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Table of Contents
REVIEW ARTICLE
Year : 2018  |  Volume : 15  |  Issue : 3  |  Page : 132-134

Novel drug - dinutuximab for high-risk neuroblastoma


1 Department of Paediatrics, Yenepoya Medical College and University, Mangalore, Karnataka, India
2 Department of Anaesthesia, Kasturba Medical College, Mangalore, Karnataka, India
3 Department of Pediatrics, Yenepoya Medical College, Mangalore, Karnataka, India

Date of Web Publication10-Sep-2018

Correspondence Address:
Supriya Kushwah
Department of Paediatrics, Yenepoya Medical College and University, Deralakatte, Mangalore, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/am.am_14_17

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  Abstract 


Neuroblastoma is the most common extracranial tumor in children aged <5 years. Prognosis of high-risk neuroblastoma is not good even after use of aggressive chemotherapy. Newer drug anti-GD2 monoclonal antibodies, dinutuximab in combination with granulocyte-macrophage colony-stimulating factor or interleukin-2, have been recently approved by Food and Drug Administration for the treatment of high-risk neuroblastoma. Dinutuximab binds to the glycolipid GD2 present on neuroblastoma cells and cells of neuroectodermal origin and enhances cell lysis through antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.

Keywords: Antibody-dependent cell-mediated cytotoxicity, anti-GD2 monoclonal antibodies, dinutuximab, extracranial tumor, neuroblastoma


How to cite this article:
Kushwah S, Kumar A, Shabnam S. Novel drug - dinutuximab for high-risk neuroblastoma. Apollo Med 2018;15:132-4

How to cite this URL:
Kushwah S, Kumar A, Shabnam S. Novel drug - dinutuximab for high-risk neuroblastoma. Apollo Med [serial online] 2018 [cited 2018 Nov 14];15:132-4. Available from: http://www.apollomedicine.org/text.asp?2018/15/3/132/240934




  Drug Update Top


Neuroblastoma is most common extracranial solid tumor affecting neural crest cells. Children under the age of 5 years are commonly affected. Neuroblastoma is the most common cancer in <1 year of age and accounts for approximately 10% of all cancers in children.[1] Most common sites involved in neuroblastoma are adrenal glands located above each kidney or nerve tissue that runs alongside the spinal cord. Other sites can also be involved, i.e., neck, chest, abdomen, or pelvis. In high-risk neuroblastomas, even after aggressive therapy, chance of long-term survival is 40%–50%. In normal human tissues, GD2 expression is restricted to neurons, skin melanocytes, and peripheral sensory nerve fibers. The high expression of GD2 in neuroblastomas and its restricted distribution in normal tissues make anti-GD2 monoclonal antibodies potentially suitable for immunotherapy. In clinical trials with the murine, anti-GD2 antibodies 3F8, 14.G2a, and the chimeric human/mouse antibody ch14.18 in neuroblastoma were effective.[2] In combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2 (IL-2), treatment became more effective by augmenting antibody-dependent cell-mediated cytotoxicity (ADCC).[3]

Dinutuximab

The Food and Drug Administration (FDA) approved dinutuximab on March 10, 2015, for the treatment of neuroblastoma in children. It is a chimeric monoclonal antibody composed of murine variable heavy and light chain regions and the human constant region for the heavy chain IgG1 and light chain kappa.[4]

Mechanism of action

Dinutuximab binds to the glycolipid GD2 present on neuroblastoma cells and normal cells of neuroectodermal origin, including the central nervous system and peripheral nerves, thereby induces cell lysis through ADCC and complement-dependent cytotoxicity (CDC).[5] GD2 belongs to a unique class of T-cell-independent carbohydrate antigens with high density, membrane proximity. Along with leukocyte-mediated killing, GD2 also acts as tumor-selective delivery of radioisotopes, liposomes, or nanoparticles.

Pharmacokinetics

The maximum plasma dinutuximab concentration (C max) is 11.5 mcg/mL with a mean volume of distribution of 5.4 L (28%). The clearance is 0.21 L/day and increases with body size with half-life of 10 days.[6]

Dose

The recommended dose of dinutuximab is 17.5 mg/m2/day intravenous (IV) infusion over 10–20 h for 4 consecutive days for a maximum of 5 cycles. An infusion rate of 0.875 mg/m2/h for 30 min was initiated. The infusion rate can be gradually increased as tolerated to a maximum rate of 1.75 mg/m2/h.

