Treatment and revaccination of children with paraneoplastic opsoclonus-myoclonus-ataxia syndrome and neuroblastoma: The Memorial Sloan Kettering experience

Abstract

Objective:

To review the treatment and revaccination of neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome (OMAS) patients at Memorial Sloan Kettering Cancer Center (MSK).

Procedure:

Institutional Review Board approval was obtained for this retrospective study of patients with neuroblastoma-associated OMAS followed at MSK from 2000–2016.

Results:

The 14 patients (9 female) were 9–21 (median 17) months old at diagnosis of neuroblastoma and OMAS syndrome. They had stage 1 (n=12), stage 2B, or intermediate-risk stage 4. Tumor histology was favorable in 11 patients, unfavorable in 2, and unknown in 1 patient. No patient had amplified-MYCN. All patients underwent tumor resection at diagnosis. Anti-neuroblastoma treatment was limited to chemotherapy in 1 patient. Overall survival is 100% at 3–16 (median 10) years. For OMAS, 13 patients received intravenous immune globulin (IVIg), adrenocorticotropic hormone (ACTH), and rituximab; and 1 received ACTH and IVIg. Seven patients experienced OMAS relapse. For these relapses, 5 patients received low-dose cyclophosphamide and 2 received rituximab. The mean total OMAS treatment was 20–96 (median 48) months. Seven patients started rituximab ≤3 months from diagnosis and did not relapse. The other 6 experienced OMAS relapse. To date, 6 patients have been revaccinated at a minimum of two years after completion of OMAS therapy without OMAS recurrence.

Conclusions:

Patients with neuroblastoma-associated OMAS had excellent overall survival. Early initiation of rituximab, IVIg and ACTH may reduce risks of OMAS relapse. Revaccination can be resumed without exacerbation of OMAS. Further investigation with a larger cohort of patients is needed.

Introduction:

Neuroblastoma (NB) is the most common cancer diagnosed during the first year of life¹. This solid tumor arises from neural crest cells of the sympathetic nervous system². Outcomes vary widely ranging from excellent to poor prognosis, and even spontaneous regression. The many prognostic factors include age, stage, and molecular and genetic features^3,4.

NB can occur with opsoclonus-myoclonus-ataxia syndrome (OMAS), a paraneoplastic syndrome in which developmentally normal children acutely present with abnormal eye movements, jerking of the extremities, and incoordination⁵. While the causes of OMAS are varied (cancer, toxins and infections), ~3% of NB patients develop OMAS^6–9. NB-associated OMAS is an autoimmune phenomenon, as evidenced by enhanced B-cell activation in the cerebrospinal fluid CSF¹⁰. OMAS-associated NB is typically low-risk and carries an excellent prognosis¹¹. Treatment for OMAS includes immunomodulatory agents such as intravenous immune globulin (IVIg), adrenocorticotropic hormone (ACTH), rituximab and steroids, with variation in treatment across institutions^12–15. Neurocognitive and neurodevelopmental recovery can be slow, with a need for long-term supportive intervention^16,17.

Due to the immunosuppressive treatment and frequency of OMAS relapse with immune stimulation, an additional challenge is when to resume standard childhood immunizations. Currently no established guidelines exist and determining when and how to re-introduce vaccines is difficult as immune reconstitution is a complex process. Among children with chronic autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease, common practice involves avoiding live vaccines while patients receive immunosuppressive therapy. Vaccinations have not been associated with exacerbations of such autoimmune conditions¹⁸. Although data on vaccine-preventable diseases in immunocompromised pediatric patients is lacking, the method of vaccine reintroduction in this vulnerable population continues to remain relevant.

We conducted a retrospective review of patients with NB-associated OMAS at Memorial Sloan Kettering Cancer Center (MSK) and our process of reintroducing vaccinations in this population to assess and inform practice.

Methods:

Institutional Review Board approval was obtained before data collection. The records of all patients with NB-associated OMAS at MSK from 2000 to 2016 were reviewed. Data collected included patient demographics, clinical presentation, treatment, and outcomes. A univariate descriptive analysis of the collected data was conducted.

