HHE Haematology supplement 2018 - Page 10

ADCC. Toxicities include pain, fever, capillary leak, O 2 requirement due to capillary leak, hypotension, mild reversible increased hepatic transaminases, and infection. 18 Anti-GD2 antibodies in clinical practice Targeted immunotherapy using anti-GD2 mAbs is an important clinical advance in the treatment of HR neuroblastoma. In a landmark study published in 2010 by the cooperative American group COG, the addition of the anti-GD2 monoclonal antibody ch14.18 (dinutuximab) combined with cytokines and isotretinoin improved the survival rates compared with isotretinoin alone in the post-consolidation phase. 19 As a consequence of this and subsequent studies, in 2015, dinutuximab was approved in Europe and the US for the treatment of HR neuroblastoma, and is now considered part of the standard of care. 20 There are two anti-GD2 antibodies approved by the European Medicines Agency (EMA): dinutuximab (Unituxin ® ) and dinutuximab beta (Qarziba ® ). Other anti-GD2 antibodies are currently being tested in clinical trials. Dinutuximab (Unituxin) Dinutuximab is a chimeric monoclonal antibody composed of the variable heavy and light-chain region of the murine anti GD2 mAb14.18 and the constant region of human IgG1 heavy-chain and k light-chain. It was initially produced in the murine myeloma cell line SP2/O. On 10 March 2015 and 14 August 2015, the US FDA and the EMA, respectively, approved IV dinutuximab, in Anti-GD2 monoclonal antibodies have undergone a very long journey from discovery to clinical practice combination with GM-CSF, IL-2 and cis-Retinoic acid (CRA), for the treatment of paediatric patients with HR-NB who achieved at least partial response with prior first-line multi agent, multimodality therapy. 20 Dinutuximab is now Unituxin ® , a registered trademark from United Therapeutics Company (UTC). Because of the pain side effects, dosing is limited. The recommended dosage of dinutuximab is 17.5 mg/m 2 /day administered IV over 10–20 hours for four consecutive days for maximum of five cycles. The infusion of dinutuximab initiated at a rate of 0.875mg/m 2 / hour over 30 minutes and the rate can be increased gradually, as tolerated, to the maximum rate of 1.75 mg/m 2 /hour. Dinutuximab should be diluted with 0.9% sodium chloride for injection prior to infusion. The supplied dinutuximab does not require filtration during preparation and does not need protection from the light during administration. Vials should be stored in the original container tightly closed at 2–8ºC. The solution is stable at room temperature for at least 24 hours when diluted to a concentration between 0.044 and 0.56mg/ml. Dinutuximab, similar to all the anti-GD2 10 HHE 2018 | hospitalhealthcare.com immunotherapies tested, is associated with potentially serious side effects. The most common include neuropathic pain, tachycardia, hypertension, hypotension, fever, and urticaria. In the COG Phase III trial, grade 3 or 4 pain was observed in 52% of patients, more frequent during cycle 1 (37%) and decreasing to 14% during cycle 5. 19 The most common site of pain was the abdomen. Grade 3 or 4 hypersensitivity reactions were reported in 25% of patients. Consequently, the US label for dinutuximab contains a warning for the risk of infusion-related reactions and neuropathy. 21 Other secondary described effects of dinutuximab include fever, hypokalaemia, hyponatraemia, liver dysfunction, hypotension, diarrhoea, and hypoxia. Recently acute-onset transverse myelitis as a novel infusion-related tox X]Hو[]^[XX\\ܚXY ^Y[]\œ\YH[\ݙY[H[\[ۈ\Y[ܝX\Y\HYZ[\\Y\[[š[[[ۘ[Xݙ\K[\ܝ[K\\[\˜]]\XH\X][ۈ\Y[؜\Y܈\ܝY]\[KQ [XY\˂ݙ\[ HZ[YHYX[XZ[HXZ܂]ؘXو[[KQ [XY\ˈ[Y\HYHYX\H][ H[[[ۘ[\[H]Y[Z\\[[BX[\Hٙ\[ۘ[\[\ܝ[ \\[ܙK[\H\[ۜ[[\X[Y]]\\YX]HZ[YHYX[XYHYHX][[ˈ܈XX\ۜ[KQ [[][\\H[H\ܛYY[YHXX[\Y[\ˈ]\Y[ۂ]Z[۝ [Y]JHXY\[ܙBٚXY[]XXH[[\ݙ[Y[ݙ\HYX\˂H܈ۙH Mˍ[Y[K]\HX[\ L \[X]Y\[\X]Z\][ۈ PB܈X[YX\\&\X\YXH\[\˂[ MHX\]XH\Z[YX]Y[]\K[HH[K[[]^[XX]H X\XH0 H[YH[^KH]\X[X\][]]ܚ\][ۈو[]^[\]]ۈ[X\H M[]\ۙ\X[Y[]\K[H\ݘ[ []^[0\Y[Y[B\Y[HTK[H[H[X\XBY[H[H\Hو[]^[XX\\Y H\ܝYHS LHYH\XB^H[Z\Y[\Y]\؛\XH]Y[XZ]H\[X[$[[ޛZYH]Z]\[\\[]\܈[]^[XX]Y[ X L[ X\ MK H]Y[\B[Z\Y ZYY[]Y[\H\YۙYš\[X[$[[ޛZYx$[\\[]\[ Mš\[X[$[[ޛZYx$[]^[XXوH N]Y[\YۙY\[X[$[[ޛZYx$[\\[]\ۙH]Y[XY]YH\X[\ۜKوH M]Y[\YۙYš\[X[$[[ޛZYx$[]^[XXYؚX]H\ۜ\[Y[\\X[\ۜ\[]H\]H\ۜ\ˈ \œYH\[YH܈܈\\[[[[][\\]]XY[Y[[B[X[\Hو[]^[XXX\Y\[BX]Y[[XHو]\؛\XK[]^[XX]H X\XH0 B[]^[XX]H [[Y M N ܂TLJH\HPX\XYYZ[