Indications

Dinutuximab can be used in combination with GM-CSF, IL-2, and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy.

Prerequisite

This prerequisite treatment is essential to avoid allergic and other complications of dinutuximab. Patients should have adequate hematologic, respiratory, hepatic, and renal function before initiating therapy with dinutuximab. Prior to drug administration patient should be well hydrated with infusion of 10ml/kg of 0.9% normal saline over 1 hour. For pain reduction morphine sulfate 50 microgram/kg intravenous can be given. In case of severe pain, fentanyl, hydromorphone, gabapentin, and lidocaine can be used. Antihistamine such as diphenhydramine (0.5–1 mg/kg; maximum dose 50 mg) intravenously can be used over 10–15 min starting 20 min before initiation of dinutuximab and as tolerated every 4–6 h during the dinutuximab infusion. Acetaminophen (10–15 mg/kg; maximum dose 650 mg) can be used 20 min before each infusion and every 4–6 h as needed for fever or pain. Ibuprofen (5–10 mg/kg) can be used every 6 h for persistent fever or pain if platelet counts are normal.

Adverse reactions

Complications due to dinutuximab are common which can be prevented by prehydration and premedication management. The patient should be strictly monitored during and after dinutuximab infusion. The most common adverse events are pain at injection site and fever. The toxic effects seen with the immunotherapy regimen are mainly due to antibody binding to GD2 expressed on normal nerve cells, causing cytokine-mediated capillary leak and hypersensitivity reactions associated with the ch14.18 antibody or cytokines. These toxic effects may also reflect the proposed mechanism of action of combination by the monoclonal antibody, including complement activation, and distinct pathways of ADCC mediated by natural killer cells, neutrophils, and monocytes.[7]

Anaphylaxis

The patient can have anaphylaxis such as life-threatening complication with symptoms of fever, rigor, urticaria, hypotension, upper airway and facial edema, dyspnea, bronchospasm, and cardiac arrest. Immediately, infusion was discontinued and supportive management was given. Patients can require hypotensive management, IV corticosteroids, and bronchodilator therapy. All medications and equipment for resuscitation should be ready.

Pain

Dinutuximab infusion can cause abdominal pain, generalized pain, extremity pain, back pain, neuralgia, musculoskeletal chest pain, and arthralgia.

Neuropathy

High-risk neuroblastoma cases can develop peripheral sensory neuropathy while patients related to GD2-binding antibodies can have severe motor neuropathy. Neuropathy is more common in adults. Premedication with opioids can prevent this complication. Dinutuximab should not be given further in patients with Grade-2 peripheral motor neuropathy, Grade-3 sensory neuropathy that interferes with daily activities for more than 2 weeks, or Grade-4 sensory neuropathy.

Capillary leak syndrome

Capillary leak syndrome has been reported as a serious adverse reaction with dinutuximab infusion. Immediately, dinutuximab was discontinued and supportive management was given in patients with symptomatic or severe capillary leak syndrome.


  Hypotension Top


Infection

Sepsis is also common with dinutuximab infusion, so appropriate antibiotics to be added.

Eye problems and cranial nerve involvement

Blurred vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve disorder, eyelid ptosis, and papilledema were observed. Dose adjustment or discontinuation of the drug can be required.

Bone marrow suppression

Anemia, neutropenia, thrombocytopenia, and febrile neutropenia were identified.

Electrolyte abnormalities

Electrolyte abnormalities including hyponatremia, hypokalemia, and hypocalcemia can occur, so electrolytes should be monitored daily. Drug can rarely cause syndrome of inappropriate antidiuretic hormone secretion, resulting in severe hyponatremia

Atypical hemolytic uremic syndrome

Hemolytic uremic syndrome in the absence of documented infection and resulting in renal insufficiency, electrolyte abnormalities, anemia, and hypertension has been reported with cases of recurrence also reported. Permanently, dinutuximab was discontinued and supportive management for signs of hemolytic uremic syndrome was instituted.

Liver dysfunction

Hypoalbuminemia, increased aspartate aminotransferase, increased alanine aminotransferase can occur.


  Specific Conditions Top


Pregnancy

As monoclonal antibodies are transported across the placenta mainly in the third trimester, the risk of major birth defects and miscarriage can occur. Females should avoid pregnancy and lactation.

Females and males of reproductive potential contraception may cause fetal harm.