Results:

Patient characteristics and clinical presentation

The 14 MSK patients (9 female) with NB and OMAS were 9–21 (median 17) months old at diagnosis of NB (Table 1). Tumors were retroperitoneal (n=7), thoracic paraspinal (n=6), and pelvic (n=1). Twelve patients had stage 1 NB, and one each had stage 2B and intermediate-risk stage 4 (with distant bony metastases). All patients were developmentally normal before onset of OMAS. Thirteen patients presented with OMAS, which led to the detection of NB. One patient developed OMAS 3 months after tumor resection. Signs of OMAS included opsoclonus, myoclonus, ataxia, speech disturbance, and/or irritability.

Table 1:

Patient, disease, and treatment characteristics

			NB characteristics		OMA Syndrome Management
Number	Gender	Age at diagnosis of NB (months)	Stage	Histology	Treatment	Tx duration (months)	OMA Syndrome Relapse
1	F	9	1	Favorable	I, A, R	96	Y
2	M	9	1	Favorable	I, A, R, C	48	Y
3	M	11	1	Favorable	I, A, R, C	72	Y
4	M	14	1	Favorable	I, A, D, R	20	N
5	F	15	1	Favorable	I, A, R	72	Y
6	F	16	2B	Favorable	I, A, D, R, C	48	Y
7	M	16	4	Unfavorable	I, A, D, R	Ongoing	N
8	F	17	1	Favorable	I, A, R, C	Transfer	N
9	M	18	1	Favorable	I, A, R	36	N
10	F	18	1	Favorable	I, A, R, C	60	Y
11	F	20	1	Unfavorable	I, A, D, R	36	N
12	F	21	1	Favorable	I, A	29	N
13	F	21	1	Favorable	I, A, D, R	Transfer	N
14	F	21	1	Not determined	I, A, R	23	N

Abbreviations: I, IVIg; A, ACTH; R, Rituximab; D, Dexamethasone; C, Cyclophosphamide.

Biological features included favorable histology in 11 patients, unfavorable in two, and unknown in one patient. No patient had MYCN amplification.

Treatment

All patients underwent a gross total resection of tumor at diagnosis of NB, including the primary tumor for one patient with stage 4 (patient #7). Post-operative anti-NB therapy was limited to 4 cycles of intermediate-risk chemotherapy in patient #7

Initial treatment for OMAS varied based on symptom severity, insurance approval and parental preference. Thirteen patients received IVIg, ACTH, and rituximab (see Table 1). One patient only received IVIg and ACTH as family declined rituximab. Dexamethasone was given to 4 patients for a limited period, while waiting for insurance approval of ACTH.

Of the 14 patients, 11 completed OMAS treatment at MSK in 20–96 (median 48) months. One patient’s OMAS treatment was discontinued when he commenced treatment for NB relapse detected at 22 months from initial diagnosis; 2 patients transferred care to other facilities and their treatment duration is unknown; and 7 patients had OMAS relapses during treatment and subsequently had longer treatment duration. The relapses were commonly seen during the ACTH taper and five patients required additional therapies including low-dose cyclophosphamide and/or 6-mercaptopurine. Two patients with OMAS relapses were retreated with rituximab after determining reconstitution of B-cell population in serum.

Of the 13 patients who received rituximab, 7 patients started it within 3 months of OMAS diagnosis; of these 6 had shorter treatment duration than the average for our cohort. One patient (#5) had OMAS relapse during ACTH taper, requiring rituximab re-initiation, and thus had longer treatment duration. The remaining 6 patients started rituximab more than 4 months after diagnosis. Five of these patients experienced OMAS exacerbation and had treatment durations in the higher end of the range for our cohort. One patient (#7) received dose-intensive chemotherapy for relapsed NB.

Revaccination

Overall survival in our cohort is 100% at 1–15 (median 9) years from diagnosis. Of the patients who completed their treatment and continued follow-up at MSK, 6 patients resumed childhood immunizations without complications, including no recurrence of OMAS. Our approach involves resuming vaccinations two years after all treatment completion barring recurrence of OMAS symptoms and assuring immune reconstitution. Initially we tested vaccine titers, however as the pediatric oncology group at our institution developed re-immunization guidelines, titers were no longer sought due to lack of evidence. Instead, immunizations were re-initiated as per the Centers for Disease Control (CDC) catch-up schedule, based on immune status at least 2 years after treatment completion and without checking titers; live vaccines were administered only after all inactivated vaccine series were complete and after adequate tetanus and pneumococcal titer responses.

