cell PTLD.
The combination of IT or intraventricular rituximab with Methotrexate (MTX) alone or triple IT therapy (MTX, cytarabine, and corticosteroid) was also well tolerated and did not appear to produce more side effects than what would be expected with conventional IT chemotherapy. Our results concerning the safety of IT/intraventricular rituximab are in line with those reported in the literature from prospective studies in adults and small cases series in children. Intrathecal administration of rituximab in monkeys showed no significant acute or delayed neurotoxicity 23. Shulz et al. described six adult cases with relapsed CNS B-cell lymphoma, treated with intraventricular or IT rituximab, without persistent side effects observed 24. Jaime-Pérez et al. 29 tested the efficacy of IT rituximab (10 mg) on seven pediatric patients with CNS relapsed CD20+ B-cell ALL refractory to triple IT therapy. Rituximab administration was well tolerated in their heavily pretreated study group, with no clinical evidence of neurotoxicity after a 24-month follow-up period. Czyzewski et al. 9 published a study describing intrathecal rituximab therapy in a group of eight children and adolescentswith CNS-EBV-PTLD. Only one patient had a short episode of seizures observed after the third intrathecal rituximab infusion. Rubenstein et al. 26 conducted the first Phase 1 study of intraventricular immunochemotherapy (10 mg or 25 mg intraventricular rituximab twice weekly, with rituximab administered as monotherapy during the first treatment each week and rituximab administered in combination with methotrexate) in 14 adult patients with recurrent CNS NHL, with more than 150 doses administered without any serious toxicity.
Although 72% of the patients in our study responded favorably to a second-line combination therapy, we cannot be sure about the specific role of IT/intraventricular rituximab because of the use of different CNS directed therapies. The generally very poor outcome of this group of patients, however, suggests that rituximab had a role in the favorable response. In addition three of six patients (50%) receiving only IT/intraventricular rituximab achieved a complete remission, attesting to the efficacy of the therapy.
The majority (17 of 25) of the patients in this series had relapsed or recurrent disease. It seems, however, that this therapy may also be useful as front line therapy for higher risk patients. Results of the FAB-96 study showed that the EFS was significantly lower in patients with mature B-NHL/ALL with isolated CNS involvement at diagnosis and even worse if the bone marrow was also positive, despite intensive systemic and intrathecal chemotherapy 3. The efficacy and relatively low toxicity of IT and intraventricular rituximab suggests that this option could be considered in a future prospective front–line study for this group of patients.
Kadoch et al. showed a rapid decrease in rituximab concentrations in CSF in patient receiving intraventricular rituximab, indicating a rapid elimination and/or distribution in the cranial-spinal axis. The distribution to serum was slow and serum levels were considerably lower than those measured in the CSF, therefore the rituximab is distributed biphasically. The biphasic CSF rituximab indicates rapid distribution to a second biologic space, consistent with penetration into brain tissue 19. These interesting findings explain why there was an excellent response to IT rituximab treatment in IPM NHL of our cohort.
The results of the present multi-institutional, international retrospective study illustrates the feasibility and safety of the use of IT/intraventricular rituximab in children with CD20+ B cell mature NHL, mature B- and precursor B-ALL or B cell PTLD involving the CNS. Well-designed prospective clinical trials should be pursued to further evaluate the effectiveness and safety of the use of IT and intraventricular rituximab in this group children with difficult to treat disease.
Acknowledgments
The authors thank Jose Luis Fuster (Pediatric Hematology Oncology Department, Murcia, Spain) and Nagore Garcia de Andoin (Pediatric Hematology Oncology Department, San Sebastian, Spain) for their work in collecting and sharing data. They also thank Brigit Burkhardt for her precious help.