  Clinical Studies Top


The safety and effectiveness of dinutuximab have been evaluated in several randomized, open-label, multicenter trial conducted in pediatric patients with high-risk neuroblastoma.[8],[9],[10] All patients had received prior therapy consisting of induction combination chemotherapy, maximum feasible surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplant, and radiation therapy who have achieved partial response before autologous stem cell transplantation. Children with adequate cardiac function (ejection fraction of 55%), pulmonary function (no dyspnea at rest and peripheral arterial oxygen saturation >94% on room air), adequate hepatic function (normal bilirubin and liver enzymes), and adequate renal function (glomerular filtration rate >70 mL/min/1.73 m2) were taken into studies. Immunosuppressed children with infection were ruled out. Dinutuximab was administered at a dose of 17.5 mg/m2/day on 4–5 consecutive days and in combination with GM-CSF or IL-2 plus RA or as per the study protocol. Studies have proven efficacy of dinutuximab in children with high-risk neuroblastoma.


  Summary Top


Dinutuximab is newer drug approved by FDA for the treatment of high-risk neuroblastoma in combination with other drugs. It is a chimeric monoclonal antibody composed of murine variable heavy and light chain regions and the human constant region for the heavy chain IgG1 and light chain kappa that acts by binding to the glycolipid GD2 present on neuroblastoma cells and induces cell lysis. Over a period, so many studies have proven efficacy of dinutuximab with well-known side effects. These side effects can be prevented by prehydration and premedications. Dinutuximab can improve survival of children with high-risk neuroblastoma in the near future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Gurney JG, Davis S, Severson RK, Fang JY, Ross JA, Robison LL. Trends in cancer incidence among children in the U.S. Cancer 1996;78:532-41.  Back to cited text no. 1
    
2.
Cheung NK, Lazarus H, Miraldi FD, Abramowsky CR, Kallick S, Saarinen UM, et al. Ganglioside GD2 specific monoclonal antibody 3F8: A phase I study in patients with neuroblastoma and malignant melanoma. J Clin Oncol 1987;5:1430-40.  Back to cited text no. 2
    
3.
Cheung NK, Sowers R, Vickers AJ, Cheung IY, Kushner BH, Gorlick R. FCGR2A polymorphism is correlated with clinical outcome after immunotherapy of neuroblastoma with anti-GD2 antibody and granulocyte macrophage colony-stimulating factor. J Clin Oncol 2006;24:2885-90.  Back to cited text no. 3
    
4.
Gillies SD, Lo KM, Wesolowski J. High-level expression of chimeric antibodies using adapted cDNA variable region cassettes. J Immunol Methods 1989;125:191-202.  Back to cited text no. 4
    
5.
Mueller BM, Romerdahl CA, Gillies SD, Reisfeld RA. Enhancement of antibody-dependent cytotoxicity with a chimeric anti-GD2 antibody. J Immunol 1990;144:1382-6.  Back to cited text no. 5
    
6.
Uttenreuther-Fischer MM, Huang CS, Reisfeld RA, Yu AL. Pharmacokinetics of anti-ganglioside GD2 mAb 14G2a in a phase I trial in pediatric cancer patients. Cancer Immunol Immunother 1995;41:29-36.  Back to cited text no. 6
    
7.
Ozkaynak MF, Sondel PM, Krailo MD, Gan J, Javorsky B, Reisfeld RA, et al. Phase I study of chimeric human/murine anti-ganglioside G(D2) monoclonal antibody (ch14.18) with granulocyte-macrophage colony-stimulating factor in children with neuroblastoma immediately after hematopoietic stem-cell transplantation: A Children's Cancer Group Study. J Clin Oncol 2000;18:4077-85.  Back to cited text no. 7
    
8.
Handgretinger R, Anderson K, Lang P, Dopfer R, Klingebiel T, Schrappe M, et al. A phase I study of human/mouse chimeric antiganglioside GD2 antibody ch14.18 in patients with neuroblastoma. Eur J Cancer 1995;31A: 261-7.  Back to cited text no. 8
    
9.
Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 2010;363:1324-34.  Back to cited text no. 9
    
10.
Frost JD, Hank JA, Reaman GH, Frierdich S, Seeger RC, Gan J, et al. A phase I/IB trial of murine monoclonal anti-GD2 antibody 14.G2a plus interleukin-2 in children with refractory neuroblastoma: A report of the Children's Cancer Group. Cancer 1997;80:317-33.  Back to cited text no. 10
    




 

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Abstract
Drug Update
Hypotension
Specific Conditions
Clinical Studies
Summary
References

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