Six patients resumed immunizations at our facility. One patient completed her revaccination over a span of 9 years and received DTaP, Hepatitis B, IPV, pneumococcal conjugate PCV7, MMRV, meningococcal MCV 4, and typhoid vaccines. The other five patients completed their vaccines locally, after receiving pneumococcal and Tdap vaccines with us. Three of the six patients received the MMRV vaccine. No OMAS recurrence was reported upon follow up.

Discussion:

We present our experience with NB-associated OMAS patients at a large referral center from 2000 – 2016. Salient findings in our experience include excellent progression-free survival from NB, as expected; lack of exacerbation of OMAS despite immune-stimulatory treatment of high-risk stage 4 relapse (patient #7); advantage of early initiation of rituximab; and exacerbations of OMAS with ACTH taper. The benefit of early addition of rituximab for OMAS treatment is increasingly recognized. A recent study focusing on developmental outcomes also showed that early addition of aggressive immunosuppressive treatment, with rituximab, was associated with fewer relapses and improved developmental outcomes¹⁹.

Six patients resumed childhood immunizations without recurrence of OMAS. There have been no reports of reinitiating vaccinations post OMAS treatment and fears of OMAS relapse lead to much caution, especially since immune stimulation, e.g. with febrile illness, has been associated with relapse. Nonetheless, revaccination remains important and our approach is to reinitiate vaccines after 2 years of treatment completion and without any OMAS recurrence. Although the primary concern surrounding vaccinations in our cohort was OMAS relapse, it is also important to consider the immunocompromised state of patients post treatment completion. The general consensus is to avoid vaccinations for 6–12 months after treatment completion to ensure safety and also allow sufficient immune recovery to adequately mount a response to the vaccination²⁰. Some studies of pediatric oncology patients have reported disappearance of protective antibody titers for vaccines received prior to chemotherapy, further adding to the dilemma of how to revaccinate these patients^20,21. In our experience, while we initially checked antibody titers and revaccinated accordingly, this practice was eventually dropped due to lack of supporting evidence. This effect is often quite prominent in healthy children as well and studies have found most children do develop protective antibody levels with revaccination after immunosuppressive agents, suggesting sufficient recovery of humoral and memory immunity²². Following normalization of lymphocyte panels, appropriate vaccinations based on the CDC catch-up immunization schedule²³ were initiated, spaced 6 months apart, with live vaccines given last, after adequate tetanus and pneumococcal titer responses were observed. Patients could receive vaccines locally with their pediatricians and there have been no reports of OMAS relapse thus far. Interestingly, while febrile illness has been associated with OMAS exacerbation in our cohort, this was not the case with vaccines, suggesting a difference in the immune system response to vaccination and infection. Three patients received the MMRV without any complications.

While concern of disease exacerbation is commonly the limiting factor in vaccinating pediatric patients with autoimmune conditions such as OMAS, the associated morbidity and mortality with vaccine-preventable infections cannot be overstated. Our experience demonstrates that patients with OMAS, despite varied histories, can be successfully re-immunized without relapse, including with live vaccines, and can mount appropriate immune responses. This supports existing literature which similarly revealed no disease flare when revaccinating children with chronic autoimmune conditions, such as rheumatic disease and systemic lupus erythematosus¹⁸.

Conclusion:

The treatment for OMAS varies across institutions. Our experience with patients with NB-associated OMAS showed improved outcomes for patients with initiation of rituximab within 3 months of diagnosis, in addition to IVIg and ACTH. Multiple patients also resumed childhood immunizations without any complications, including OMAS relapse. The small sample size and retrospective nature are limitations to our study. A multicenter study with a larger sample size and controls will help to reinforce the effectiveness of early initiation of rituximab in addition to IVIg and ACTH and will help establish a protocol for resumption of childhood immunizations in children with NB-associated OMAS. Further study is also needed to determine revaccination strategies during pandemics and outbreaks of infectious diseases.

Abbreviations:

OMAS

Opsoclonus-myoclonus-ataxia syndrome

MSK

Memorial Sloan Kettering Cancer Center

NB

Neuroblastoma

IVIg

Intravenous Immune Globulin

ACTH

Adrenocorticotropic hormone